PRESCRIBING INFORMATION: For the use of an Oncologist or a Hospital or a Laboratory only. Preparation for Delayed Subcutaneous Administration: The reconstituted product may be kept in the vial or drawn into a syringe. Doses greater than 4 mL should be AZADINE 50 divided equally into 2 syringes. The product must be refrigerated immediately. When for injection is reconstituted using water for injection that has not been refrigerated, the reconstituted product may be held (AZACITIDINE FOR INJECTION 50 mg) under refrigerated conditions (2° -8°C, 36° -46°F) for up to 8 hours. When azacitidine for injection is reconstituted using refrigerated (2° -8°C, 36° -46°F) water for injection, the reconstituted product may be stored under refrigerated conditions (2° -8°C, 36°-46°F) for up to 22 hours. After removal from refrigerated conditions, the suspension may be allowed to equilibrate to room temperature for up to 30 minutes prior to administration. Subcutaneous Administration COMPOSITION: Each vial contains: To provide a homogeneous suspension, the contents of the dosing syringe must be re-suspended immediately Azacitidine IP 50 mg prior to administration. To re-suspend, vigorously roll the syringe between the palms until a uniform, cloudy Excipients: Q.S. suspension is achieved. Azacitidine suspension is administered subcutaneously. Doses greater than 4 mL should be divided equally DESCRIPTION Azacitidine is a pyrimidine nucleoside analog of cytidine. Azacitidine is into 2 syringes and injected into 2 separate sites. Rotate sites for each injection (thigh, abdomen, or upper 4-amino-1-β-D-ribofuranosyl-s-triazin-2(1H)-one. The structural formula is shown in arm). Figure 1. The empirical formula is C H N O The molecular weight is 244. Suspension Stability 8 12 4 5 Azacitidine reconstituted for subcutaneous administration may be stored for up to 1 hour at 25°C (77°F) or for CLINICAL PHARMACOLOGY Figure 1. Azacitidine up to 8 hours between 2°C and 8°C (36°F and 46°F). Mechanism of action Azacitidine is a pyrimidine nucleoside analog of cytidine, believed to exert its antineoplastic effects by DNA Instructions for Intravenous Administration hypomethylation and direct cytotoxicity on abnormal hematopoietic cells in the bone marrow. The Reconstitute the appropriate number of azacitidine vials to achieve the desired dose. Reconstitute each vial concentration of azacitidine required for maximum inhibition of DNA methylation in vitro does not cause major with 5 mL sterile water for injection. Vigorously shake or roll the vial until all solids are dissolved. The resulting suppression of DNA synthesis. Hypomethylation may restore normal function to genes that are critical for solution will contain azacitidine 10 mg/mL. The solution should be clear. Parenteral drug product should be differentiation and proliferation. The cytotoxic effects of azacitidine cause the death of rapidly dividing cells, inspected visually for particulate matter and discoloration prior to administration, whenever solution and including cancer cells that are no longer responsive to normal growth control mechanisms. Non-proliferating container permit. cells are relatively insensitive to azacitidine. Withdraw the required amount of azacitidine solution to deliver the desired dose and inject into a 25 - 50 mL infusion bag of either 0.9% Sodium Chloride Injection or Lactated Ringer’s Injection. Clinical Studies As a form of relatively low-intensity , the DNA methyltransferase inhibitor (DMTI) Intravenous Administration hypomethylating agent 5-azacytidine has been shown in randomized phase III trials to improve overall survival Azacitidine solution is administered intravenously. Administer the total dose over a period of 10-40 minutes. and quality of life and to decrease the risk of leukemic transformation. Hematologic responses occurred in 60% The administration must be completed within 1 hour of reconstitution of the azacitidine vial. of patients in the azacitidine arm (10-17% complete response, 16% partial response, 23-36% hematological Solution Stability improvement) compared with an overall 5% response rate (only hematologic improvements) in those receiving Azacitidine reconstituted for intravenous administration may be stored at 25°C (77°F), but administration must supportive care. Additionally, the time to progression to AML or death was improved in those who received be completed within 1 hour of reconstitution. azacitidine earlier in the course of disease, suggesting that the drug prolonged the duration of stable disease. USE IN SPECIAL POPULATIONS Median number of cycles to first response was 3. Data from a randomized trial for higher-risk MDS concluded Dosage Adjustment Based on Renal Function and Serum Electrolytes that azacitidine was superior to conventional care (standard chemotherapy or supportive care) in overall If unexplained elevations of BUN or serum creatinine occur, the next cycle should be delayed until values survival. Azacitidine treatment was associated with a median survival of 24.46 months versus 15.02 months for return to normal or baseline and the dose should be reduced by 50% on the next treatment course [see those receiving conventional care, a difference of 9.4 months (p= 0.0001). The hazard ratio for the treatment Warning and Precautions]. effect was 0.58 (95 % CI: 0.43-0.77) with two-year survival rates of 50.8 % with azacitidine compared to 26.2 Use in Geriatric Patients % with conventional care (p <0.0001). The survival benefits of azacitidine were consistent regardless of the Azacitidine and its metabolites are known to be substantially excreted by the kidney, and the risk of toxic conventional care option, cytogenetic subgroups, or age. Azacitidine treatment was associated with a median reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are time to death or transformation to AML of 13.0 months versus 7.6 months for those receiving CCR treatment, more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to an improvement of 5.4 months (p= 0.0025). Azacitidine treatment was also associated with a reduction in monitor renal function cytopenias, and their related symptoms; higher proportion of transfusion independency for longer duration. No overall differences in effectiveness were observed between geriatric patients and younger patients in clinical trials. In addition there were no relevant differences in the frequency of adverse reactions observed in Pharmacokinetics The pharmacokinetics of azacitidine were studied in 6 MDS patients following a single 75 mg/m2 subcutaneous patients 65 years and older compared to younger patients. (SC) dose and a single 75 mg/m2 intravenous (IV) dose. Azacitidine is rapidly absorbed after SC administration; Pregnancy the peak plasma azacitidine concentration of 750 ± 403 ng/ml occurred in 0.5 hour with relative bioavailability Pregnancy Category D. of approximately 89% for SC azacitidine. Mean volume of distribution following IV dosing is 76 ± 26 L with mean Azacitidine is teratogenic in animals. Developmental abnormalities in the brain have been detected in mice given azacitidine on or before gestation day 15 at doses of ~3-12 mg/m2 (approximately 4%-16% the SC clearance is 167 ± 49 L/hour and mean half-life after SC administration is 41 ± 8 minutes. Published studies 2 indicate that urinary excretion is the primary route of elimination of azacitidine and its metabolites. Following IV recommended human daily dose on a mg/m basis). Azacitidine may cause fetal harm when administered to a administration of radioactive azacitidine to 5 cancer patients, the cumulative urinary excretion was 85% of the pregnant woman. There are no adequate and well controlled studies with Azacitidine in pregnant women. radioactive dose. Fecal excretion accounted for <1% of administered radioactivity over 3 days. Women of childbearing potential should be advised to avoid pregnancy during treatment with azacitidine. If this drug is used during pregnancy or if a patient becomes pregnant while taking this drug, the patient should be NONCLINICAL TOXICOLOGY apprised of the potential hazard to the fetus. Carcinogenesis, mutagenesis, impairment of fertility Azacitidine is carcinogenic, mutagenic & teratogenic in both mammalian cell lines and rodents at approximately Female partners of male patients receiving azacitidine should not become pregnant [see Nonclinical 8-9% the recommended human daily dose on a mg/m2 basis. In animal studies, azacitidine resulted in toxicology]. decreased fertility in male and decreased pregnancy rates and increased loss of offspring during subsequent Nursing mothers embryonic and postnatal development. It is not known whether azacitidine or its metabolites are excreted in human milk. Because of the potential for The potential carcinogenicity of azacitidine reported to evaluated in mice and rats. Azacitidine induced tumors tumorigenicity shown for azacitidine in animal studies and the potential for serious adverse reactions in nursing of the hematopoietic system in female mice at 2.2 mg/kg (6.6 mg/m2, approximately 8% the recommended infants from azacitidine, a decision should be made to continue drug or not taking into consideration the human daily dose on a mg/m2 basis) administered IV three times per week for 52 weeks. An increased importance of the drug to the mother. incidence of tumors in the lymphoreticular system, lung, mammary gland, and skin was seen in mice treated Pediatric use with azacitidine IV at 2.0 mg/kg (6.0 mg/m2, approximately 8% the recommended human daily dose on a mg/m2 Safety and effectiveness in pediatric patients have not been established. basis) once a week for 50 weeks. CONTRAINDICATIONS A tumorigenicity study in rats dosed twice weekly at 15 or 60 mg/m2 (approximately 20-80% the recommended Advanced Malignant Hepatic Tumors human daily dose on a mg/m2 basis) revealed an increased incidence of testicular tumors compared with Azacitidine is contraindicated in patients with advanced malignant hepatic tumor. controls. The mutagenic and clastogenic potential of azacitidine reported to be tested in in vitro bacterial Hypersensitivity to Azacitidine or Mannitol systems Salmonella typhimurium strains TA100 and several strains of trpE8, Escherichia coli strains WP14 Azacitidine is contraindicated in patients with a known hypersensitivity to azacitidine or mannitol. Pro, WP3103P, WP3104P, and CC103; in in vitro forward gene mutation assay in mouse lymphoma cells and WARNING AND PRECAUTIONS human lymphoblast cells; and in an in vitro micronucleus assay in mouse L5178Y lymphoma cells and Syrian Anemia, Neutropenia and Thrombocytopenia hamster embryo cells. Azacitidine was mutagenic in bacterial and mammalian cell systems. The clastogenic Treatment with azacitidine is associated with anemia, neutropenia and thrombocytopenia. Complete blood effect of azacitidine was shown by the induction of micronuclei in L5178Y mouse cells and Syrian hamster counts should be performed as needed to monitor response and toxicity, but at a minimum, prior to each dosing embryo cells. Administration of azacitidine to male mice at 9.9 mg/m2 (approximately 9% the recommended cycle. After administration of the recommended dosage for the first cycle, dosage for subsequent cycles should human daily dose on a mg/m2 basis) daily for 3 days prior to mating with untreated female mice resulted in be reduced or delayed based on nadir counts and hematologic response [see Dosage and Administration]. decreased fertility and loss of offspring during subsequent embryonic and postnatal development. Treatment Severe Pre-existing Hepatic Impairment of male rats 3 times per week for 11 or 16 weeks at doses of 15-30 mg/m2 (approximately 20-40%, the Because azacitidine is potentially hepatotoxic in patients with severe pre-existing hepatic impairment, caution recommended human daily dose on a mg/m2 basis) resulted in decreased weight of the testes and is needed in patients with liver disease. Patients with extensive tumor burden due to metastatic disease have epididymides, and decreased sperm counts accompanied by decreased pregnancy rates and increased loss been reported to experience progressive hepatic coma and death during azacitidine treatment, especially in of embryos in mated females. In a related study, male rats treated for 16 weeks at 24 mg/m2 resulted in an such patients with baseline albumin <30 g/L. increase in abnormal embryos in mated females when examined on day 2 of gestation. Renal Abnormalities Patients with renal impairment should be closely monitored for toxicity since azacitidine and its metabolites are INTRAVENOUS SOLUTION INCOMPATIBILITY Azacitidine is incompatible with 5% Dextrose solutions, Hespan, or solutions that contain bicarbonate. These primarily excreted by the kidneys. Renal abnormalities ranging from elevated serum creatinine to renal failure solutions have the potential to increase the rate of degradation of azacitidine and should therefore be avoided. and death have been reported in patients treated with intravenous azacitidine in combination with other chemotherapeutic agents for nonMDS conditions. In addition, renal tubular acidosis, defined as a fall in serum INDICATIONS AND USAGE Azacitidine is indicated for treatment of adult patients with all subtypes of (MDS). bicarbonate to <20 mEq/L in association with an alkaline urine and hypokalemia (serum potassium <3 mEq/L) developed in 5 patients with CML treated with azacitidine and . If unexplained reductions in serum DOSAGE AND ADMINISTRATION bicarbonate <20 mEq/L or elevations of BUN or serum creatinine occur, the dosage should be reduced or held First Treatment Cycle The recommended starting dose of azacitidine for the first treatment cycle, for all patients regardless of [see Use in Special Populations]. baseline hematology laboratory values, is 75 mg/m2 subcutaneously or intravenously, daily for 7 days. Patients Monitoring Laboratory Tests should be premedicated for nausea and vomiting. Complete blood counts should be performed as needed to monitor response and toxicity, but at a minimum, prior to each cycle. Liver chemistries and serum creatinine should be obtained prior to initiation of therapy. Subsequent Treatment Cycles Cycles should be repeated every 4 weeks. The dose may be increased to 100 mg/m2 if no beneficial effect is ADVERSE REACTIONS seen after 2 treatment cycles and if no toxicity other than nausea and vomiting has occurred. It is Most Commonly Occurring Adverse Reactions (SC or IV Route): recommended that patients be treated for a minimum of 4 to 6 cycles. However, complete or partial response Nausea, anemia, thrombocytopenia, vomiting, pyrexia, leukopenia, diarrhea, injection site erythema, may require additional treatment cycles. Treatment may be continued as long as the patient continues to constipation, neutropenia, ecchymosis. The most common adverse reactions by IV route also included benefit. Patients should be monitored for hematologic response and renal toxicities [Warning and Precautions], petechiae, rigors, weakness and hypokalemia. and dosage delay or reduction as described below may be necessary.

Dosage Adjustment Based on Hematology Laboratory Values System Organ Class Adverse events • For patients with baseline (start of treatment) WBC ≥3.0 x109/L, ANC ≥1.5 x109/L, and platelets ≥75.0 x109/L, Blood and lymphatic Anemia, febrile neutropenia, leukopenia, thrombocytopenia, adjust the dose as in Table 1, based on nadir counts for any given cycle: system disorders agranulocytosis,bone marrow failure, pancytopenia, splenomegaly Cardiac disorders Atrial fibrillation, cardiac failure, cardiac failure congestive, cardio-respiratory Table 1. Dose adjustment based on Hematology values arrest, congestive cardiomyopathy (WBC ≥3X109/L, ANC ≥1.5X109/L & PC ≥75X109/L) Eye disorders Eye hemorrhage Nadir Counts % Dose in the next course Gastrointestinal disorders Gingival bleeding, mouth haemorrhage, abdominal pain & tenderness, constipation, dyspepsia, loose stool, nausea, vomiting, diverticulitis, ANC ( x 109/L) Platelets ( x 109/L) gastrointestinal hemorrhage, melena, perirectal abscess <0.5 <25.0 50% General disorders and Fatigue, pyrexia, catheter site, hemorrhage, general physical health 0.5-1.5 25.0-50.0 67% administration site deterioration, systemic inflammatory response syndrome >1.5 >50.0 100% conditions

Hepatobiliary disorders Cholecystitis, hyperbilirubinemia 9 9 9 • For patients whose baseline counts are WBC <3.0 x10 /L, ANC <1.5 x10 /L, or platelets <75.0 x10 /L, dose Immune system disorders Anaphylactic shock, hypersensitivity adjustments should be based on nadir counts and bone marrow biopsy cellularity at the time of the nadir as URTI, UTI, pneumonia, abscess limb, bacterial infection, cellulitis, injection shown in Table 2, unless there is clear improvement in differentiation (percentage of mature granulocytes is Infections and infestations site infection, sepsis, septic shock, bacteremia higher and ANC is higher than at onset of that course) at the time of the next cycle, in which case the dose of the current treatment should be continued. Musculoskeletal Arthralgia, myalgia, bone pain aggravated, muscle weakness, neck pain Nervous system disorders Dizziness, headache, cerebral hemorrhage, convulsions, intracranial Table 2. Dose adjustment based on Hematology values hemorrhage, anxiety, insomnia (WBC <3X109/L, ANC <1.5X109/L & PC <75X109/L) Renal and urinary disorders Loin pain, renal failure WBC or Platelet Nadir Bone Marrow Biopsy Cellularity at Time of Nadir (%) Respiratory Hemoptysis, lung infiltration, pneumonitis, respiratory distress (% decrease in counts Skin and subcutaneous Pyoderma gangrenosum, rash pruritic, skin induration, injection site bruising, from baseline) 30-60 15-30 <15 tissue disorders erythema, hematoma, induration, pigmentation, pruritus, pain, rash % Dose in the Next Course DRUG INTERACTIONS 50-75 100 50 33 No formal clinical assessments of drug-drug interactions between azacitidine and other agents have been >75 75 50 33 conducted. An in vitro study of azacitidine incubation in human liver fractions indicated that azacitidine may be metabolized by the liver. An in vitro study with cultured human hepatocytes indicated that azacitidine at If a nadir as defined in the table above has occurred, the next course of treatment should be given 28 days after concentrations up to 100 μM (IV Cmax = 10.6 μM) does not cause any inhibition of CYP2B6 and CYP2C8. In the start of the preceding course, provided that both the WBC and the platelet counts are >25% above the nadir vitro studies with human cultured hepatocytes indicate that azacitidine at concentrations of 1.0 μM to 100 μM and rising. If a >25% increase above the nadir is not seen by day 28, counts should be reassessed every 7 does not induce CYP 1A2, 2C19, or 3A4/5. days. If a 25% increase is not seen by day 42, then the patient should be treated with 50% of the scheduled OVERDOSAGE dose. One case of overdose with azacitidine was reported during clinical trials. A patient experienced diarrhea, Preparation of AZACITIDINE nausea, and vomiting after receiving a single IV dose of approximately 290 mg/m2; almost 4 times the Azacitidine is a cytotoxic drug. If reconstituted azacitidine comes into contact with the skin, immediately and recommended starting dose. The events resolved without sequelae, and the correct dose was resumed the thoroughly wash with soap and water. If it comes into contact with mucous membranes, flush thoroughly with following day. In the event of overdosage, the patient should be monitored with appropriate blood counts and water. should receive supportive treatment, as necessary. There is no known specific antidote for azacitidine The azacitidine vial is single-use and does not contain any preservatives. Unused portions of each vial should overdosage. be discarded properly. Do not save any unused portions for later administration. PACKAGING INFORMATION Instructions for Subcutaneous Administration USP Type I clear glass vials Azacitidine should be reconstituted aseptically with 2 mL sterile water for injection. The diluent should be PRESENTATION: AZADINE 50 is available as 50 mg lyophilized powder in a 10 ml size sterile single use vial. injected slowly into the vial. Vigorously shake or roll the vial until a uniform suspension is achieved. The STORAGE suspension will be cloudy. The resulting suspension will contain azacitidine 25 mg/mL. Do not filter the Store at 25 C (77 F); excursions permitted to 15 – 30 C (59 – 86 F) suspension after reconstitution. Keep out of reach of children. ⁰ ⁰ ⁰ ⁰ ⁰ ⁰ Preparation for Immediate Subcutaneous Administration Manufactured by: Doses greater than 4 mL should be divided equally into 2 syringes. The product may be held at room INTAS PHARMACEUTICALS LTD. temperature for up to 1 hour, but must be administered within 1 hour after reconstitution. Plot No. 5-6 & 7, Pharmez-382 213, Near Village Matoda, Ta: Sanand, Dist: Ahmedabad. 51 3102 0 717370 INP001

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File Name: AZADINE 50 mg_PIL_(717370) File Name: AZADINE 50 mg_PIL_(717370) Size: 170 x 550 (mm) Size: 170 x 550 (mm) Colour: Pan Black Colour: Pan Black Date: 27/09/2018, 29/09/2018 Date: 27/09/2018, 29/09/2018 ARTWORK APPROVAL REPORT

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Product Name for Injection Division ARISTA Country India Pack Type Vials Pack Style 1 vial Component Type PIL Client Intas Strength 3.5mg Numeric Code 51 2934 0 715602 Material Code 715602

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PIL IS REQUIRED CENTRALLY FOLDED.

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For the use of an Oncologist or a Hospital or a Cancer Institute Dose Modification Guidelines for BORVIZ When Given in Parenteral drug products should be inspected visually for STABILITY: BORVIZ 3.5 Combination with and Prednisone particulate matter and discoloration prior to administration Unopened vials of BORVIZ are stable until the date indicated (BORTEZOMIB INJECTION IP 3.5 mg/vial) whenever solution and container permit. If any discoloration or on the package when stored in the original package protected Prior to initiating any cycle of therapy with BORVIZ in particulate matter is observed, the reconstituted product from light. combination with melphalan and prednisone: should not be used. COMPOSITION ● Platelet count should be at least 70 x 109/L and the absolute Each vial contains: BORVIZ contains no antimicrobial preservative. Reconstituted neutrophil count (ANC) should be at least 1.0 x 109/L CONTRAINDICATIONS Bortezomib IP 3.5 mg BORVIZ should be administered within 8 hours of preparation. ● Non-hematological toxicities should have resolved to BORVIZ is contraindicated in patients with hypersensitivity (not Excipients: Q.S. When reconstituted as directed, BORVIZ may be stored at Grade 1 or baseline. including local reactions) to bortezomib, boron, or mannitol. Reactions have included anaphylactic reactions. 25ºC (77ºF). The reconstituted material may be stored in the DESCRIPTION original vial and/or the syringe prior to administration. The product may be Table 2: Dose Modifications during Cycles of Combination Bortezomib, BORVIZ is contraindicated for intrathecal administration. Fatal events have stored for up to 8 hours in a syringe; however, total storage time for the BORVIZ (bortezomib) for Injection is an antineoplastic agent Melphalan and Prednisone Therapy occurred with intrathecal administration of BORVIZ. reconstituted material must not exceed 8 hours when exposed to normal indoor lighting. available for intravenous injection use. Each single use vial Toxicity Dose modification or delay WARNINGS contains 3.5 mg of bortezomib as a sterile lyophilized powder. Hematological toxicity during a cycle: Consider reduction of the melphalan BORVIZ should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. PRESENTATION / HOW SUPPLIED Bortezomib is a modified dipeptidyl boronic acid. The product is provided as a If prolonged Grade 4 neutropenia or dose by 25% in the next cycle BORVIZ 3.5 is available in lyophilized vial containing 3.5 mg Bortezomib mannitol boronic ester which, in reconstituted form, consists of the mannitol thrombocytopenia, or Pregnancy Category D Injection IP is packed in a vial and is placed in printed carton along with a pack ester in equilibrium withits hydrolysis product, the monomeric boronic acid. BORVIZ should be avoided in women of childbearing potential and Bortezomib insert. thrombocytopenia with bleeding is was not terato-genic when toxicity studies were conducted on rats and rabbits. The drug substance exists in its cyclic anhydride form as a trimeric boroxine. observed in the previous cycle No placental transfer studies have been conducted with Bortezomib. There are STORAGE 9 no adequate and well-controlled studies in pregnant women. The chemical name for bortezomib, the monomeric boronic acid, is [(1R)-3- If platelet count is not above 30 x 10 /L Withhold BORVIZ dose Store protected from light and moisture. methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino] or KEEP OUT OF REACH OF CHILDREN. 9 PRECAUTIONS butyl] boronic acid. ANC is not above 0.75 x 10 /L on a Peripheral Neuropathy BORVIZ dosing day (other than day 1) Bortezomib treatment causes peripheral neuropathy that is predominantly Manufactured by: sensory, although cases of motor neuropathy have also been reported. O OH If several BORVIZ doses in Reduce BORVIZ dose by 1 dose 2 2 Patents with preexisting symptoms (numbness, pain or a burning feeling in consecutive cycles are withheld due to level (from 1.3 mg/m to 1 mg/m , or INTAS PHARMACEUTICALS LTD. N H B 2 2 the feet or hands) and/or signs of peripheral neuropathy may experience N OH toxicity from 1 mg/m to 0.7 mg/m ) Plot No.: 5, 6 and 7, Pharmez - 382 213, H N worsening peripheral neuropathy (including >/= Grade 3) during treatment. So N O all the Patients on Bortezomib should be monitored for symptoms of Near Village Matoda, Ta: Sanand, Dist: Ahmedabad. Grade 3 or higher non-hematological Withhold BORVIZ therapy until neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, toxicities symptoms of toxicity have resolved paresthesia, discomfort or neuropathic pain. Patients experiencing new or The molecular weight is 384.24. The molecular formula is C19H25BN404. The solubility of bortezomib, as the monomeric boronic acid, in water is 3.3-3.8 to Grade 1 or baseline. Then, worsening peripheral neuropathy may require changes in the dose and mg/ml in a pH range of 2.0-6.5. BORVIZ may be reinitiated with one schedule of bortezomib (see dosage and administration) dose level reduction (from 1.3 mg/m2 to 1 mg/m2, or from 1 mg/m2 to 0.7 Hypotension: CLINICAL PHARMACOLOGY mg/m2). For BORVIZ –related Caution should be exercised when treating patients with a history of Mechanism of action hypotension, syncope and patients who are dehydrated. Management of neuropathic pain and/or peripheral Bortezomib is a reversible inhibitor of the chymotrypsin-like activity of the 26S hypotension may include adjustment of antihypertensive , neuropathy, hold or modify BORVIZ proteasome in mammalian cells. The 26S proteasome is a large protein hydration and administration of mineralocortiocids (see Adverse Reactions) as outlined in complex that degrades ubiquitinated proteins. The ubiquitin-proteasome Table 3. Cardiac Disorders: pathway plays an essential role in regulating the intracellular concentration of Patients with risk factors for, or existing heart disease should be closely specific proteins, thereby maintaining homeostasis within cells. Inhibition of Dosage and Dose Modifications for Relapsed Multiple Myeloma and monitored, particularly for the Q-T interval prolongation. the 26S proteasome prevents this targeted proteolysis, which can affect Mantle Cell Lymphoma multiple signaling cascades within the cell. This disruption of normal Laboratory Tests: homeostatic mechanisms can lead to cell death. Experiments have demo BORVIZ (1.3 mg/m2/dose) is administered twice weekly for 2 weeks (Days 1, Complete blood counts (CBC) should be frequently monitored throughout nstrated that bortezomib is cytotoxic to a variety of cancer cell types in vitro. 4, 8, and 11) followed by a 10-day rest period (Days 12-21). For extended treatment with Bortezomib. Bortezomib causes a delay in tumor growth in vivoin nonclinical tumor therapy of more than 8 cycles, BORVIZ may be administered on the standard Gastrointestinal Adverse Events: schedule or on a maintenance schedule of once weekly for 4 weeks (Days 1, models, including multiple myeloma. Treatment with Bortezomib leads to nausea, constipation, diarrhea, and 8, 15, and 22) followed by a 13-day rest period (Days 23 to 35). At least 72 vomiting (see adverse events); this can be taken care by ant-emetic and Pharmacodynamics hours should elapse between consecutive doses of BORVIZ. anti-diarrheal medications. Fluid and electrolyte replacement should be Following twice weekly administration of 1 mg/m2 and 1.3 mg/m2 bortezomib administered to prevent dehydration. doses (n=12 per each dose level), the maximum inhibition of 20S proteasome BORVIZ therapy should be withheld at the onset of any Grade 3 activity (relative to baseline) in whole blood was observed 5 minutes after drug non-hematological or Grade 4 hematological toxicities excluding neuropathy Thrombocytopenia: Bortezomib is associated with thrombocytopenia usually platelets were lowest administration. Comparable maximum inhibition of 20S proteasome activity as discussed below. Once the symptoms of the toxicity have resolved, 2 2 at Day 11 of each cycle and recovers to the basline by the next cycle.The was observed between 1 and 1.3 mg/m doses. Maximal inhibition ranged BORVIZ therapy may be reinitiated at a 25% reduced dose (1.3 mg/m /dose platelet count decrease and recovery remained consistent over the treatment from 70% to 84% and from 73% to 83% for the 1 mg/m2 and 1.3 mg/m2 dose reduced to 1 mg/m2/dose; 1 mg/m2/dose reduced to 0.7 mg/m2/dose). and there was no evidence of cummulative thrombocytopenia. Treatment regimens, respectively. should be held when the platelet count is <25,000/pL and reinitiated at a Dose Modifications for Peripheral Neuropathy reduced dose (see dosage and administration and adverse events). Pharmacokinetics Patients with pre-existing severe neuropathy should be treated with BORVIZ Following intravenous administration of 1 mg/m2 and 1.3 mg/m2 doses to 24 only after careful risk-benefit assessment. Tumor Lysis Syndrome: As Bortezomib is a cytotoxic agent and can rapidly kill malignant cells, the patients with multiple myeloma (n=12, per each dose level), the mean complications of tumor lysis syndrome may occur. Patients at risk of tumor lysis maximum plasma concentrations of bortezomib (Cmax) after the first dose (Day Patients experiencing new or worsening peripheral neuropathy during BORVIZ syndrome are those with high tumor burden prior to treatment. These patients 1) were 57 and 112 ng/mL, respectively. In subsequent doses, when therapy may require a decrease in the dose and/or a less dose-intense schedule. should be monitored closely and appropriate precautions need to be taken. administered twice weekly, the mean maximum observed plasma concentrations ranged from 67 to 106 ng/mL for the 1 mg/m2 dose and 89 to For dose or schedule modification guidelines for patients who experience Hepatic Events 120 ng/mL for the 1.3 mg/m2 dose. The mean elimination half-life of BORVIZ -related neuropathic pain and/or peripheral neuropathy see Table 3. Patients who are on multiple concomitant medications and with serious bortezomib upon multiple dosing ranged from 40 to 193 hours after the 1 medical conditions have to be monitored for liver failure (Rare cases of acute 2 2 liver failure have been reported). Other reported hepatic events include mg/m dose and 76 to 108 hours after the 1.3mg/m dose. The mean total Table 3: Recommended Dose Modification for BORVIZ related asymptomatic increases in liver enzymes, hyperbilimbinemia, and hepatitis. body clearances was 102 and 112 L/h following the first dose for doses of 1 Neuropathic Pain and/or Peripheral Sensory or Motor Neuropathy Such changes may be reversible upon discontinuation of Bortezomib. 2 2 mg/m and 1.3 mg/m , respectively, and ranged from 15 to 32 L/h following Severity of Peripheral Neuropathy Modification of Dose and Regimen 2 subsequent doses for doses of 1 and 1.3 mg/m , respectively. Signs and Symptoms* Patients with Hepatic Impairment: Liver enzymes metabolize Bortezomib and Bortezomib's clearance may Grade 1 (asymptomatic; loss of deep No action Distribution decrease in patients with hepatic impairment. These patients should be tendon reflexes or paresthesia) without closely monitored for toxicities when treated with Bortezomib. The mean distribution volume of bortezomib ranged from approximately 498 pain or loss of function to 1884 L/m2 following single- or repeat-dose administration of 1 mg/m2 or 2 Patients with Renal Impairment: 1.3 mg/m2 to patients with multiple myeloma. This suggests bortezomib distributes Grade 1 with pain or Grade 2 (moderate Reduce BORVIZ to 1 mg/m symptoms; limiting instrumental No clinical information is available on the use of bortezomib in patients with widely to peripheral tissues. The binding of bortezomib to human plasma proteins Activities of Daily Living (ADL)**) creatinine clearance values less than 13 mUmin and patients on averaged 83% over the concentration range of 100 to 1000 ng/mL. hemodialysis. Patients with renal impairment should be closely monitored for Grade 2 with pain or Grade 3 (severe Withhold BORVIZ therapy until toxicity toxidties when treated with bortezomib. symptoms; limiting self care ADL ***) resolves. When toxicity resolves Metabolism reinitiate with a reduced dose of BORVIZ In vitro studies with human liver microsomes and human cDNA-expressed at 0.7 mg/m2 once per week. Drug Interactions cytochrome P450 isozymes indicate that bortezomib is primarily oxidatively Grade 4 (life-threatening consequences; Discontinue BORVIZ In vitro studies indicate that Bortezomib is primarily a substrate metabolized via cytochrome P450 enzymes 3A4, 2C19, and 1A2. Bortezomib urgent intervention indicated) for cytochrome P450 3A4, 2C19, and 1 A2. Patients who are metabolism by CYP 2D6 and 2C9 enzymes is minor. The major metabolic *Grading based on NCI Common Terminology Criteria CTCAE v4.0 concomitantly receiving Bortezomib and other drugs which either induces or inhibitors of cytochrome P450 should be pathway is deboronation to form 2 deboronated metabolites that subsequently **Instrumental ADL: refers to preparing meals, shopping for undergo hydroxylation to several metabolites. Deboronated bortezomib closely monitored for either toxicity or reduced efficacy. groceries or clothes, using telephone, managing money etc; Patients on oral antidiabetic drugs receiving Bortezomib metabolites are inactive as 26S proteasome inhibitors. Pooled plasma data ***Self care ADL: refers to bathing, dressing and undressing, treatment may require close monitoring of their blood glucose from 8 patients at 10 min and 30 min after dosing indicate that the plasma feeding self, using the toilet, taking medications, and not levels and adjustment of the dose of antidiabetic . levels of metabolites are low compared to the parent drug. bedridden No formal drug interaction studies have been conducted with Bortezomib. Elimination Dosage in Patients with Hepatic Impairment The pathways of elimination of Bortezomib have not been characterized in Patients with mild hepatic impairment do not require a starting humans. Use in special population: dose adjustment and should be treated per the recommended BORVIZ dose. Patients with moderate or severe hepatic Pregnancy/Nursing: Carcinogenesis, Mutagenesis, Impairment of Fertility impairment should be started on BORVIZ at a reduced dose of 0.7 mg/m2 per Patients should be advised to use effective contraceptive measures to injection during the first cycle, and a subsequent dose escalation to 1.0 mg/m2 prevent pregnancy. Carcinogenicity studies have not been conducted with bortezomib. 2 or further dose reduction to 0.5 mg/m may be considered based on patient Nursing Mothers tolerance. Bortezomib showed clastogenic activity (structural chromosomal aberrations) It is not known whether Bortezomib is excreted in human milk. Women should in the in vitro chromosomal aberration assay using Chinese hamster ovary be advised against breast-feeding while receiving Bortezomib therapy. Table 4: Recommended Starting Dose Modification for BORVIZ in cells. Bortezomib was not genotoxic when tested in the in vitro mutagenicity Patients with Hepatic Impairment Paediatric Use assay (Ames test) and in vivo micronucleus assay in mice. Fertility studies The safety and effectiveness of Bortezomib in children has not been established. with bortezomib were not performed but evaluation of reproductive tissues Bilirubin Level SGOT (AST) Modification of Starting has been performed in the general toxicity studies. In the 6-month rat toxicity Levels Dose Geriatric Use 2 study, degenerative effects in the ovary were observed at doses ≥ 0.3 mg/m Mild Less than or More than ULN None No overall differences in safety or effectiveness were observed between patients >/= age 65 and younger patients receiving Bortezomib; but greater (one-fourth of the recommended clinical dose), and degenerative changes in equal to sensitivity of some older individuals cannot be ruled out. the testes occurred at 1.2 mg/m2. 1.0xULN More than 1.0x- Any None Patients with Renal Impairment Bortezomib could have a potential effect on either male or female fertility. 1.5xULN The pharmacokinetics of bortezomib are not influenced by the degree of renal Moderate More than 1.5x- Any Reduce BORVIZ to 0.7 impairment. Therefore, dosing adjustments of bortezomib are not necessary for INDICATIONS AND USAGE 3xULN mg/m2 in the first cycle. patients with renal insufficiency. Since dialysis may reduce bortezomib concentrations, bortezomib should be administered after the dialysis procedure. Consider dose escalation to BORVIZ 3.5 (Bortezomib) is indicated for the treatment of patients with 1.0 mg/m2 or further dose 2 Patients with Hepatic Impairment multiple myeloma. reduction to 0.5 mg/m in The exposure of bortezomib is increased in patients with moderate (bilirubin BORVIZ 3.5 (Bortezomib) is indicated for the treatment of patients with mantle Severe More than 3x Any subsequent cycles based on ≥ 1.5 – 3x ULN) and severe (bilirubin > 3 x ULN) hepatic impairment. Starting cell lymphoma who have received at least 1 prior therapy. ULN patient tolerability. dose should be reduced in those patients

DOSAGE AND ADMINISTRATION Abbreviations: SGOT = serum glutamic oxaloacetic transaminase; ADVERSE EVENTS AST = aspartate aminotransferase; ULN = upper limit of the normal range. Adverse Events during Treatment Reported by 15 percent or More of Patients Receiving Bortezomib or Dexamethasone, Including Grade 3 and Grade 4 General Dosing Guidelines Events. (Table.) The recommended starting dose of BORVIz is 1.3 mg/m2. BORVIZ may be ADMINISTRATION PRECAUTIONS administered intravenously at a concentration of 1 mg/mL. When The drug quantity contained in one vial (3.5 mg) may exceed the usual dose administered intravenously, BORVIZ is administered as a 3 to 5 second bolus required. Caution should be used in calculating the dose to prevent overdose. intravenous injection. BORVIZ is an antineoplastic. Procedures for proper handling and disposal Dosage in Previously Untreated Multiple Myeloma should be considered.

BORVIZ is administered in combination with oral melphalan and oral Reconstitution/Preparation for Intravenous/subcutaneous Administration prednisone for nine 6-week treatment cycles as shown in Table 1. In Cycles 1-4, BORVIZ is administered twice weekly (days 1, 4, 8, 11, 22, 25, 29 and Proper aseptic technique should be used. Reconstitute only with 0.9% 32). In Cycles 5-9, BORVIZ is administered once weekly (days 1, 8, 22 and sodium chloride. The reconstituted product should be a clear and colorless 29). At least 72 hours should elapse between consecutive doses of BORVIZ. solution.

The recommended dose of BORVIZ is 1.3 mg/m2/dose administered as a 3 to Different volumes of 0.9% sodium chloride are used to reconstitute the 5 second bolus intravenous injection twice weekly for 2 weeks (Days 1, 4, 8, product for the different routes of administration. The reconstituted and 11) followed by a 10-day rest period (Days 12-21). For extended therapy concentration of bortezomib for intravenous administration is 1 mg/mL. of more than 8 cycles, BORVIZ may be administered on the standard schedule or on a maintenance schedule of once weekly for 4 weeks (Days 1, For each 3.5 mg single-use vial of bortezomib reconstitute with the following 8, 15, and 22) followed by a 13-day rest period (Days 23 to 35). At least 72 volume of 0.9% sodium chloride based on route of administration (Table 5): hours should elapse between consecutive doses of BORVIZ. Table 5: Reconstitution Volumes and Final Concentration for Table 1: Dosage Regimen for Patients with Previously Untreated Intravenous Administration Multiple Myeloma Route of Bortezomib Diluent (0.9% Final Bortezomib Twice Weekly BORVIZ (Cycles 1-4) administration (mg/vial) Sodium Chloride) concentration Week 1 2 3 4 5 6 (mg/mL) BORVIZ Day — — Day Day Day rest Day Day Day Day rest Intravenous 3.5 mg 3.5 mL 1 mg/mL period period Subcutaneous 3.5 mg 1.4 mL 2.5 mg/mL (1.3 mg/m2) 1 4 8 11 22 25 29 32 Melphalan Day Day Day Day — — rest — — — — rest Dose must be individualized to prevent overdosage. After determining patient (9 mg/m2) period period body surface area (BSA) in square meters, use the following equations to Prednisone calculate the total volume (mL) of reconstituted Bortezomib to be administered: (60 mg/m2) 1 2 3 4 Once Weekly BORVIZ (Cycles 5-9 when used in combination with Melphalan Intravenous Administration [1 mg/mL concentration] a Based on High Level Term and Prednisone) Bortezomib dose (mg/m2) x Week 1 2 3 4 5 6 2 patient BSA (m ) = Total Bortezomib volume ( mL) BORVIZ Day — — Day rest Day Day rest OVERDOSAGE to be administered period period 1 mg/mL There is no known specific antidote for bortezomib overdosage. In humans,

2 Subcutaneous Administration [2.5 mg/mL concentration] fatal outcomes following the administration of more than twice the (1.3 mg/m ) 1 8 22 29 recommended therapeutic dose have been reported, which were associated Melphalan Day Day Day Day — — rest — — — — rest 2 Bortezomib dose (mg/m ) x with the acute onset of symptomatic hypotension and thrombocytopenia. In (9 mg/m2) period period patient BSA (m2) = Total Bortezomib volume ( mL) the event of an overdosage, the patient’s vital signs should be monitored and Prednisone to be administered (60 mg/m2) 1 2 3 4 2.5 mg/ml appropriate supportive care given.

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File Name : 51 2934 0 715602-BORVIZ 3.5-PIL Size : 170 x 550 (mm) Colour : Pantone Black Date : 02/04/18, 12/04/18, 21/04/18

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For the use of an Oncologist or a Hospital or a Cancer Institute Dose Modification Guidelines for BORVIZ When Given in Parenteral drug products should be inspected visually for STABILITY: BORVIZ 3.5 Combination with Melphalan and Prednisone particulate matter and discoloration prior to administration Unopened vials of BORVIZ are stable until the date indicated (BORTEZOMIB INJECTION IP 3.5 mg/vial) whenever solution and container permit. If any discoloration or on the package when stored in the original package protected Prior to initiating any cycle of therapy with BORVIZ in particulate matter is observed, the reconstituted product from light. combination with melphalan and prednisone: should not be used. COMPOSITION ● Platelet count should be at least 70 x 109/L and the absolute Each vial contains: BORVIZ contains no antimicrobial preservative. Reconstituted neutrophil count (ANC) should be at least 1.0 x 109/L CONTRAINDICATIONS Bortezomib IP 3.5 mg BORVIZ should be administered within 8 hours of preparation. ● Non-hematological toxicities should have resolved to BORVIZ is contraindicated in patients with hypersensitivity (not Excipients: Q.S. When reconstituted as directed, BORVIZ may be stored at Grade 1 or baseline. including local reactions) to bortezomib, boron, or mannitol. Reactions have included anaphylactic reactions. 25ºC (77ºF). The reconstituted material may be stored in the DESCRIPTION original vial and/or the syringe prior to administration. The product may be Table 2: Dose Modifications during Cycles of Combination Bortezomib, BORVIZ is contraindicated for intrathecal administration. Fatal events have stored for up to 8 hours in a syringe; however, total storage time for the BORVIZ (bortezomib) for Injection is an antineoplastic agent Melphalan and Prednisone Therapy occurred with intrathecal administration of BORVIZ. reconstituted material must not exceed 8 hours when exposed to normal indoor lighting. available for intravenous injection use. Each single use vial WARNINGS contains 3.5 mg of bortezomib as a sterile lyophilized powder. BORVIZ should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. PRESENTATION / HOW SUPPLIED Bortezomib is a modified dipeptidyl boronic acid. The product is provided as a BORVIZ 3.5 is available in lyophilized vial containing 3.5 mg Bortezomib mannitol boronic ester which, in reconstituted form, consists of the mannitol Pregnancy Category D Injection IP is packed in a vial and is placed in printed carton along with a pack ester in equilibrium withits hydrolysis product, the monomeric boronic acid. BORVIZ should be avoided in women of childbearing potential and Bortezomib insert. was not terato-genic when toxicity studies were conducted on rats and rabbits. The drug substance exists in its cyclic anhydride form as a trimeric boroxine. No placental transfer studies have been conducted with Bortezomib. There are no adequate and well-controlled studies in pregnant women. STORAGE The chemical name for bortezomib, the monomeric boronic acid, is [(1R)-3- Store protected from light and moisture. methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino] PRECAUTIONS KEEP OUT OF REACH OF CHILDREN. butyl] boronic acid. Peripheral Neuropathy Bortezomib treatment causes peripheral neuropathy that is predominantly Manufactured by: sensory, although cases of motor neuropathy have also been reported. Patents with preexisting symptoms (numbness, pain or a burning feeling in INTAS PHARMACEUTICALS LTD. the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including >/= Grade 3) during treatment. So Plot No.: 5, 6 and 7, Pharmez - 382 213, all the Patients on Bortezomib should be monitored for symptoms of Near Village Matoda, Ta: Sanand, Dist: Ahmedabad. neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort or neuropathic pain. Patients experiencing new or The molecular weight is 384.24. The molecular formula is C19H25BN404. The solubility of bortezomib, as the monomeric boronic acid, in water is 3.3-3.8 worsening peripheral neuropathy may require changes in the dose and mg/ml in a pH range of 2.0-6.5. schedule of bortezomib (see dosage and administration) Hypotension: CLINICAL PHARMACOLOGY Caution should be exercised when treating patients with a history of Mechanism of action hypotension, syncope and patients who are dehydrated. Management of Bortezomib is a reversible inhibitor of the chymotrypsin-like activity of the 26S hypotension may include adjustment of antihypertensive medications, proteasome in mammalian cells. The 26S proteasome is a large protein hydration and administration of mineralocortiocids (see Adverse Reactions) complex that degrades ubiquitinated proteins. The ubiquitin-proteasome Cardiac Disorders: pathway plays an essential role in regulating the intracellular concentration of Patients with risk factors for, or existing heart disease should be closely specific proteins, thereby maintaining homeostasis within cells. Inhibition of Dosage and Dose Modifications for Relapsed Multiple Myeloma and monitored, particularly for the Q-T interval prolongation. the 26S proteasome prevents this targeted proteolysis, which can affect Mantle Cell Lymphoma multiple signaling cascades within the cell. This disruption of normal Laboratory Tests: homeostatic mechanisms can lead to cell death. Experiments have demo BORVIZ (1.3 mg/m2/dose) is administered twice weekly for 2 weeks (Days 1, Complete blood counts (CBC) should be frequently monitored throughout nstrated that bortezomib is cytotoxic to a variety of cancer cell types in vitro. 4, 8, and 11) followed by a 10-day rest period (Days 12-21). For extended treatment with Bortezomib. Bortezomib causes a delay in tumor growth in vivoin nonclinical tumor therapy of more than 8 cycles, BORVIZ may be administered on the standard Gastrointestinal Adverse Events: schedule or on a maintenance schedule of once weekly for 4 weeks (Days 1, models, including multiple myeloma. Treatment with Bortezomib leads to nausea, constipation, diarrhea, and 8, 15, and 22) followed by a 13-day rest period (Days 23 to 35). At least 72 vomiting (see adverse events); this can be taken care by ant-emetic and Pharmacodynamics hours should elapse between consecutive doses of BORVIZ. anti-diarrheal medications. Fluid and electrolyte replacement should be Following twice weekly administration of 1 mg/m2 and 1.3 mg/m2 bortezomib administered to prevent dehydration. doses (n=12 per each dose level), the maximum inhibition of 20S proteasome BORVIZ therapy should be withheld at the onset of any Grade 3 activity (relative to baseline) in whole blood was observed 5 minutes after drug non-hematological or Grade 4 hematological toxicities excluding neuropathy Thrombocytopenia: Bortezomib is associated with thrombocytopenia usually platelets were lowest administration. Comparable maximum inhibition of 20S proteasome activity as discussed below. Once the symptoms of the toxicity have resolved, 2 2 at Day 11 of each cycle and recovers to the basline by the next cycle.The was observed between 1 and 1.3 mg/m doses. Maximal inhibition ranged BORVIZ therapy may be reinitiated at a 25% reduced dose (1.3 mg/m /dose platelet count decrease and recovery remained consistent over the treatment from 70% to 84% and from 73% to 83% for the 1 mg/m2 and 1.3 mg/m2 dose reduced to 1 mg/m2/dose; 1 mg/m2/dose reduced to 0.7 mg/m2/dose). and there was no evidence of cummulative thrombocytopenia. Treatment regimens, respectively. should be held when the platelet count is <25,000/pL and reinitiated at a Dose Modifications for Peripheral Neuropathy reduced dose (see dosage and administration and adverse events). Pharmacokinetics Patients with pre-existing severe neuropathy should be treated with BORVIZ Following intravenous administration of 1 mg/m2 and 1.3 mg/m2 doses to 24 only after careful risk-benefit assessment. Tumor Lysis Syndrome: As Bortezomib is a cytotoxic agent and can rapidly kill malignant cells, the patients with multiple myeloma (n=12, per each dose level), the mean complications of tumor lysis syndrome may occur. Patients at risk of tumor lysis maximum plasma concentrations of bortezomib (Cmax) after the first dose (Day Patients experiencing new or worsening peripheral neuropathy during BORVIZ syndrome are those with high tumor burden prior to treatment. These patients 1) were 57 and 112 ng/mL, respectively. In subsequent doses, when therapy may require a decrease in the dose and/or a less dose-intense schedule. should be monitored closely and appropriate precautions need to be taken. administered twice weekly, the mean maximum observed plasma concentrations ranged from 67 to 106 ng/mL for the 1 mg/m2 dose and 89 to For dose or schedule modification guidelines for patients who experience Hepatic Events 120 ng/mL for the 1.3 mg/m2 dose. The mean elimination half-life of BORVIZ -related neuropathic pain and/or peripheral neuropathy see Table 3. Patients who are on multiple concomitant medications and with serious bortezomib upon multiple dosing ranged from 40 to 193 hours after the 1 medical conditions have to be monitored for liver failure (Rare cases of acute 2 2 liver failure have been reported). Other reported hepatic events include mg/m dose and 76 to 108 hours after the 1.3mg/m dose. The mean total Table 3: Recommended Dose Modification for BORVIZ related asymptomatic increases in liver enzymes, hyperbilimbinemia, and hepatitis. body clearances was 102 and 112 L/h following the first dose for doses of 1 Neuropathic Pain and/or Peripheral Sensory or Motor Neuropathy Such changes may be reversible upon discontinuation of Bortezomib. mg/m2 and 1.3 mg/m2, respectively, and ranged from 15 to 32 L/h following subsequent doses for doses of 1 and 1.3 mg/m2, respectively. Patients with Hepatic Impairment: Liver enzymes metabolize Bortezomib and Bortezomib's clearance may Distribution decrease in patients with hepatic impairment. These patients should be closely monitored for toxicities when treated with Bortezomib. The mean distribution volume of bortezomib ranged from approximately 498 2 2 to 1884 L/m following single- or repeat-dose administration of 1 mg/m or Patients with Renal Impairment: 1.3 mg/m2 to patients with multiple myeloma. This suggests bortezomib distributes No clinical information is available on the use of bortezomib in patients with widely to peripheral tissues. The binding of bortezomib to human plasma proteins creatinine clearance values less than 13 mUmin and patients on averaged 83% over the concentration range of 100 to 1000 ng/mL. hemodialysis. Patients with renal impairment should be closely monitored for toxidties when treated with bortezomib. Metabolism In vitro studies with human liver microsomes and human cDNA-expressed Drug Interactions cytochrome P450 isozymes indicate that bortezomib is primarily oxidatively In vitro studies indicate that Bortezomib is primarily a substrate metabolized via cytochrome P450 enzymes 3A4, 2C19, and 1A2. Bortezomib for cytochrome P450 3A4, 2C19, and 1 A2. Patients who are metabolism by CYP 2D6 and 2C9 enzymes is minor. The major metabolic *Grading based on NCI Common Terminology Criteria CTCAE v4.0 concomitantly receiving Bortezomib and other drugs which either induces or inhibitors of cytochrome P450 should be pathway is deboronation to form 2 deboronated metabolites that subsequently **Instrumental ADL: refers to preparing meals, shopping for undergo hydroxylation to several metabolites. Deboronated bortezomib closely monitored for either toxicity or reduced efficacy. groceries or clothes, using telephone, managing money etc; Patients on oral antidiabetic drugs receiving Bortezomib metabolites are inactive as 26S proteasome inhibitors. Pooled plasma data ***Self care ADL: refers to bathing, dressing and undressing, treatment may require close monitoring of their blood glucose from 8 patients at 10 min and 30 min after dosing indicate that the plasma feeding self, using the toilet, taking medications, and not levels and adjustment of the dose of antidiabetic medication. levels of metabolites are low compared to the parent drug. bedridden No formal drug interaction studies have been conducted with Bortezomib. Elimination Dosage in Patients with Hepatic Impairment The pathways of elimination of Bortezomib have not been characterized in Patients with mild hepatic impairment do not require a starting humans. Use in special population: dose adjustment and should be treated per the recommended BORVIZ dose. Patients with moderate or severe hepatic Pregnancy/Nursing: Carcinogenesis, Mutagenesis, Impairment of Fertility impairment should be started on BORVIZ at a reduced dose of 0.7 mg/m2 per Patients should be advised to use effective contraceptive measures to injection during the first cycle, and a subsequent dose escalation to 1.0 mg/m2 prevent pregnancy. Carcinogenicity studies have not been conducted with bortezomib. 2 or further dose reduction to 0.5 mg/m may be considered based on patient Nursing Mothers tolerance. Bortezomib showed clastogenic activity (structural chromosomal aberrations) It is not known whether Bortezomib is excreted in human milk. Women should in the in vitro chromosomal aberration assay using Chinese hamster ovary be advised against breast-feeding while receiving Bortezomib therapy. Table 4: Recommended Starting Dose Modification for BORVIZ in cells. Bortezomib was not genotoxic when tested in the in vitro mutagenicity Patients with Hepatic Impairment Paediatric Use assay (Ames test) and in vivo micronucleus assay in mice. Fertility studies The safety and effectiveness of Bortezomib in children has not been established. with bortezomib were not performed but evaluation of reproductive tissues has been performed in the general toxicity studies. In the 6-month rat toxicity Geriatric Use study, degenerative effects in the ovary were observed at doses ≥ 0.3 mg/m2 No overall differences in safety or effectiveness were observed between (one-fourth of the recommended clinical dose), and degenerative changes in patients >/= age 65 and younger patients receiving Bortezomib; but greater sensitivity of some older individuals cannot be ruled out. the testes occurred at 1.2 mg/m2. Patients with Renal Impairment Bortezomib could have a potential effect on either male or female fertility. The pharmacokinetics of bortezomib are not influenced by the degree of renal impairment. Therefore, dosing adjustments of bortezomib are not necessary for INDICATIONS AND USAGE patients with renal insufficiency. Since dialysis may reduce bortezomib concentrations, bortezomib should be administered after the dialysis procedure. BORVIZ 3.5 (Bortezomib) is indicated for the treatment of patients with Patients with Hepatic Impairment multiple myeloma. The exposure of bortezomib is increased in patients with moderate (bilirubin BORVIZ 3.5 (Bortezomib) is indicated for the treatment of patients with mantle ≥ 1.5 – 3x ULN) and severe (bilirubin > 3 x ULN) hepatic impairment. Starting cell lymphoma who have received at least 1 prior therapy. dose should be reduced in those patients

DOSAGE AND ADMINISTRATION Abbreviations: SGOT = serum glutamic oxaloacetic transaminase; ADVERSE EVENTS AST = aspartate aminotransferase; ULN = upper limit of the normal range. Adverse Events during Treatment Reported by 15 percent or More of Patients Receiving Bortezomib or Dexamethasone, Including Grade 3 and Grade 4 General Dosing Guidelines Events. (Table.) The recommended starting dose of BORVIz is 1.3 mg/m2. BORVIZ may be ADMINISTRATION PRECAUTIONS administered intravenously at a concentration of 1 mg/mL. When The drug quantity contained in one vial (3.5 mg) may exceed the usual dose Bortezomib Dexamethasone required. Caution should be used in calculating the dose to prevent overdose. administered intravenously, BORVIZ is administered as a 3 to 5 second bolus N=331 N=332 intravenous injection. Preferred Term All Grade 3 Grade 4 All Grade 3 Grade 4 BORVIZ is an antineoplastic. Procedures for proper handling and disposal Adverse Reactions 324 (98) 193 (58) 28(8) 297 (89) 110(33) 29(9) Dosage in Previously Untreated Multiple Myeloma should be considered. Nausea 172 (52) 8(2) 0 31(9) 0 0 Diarrhea NOS 171 (52) 22(7) 0 36(11) 2(<1) 0 Reconstitution/Preparation for Intravenous/subcutaneous Administration BORVIZ is administered in combination with oral melphalan and oral Fatigue 130 (39) 15(5) 0 82 (25) 8(2) 0 prednisone for nine 6-week treatment cycles as shown in Table 1. In Cycles Peripheral 115(35) 23(7) 2(<1) 14(4) 0 1(<1) 1-4, BORVIZ is administered twice weekly (days 1, 4, 8, 11, 22, 25, 29 and Proper aseptic technique should be used. Reconstitute only with 0.9% neuropathies NECa 32). In Cycles 5-9, BORVIZ is administered once weekly (days 1, 8, 22 and sodium chloride. The reconstituted product should be a clear and colorless Thrombocytopenia 109 (33) 80 (24) 12(4) 11(3) 5(2) 1(<1) 29). At least 72 hours should elapse between consecutive doses of BORVIZ. solution. Bortezomib Dexamethasone 2 Different volumes of 0.9% sodium chloride are used to reconstitute the The recommended dose of BORVIZ is 1.3 mg/m /dose administered as a 3 to N=331 N=332 5 second bolus intravenous injection twice weekly for 2 weeks (Days 1, 4, 8, product for the different routes of administration. The reconstituted and 11) followed by a 10-day rest period (Days 12-21). For extended therapy concentration of bortezomib for intravenous administration is 1 mg/mL. Preferred Term All Grade 3 Grade 4 All Grade 3 Grade 4 of more than 8 cycles, BORVIZ may be administered on the standard Constipation 99 (30) 6(2) 0 27(8) 1 (< 1) 0 schedule or on a maintenance schedule of once weekly for 4 weeks (Days 1, For each 3.5 mg single-use vial of bortezomib reconstitute with the following Vomiting NOS 96 (29) 8(2) 0 10(3) 1 1)(< 0 8, 15, and 22) followed by a 13-day rest period (Days 23 to 35). At least 72 volume of 0.9% sodium chloride based on route of administration (Table 5): hours should elapse between consecutive doses of BORVIZ. Anorexia 68 (21) 8(2) 0 8(2) 1 (< 1) 0 Table 5: Reconstitution Volumes and Final Concentration for Pyrexia 66 (20) 2(< 1) 0 21(6) 3 (< 1) 1 (< 1) Table 1: Dosage Regimen for Patients with Previously Untreated Intravenous Administration Paresthesia 64 (19) 5(2) 0 24(7) 0 0 Multiple Myeloma Anemia NOS 63 (19) 20(6) 1 (< 1) 21(6) 8(2) 0 Headache NOS 62 (19) 3 (< 1) 0 23(7) 1 (< 1) 0 Neutropenia 58(18) 37(11) 8(2) 1 (< 1) 1 (< 1) 0 Rash NOS 43 (13) 3 (< 1) 0 7(2) 0 0 Appetite decreased NOS 36(11) 0 0 12(4) 0 0 Dose must be individualized to prevent overdosage. After determining patient Dyspnea NOS 35(11) 11(3) 1 (< 1) 37(11) 7(2) 1 (< 1) body surface area (BSA) in square meters, use the following equations to calculate the total volume (mL) of reconstituted Bortezomib to be administered: Abdominal pain NOS 35(11) 5(2) 0 7(2) 0 0 Weakness 34 (10) 10(3) 0 28(8) 8(2) 0 Intravenous Administration [1 mg/mL concentration] a Based on High Level Term

OVERDOSAGE There is no known specific antidote for bortezomib overdosage. In humans, Subcutaneous Administration [2.5 mg/mL concentration] fatal outcomes following the administration of more than twice the recommended therapeutic dose have been reported, which were associated with the acute onset of symptomatic hypotension and thrombocytopenia. In the event of an overdosage, the patient’s vital signs should be monitored and appropriate supportive care given. INP113 51 2934 0 715602

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To Be Sold by Retail on the Prescription of Oncologist Only. perforations in patients with metastatic carcinoma of the colon or rectum, therefore, caution should be exercised when SN38), , (as determined by measurement of free and total platinum), and . Conclusions Cardiac Skin and subcu- Wound healing c Haemorrhage grade glioma, the safety profile was comparable with that observed in other tumour types in adults treated with The efficacy results are presented in Table 6. a,b treating these patients. Prior radiation is a risk factor for GI perforation in patients treated for persistent, recurrent or on the impact of bevacizumab on pharmacokinetics cannot be drawn. disorders Congestive taneous tissue omplications , In clinical trials across all indications the overall incidence of NCI-CTCAE v.3 Grade 3-5 bleeding reactions ranged from bevacizumab. Table 6: Efficacy Results for Trial BO17704 b,d 0.4% to 6.9% in bevacizumab treated patients, compared with up to 4.5% of patients in the chemotherapy control 1 NAME OF THE MEDICINAL PRODUCT metastatic cervical cancer with bevacizumab and all patients with GI perforation had a history of prior radiation. Therapy Combination of bevacizumab and sunitinib malate heart failure , disorders Palmar-plantar In study BO20924 of bevacizumab with current standard of care in rhabdomyosarcoma and nonrhabdomyosarcoma should be permanently discontinued in patients who develop gastrointestinal perforation. Supraventricular erythro- group. soft tissue sarcoma, the safety profile of bevacizumab treated children was comparable with that observed in adults Cisplatin/Gemcitabine Cisplatin/Gemcitabine + Beva- Cisplatin/Gemcitabine + Beva- In two clinical trials of metastatic renal cell carcinoma, microangiopathic haemolytic anaemia (MAHA) was reported in 7 From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (study GOG-0240), grade 3-5 treated with bevacizumab. GI-vaginal Fistulae of 19 patients treated with bevacizumab (10 mg/kg every two weeks) and sunitinib malate (50 mg daily) combination. tachycardia dysaesthesia + placebo cizumab 7.5 mg/kg q3weeks cizumab 15 mg/kg q3weeks syndrome bleeding reactions have been reported in up to 8.3% of patients treated with bevacizumab in combination with Bevacizumab is not approved for use in patients under the age of 18 years. In published literature reports, cases of non- MAHA is a haemolytic disorder which can present with red cell fragmentation, anaemia, and thrombocytopenia. In b,d Patients treated for persistent, recurrent, or metastatic cervical cancer with bevacizumab are at increased risk of Vascular Hypertension , Thrombo- Renal and compared with up to 4.6% of patients treated with paclitaxel and topotecan. mandibular osteonecrosis have been observed in patients under the age of 18 years treated with bevacizumab. Number of 347 345 351 fistulae between the vagina and any part of the GI tract (Gastrointestinal-vaginal fistulae). Prior radiation is a major risk addition, hypertension (including hypertensive crisis), elevated creatinine, and neurological symptoms were observed disorders Thrombo- embolism thrombotic The haemorrhagic reactions that have been observed in clinical trials were predominantly tumour-associated Post-marketing experience (Avastin, Roche/Genentech) patients factor for the development of GI-vaginal fistulae and all patients with GI-vaginal fistulae had a history of prior radiation. in some of these patients. All of these findings were reversible upon discontinuation of bevacizumab and sunitinib b,d haemorrhage and minor mucocutaneous haemorrhage (e.g. epistaxis). Bevacizumab 100 mg/4 mL or 400 mg/16 mL concentrate for solution in single use vial for intravenous (IV) infusion embolism (arterial) , micro- a,b Recurrence of cancer within the field of prior radiation is an additional important risk factor for the development of GI- malate. b,d b,d a,b Musculoskeletal Fistula , Osteone- 2 QUALITATIVE AND QUANTITATIVE COMPOSITION (venous) Haemorrhage , angiopathy Tumour-associated haemorrhage Table 3: Adverse Reactions Reported in Post-marketing Setting Progression-free survival vaginal fistulae. Combination with platinum- or -based therapies and connective Myalgia, crosis of the Active ingredient: Bevacizumab (humanized anti-VEGF monoclonal antibody) Deep vein tissue disorders Arthralgia, jawb,c Major or massive pulmonary haemorrhage/haemoptysis has been observed primarily in trials in patients with non-small System organ class (SOC) Reactions (frequency*) Non-GI Fistulae Increased rates of severe neutropenia, febrile neutropenia, or infection with or without severe neutropenia (including thrombosis cell lung cancer (NSCLC). Possible risk factors include squamous cell histology, treatment with antirheumatic/anti- Median 6.1 6.7 (p=0.0026) 6.5 (p=0.0301) BEVATAS 100: Muscular (months) some fatalities) have been observed mainly in patients treated with platinum or taxane-based therapies in the treatment inflammatory substances, treatment with anticoagulants, prior radiotherapy, bevacizumab therapy, previous medical Infections and Infestations Necrotizing fasciitis, usually secondary to wound healing Each single use vial contains 100 mg of bevacizumab in 4 mL (25 mg/mL) Patients may be at increased risk for the development of fistulae when treated with bevacizumab. Permanently of NSCLC and mBC. weakness, Respiratory, Dyspnoea, Pulmonary Pulmonary history of atherosclerosis, central tumour location and cavitation of tumours prior to or during therapy. The only complications, gastrointestinal perforation or fistula formation discontinue bevacizumab in patients with tracheoesophageal (TE) fistula or any Grade 4 fistula. Limited information is Back Pain variables that showed statistically significant correlations with bleeding were bevacizumab therapy and squamous cell Hazard ratio 0.75 [0.62; 0.91] 0.82 [0.68; 0.98] BEVATAS 400: available on the continued use of bevacizumab in patients with other fistulae. In cases of internal fistula not arising in the Radiotherapy thoracic and Rhinitis haemorrhage/ hyper- (rare) a histology. Patients with NSCLC of known squamous cell histology or mixed cell type with predominant squamous cell Each single use vial contains 400 mg of bevacizumab in 16 mL (25 mg/mL) gastrointestinal tract, discontinuation of bevacizumab should be considered. The safety and efficacy of concomitant administration of radiotherapy and bevacizumab have not been established. mediastinal Haemoptysis- tension , Renal and uri- Proteinuriaa,b Best overall 20.1% 34.1% (p<0.0001) 30.4% (p=0.0023) b,d histology were excluded from subsequent phase III trials, while patients with unknown tumour histology were included. Immune system disorders Hypersensitivity reactions and infusion reactions (not known); response Wound healing complications disorders , Pulmonary Nasal nary disorders Quantity per vial EGFR monoclonal antibodies in combination with bevacizumab chemotherapy regimens In patients with NSCLC excluding predominant squamous histology, all Grade reactions were seen with a frequency of with the following possible co-manifestations: dyspnoea/ ratea Ingredients embolism, septum Bevacizumab may adversely affect the wound healing process. Serious wound healing complications, including No interaction studies have been performed. EGFR monoclonal antibodies should not be administered for the Epistaxis, perfora- Reproductive Pelvic pain Ovarian up to 9.3% when treated with bevacizumab plus chemotherapy compared with up to 5% in the patients treated with difficulty breathing, flushing/redness/rash, hypotension or BEVATAS 100 BEVATAS 400 a,b anastomotic complications, with a fatal outcome have been reported. Therapy should not be initiated for at least 28 treatment of mCRC in combination with bevacizumab-containing chemotherapy. Results from the two randomised Hypoxia, tiona system and failure chemotherapy alone. Grade 3-5 reactions have been observed in up to 2.3% of patients treated with bevacizumab plus hypertension, oxygen desaturation, chest pain, rigors and Overall survival chemotherapy as compared with <1% with chemotherapy alone (NCI-CTCAE v.3). Major or massive pulmonary Bevacizumab 100 mg 400 mg days following major surgery or until the surgical wound is fully healed. In patients who experienced wound healing phase III studies in patients with mCRC suggest that the use of anti-EGFR monoclonal antibodies panitumumab and Dysphoniaa breast disorders nausea/vomiting complications during therapy, treatment should be withheld until the wound is fully healed. Therapy should be withheld cetuximab, respectively, in combination with bevacizumab plus chemotherapy, is associated with decreased PFS haemorrhage/haemoptysis can occur suddenly and up to two thirds of the serious pulmonary haemorrhages resulted in Median 13.1 13.6 (p=0.4203) 13.4 (p=0.7613) Trehalose dihydrate 240 mg 960 mg for elective surgery. and/or OS, and with increased toxicity compared with bevacizumab plus chemotherapy alone. Gastrointestinal Rectal Gastro- Gastro-in- Congenital, Foetal abnor- a fatal outcome. Nervous system disorders Hypertensive encephalopathy (very rare) (months) familial, and ge- malitiesa,c Gastrointestinal haemorrhages, including rectal bleeding and melaena have been reported in colorectal cancer Necrotising fasciitis, including fatal cases, has rarely been reported in patients treated with bevacizumab. This 4.6 Fertility, Pregnancy and Lactation disorders haemorrhage, intestinal testinal Posterior Reversible Encephalopathy Syndrome (PRES), (rare) Hazard ratio 0.93 [0.78; 1.11] 1.03 [0.86, 1.23] Mono-Sodium dihydrogen Phosphate monohydrate 23.20 mg 92.80 mg Stomatitis, perforationb,d, ulcera netic disorder patients, and have been assessed as tumour-associated haemorrhages. condition is usually secondary to wound healing complications, gastrointestinal perforation or fistula formation. Information provided in this section is based on innovator data (Avastin, Roche/Genentech). Tumour-associated haemorrhage was also seen rarely in other tumour types and locations, including cases of central Bevacizumab therapy should be discontinued in patients who develop necrotising fasciitis, and appropriate treatment Constipation, Intestinal Vascular disorders Renal thrombotic microangiopathy, which may be clinically a patients with measurable disease at baseline di-Sodium hydrogen Phosphate anhydrous 4.80 mg 19.20 mg Women of childbearing potential General Asthenia, Pain, Lethargy, nervous system (CNS) bleeding in patients with CNS metastases. should be promptly initiated. Diarrhoea, perforation, Il- disorders and Fatigue, Mucosal The incidence of CNS bleeding in patients with untreated CNS metastases receiving bevacizumab has not been manifested as proteinuria (not known) with or without Polysorbate 20 1.60 mg 6.40 mg First-line treatment of non-squamous NSCLC with EGFR activating mutations in combination with erlotinib Hypertension Women of childbearing potential have to use effective contraception during (and up to 6 months after) treatment. Nausea, eus, Intestinal administration Inflammation prospectively evaluated in randomised clinical trials. In an exploratory retrospective analysis of data from 13 completed concomitant sunitinib use. Vomiting, Ab- obstruction, Jo25567 Ortho phosphoric acid q.s. to pH 6.20 ± 0.20 q.s. to pH 6.20 ± 0.20 Pregnancy site conditions randomised trials in patients with various tumour types, 3 patients out of 91 (3.3%) with brain metastases experienced An increased incidence of hypertension was observed in bevacizumab-treated patients. Clinical safety data suggest dominal pain Recto-vaginal Respiratory, thoracic and mediastinal disorders Nasal septum perforation (not known) There are no clinical trial data on the use of bevacizumab in pregnant women. Studies in animals have shown CNS bleeding (all Grade 4) when treated with bevacizumab, compared to 1 case (Grade 5) out of 96 patients (1%) that Study JO25567 was a randomized, open-label, multi-center Phase II study conducted in Japan to evaluate the efficacy that the incidence of hypertension is likely to be dose-dependent. Pre-existing hypertension should be adequately d,e were not exposed to bevacizumab. In two subsequent studies in patients with treated brain metastases (which included Pulmonary hypertension (not known) Sodium hydroxide q.s. to pH 6.20 ± 0.20 q.s. to pH 6.20 ± 0.20 controlled before starting bevacizumab treatment. There is no information on the effect of bevacizumab in patients with reproductive toxicity including malformations. IgGs are known to cross the placenta, and bevacizumab is anticipated to fistulae , Table 2 provides the frequency of severe adverse reactions. Severe reactions are defined as adverse events with and safety of bevacizumab used in addition to erlotinib in patients with non-squamous NSCLC with EGFR activating Gastrointesti- around 800 patients), one case of Grade 2 CNS haemorrhage was reported in 83 subjects treated with bevacizumab Dysphonia (common) mutations (exon 19 deletion or exon 21 L858R mutation) who had not received prior systemic therapy for Stage IIIB/IV WFI q.s. to 4 mL q.s. to 16 mL uncontrolled hypertension at the time of initiating therapy. Monitoring of blood pressure is generally recommended inhibit angiogenesis in the foetus, and thus is suspected to cause serious birth defects when administered during at least a 2% difference compared to the control arm in clinical studies for NCI-CTCAE Grade 3-5 reactions. Ta- (1.2%) at the time of interim safety analysis (NCI-CTCAE v.3). during therapy. pregnancy. In the post-marketing setting, cases of foetal abnormalities in women treated with bevacizumab alone or in nal Disorder, ble 2 also includes adverse reactions which are considered to be clinically significant or severe. These clinically Gastrointestinal disorders Gastrointestinal ulcer (not known) or recurrent disease. The primary endpoint was progression-free survival (PFS) based on independent review Proctalgia Across all clinical trials, mucocutaneous haemorrhage has been seen in up to 50% of bevacizumab-treated patients. assessment. Secondary endpoints included overall survival, response rate, disease control rate, duration of response, In most cases hypertension was controlled adequately using standard antihypertensive treatment appropriate for the combination with known embryotoxic chemotherapeutics have been observed. significant adverse reactions were reported in clinical trials but the grade 3-5 reactions did not meet the threshold These were most commonly NCI-CTCAE v.3 Grade 1 epistaxis that lasted less than 5 minutes, resolved without 3 PHARMACEUTICAL FORM Hepatobiliary disorders Gall bladder perforation (not known) and safety. Concentrate for solution in single use vial for intravenous (IV) infusion. individual situation of the affected patient. The use of diuretics to manage hypertension is not advised in patients who Bevacizumab is contraindicated in pregnancy. Hepatobiliary Gallblad- of at least a 2% difference compared to the control arm. Table 2 also includes clinically significant adverse reac- medical intervention and did not require any changes in the bevacizumab treatment regimen. Clinical safety data EGFR mutation status was determined for each patient prior to patient screening and 154 patients were randomised to Clear to slightly opalescent, colorless to pale brown solution. receive a cisplatin-based . Bevacizumab should be permanently discontinued if medically Breast-feeding disorders der perfo- tions that were observed only in the postmarketing setting, therefore, the frequency and NCI-CTCAE grade is not suggest that the incidence of minor mucocutaneous haemorrhage (e.g. epistaxis) may be dose-dependent. Musculoskeletal and connective tissue Cases of Osteonecrosis of the Jaw (ONJ) have been significant hypertension cannot be adequately controlled with antihypertensive therapy, or if the patient develops a,b known. These clinically significant reactions have therefore been included in Table 2 There have also been less common reactions of minor mucocutaneous haemorrhage in other locations, such as receive either erlotinib + bevacizumab (erlotinib 150 mg oral daily + bevacizumab [15 mg/kg IV every 3 weeks]) or Sterile/radioactive statement It is not known whether bevacizumab is excreted in human milk. As maternal IgG is excreted in milk and bevacizumab ration disorders reported in patients treated with Bevacizumab, most of which hypertensive crisis or hypertensive encephalopathy. could harm infant growth and development, women must discontinue breast-feeding during therapy and not breast- within the column entitled “Frequency Not Known.” gingival bleeding or vaginal bleeding. erlotinib monotherapy (150 mg oral daily) until disease progression (PD) or unacceptable toxicity. In the absence of PD, Sterile Skin and Wound healing Palmar-plantar a occurred in patients who had identified risk factors for ONJ, discontinuation of one component of study treatment in the erlotinib + bevacizumab arm did not lead to discontinuation Posterior Reversible Encephalopathy Syndrome (PRES) feed for at least six months following the last dose of bevacizumab. Terms represent a group of events that describe a medical concept rather than a single condition or MedDRA Thromboembolism in particular exposure to IV bisphosphonates and/or a history 4 CLINICAL PARTICULARS subcutaneous complications- erythro- (Medical Dictionary for Regulatory Activities) preferred term. This group of medical terms may involve the same Arterial thromboembolism: An increased incidence of arterial thromboembolic reactions was observed in patients of the other component of study treatment as specified in the study protocol. There have been rare reports of bevacizumab-treated patients developing signs and symptoms that are consistent with Fertility tissue disorders b,d, Exfoliative dysaesthesia of dental disease requiring invasive dental procedures 4.1 Therapeutic Indications Repeat dose toxicity studies in animals have shown that bevacizumab may have an adverse effect on female fertility. In underlying pathophysiology (e.g. arterial thromboembolic reactions include cerebrovascular accident, myocardi- treated with bevacizumab across indications, including cerebrovascular accidents, myocardial infarction, transient The efficacy results of the study are presented in Table 7. PRES, a rare neurologic disorder, which can present with the following signs and symptoms among others: seizures, dermatitis, syndrome ischaemic attacks, and other arterial thromboembolic reactions. Bevacizumab (BEVATAS) is indicated for the treatment of: headache, altered mental status, visual disturbance, or cortical blindness, with or without associated hypertension. A a phase III trial in the adjuvant treatment of patients with colon cancer, a substudy with premenopausal women has al infarction, transient ischaemic attack and other arterial thromboembolic reactions). Cases of non-mandibular osteonecrosis have been observed Dry skin, Skin b In clinical trials, the overall incidence of arterial thromboembolic reactions ranged up to 3.8% in the bevacizumab Table 7: Efficacy Results for Study JO25567 1. In addition to platinum-based chemotherapy, indicated for first-line treatment of adult patients with shown a higher incidence of new cases of ovarian failure in the bevacizumab group compared to the control group. After For additional information refer below within section “Further information on selected serious adverse in Bevacizumab treated paediatric patients diagnosis of PRES requires confirmation by brain imaging, preferably magnetic resonance imaging (MRI). In patients discoloration containing arms compared with up to 2.1% in the chemotherapy control arms. Fatal outcome was reported in 0.8% of unresectable advanced, metastatic or recurrent non-small cell lung cancer other than predominantly developing PRES, treatment of specific symptoms including control of hypertension is recommended along with discontinuation of bevacizumab treatment, ovarian function recovered in the majority of patients. Long term effects of reactions” Erlotinib Erlotinib + Bevacizumab c patients receiving bevacizumab compared to 0.5% in patients receiving chemotherapy alone. Cerebrovascular HR (95% CI) p-value squamous cell histology. discontinuation of bevacizumab. The safety of reinitiating Bevacizumab therapy in patients previously experiencing the treatment with bevacizumab on fertility are unknown. Musculoskel- Arthralgia Fistulab,d, Osteone- For further information please refer to Table 3 ‘Adverse reactions reported in post-marketing setting.’ Congenital, familial, and genetic disorder Cases of foetal abnormalities in women treated with beva- N = 77# N = 75# 2. Metastatic carcinoma of the colon or rectum in adult patients in combination with fluoropyrimidine- d accidents (including transient ischaemic attacks) were reported in up to 2.7% of patients treated with bevacizumab in PRES is not known. 4.7 Effects on Ability to Drive and Use Machines etal and con- Myalgia, crosis of Recto-vaginal fistulae are the most common fistulae in the GI-vaginal fistula category. combination with chemotherapy compared to up to 0.5% of patients treated with chemotherapy alone. Myocardial cizumab alone or in combination with known embryotoxic based chemotherapy. PFS^ (months) nective tissue Muscular the jawa,b, Safety profile of bevacizumab in treatment of glioblastoma was assessed in 163 patients who received bevacizumab infarction was reported in up to 1.4% of patients treated with bevacizumab in combination with chemotherapy chemotherapeutics have been observed 9.7 16.0 0.54 (0.36; 0.79) 0.0015 3. Advanced and/or metastatic renal cell cancer in adult patients as first line treatment in combination Proteinuria Information provided in this section is based on innovator data (Avastin, Roche/Genentech). Median with Interferon alfa-2a. disorders weakness, Non-man- alone or bevacizumab plus . All patients received prior radiotherapy and . Bevacizumab was compared to up to 0.7% of patients treated with chemotherapy alone. Patients with a history of hypertension may be at increased risk for the development of proteinuria when treated with Bevacizumab has no or negligible influence on the ability to drive and use machines. However, somnolence and administered at 10 mg/kg every 2 weeks alone or in combination with irinotecan. Bevacizumab was discontinued due to * if specified, frequency has been derived from clinical trial data. 4. Advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer in adult patients as the front- Back pain dibular In one clinical trial evaluating bevacizumab in combination with 5-/folinic acid, AVF2192g, patients with Overall Response Rate bevacizumab. There is evidence suggesting that all Grade proteinuria may be related to the dose. Monitoring of syncope have been reported with bevacizumab use. If patients are experiencing symptoms that affect their vision or adverse events in 4.8% of patients treated with bevacizumab alone. metastatic colorectal cancer who were not candidates for treatment with irinotecan were included. In this trial arterial 4.9 O verdose 63.6% (49) 69.3% (52) Not Applicable 0.4951 line treatment in combination with and paclitaxel. For treatment of adult patients with first proteinuria by dipstick urinalysis is recommended prior to starting and during therapy. Grade 4 proteinuria (nephrotic concentration, or their ability to react, they should be advised not to drive and use machines until symptoms abate. osteone- Rate (n) a,f thromboembolic reactions were observed in 11% (11/100) of patients compared to 5.8% (6/104) in the chemotherapy Information provided in this section is based on innovator data (Avastin, Roche/Genentech). recurrence of platinum-sensitive epithelial ovarian, fallopian tube or primary peritoneal cancer and syndrome) was seen in up to 1.4% of patients treated with bevacizumab. Therapy should be permanently discontinued crosis In patients receiving bevacizumab alone (N = 84), the most frequently reported adverse events of any grade were 4.8 Undesirable Effects infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%) and diarrhea (21%). Of these, control group. The highest dose tested in humans (20 mg/kg of body weight, IV every 2 weeks) was associated with severe migraine in Overall Survival* naïve to VEGF receptor-targeted agents including bevacizumab in patients who develop nephrotic syndrome. b,d 5. Platinum-resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in adult Information provided below is based on study conducted with Bevacizumab (BEVATAS). Renal and uri- Proteinuria the incidence of Grade ≥3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%) and Venous thromboembolism: The incidence of venous thromboembolic reactions in clinical trials was similar in patients several patients. (months) 48.5 48.4 0.91 (0.56; 1.46) 0.6838 patients in combination with paclitaxel, topotecan or pegylated who received only upto Arterial thromboembolism nary disorders diarrhea (1%). Two deaths on study were possibly related to bevacizumab: one retroperitoneal hemorrhage and one receiving bevacizumab in combination with chemotherapy compared to those receiving the control chemotherapy 5 PHARMACOLOGICAL PROPERTIES Median In a prospective, randomized, open label, multicenter, comparative, parallel-group, active controlled phase III study, neutropenic infection. two prior chemotherapy regimens and naïve to VEGF receptor-targeted agents including In clinical trials, the incidence of arterial thromboembolic reactions including cerebrovascular accidents (CVAs), 129 Indian patients with unresectable or metastatic NSCLC were administered with 7.5 mg/kg BEVATAS or AvastinTM Reproduc- Ovarian Pelvic Pain alone. Venous thromboembolic reactions include deep venous thrombosis, pulmonary embolism and 5.1 Pharmacodynamic properties 2 thrombophlebitis. bevacizumab. transient ischaemic attacks (TIAs) and myocardial infarctions (MIs) was higher in patients receiving bevacizumab in (F. Hoffman-La Roche Limited, Switzerland) every 3 weeks, in combination with cisplatin (80 mg/m on day 1 of each tive system failureb,c,d In patients receiving bevacizumab alone or bevacizumab plus irinotecan (N = 163), the incidence of bevacizumab- Pharmacotherapeutic group: antineoplastic and immunomodulating agents, antineoplastic agents, other # A total of 154 patients (ECOG Performance Status 0 or 1) were randomized. However, two of the randomized 2 related adverse events (Grade 1−4) were bleeding/hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), In clinical trials across indications, the overall incidence of venous thromboembolic reactions ranged from 2.8% to 6. Persistent, recurrent, or metastatic carcinoma of the cervix in adult patients in combination with combination with chemotherapy compared to those who received chemotherapy alone. cycle) and gemcitabine (1250 mg/m on day 1 and 8 of each cycle), for four cycles. Of 129 patients, 87 received and breast antineoplastic agents, monoclonal antibodies, ATC code: L01X C07 patients discontinued the study before receiving any study treatment paclitaxel and cisplatin/topotecan who cannot receive platinum therapy. Patients receiving bevacizumab plus chemotherapy, with a history of arterial thromboembolism, diabetes or age hypertension (32%), venous thromboembolic event (8%), arterial thromboembolic event (6%), wound-healing 17.3% of bevacizumab-treated patients compared with 3.2% to 15.6% in the control arms. Grade 3-5 (NCI-CTCAE v.3) BEVATAS and 42 received Avastin. A total of 419 adverse events (AEs) were reported by 99 patients during the conduct disorders Mechanism of action ^ Blinded independent review (protocol-defined primary analysis) 7. Glioblastoma with progressive disease in adult patients following prior therapy as a single agent. greater than 65 years have an increased risk of developing arterial thromboembolic reactions during therapy. Caution of study: 312 in patients treated with BEVATAS and 107 in patients treated with Avastin. Of these adverse events, 258 complications (6%), proteinuria (4%), gastrointestinal perforation (2%), and PRES (1%). The incidence of Grade 3−5 venous thromboembolic reactions have been reported in up to 7.8% of patients treated with chemotherapy plus events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous Bevacizumab binds to vascular endothelial growth factor (VEGF), the key driver of vasculogenesis and angiogenesis, * Exploratory analysis; OS updated analysis at clinical cut-off on 28 October 2015, approx. 45% patient had died 8. Metastatic breast cancer as first line treatment in combination with capecitabine in adult patients in should be taken when treating these patients with bevacizumab. AEs were grade 1 (mild), 118 AEs were grade 2 (moderate), 38 AEs were grade 3 (severe) and 4 AEs were grade 5 Congenital, Foetal bevacizumab compared with up to 4.9% in patients treated with chemotherapy alone (across indications, excluding and thereby inhibits the binding of VEGF to its receptors, Flt-1 (VEGFR-1) and KDR (VEGFR-2), on the surface of whom treatment with other chemotherapy options including or is not Therapy should be permanently discontinued in patients who develop arterial thromboembolic reactions. (death) in nature. Majority of AEs were judged unlikely to be related to the administered drug and were recovered thromboembolic event (7%), arterial thromboembolic event (3%), wound-healing complications (3%), proteinuria (1%), persistent, recurrent, or metastatic cervical cancer). and OS is therefore considered immature. familial, abnormali- and gastrointestinal perforation (2%). From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (study GOG-0240), grade 3-5 endothelial cells. Neutralizing the biological activity of VEGF regresses the vascularization of tumours, normalizes considered appropriate. Metastatic breast cancer as first line treatment in adult patients in completely. Total 10 deaths were reported in the study: 4 in patients receiving BEVATAS and 6 in patients receiving a,b CI, confidence interval; HR, Hazard ratio from unstratified Cox regression analysis; NR, not reached. Venous thromboembolism and genetic ties venous thromboembolic events have been reported in up to 15.6% of patients treated with bevacizumab in combination remaining tumour vasculature, and inhibits the formation of new tumour vasculature, thereby inhibiting tumour growth. combination with paclitaxel. Avastin. Description of selected serious adverse reactions Pharmacodynamic effects Patients may be at risk of developing venous thromboembolic reactions, including pulmonary embolism under disorder with paclitaxel and cisplatin compared with up to 7.0% of patients treated with paclitaxel and cisplatin. Metastatic carcinoma of the colon or rectum (mCRC) 4.2 Posology and Method of Administration The most frequently reported AEs with incidence of more than 4% during the study were nausea, vomiting, Gastrointestinal (GI) perforations and Fistulae Administration of bevacizumab or its parental murine antibody to xenotransplant models of cancer in nude mice bevacizumab treatment. General Asthenia, Fa- Lethargy Patients who have experienced a venous thromboembolic reaction may be at higher risk for a recurrence if they receive The safety and efficacy of the recommended dose (5 mg/kg of body weight every two weeks) in metastatic carcinoma of hypertension, asthenia, anemia, leukopenia, neutropenia, thrombocytopenia, tachycardia, constipation, diarrhea, Bevacizumab has been associated with serious cases of gastrointestinal perforation. bevacizumab in combination with chemotherapy versus chemotherapy alone. resulted in extensive anti-tumour activity in human cancers, including colon, breast, pancreas and prostate. Metastatic BEVATAS was administered at the dose level of 7.5 mg/kg of body weight every 3 weeks as an IV infusion in Patients treated for persistent, recurrent, or metastatic cervical cancer with bevacizumab in combination with paclitaxel disorders and tigue, Pyrexia, disease progression was inhibited and microvascular permeability was reduced. the colon or rectum were studied in three randomised, active-controlled clinical trials in combination with addition to platinum-based chemotherapy during clinical trial in patients with unresectable or metastatic NSCLC. abdominal pain, hypochlorhydria, pyrexia, mucosal ulceration, loss of appetite, pain, fatigue, respiratory distress, fluoropyrimidine-based first-line chemotherapy. Bevacizumab was combined with two chemotherapy regimens: and cisplatin may be at increased risk of venous thromboembolic events. Bevacizumab should be discontinued in dizziness, alopecia, dyspnoea and cough, hypokalemia, hyponatremia, headache and back pain. These were the administration Pain, Mucosal Gastrointestinal perforations have been reported in clinical trials with an incidence of less than 1% in patients with non- Congestive heart failure (CHF) Clinical efficacy Information provided below is based on the innovator data (Avastin, Roche/Genentech). patients with life-threatening (Grade 4) thromboembolic reactions, including pulmonary embolism. Patients with site conditions inflammation squamous non-small cell lung cancer, up to 1.3% in patients with metastatic breast cancer, up to 2.0% in patients with In clinical trials with bevacizumab, congestive heart failure (CHF) was observed in all cancer indications studied to date, Information provided in this section is based on study conducted with BEVATAS. • AVF2107g: A weekly schedule of irinotecan/bolus 5-fluorouracil/folinic acid (IFL) for a total of 4 weeks of each 6 expected AEs reported with the use of Bevacizumab and other chemotherapy agents used during the conduct of the metastatic renal cell cancer or in patients with ovarian cancer receiving front-line treatment, and up to 2.7% (including thromboembolic reactions ≤ Grade 3 need to be closely monitored. study. Overall, BEVATAS and Avastin were well tolerated in patients with NSCLC. but occurred predominantly in patients with metastatic breast cancer. In four phase III trials (AVF2119g, E2100, Efficacy and safety profile of BEVATAS and AvastinTM (F. Hoffman-La Roche Limited, Switzerland) was evaluated week-cycle (Saltz regimen). Non-small cell lung cancer (NSCLC) Investigations Weight gastrointestinal fistula and abscess) in patients with metastatic colorectal cancer. From a clinical trial in patients with Haemorrhage BO17708 and AVF3694g) in patients with metastatic breast cancer CHF Grade 3 (NCI-CTCAE v.3) or higher was during a prospective, randomized, open label, multicenter, comparative, parallel-group, active controlled, phase III First-line treatment of non-squamous NSCLC in combination with platinum-based chemotherapy Information provided below is based on innovator data (Avastin, Roche/Genentech). decreased persistent, recurrent, or metastatic cervical cancer (study GOG-0240), GI perforations (all grade) were reported in 3.2% study in 129 Indian patients with unresectable or metastatic NSCLC. Chemotherapy-naïve male or female patients with • AVF0780g: In combination with bolus 5-fluorouracil/folinic acid (5-FU/FA) for a total of 6 weeks of each 8 week- of patients, all of whom had a history of prior pelvic radiation. reported in up to 3.5% of patients treated with bevacizumab in combination with chemotherapy compared with up to cycle (Roswell Park regimen). Bevacizumab is administered in addition to platinum-based chemotherapy for up to 6 cycles of treatment followed Patients treated with bevacizumab have an increased risk of haemorrhage, especially tumour-associated Summary of the safety profile 0.9% in the control arms. For patients in study AVF3694g who received anthracyclines concomitantly with histologically or cytologically confirmed NSCLC were randomized (2:1) to receive IV cisplatin 80 mg/m² on day 1 and IV haemorrhage. Bevacizumab should be discontinued permanently in patients who experience Grade 3 or 4 bleeding by bevacizumab as a single agent until disease progression. The overall safety profile of bevacizumab is based on data from over 5,400 patients with various malignancies, a For further information please refer to Table 3 ‘Adverse reactions reported in post-marketing setting.’ The occurrence of those events varied in type and severity, ranging from free air seen on the plain abdominal X-ray, bevacizumab, the incidences of Grade 3 or higher CHF for the respective bevacizumab and control arms were similar to gemcitabine 1250 mg/m² on day 1 and 8 of each cycle in combination with either BEVATAS (n=87) or Avastin (n=35) at a • AVF2192g: In combination with bolus 5-FU/FA for a total of 6 weeks of each 8 week-cycle (Roswell Park regimen) in during bevacizumab therapy. b which resolved without treatment, to intestinal perforation with abdominal abscess and fatal outcome. In some cases those in the other studies in metastatic breast cancer: 2.9% in the + bevacizumab arm and 0% in the dose of 7.5 mg/kg every three weekly for total of four cycles. Patients with predominant squamous histology, brain patients who were not optimal candidates for first-line irinotecan treatment. The recommended dose of bevacizumab is 7.5 mg/kg or 15 mg/kg of body weight given once every 3 weeks as an predominantly treated with bevacizumab in combination with chemotherapy in clinical trials. Terms represent a group of events that describe a medical concept rather than a single condition or MedDRA underlying intra-abdominal inflammation was present, either from gastric ulcer disease, tumour necrosis, diverticulitis, Patients with untreated CNS metastases were routinely excluded from clinical trials with bevacizumab, based on anthracycline + placebo arm. In addition, in study AVF3694g the incidences of all Grade CHF were similar between the metastasis, gross hemoptysis (≥1/2 tsp of bright red blood), unstable angina, or receiving anticoagulant therapy were Three additional studies with bevacizumab have been conducted in mCRC patients: first-line (No16966), second-line IV infusion. Clinical benefit in NSCLC patients has been demonstrated with both 7.5 mg/kg and 15 mg/kg doses. It The most serious adverse reactions were: (Medical Dictionary for Regulatory Activities) preferred term. This group of medical terms may involve the same or chemotherapy-associated colitis. anthracycline + bevacizumab (6.2%) and the anthracycline + placebo arms (6.0%). excluded. The primary efficacy parameter was best overall response (best response recorded across all time points is recommended that treatment be continued until progression of the underlying disease or until unacceptable imaging procedures or signs and symptoms. Therefore, the risk of CNS haemorrhage in such patients has not been underlying pathophysiology (e.g. arterial thromboembolic reactions include cerebrovascular accident, myocardial with no previous bevacizumab treatment (E3200), and second-line with previous bevacizumab treatment following prospectively evaluated in randomised clinical trials. Patients should be monitored for signs and symptoms of CNS • Gastrointestinal perforations. Fatal outcome was reported in approximately a third of serious cases of gastrointestinal perforations, which represents Most patients who developed CHF during mBC trials showed improved symptoms and/or left ventricular function from start of treatment until end of treatment; complete response [CR] + partial response [PR]) at the end of 4th disease progression in first-line (ML18147). In these studies, bevacizumab was administered at the following dosing toxicity. • Haemorrhage, including pulmonary haemorrhage/haemoptysis, which is more common in NSCLC patients. infarction, transient ischaemic attack and other arterial thromboembolic reactions). between 0.2%-1% of all bevacizumab treated patients. following appropriate medical therapy. chemotherapy cycle. Other efficacy parameters included disease control rate (CR + PR + stable disease) and overall bleeding, and bevacizumab treatment discontinued in cases of intracranial bleeding. c regimens in combination with FOLFOX-4 (5-FU/LV/oxaliplatin), XELOX (capecitabine/oxaliplatin), and Metastatic carcinoma of the colon or rectum (mCRC) • Arterial thromboembolism. Based on a substudy from NSABP C-08 with 295 patients In most clinical trials of bevacizumab, patients with pre-existing CHF of NYHA (New York Heart Association) II-IV were response rate (CR + PR) at the end of 4th chemotherapy cycle. Out of 129 patients enrolled and dosed, 110 patients There is no information on the safety profile of bevacizumab in patients with congenital bleeding diathesis, acquired d In bevacizumab clinical trials, gastrointestinal fistulae (all grade) have been reported with an incidence of up to 2% in fluoropyrimidine/irinotecan and fluoropyrimidine/oxaliplatin: The recommended dose of bevacizumab, administered as an IV infusion, is either 5 mg/kg or 10 mg/kg of body coagulopathy or in patients receiving full dose of anticoagulants for the treatment of thromboembolism prior to starting For additional information refer below within section “Further information on selected serious adverse reactions.” patients with metastatic colorectal cancer and ovarian cancer, but were also reported less commonly in patients with excluded, therefore, no information is available on the risk of CHF in this population. (n=75 for BEVATAS and n=35 for Avastin) were included in per protocol population. The most frequently observed adverse reactions across clinical trials in patients receiving bevacizumab were e • NO16966: Bevacizumab 7.5 mg/kg of body weight every 3 weeks in combination with oral capecitabine and IV weight given once every 2 weeks or 7.5 mg/kg or 15 mg/kg of body weight given once every 3 weeks. It is bevacizumab treatment, as such patients were excluded from clinical trials. Therefore, caution should be exercised hypertension, fatigue or asthenia, diarrhoea and abdominal pain. Recto-vaginal fistulae are the most common fistulae in the GI-vaginal fistula category. other types of cancer. Prior anthracyclines exposure and/or prior radiation to the chest wall may be possible risk factors for the development of Efficacy results at the end of study (4th cycle) as measured by best overall response rate, disease control rate and recommended that treatment be continued until progression of the underlying disease or until unacceptable toxicity. before initiating therapy in these patients. However, patients who developed venous thrombosis while receiving f Observed in pediatric population only CHF. overall response rate are summarized in below Table 4. Overall, efficacy profile of BEVATAS and Avastin was found to oxaliplatin (XELOX) or bevacizumab 5 mg/kg every 2 weeks in combination with leucovorin plus 5-fluorouracil Analyses of the clinical safety data suggest that the occurrence of hypertension and proteinuria with bevacizumab GI-vaginal Fistulae in study GOG-0240 An increased incidence of CHF has been observed in a clinical trial of patients with diffuse large B-cell lymphoma when be similar. bolus, followed by 5-fluorouracil infusion, with IV oxaliplatin (FOLFOX-4). 300 mm therapy did not appear to have an increased rate of Grade 3 or above bleeding when treated with a full dose of warfarin 2 Table 4: Efficacy Results of BEVATAS in NSCLC (Per Protocol Population) Advanced and/or metastatic renal cell cancer (mRCC) therapy are likely to be dose-dependent. In a trial of patients with persistent, recurrent or metastatic cervical cancer, the incidence of GI-vaginal fistulae was receiving bevacizumab with a cumulative doxorubicin dose greater than 300 mg/m . This phase III clinical trial • E3200: Bevacizumab 10 mg/kg of body weight every 2 weeks in combination with leucovorin and 5-fluorouracil The recommended dose of bevacizumab is 10 mg/kg of body weight given once every 2 weeks as an IV infusion. It and bevacizumab concomitantly. Table 2: Severe Adverse Reactions by Frequency Tabulated list of adverse reactions 8.3% in bevacizumab-treated patients and 0.9% in control patients, all of whom had a history of prior pelvic radiation. compared rituximab//doxorubicin//prednisone (R-CHOP) plus bevacizumab to RCHOP Per-protocol Population, N (%) bolus, followed by 5-fluorouracil infusion, with IV oxaliplatin (FOLFOX-4) in bevacizumab-naïve patients. is recommended that treatment be continued until progression of the underlying disease or until unacceptable Pulmonary haemorrhage/haemoptysis The frequency of GI-vaginal fistulae in the group treated with bevacizumab + chemotherapy was higher in patients with without bevacizumab. While the incidence of CHF was, in both arms, above that previously observed for doxorubicin Difference of Treatments • ML18147: Bevacizumab 5.0 mg/kg of body weight every 2 weeks or bevacizumab 7.5 mg/kg of body weight every 3 toxicity. System organ Very Frequency Response The adverse reactions listed in this section fall into the following frequency categories: Very common (≥1/10); common Common Uncommon Rare recurrence within the field of prior radiation (16.7%) compared with patients with recurrence outside the field of prior therapy, the rate was higher in the R-CHOP plus bevacizumab arm. These results suggest that close clinical BEVATAS Avastin [95% CI] weeks in combination with fluoropyrimidine/irinotecan or fluoropyrimidine/oxaliplatin in patients with disease Patients with non-small cell lung cancer treated with bevacizumab may be at risk of serious, and in some cases fatal, (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known class Very common rare not known Epithelial ovarian, fallopian tube and primary peritoneal cancer pulmonary haemorrhage/haemoptysis. Patients with recent pulmonary haemorrhage/ haemoptysis (>2.5 mL of red radiation (3.6%). The corresponding frequencies in the control group receiving chemotherapy alone were 1.1% vs. observation with appropriate cardiac assessments should be considered for patients exposed to cumulative (N=75) (N=35) progression following first-line treatment with bevacizumab. Use of irinotecan- or oxaliplatin-containing regimen (cannot be estimated from the available data). 0.8%, respectively. Patients who develop GI-vaginal fistulae may also have bowel obstructions and require surgical doxorubicin doses greater than 300 mg/m2 when combined with bevacizumab. Front-line treatment: Bevacizumab is administered in addition to carboplatin and paclitaxel for up to 6 cycles of blood) should not be treated with bevacizumab. Infections and Sepsis, Celluli- Necrotising was switched depending on first-line usage of either oxaliplatin or irinotecan. Tables 1 and 2 list adverse reactions associated with the use of bevacizumab in combination with different intervention as well as diverting ostomies. Best overall response rate (CR + PR) 31 (41.33%) 14 (40.00%) 1.33% [-18.35, 21.02%] treatment followed by continued use of bevacizumab as single agent until disease progression or for a maximum of infestations tis, Abscessa,b, fasciitisc Hypersensitivity reactions/infusion reactions AVF2107g 15 months or until unacceptable toxicity, whichever occurs earlier. The recommended dose of bevacizumab is 15 Congestive heart failure (CHF) chemotherapy regimens in multiple indications. Non-GI Fistulae Infection, In some clinical trials anaphylactic and anaphylactoid-type reactions were reported more frequently in patients Disease control rate (CR + PR + SD) 71 (94.67%) 33 (94.29%) 0.38% [-8.84, 9.60%] This was a phase III randomised, double-blind, active-controlled clinical trial evaluating bevacizumab in combination mg/kg of body weight given once every 3 weeks as an IV infusion. Reactions consistent with CHF were reported in clinical trials. The findings ranged from asymptomatic declines in left Table 1 provides all adverse reactions by frequency that were determined to have a causal relationship with Bevacizumab use has been associated with serious cases of fistulae including reactions resulting in death. ventricular ejection fraction to symptomatic CHF, requiring treatment or hospitalization. Caution should be exercised Urinary tract receiving bevacizumab in combination with chemotherapy than with chemotherapy alone. The incidence of these with IFL as first-line treatment for metastatic carcinoma of the colon or rectum. Eight hundred and thirteen patients were Treatment of platinum-sensitive recurrent disease: Bevacizumab is administered in combination with carboplatin bevacizumab through: infection From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (GOG-240), 1.8% of reactions in some clinical trials of bevacizumab is common (up to 5% in bevacizumab-treated patients). Overall response rate (CR + PR) 27 (36.00%) 12 (34.29%) 1.71% [-17.40, 20.83%] randomised to receive IFL + placebo (Arm 1) or IFL + bevacizumab (5 mg/kg every 2 weeks, Arm 2). A third group of 110 and gemcitabine for 6 cycles and up to 10 cycles followed by continued use of bevacizumab as single agent until when treating patients with clinically significant cardiovascular disease such as pre-existing coronary artery disease, or bevacizumab-treated patients and 1.4% of control patients were reported to have had non-gastrointestinal vaginal, congestive heart failure with bevacizumab. • comparative incidences noted between clinical trial treatment arms (with at least a 10% difference Infections patients received bolus 5-FU/FA + bevacizumab (Arm 3). Enrolment in Arm 3 was discontinued, as pre-specified, once disease progression. The recommended dose of bevacizumab is 15 mg/kg of body weight given once every 3 compared to the control arm for NCI-CTCAE Grade 1-5 reactions or at least a 2% difference compared to Blood and lym- Febrile Anaemia, vesical, or female genital tract fistulae. Information provided in this section is based on innovator data (Avastin, Roche/Genentech). safety of bevacizumab with the IFL regimen was established and considered acceptable. All treatments were continued weeks as an IV infusion. Most of the patients who experienced CHF had metastatic breast cancer and had received previous treatment with From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (study GOG-0240), grade 3-5 the control arm for NCI-CTCAE Grade 3-5 reactions, phatic system neutropenia, Lymphopenia Uncommon (≥0.1% to <1%) reports of fistulae that involve areas of the body other than the gastrointestinal tract (e.g. Non-small cell lung cancer (NSCLC) until disease progression. The overall mean age was 59.4 years; 56.6% of patients had an ECOG performance status Treatment of platinum-resistant recurrent disease: Bevacizumab is administered in combination with one of the anthracyclines, prior radiotherapy to the left chest wall or other risk factors for CHF were present. • post-authorisation safety studies, disorders Leucopenia, bronchopleural and biliary fistulae) were observed across various indications. Fistulae have also been reported in post- infections have been reported in up to 24% of patients treated with bevacizumab in combination with paclitaxel and of 0, 43% had a value of 1 and 0.4% had a value of 2. 15.5% had received prior radiotherapy and 28.4% prior following agents – paclitaxel, topotecan (given weekly) or pegylated liposomal doxorubicin. The recommended In patients who received treatment with anthracyclines and who had not received anthracyclines before, no increased • spontaneous reporting, Neutropeniaa, marketing experience. topotecan compared with up to 13% of patients treated with paclitaxel and topotecan. First-line treatment of non-squamous NSCLC in combination with platinum-based chemotherapy chemotherapy. dose of bevacizumab is 10 mg/kg of body weight given once every 2 weeks as an IV infusion. When bevacizumab incidence of all Grade CHF was observed in the anthracycline + bevacizumab group compared to the treatment with • epidemiological studies\non-interventional or observational studies, Thrombo- Reactions were reported at various time points during treatment ranging from one week to greater than 1 year from Ovarian failure/fertility The safety and efficacy of bevacizumab, in addition to platinum-based chemotherapy, in the first-line treatment of • or through an evaluation of individual case reports. The primary efficacy variable of the trial was overall survival. The addition of bevacizumab to IFL resulted in statistically is administered in combination with topotecan (given on days 1-5, every 3 weeks), the recommended dose of anthracyclines only. CHF Grade 3 or higher reactions were somewhat more frequent among patients receiving cytopenia initiation of bevacizumab, with most reactions occurring within the first 6 months of therapy. In NSABP C-08, a phase III trial of bevacizumab in adjuvant treatment of patients with colon cancer, the incidence of patients with non-squamous NSCLC, was investigated in trials E4599 and BO17704. An overall survival benefit has significant increases in overall survival, progression-free survival and overall response rate (see Table 8). The clinical bevacizumab is 15 mg/kg of body weight given once every 3 weeks as an IV infusion. It is recommended that bevacizumab in combination with chemotherapy than in patients receiving chemotherapy alone. This is consistent with Table 2 provides the frequency of severe adverse reactions. Severe reactions are defined as adverse events with at Wound healing new cases of ovarian failure, defined as amenorrhoea lasting 3 or more months, FSH level ≥ 30 mIU/mL and a negative been demonstrated in trial E4599 with a 15 mg/kg/q3wk dose of bevacizumab. Trial BO17704 has demonstrated that benefit, as measured by overall survival, was seen in all pre-specified patient subgroups, including those defined by treatment be continued until disease progression or unacceptable toxicity. results in patients in other studies of metastatic breast cancer who did not receive concurrent anthracycline treatment. least a 2% difference compared to the control arm in clinical studies for NCI-CTCAE Grade 3-5 reactions. Table 2 also Immune system Hyper-sensi- both 7.5 mg/kg/q3wk and 15 mg/kg/q3wk bevacizumab doses increase progression free survival and response rate. As bevacizumab may adversely impact wound healing, patients who had major surgery within the last 28 days were serum β-HCG pregnancy test, has been evaluated in 295 premenopausal women. New cases of ovarian failure were age, sex, performance status, location of primary tumour, number of organs involved and duration of metastatic Cervical Cancer Neutropenia and infections includes adverse reactions which are considered to be clinically significant or severe. disorders tivity, infusion reported in 2.6% patients in the mFOLFOX-6 group compared to 39% in the mFOLFOX-6 + bevacizumab group. After E4599 disease. reactionsa,b,c excluded from participation in phase III clinical trials. Bevacizumab is administered in combination with one of the following chemotherapy regimens: paclitaxel and Increased rates of severe neutropenia, febrile neutropenia, or infection with or without severe neutropenia (including Post-marketing adverse reactions (Avastin, Roche/Genentech) are included in both Tables 1 and 2, where applicable. discontinuation of bevacizumab treatment, ovarian function recovered in 86.2% of these evaluable women. Long term E4599 was an open-label, randomised, active-controlled, multicentre clinical trial evaluating bevacizumab as first-line The efficacy results of bevacizumab in combination with IFL-chemotherapy are displayed in Table 8. cisplatin or paclitaxel and topotecan. The recommended dose of bevacizumab is 15 mg/kg of body weight given Detailed information about these post-marketing reactions are provided in Table 3. In clinical trials of metastatic carcinoma of the colon or rectum, there was no increased risk of postoperative bleeding or effects of the treatment with bevacizumab on fertility are unknown. some fatalities) have been observed in patients treated with some myelotoxic chemotherapy regimens plus Metabolism Dehydration wound healing complications observed in patients who underwent major surgery 28-60 days prior to starting treatment of patients with locally advanced (stage IIIb with malignant pleural effusion), metastatic or recurrent NSCLC once every 3 weeks as an IV infusion. It is recommended that treatment be continued until progression of the bevacizumab in comparison to chemotherapy alone. This has mainly been seen in combination with platinum- or Adverse reactions are added to the appropriate frequency category in the tables below according to the highest and nutrition Laboratory abnormalities other than predominantly squamous cell histology. Table 8: Efficacy Results for Trial AVF2107g underlying disease or until unacceptable toxicity. bevacizumab. An increased incidence of post-operative bleeding or wound healing complication occurring within 60 taxane-based therapies in the treatment of NSCLC, mBC, and in combination with paclitaxel and topotecan in incidence seen in any indication. disorders days of major surgery was observed if the patient was being treated with bevacizumab at the time of surgery. The Decreased neutrophil count, decreased white blood cell count and presence of urine protein may be associated with 2 Patients were randomised to platinum-based chemotherapy (paclitaxel 200 mg/m ) and carboplatin AUC = 6.0, both by AVF2107g Glioblastoma persistent, recurrent, or metastatic cervical cancer. Within each frequency category, adverse reactions are presented in the order of decreasing seriousness. incidence varied between 10% (4/40) and 20% (3/15). bevacizumab treatment. IV infusion (PC) on day 1 of every 3-week cycle for up to 6 cycles or PC in combination with bevacizumab at a dose of 15 The recommended dose of bevacizumab is 10 mg/kg every 2 weeks as an IV infusion. Nervous system Peripheral Cerebrovas- Posterior Serious wound healing complications, including anastomotic complications, have been reported, some of which had a Across clinical trials, the following Grade 3 and 4 (NCI-CTCAE v.3) laboratory abnormalities occurred in patients treated Hypersensitivity reactions/infusion reactions Some of the adverse reactions are reactions commonly seen with chemotherapy; however, bevacizumab may mg/kg IV infusion day 1 of every 3-week cycle. After completion of six cycles of carboplatin-paclitaxel chemotherapy or Arm 1: IFL + placebo Arm 2: IFL + Bevacizumaba disorders sensory cular accident, reversible fatal outcome. with bevacizumab with at least a 2% difference compared to the corresponding control groups: hyperglycaemia, upon premature discontinuation of chemotherapy, patients on the Bevacizumab + carboplatin–paclitaxel arm Metastatic breast cancer (mBC) exacerbate these reactions when combined with chemotherapeutic agents. Examples include palmar-plantar a Patients may be at risk of developing infusion/hypersensitivity reactions. Close observation of the patient during and neuropathy Syncope, encephalo-pathy decreased haemoglobin, hypokalaemia, hyponatraemia, decreased white blood cell count, increased international The recommended dose of bevacizumab is 10 mg/kg of body weight given once every 2 weeks or 15mg/kg of body following the administration of bevacizumab is recommended as expected for any infusion of a therapeutic humanized erythrodysaesthesia syndrome with pegylated liposomal doxorubicin or capecitabine, peripheral sensory neuropathy a,b,c In locally recurrent and metastatic breast cancer trials, Grade 3-5 wound healing complications were observed in up to continued to receive bevacizumab as a single agent every 3 weeks until disease progression. 878 patients were Number of patients 411 402 Somnolence, syndrome , normalised ratio (INR). randomised to the two arms. weight given once every 3 weeks as an IV infusion. It is recommended that treatment be continued until monoclonal antibody. If a reaction occurs, the infusion should be discontinued and appropriate medical therapies with paclitaxel or oxaliplatin, nail disorders or alopecia with paclitaxel, and paronychia with erlotinib. Hypertensive 1.1% of patients receiving bevacizumab compared with up to 0.9% of patients in the control arms (NCI-CTCAE v.3). progression of the underlying disease or until unacceptable toxicity. Headache Clinical trials have shown that transient increases in serum creatinine (ranging between 1.5-1.9 times baseline level), Overall survival should be administered. A systematic premedication is not warranted. For those events presented in the Table 1 below, for which grade was noted as both all grade and grade 3-5 adverse encephalo- In clinical trials of ovarian cancer, Grade 3-5 wound healing complications were observed in up to 1.2% of patients in the both with and without proteinuria, are associated with the use of Bevacizumab. The observed increase in serum During the trial, of the patients who received trial treatment, 32.2% (136/422) of patients received 7-12 administrations Special populations Osteonecrosis of the jaw (ONJ) drug reactions in clinical trials, the highest frequency observed in patients has been reported. Data was unadjusted for pathyc bevacizumab arm versus 0.1% in the control arm (NCI-CTCAE v.3). creatinine was not associated with a higher incidence of clinical manifestations of renal impairment in patients treated of bevacizumab and 21.1% (89/422) of patients received 13 or more administrations of bevacizumab. Median time (months) 15.6 20.3 the differential time on treatment. Elderly patients Cases of ONJ have been reported in cancer patients treated with bevacizumab, the majority of whom had received prior Hypertension with bevacizumab. The primary endpoint was duration of survival. Results are presented in Table 5. 95% CI 14.29 – 16.99 18.46 – 24.18 No dose adjustment is required in the elderly. Table 1: Adverse Reactions by Frequency Cardiac dis- Congestive In clinical trials, with the exception of study JO25567, the overall incidence of hypertension (all grades) ranged up to or concomitant treatment with IV bisphosphonates, for which ONJ is an identified risk. Caution should be exercised a,b Immunogenicity Table 5: Efficacy Results for Trial E4599 Patients with renal impairment when bevacizumab and IV bisphosphonates are administered simultaneously or sequentially. orders heart failure , 42.1% in the bevacizumab containing arms compared with up to 14% in the control arms. The overall incidence of NCI- Hazard ratiob 0.660 (p=0.00004) System organ Very common Common Uncommon Rare Very rare Frequen- CTC Grade 3 and 4 hypertension in patients receiving Bevacizumab ranged from 0.4% to 17.9%. Grade 4 hypertension As with all therapeutic proteins, there is a potential for immune response to bevacizumab. The detection of antibody The safety and efficacy have not been studied in patients with renal impairment. class cy not Supraventricu- Arm 1: Carboplatin/Paclitaxel Arm 2: Carboplatin/Paclitaxel + Bevacizumab 15 Invasive dental procedures are also an identified risk factor. A dental examination and appropriate preventive dentistry lar tachycardia (hypertensive crisis) occurred in up to 1.0% of patients treated with bevacizumab and chemotherapy compared to up to formation is highly dependent on the sensitivity and specificity of assay. Additionally, observed incidence of antibody Progression-free survival Patients with hepatic impairment should be considered prior to starting the treatment with bevacizumab. In patients who have previously received or are known 0.2% of patients treated with the same chemotherapy alone. (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay mg/kg q3weeks methodology, sample handling, timing of sample collection, concomitant medications and underlying disease. For Median time (months) 6.2 10.4 The safety and efficacy have not been studied in patients with hepatic impairment. receiving IV bisphosphonates invasive dental procedures should be avoided, if possible. Infections and Sepsis, Necro- Vascular Hyperten- Thromboembolism Renal In study JO25567, all grade hypertension was observed in 77.3% of the patients who received bevacizumab in Number of patients 444 434 a,b a,b these reasons, comparison of incidence of antibodies to bevacizumab in studies described below with incidence of Paediatric population Intravitreal use b,d disorders sion thrombotic combination with erlotinib as first-line treatment for non-squamous NSCLC with EGFR activating mutations, compared infestations Abscess , tising arterial , antibodies in other studies or other products may be misleading. Hazard ratio 0.54 (p<0.0001) a a,b micro-angiop- to 14.3% of patients treated with erlotinib alone. Grade 3 hypertension was 60.0% in patients treated with bevacizumab Overall survival The safety and efficacy of bevacizumab in children less than 18 years old have not been established. There is no Bevacizumab is not formulated for intravitreal use. Cellulitis, fasciitis Haemorrhage athyb,c in combination with erlotinib compared to 11.7% in patients treated with erlotinib alone. There were no grade 4 or 5 In clinical trials of adjuvant colon carcinoma, 14 of 2233 evaluable patients (0.63%) tested positive for treatment- Overall response rate relevant use of bevacizumab in the paediatric population in the indications for treatment of cancers of the colon, Infection, Thrombo- emergent anti-bevacizumab antibodies detected by an electrochemiluminescent (ECL) based assay. Among these 14 rectum, breast, lung, ovarian, fallopian tube, peritoneum, cervix and kidney. Eye disorders hypertension events. Median (months) 10.3 12.3 Urinary tract embolism Hypertension was generally adequately controlled with oral anti-hypertensives such as angiotensin-converting patients, three tested positive for neutralizing antibodies against bevacizumab (Avastin) using an enzyme-linked Rate (%) 34.8 44.8 Antitumor activity was not observed among eight children with relapsed glioblastoma treated with bevacizumab and Individual cases and clusters of serious ocular adverse reactions have been reported following unapproved intravitreal infection (venous)a,b,Deep enzyme inhibitors, diuretics and calcium-channel blockers. It rarely resulted in discontinuation of bevacizumab immunosorbent assay (ELISA). The clinical significance of these anti-product antibody responses to bevacizumab is Hazard ratio 0.80 (p=0.003) 95% CI (0.69; 0.93) irinotecan. There is insufficient information to determine the safety and efficacy of bevacizumab in children with use of bevacizumab compounded from vials approved for IV administration in cancer patients. These reactions vein thrombosis treatment or hospitalization. unknown. (p=0.0036) glioblastoma. included infectious endophthalmitis, intraocular inflammation such as sterile endophthalmitis, uveitis and vitritis, retinal Blood and lym- Febrile Anaemia, Very rare cases of hypertensive encephalopathy have been reported, some of which were fatal. Immunogenicity of BEVATAS was evaluated during a prospective, randomized, open-label, multicenter, parallel-group, Progression-free survival a detachment, retinal pigment epithelial tear, intraocular pressure increased, intraocular haemorrhage such as vitreous phatic system neutropenia, Lymphopenia Respiratory, Pulmonary Pulmonary The risk of bevacizumab-associated hypertension did not correlate with the patients’ baseline characteristics, active-controlled study in 129 Indian patients with unresectable or metastatic NSCLC. Patients were administered with 5 mg/kg every 2 weeks. Method of administration haemorrhage or retinal haemorrhage and conjunctival haemorrhage. Some of these reactions have resulted in various disorders Leucopenia, Median (months) 4.8 6.4 b The initial dose should be delivered over 90 minutes as an IV infusion. If the first infusion is well tolerated, the thoracic and haemorrhage/ hyperten- underlying disease or concomitant therapy. BEVATAS (N=87) or Avastin (N=42) at the dose level of 7.5 mg/kg every 3 weeks, in combination with cisplatin and Relative to control arm. degrees of visual loss, including permanent blindness. Neutropeniab, second infusion may be administered over 60 minutes. If the 60-minute infusion is well tolerated, all subsequent mediastinal Haemoptysi- sionc,Nasal Posterior Reversible Encephalopathy Syndrome gemcitabine, for four cycles. Pre-dose (baseline) and post-dose (end of 4 cycles) samples were analyzed from 20 Hazard ratio 0.65 (p<0.0001) 95% CI (0.56; 0.76) Among the 110 patients randomised to Arm 3 (5-FU/FA + Bevacizumab) prior to discontinuation of this arm, the median Systemic effects following intravitreal use Thrombocyto a,b patients from BEVATAS arm. No incidence of anti-drug antibodies against bevacizumab was observed in any patient. infusions may be administered over 30 minutes. disorders s , Pulmonary septum There have been rare reports of bevacizumab-treated patients developing signs and symptoms that are consistent with overall survival was 18.3 months and the median progression free survival was 8.8 months. It should not be administered as an IV push or bolus. penia c Overall response rate A reduction of circulating VEGF concentration has been demonstrated following intravitreal anti- VEGF therapy. embolism, perforation PRES, a rare neurological disorder. Presentation may include seizures, headache, altered mental status, visual Other special populations AVF2192g Dose reduction for adverse reactions is not recommended. If indicated, therapy should either be permanently Systemic adverse reactions including non-ocular haemorrhages and arterial thromboembolic reactions have been Immune sys- Hyper-sensitivity, Epistaxis, disturbance, or cortical blindness, with or without associated hypertension. The clinical presentation of PRES is often Elderly patients Rate (percent) 12.9 29.0 (p<0.0001) reported following intravitreal injection of VEGF inhibitors. This was a phase II randomised, double-blind, active-controlled clinical trial evaluating the efficacy and safety of discontinued or temporarily suspended. tem disorders infusion Dyspnoea, Hypoxia nonspecific, and therefore the diagnosis of PRES requires confirmation by brain imaging, preferably MRI. In randomised clinical trials, age >65 years was associated with an increased risk of developing arterial a,b,d In an exploratory analysis, the extent of bevacizumab benefit on overall survival was less pronounced in the subgroup bevacizumab in combination with 5-FU/FA as first-line treatment for metastatic colorectal cancer in patients who were Ovarian failure/fertility reactions In patients developing PRES, early recognition of symptoms with prompt treatment of specific symptoms including Precautions to be taken before handling or administering the medicinal product: Gastrointestinal Diarrhoea, Intestinal Gastro-in- thromboembolic reactions, including cerebrovascular accidents (CVAs), transient ischaemic attacks (TIAs) and of patients who did not have adenocarcinoma histology. not optimal candidates for first-line irinotecan treatment. One hundred and five patients were randomised to 5-FU/FA + For instructions on dilution of the medicinal product before administration, see section 6.6. Bevacizumab infusions control of hypertension (if associated with severe uncontrolled hypertension) is recommended in addition to myocardial infarctions (MIs). Other reactions with a higher frequency seen in patients over 65 were Grade 3-4 Bevacizumab may impair female fertility. Therefore, fertility preservation strategies should be discussed with women of Metabolism Anorexia Dehydration disorders Nausea, perforation, testinal placebo arm and 104 patients to 5-FU/FA + bevacizumab (5 mg/kg every 2 weeks) arm. All treatments were continued should not be administered or mixed with glucose solutions. This medicinal product must not be mixed with other discontinuation of bevacizumab therapy. Symptoms usually resolve or improve within days after treatment leucopenia and thrombocytopenia (NCI-CTCAE v.3); and all Grade neutropenia, diarrhoea, nausea, headache and Bo17704 until disease progression. The addition of bevacizumab 5 mg/kg every two weeks to 5-FU/FA resulted in higher child-bearing potential prior to starting treatment with bevacizumab. and nutrition Vomiting, Ileus, Intestinal perforationa,b, medicinal products except those mentioned in section 6.6. discontinuation, although some patients have experienced some neurologic sequelae. The safety of reinitiating fatigue as compared to those aged ≤65 years when treated with bevacizumab. In one clinical trial, the incidence of Trial BO17704 was a randomised, double-blind phase III trial of bevacizumab in addition to cisplatin and gemcitabine objective response rates, significantly longer progression-free survival, and a trend in longer survival as compared to 5- 4.5 Interactions with Other Medicinal Products and Other Forms of Interaction disorders Abdominal obstruction, Gastro-intesti- bevacizumab therapy in patients previously experiencing PRES is not known. hypertension of grade ≥3 was two-fold higher in patients aged >65 years than in the younger age group (<65 years). In a 4.3 Contraindications c versus placebo, cisplatin and gemcitabine in patients with locally advanced (stage IIIb with supraclavicular lymph node FU/FA chemotherapy alone. Information provided in this section is based on innovator data (Avastin, Roche/Genentech). Nervous sys- Peripheral Cerebro- Posterior Hyper- pain Recto-vaginal nal ulcer , Across clinical trials, 8 cases of PRES have been reported. Two of the eight cases did not have radiological confirmation study of platinum-resistant recurrent ovarian cancer patients, alopecia, mucosal inflammation, peripheral sensory metastases or with malignant pleural or pericardial effusion), metastatic or recurrent non-squamous NSCLC, who had • Hypersensitivity to the active substance or to any of the excipients. fistulaec,d, Rectal haem- via MRI. AVF0780g • Hypersensitivity to Chinese Hamster Ovary (CHO) cell products or other recombinant human or Effect of antineoplastic agents on bevacizumab pharmacokinetics tem disorders sensory vascular reversible tensive neuropathy, proteinuria and hypertension were also reported and occurred at a rate at least 5% higher in the CT + BV not received prior chemotherapy. The primary endpoint was progression free survival, secondary endpoints for the trial humanized antibodies. neuropathyb, accident, encephalop encepha- Gastrointestinal orrhage Proteinuria arm for bevacizumab-treated patients ≥65 years of age compared with bevacizumab-treated patients aged <65 years. included the duration of overall survival. This was a phase II randomised, active-controlled, open-labelled clinical trial investigating bevacizumab in combination No clinically relevant interaction of co-administered chemotherapy on bevacizumab pharmacokinetics was observed disorder, Stomatitis, No increase in the incidence of other reactions, including gastrointestinal perforation, wound healing complications, with 5-FU/FA as first-line treatment of metastatic colorectal cancer. The median age was 64 years. 19% of the patients had • Pregnancy Dysarthria, Syncope, athy- lo-pathya In clinical trials, proteinuria has been reported within the range of 0.7% to 54.7% of patients receiving bevacizumab. 2 based on the results of population pharmacokinetic analyses. There were neither statistically significant nor clinically Proctalgia congestive heart failure, and haemorrhage was observed in elderly patients (>65 years) receiving bevacizumab as Patients were randomised to platinum-based chemotherapy, cisplatin 80 mg/m IV infusion on day 1 and gemcitabine received prior chemotherapy and 14% prior radiotherapy. Seventy-one patients were randomised to receive bolus 5-FU/FA Headache, Somnolence syndromea,b,d Proteinuria ranged in severity from clinically asymptomatic, transient, trace proteinuria to nephrotic syndrome, with the 2 4.4 Special Warnings and Precautions for Use relevant differences in bevacizumab clearance in patients receiving bevacizumab monotherapy compared to patients great majority as Grade 1 proteinuria (NCI-CTCAE v.3). Grade 3 proteinuria was reported in up to 8.1% of treated compared to those aged ≤65 years treated with bevacizumab. 1250 mg/m IV infusion on days 1 and 8 of every 3-week cycle for up to 6 cycles (CG) with placebo or CG with or 5-FU/FA + bevacizumab (5 mg/kg every 2 weeks). A third group of 33 patients received bolus 5-FU/FA + bevacizumab receiving bevacizumab in combination with interferon alfa-2a, erlotinib or (IFL, 5-FU/LV, Dysguesia bevacizumab at a dose of 7.5 or 15 mg/kg IV infusion day 1 of every 3-week cycle. In the bevacizumab-containing arms, Information provided in this section is based on the innovator data (Avastin, Roche/Genentech). Hepatobiliary Gallbladder patients. Grade 4 proteinuria (nephrotic syndrome) was seen in up to 1.4% of treated patients. Testing for proteinuria is Paediatric population (10 mg/kg every 2 weeks). Patients were treated until disease progression. The primary endpoints of the trial were objective carboplatin/paclitaxel, capecitabine, doxorubicin or cisplatin/gemcitabine). disorders perforationb,c recommended prior to start of bevacizumab therapy. In most clinical trials urine protein levels of ≥2g/24 hrs led to the patients could receive bevacizumab as a single-agent every 3 weeks until disease progression or unacceptable toxicity. response rate and progression-free survival. The addition of bevacizumab 5 mg/kg every two weeks to 5-FU/FA resulted in Gastrointestinal (GI) perforations and Fistulae Effect of bevacizumab on the pharmacokinetics of other antineoplastic agents Eye disorders Eye disorder, The safety and efficacy of bevacizumab in children less than 18 years old have not been established. Trial results show that 94% (277/296) of eligible patients went on to receive single agent bevacizumab at cycle 7. A high Lacrimation holding of bevacizumab until recovery to < 2g/24 hrs. In study BO25041 of bevacizumab added to postoperative radiation therapy (RT) with concomitant and adjuvant higher objective response rates, longer progression-free survival, and a trend in longer survival, compared with 5-FU/FA Patients may be at an increased risk for the development of gastrointestinal perforation and gall bladder perforation No clinically relevant interaction of bevacizumab was observed on the pharmacokinetics of co-administered interferon proportion of patients (approximately 62%) went on to receive a variety of non-protocol specified anticancer therapies, chemotherapy alone (see Table 9). These efficacy data are consistent with the results from trial AVF2107g. when treated with bevacizumab. Intra-abdominal inflammatory process may be a risk factor for gastrointestinal alpha 2a, erlotinib (and its active metabolite OSI-420), or the chemotherapies irinotecan (and its active metabolite increased temozolomide in paediatric patients with newly diagnosed supratentorial, infratentorial, cerebellar, or peduncular high- which may have impacted the analysis of overall survival.

FRONT SIDE

The efficacy data from trials AVF0780g and AVF2192g investigating bevacizumab in combination with 5-FU/FA- A total of 1873 patients were randomised in equal proportions to the following three arms: Eligible patients had epithelial ovarian, fallopian tube or primary peritoneal cancer that progressed within <6 months of Table 25: Trial E2100 Efficacy Results Elimination Rate 8.6% 22.2% CP (n = 764) CPB7.5+ (n = 764) Hazard ratio [95% CI] 0.74 [0.58, 0.94] (p-value5 = 0.0132) chemotherapy are summarized in Table 9. • CPP arm: Five cycles of placebo (started cycle 2) in combination with carboplatin (AUC 6) and paclitaxel (175 previous platinum therapy consisting of a minimum of 4 platinum therapy cycles. Patients should have had a life 2 The value for clearance is, on average, equal to 0.188 and 0.220 L/day for female and male patients, respectively. After Table 9: Efficacy Results for Trials AVF0780g and AVF2192g (p<0.0001) mg/m ) for 6 cycles followed by placebo alone, for a total of up to 15 months of therapy Median (months) 58.0 57.4 expectancy of ≥12 weeks and no prior radiotherapy to the pelvis or abdomen. Most patients were FIGO Stage IIIC or Progression-free survival correcting for body weight, male patients had a higher bevacizumab clearance (+17%) than females. According to the Stage IV. The majority of patients in both arms had an ECOG Performance Status (PS) of 0 (CT: 56.4% vs. CT + BV: Overall Survival – Follow-up analysis7 a • CPB15 arm: Five cycles of bevacizumab (15 mg/kg q3w started cycle 2) in combination with carboplatin (AUC 6) two-compartmental model, the elimination half-life is 18 days for a typical female patient and 20 days for a typical male 10 mg/kg every 2 weeks and paclitaxel (175 mg/m2) for 6 cycles followed by placebo alone, for a total of up to 15 months of therapy Hazard ratio [95% CI] 0.99 [0. 85; 1. 15] (p-value = 0. 8910) 61.2%). The percentage of patients with an ECOG PS of 1 or ≥ 2 was 38.7% and 5.0% in the CT arm, and 29.8% and AVF0780g AVF2192g b Investigator assessment* IRF assessment patient. Relative to control arm 1 • CPB15+ arm: Five cycles of bevacizumab (15 mg/kg q3w started cycle 2) in combination with carboplatin (AUC 6) 1 9.0% in the CT + BV arm. Information on race exists for 29.3% of patients and nearly all patients were white. The median Median (months) 13.3 16.8 2 In patients with measurable disease at baseline. and paclitaxel (175 mg/m ) for 6 cycles followed by continued use of Bevacizumab (15 mg/kg q3w) as single agent age of patients was 61.0 (range: 25−84) years. A total of 16 patients (4.4%) were >75 years old. The overall rates of Low albumin and high tumour burden are generally indicative of disease severity. Bevacizumab clearance was 5-FU/FA 5-FU/FA + 5-FU/FA + 5-FU/FA + 5-FU/FA + No significant difference was observed in the duration of overall survival between patients who received bevacizumab 2 Investigator assessed PFS analysis with data cut-off date of 30 November 2010. Paclitaxel Paclitaxel/Bevaci- Paclitaxel Paclitaxel/Bevaci- approximately 30% faster in patients with low levels of serum albumin and 7% faster in subjects with higher tumour a b for a total of up to 15 months of therapy. discontinuation due to adverse events were 8.8% in the CT arm and 43.6% in the CT + BV arm (mostly due to Grade 2-3 5,8 Bevacizumab Bevacizumab placebo Bevaci- monotherapy compared to patients treated with FOLFOX-4. Progression-free survival and objective response rate 3 Final overall survival analysis performed when 46.7% of the patients had died with data cut-off date of 31 Hazard ratio [95% CI] 0.76 [0.62, 0.94] (p-value = 0.0126) (n=354) zumab (n=368) (n=354) zumab (n=368) burden when compared with a typical patient with median values of albumin and tumour burden. were inferior in the bevacizumab monotherapy arm compared to the FOLFOX-4 arm. adverse events) and the median time to discontinuation in the CT + BV arm was 5.2 months compared with 2.4 months zumab The majority of patients included in the study were White (87% in all three arms); the median age was 60 years in CPP March 2013. in the CT arm. The rates of discontinuation due to adverse events in the subgroup of patients >65 years old were 8.8% in and CPB15 arms and 59 years in CPB15+ arm; and 29% of patients in CPP or CPB15 and 26% in CPB15+ were over 65 Pharmacokinetics in special populations Number of patients 36 35 33 105 104 Ml18147 the CT arm and 50.0% in the CT + BV arm. The HR for PFS was 0.47 (95% CI: 0.35, 0.62) and 0.45 (95% CI: 0.31, 0.67) Secondary Endpoints Median PFS (months) 5.8 11.4 5.8 11.3 years of age. Overall approximately 50% of patients had a GOG PS of 0 at baseline, 43% a GOG PS score of 1, and 7% The primary analysis of investigator-assessed PFS with a data cut-off date of 28 February 2010 shows an unstratified for the <65 and ≥65 subgroups, respectively. The population pharmacokinetics were analyzed in adult and pediatric patients to evaluate the effects of demographic This was a Phase III randomised, controlled, open-label trial investigating bevacizumab 5.0 mg/kg every 2 weeks or 7.5 a GOG PS score of 2. Most patients had EOC (82% in CPP and CPB15, 85% in CPB15+) followed by PPC (16% in CPP, characteristics. In adults, the results showed no significant difference in the pharmacokinetics of bevacizumab in Overall survival hazard ratio of 0.79 (95% CI: 0.68-0.91, 2-sided log-rank p-value 0.0010) with a median PFS of 16.0 months in the CP 6 mg/kg every 3 weeks in combination with fluoropyrimidine-based chemotherapy versus fluoropyrimidine-based 15% in CPB15, 13% in CPB15+) and FTC (1% in CPP, 3% in CPB15, 2% in CPB15+). The majority of patients had The primary endpoint was progression-free-survival, with secondary endpoints including objective response rate and Progression-free survival – Primary analysis HR (95% CI) 0.421 (0.343; 0.516) 0.483 (0.385; 0.607) relation to age. chemotherapy alone in patients with mCRC who have progressed on a first line bevacizumab-containing regimen. arm and 18.3 months in the CPB7.5+ arm. PFS subgroup analyses by disease stage and debulking status are Median time (months) 13.6 17.7 15.2 12.9 16.6 serous adenocarcinoma histologic type (85% in CPP and CPB15, 86% in CPB15+). Overall approximately 34% of summarized in Table 18. These results demonstrate robustness of the primary analysis of PFS as shown in Table 17. overall survival. Results are presented in Table 21. 1 Paediatric population Patients with histologically confirmed mCRC and disease progression were randomised 1:1 within 3 months after patients were FIGO Stage III optimally debulked with gross residual disease, 40% Stage III sub-optimally debulked, Table 21: Efficacy Results from Study MO22224 Median PFS (months) 6.0 8.3 p-value <0.0001 <0.0001 95% CI 10.35 – 16.95 13.63 – discontinuation of bevacizumab first-line therapy to receive fluoropyrimidine/oxaliplatin or fluoropyrimidine/irinotecan- and 26% were Stage IV patients. 1 The pharmacokinetics of bevacizumab were evaluated in 152 children, adolescents and young adults (7 months to 21 Table 18: PFS Results by Disease Stage and Debulking Status from Study BO17707 (ICON7) years, 5.9 to 125 kg) across 4 clinical studies using a population pharmacokinetic model. The pharmacokinetic results 19.32 based chemotherapy (chemotherapy switched depending on first-line chemotherapy) with or without bevacizumab. The primary endpoint was PFS based on investigator's assessment of disease progression based onbradiological Primary Endpoint Hazard ratio [95% CI] 0.66 [0.54, 0.81] (p-value5 <0.0001) Response rates (for patients with measurable disease) Treatment was given until progressive disease or unacceptable toxicity. The primary outcome measure was overall 2,3 show that the clearance and volume of distribution of bevacizumab were comparable between paediatric and young c scans or CA 125 levels, or symptomatic deterioration per protocol. In addition, a prespecified analysis of the data Randomised patients stage III optimally debulked disease Hazard ratio - 0.52 1.01 0.79 survival defined as the time from randomisation until death from any cause. adult patients when normalized by body weight, with exposure trending lower as body weight decreased. Age was not censoring for CA-125 progression events was conducted, as well as an independent review of PFS as determined by 6 CP (n = 368) CPB7.5+ (n =383) Progression-Free Survival* Best Overall Response – Primary analysis Investigator assessment* IRF assessment associated with the pharmacokinetics of bevacizumab when body weight was taken into account. p-value 0.073 0.978 0.16 A total of 820 patients were randomised. The addition of bevacizumab to fluoropyrimidine-based chemotherapy radiological scans. resulted in a statistically significant prolongation of survival in patients with mCRC who have progressed on a first-line The pharmacokinetics of bevacizumab was well characterized by the paediatric population PK model for 70 patients in The trial met its primary objective of PFS improvement. Compared to patients treated with chemotherapy (carboplatin Median PFS (months) 17.7 19.3 CT (n=182) CT+BV (n=179) Responders (Response rate2) 76 (33.8 %) 103 (45.4 %) Paclitaxel Paclitaxel/Bevaci- Paclitaxel Paclitaxel/Bevaci- Study BO20924 ((1.4 to 17.6 years; 11.6 to 77.5 kg) and 59 patients in Study BO25041 (1 to 17 years; 11.2 to 82.3 kg). In Progression-free survival bevacizumab-containing regimen (ITT = 819) (see Table 13). and paclitaxel) alone in the front-line setting, patients who received bevacizumab at a dose of 15 mg/kg q3w in Hazard ratio [95% CI]4 0.89 (0.74, 1.07) (n=273) zumab (n=252) (n=243) zumab (n=229) Study BO20924, bevacizumab exposure was generally lower compared to a typical adult patient at the same dose. In Median time (months) 5.2 9.0 7.2 5.5 9.2 combination with chemotherapy and continued to receive bevacizumab alone (CPB15+), had a clinically meaningful 3 Table 13: Efficacy Results for Study ML18147 (ITT Population) Median (months) 3.4 6.7 95% CI for Response Rates [27.6%, 40.4%] [38.8%, 52.1%] Study BO25041, bevacizumab exposure was similar compared to a typical adult at the same dose. In both studies, and statistically significant improvement in PFS. Randomised patients with stage III suboptimally debulked disease3 bevacizumb exposure trended lower as body weight decreased. Hazard ratio 0.44 0.69 0.5 % pts with objective response 23.4 48.0 22.2 49.8 ML18147 In patients who only received bevacizumab in combination with chemotherapy and did not continue to receive Hazard ratio (95% CI) 0.379 [0.296, 0.485] Difference in Response Rates 11.60% The European Medicines Agency had waived the obligation to submit the results of studies, in all subsets of the bevacizumab alone (CPB15), no clinically meaningful benefit in PFS was observed. CP (n = 154) CPB7.5+ (n = 140) p-value - 0.0049 0.217 0.0002 p-value <0.0001 <0.0001 paediatric population, in breast carcinoma, adenocarcinoma of the colon and rectum, lung carcinoma (small cell and fluoropyrimidine/irinotecan or fluoropyrimidine/irinotecan or The results of this study are summarized in Table 15. Median PFS (months) 10.1 16.9 p-value <0.0001 95% CI for Difference in Response Rates4 [2.4%, 20.8%] non-small cell carcinoma), kidney and renal pelvis carcinoma (excluding nephroblastoma, nephroblastomatosis, clear Overall response rate fluoropyrimidine/oxaliplatin fluoropyrimidine/oxaliplatin based cell sarcoma, mesoblastic nephroma, renal medullary carcinoma and rhabdoid tumour of the kidney), ovarian based chemotherapy chemotherapy + Bevacizumaba Table 15: Efficacy Results from Study GOG-0218 Hazard ratio [95% CI]4 0.67 (0.52, 0.87) Overall survival carcinoma (excluding rhabdomyosarcoma and germ cell tumours), fallopian tube carcinoma (excluding Rate (percent) 16.7 40.0 24.2 15.2 26 p-value (Chi-squared Test) 0.0117 1 Secondary Endpoints rhabdomyosarcoma and germ cell tumours), peritoneal carcinoma (excluding blastomas and sarcomas) and cervix Number of Patients 410 409 Progression-free survival Randomised patients with stage IV disease 95% CI 7.0 - 33.5 24.4 – 57.8 11.7 – 42.6 9.2 – 23.9 18.1 – 35.6 Paclitaxel (n=354) Paclitaxel/Bevacizumab (n=368) and corpus uteri carcinoma for bevacizumb (Avastin, Roche/Genentech). 1 Kaplan-Meier estimates Overall Survival CPP (n = 625) CPB15 (n = 625) CPB15+ (n = 623) CP (n = 97) CPB7.5+ (n = 104) Objective Response Rate** Renal impairment p-value 0.029 0.43 0.055 2 Patients and percentage of patients with best overall response of confirmed CR or PR; percentage calculated on Median OS (months) 24.8 26.5 No trials have been conducted to investigate the pharmacokinetics of bevacizumab in renally impaired patients since Median (months) 9.8 11.2 Median PFS (months) 10.6 11.6 14.7 Median PFS (months) 10.1 13.5 CT (n=144) CT+BV (n=142) patients with measurable disease at baseline Duration of response 3 the kidneys are not a major organ for bevacizumab metabolism or excretion. 95% CI for one sample binomial using Pearson-Clopper method HR (95% CI) 0.869 (0.722; 1.046) Hazard ratio (95% CI) 0.81 (0.69, 0.94) (p=0.0062) 2 Hazard ratio [95% CI] 0.74 (0.55, 1.01) 4 Median time (months) NR 9.3 5.0 6.8 9.2 Hazard Ratio (95% CI) 0.89 (0.78, 1.02) 0.70 (0.61, 0.81) % patients with objective response 18 (12.5%) 40 (28.2%) Approximate 95% CI for difference of two rates using Hauck-Anderson method Hepatic impairment 5 log-rank test (stratified) 3,4 1 No trials have been conducted to investigate the pharmacokinetics of bevacizumab in patients with hepatic impairment Progression-Free Survival p-value 0.0437 <0.0001 Investigator assessed PFS analysis with data cut-off date of 30 November 2010. 6 p-value 0.1374 25–75 percentile 5.5 – NR 6.1 - NR 3.8 – 7.8 5.59 – 9.17 5.88 – 2 Primary analysis was performed with a data cut-off date of 12 December 2012 and is considered the final analysis since the liver is not a major organ for bevacizumab metabolism or excretion. With or without gross residual disease. p –value 0.0007 7 (months) 13.01 Median (months) 4.1 5.7 5 Follow-up analysis was performed with a data cut-off date of 07 March 2014 Objective response Rate 3 5.3 Preclinical Safety Data 5.8% of the overall randomised patient population had Stage IIIB disease. 8 p-value displayed for descriptive purpose only * primary analysis a Hazard ratio (95% CI) 0.68 (0.59, 0.78) (p<0.0001) 4 Relative to the control arm. Overall Survival (final analysis)*** 5 mg/kg every 2 weeks. CPP (n = 396) CPB15 (n = 393) CPB15 + (n = 403) The clinical benefit of bevacizumab as measured by PFS was seen in all pre-specified subgroups tested (including Information provided below is based on studies conducted with BEVATAS. b 10 mg/kg every 2 weeks. Table 24: Overall Survival Results from Study GOG-0240 by Trial Treatment disease-free interval, number of metastatic sites, prior receipt of adjuvant chemotherapy and oestrogen receptor (ER) In acute toxicity studies, maximum tolerated dose of BEVATAS was found to be 1845 mg/kg and 915 mg/kg in mice and c Objective Response Rate (ORR) % pts with objective response 63.4 66.2 66.0 Recurrent ovarian cancer Relative to control arm. The safety and efficacy of bevacizumab in the treatment of recurrent epithelial ovarian, fallopian tube or primary CT (n=182) CT+BV (n=179) status). rats, respectively when administered by IV route. In 28-day repeat-dose toxicity studies, no observed adverse effect NR = not reached. Patients included in analysis 406 404 p-value 0.2341 0.2041 peritoneal cancer was studied in two phase III trials (AVF4095g and MO22224) with different patient populations and 2 level of BEVATAS was found to be 91.5 and 192 mg/kg/week in rats and rabbits, respectively when administered by IV Treatment Other Factor Overall survival – Primary Overall survival - Follow-up analysis AVF3694g route. In local tolerance studies, BEVATAS was found to be non-irritant and non-sensitizer in rabbits and guinea pigs, No16966 chemotherapy regimens. Median OS (months) 13.3 16.6 Comparison analysis1 Hazard Ratio (95% CI) Rate 3.9% 5.4% Overall survival6 Study AVF3694g was a Phase III, multicentre, randomised, placebo-controlled trial designed to evaluate the efficacy respectively. This was a phase III randomised, double-blind (for bevacizumab), clinical trial investigating bevacizumab 7.5 mg/kg in • AVF4095g evaluated the efficacy and safety of bevacizumab in combination with carboplatin and gemcitabine in Hazard Ratio (95% CI) and safety of bevacizumab in combination with chemotherapy compared to chemotherapy plus placebo as first-line combination with oral capecitabine and IV oxaliplatin (XELOX), administered on a 3-weekly schedule; or bevacizumab (p=0.3113) CPP (n = 625) CPB15 (n = 625) CPB15 + (n = 623) patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer. Hazard Ratio (95% CI) 0.870 [0.678, 1.116] Information provided below is based on innovator data (Avastin, Roche/Genentech). 5 mg/kg in combination with leucovorin with 5-fluorouracil bolus, followed by 5-fluorouracil infusional, with IV oxaliplatin treatment for patients with HER2-negative metastatic or locally recurrent breast cancer. In studies of up to 26 weeks duration in cynomolgus monkeys, physeal dysplasia was observed in young animals with a 5.0 mg/kg every 2 weeks or 7.5 mg/kg every 3 weeks • MO22224 evaluated the efficacy and safety of bevacizumab in combination with paclitaxel, topotecan, or pegylated Bevacizum- Cisplatin + 0.72 (0.51, 1.02) 0.75 (0.55, 1.01) (FOLFOX-4), administered on a 2-weekly schedule. The trial contained two parts: an initial unblinded 2-arm part (Part I) Median OS (months) 40.6 38.8 43.8 liposomal doxorubicin in patients with platinum-resistant recurrent epithelial ovarian, fallopian tube or primary p-value 0.2711 ab vs. No Paclitaxel (17.5 vs.14.3 months; p= 0.0609) (17.5 vs.15.0 months; p= 0.0584) Chemotherapy was chosen at the investigator's discretion prior to randomisation in a 2:1 ratio to receive either open growth plates, at bevacizumab average serum concentrations below the expected human therapeutic average in which patients were randomised to two different treatment groups (XELOX and FOLFOX-4) and a subsequent 2 x 2 Statistically significant improvements in progression-free survival were also observed. Objective response rate was 2 peritoneal cancer. bevaci- chemotherapy plus bevacizumab or chemotherapy plus placebo. The choices of chemotherapy included capecitabine, serum concentrations. In rabbits, bevacizumab was shown to inhibit wound healing at doses below the proposed factorial 4-arm part (Part II) in which patients were randomised to four treatment groups (XELOX + placebo, FOLFOX-4 Hazard Ratio (95% CI) 1.07 (0.91, 1.25) 0.88 (0.75, 1.04) All analyses presented in this table are stratified analyses. clinical dose. Effects on wound healing were shown to be fully reversible. low in both treatment arms and the difference was not significant. AVF4095g zumab Topotecan + 0.76 (0.55, 1.06) 0.79 (0.59, 1.07) (16.2 vs. 12.0 taxane (protein-bound paclitaxel, ), and anthracycline-based agents (doxorubicin/ cyclophosphamide, + placebo, XELOX + Bevacizumab, FOLFOX-4 + Bevacizumab). In Part II, treatment assignment was double-blind with p-value3 0.2197 0.0641 * Primary analysis was performed with a data cut-off date of 14 November 2011. e p i r u b i c i n / c y c l o p h o s p h a m i d e , 5 - f l u o r o u r a c i l / d o x o r u b i c i n / c y c l o p h o s p h a m i d e , 5 - Studies to evaluate the mutagenic and carcinogenic potential of bevacizumab have not been performed. No specific respect to bevacizumab. Study E3200 used a 5 mg/kg/week equivalent dose of bevacizumab in bevacizumab-naïve patients, while study The safety and efficacy of bevacizumab in the treatment of patients with platinum-sensitive, recurrent epithelial ovarian, Paclitaxel (14.9 vs. 11.9 months; p=0.1061) months; p=0.1342) **Randomized Patients with Measurable Disease at Baseline. fluorouracil//cyclophosphamide) given every three weeks (q3w). Bevacizumab or placebo was administered studies in animals have been conducted to evaluate the effect on fertility. An adverse effect on female fertility can ML18147 used a 2.5 mg/kg/week equivalent dose of bevacizumab in bevacizumab-pretreated patients. A cross-trial 1 Investigator assessed GOG protocol-specified PFS analysis (neither censored for CA-125 progressions nor fallopian tube or primary peritoneal cancer, who have not received prior chemotherapy in the recurrent setting or prior ***The final analysis of overall survival was performed when 266 deaths, which Approximately 350 patients were randomised into each of the 4 trial arms in the Part II of the trial (Table 10). comparison of the efficacy and safety data is limited by differences between these studies, most notably in patient at a dose of 15 mg/kg q3w. however be expected as repeat dose toxicity studies in animals have shown inhibition of the maturation of ovarian censored for NPT prior to disease progression) with data cut-off date of 25 February, 2010. bevacizumab treatment, was studied in a phase III randomised, double-blind, placebo-controlled trial (AVF4095g). The account for 73.7 % of enrolled patients, were observed. Topotecan+ Bevacizumab 1.15 (0.82, 1.61) 1.15 (0.85, 1.56) follicles and a decrease/absence of corpora lutea and associated decrease in ovarian and uterus weight as well as a populations, previous bevacizumab exposure and chemotherapy regimens. Both the 5 mg/kg/week and 2.5 2 Table 10: Treatment Regimens in Trial NO16966 (mCRC) Relative to the control arm; stratified hazard ratio. study compared the effect of adding bevacizumab to carboplatin and gemcitabine chemotherapy and continuing Paclitaxel (14.9 vs. 17.5 months; p=0.4146) (16.2 vs 17.5 months; p=0.3769) This study included a blinded treatment phase, an optional open-label post-progression phase, and a survival follow-up decrease in the number of menstrual cycles. mg/kg/week equivalent doses of bevacizumab provided a statistically significant benefit with regards to OS (HR 0.751 3 One-sided log-rank p-value bevacizumab as a single agent to progression, to carboplatin and gemcitabine alone. The trial met its primary objective of PFS improvement. Compared to patients treated with chemotherapy (paclitaxel, vs. phase. During the blinded treatment phase, patients received chemotherapy and medicinal product (bevacizumab or Treatment Starting dose Schedule in study E3200; HR 0.81 in study ML18147) and PFS (HR 0.518 in study E3200; HR 0.68 in study ML18147). In terms of 4 topotecan or PLD) alone in the recurrent platinum-resistant setting, patients who received bevacizumab at a dose of 10 Cisplatin+ Bevacizumab has been shown to be embryotoxic and teratogenic when administered to rabbits. Observed effects safety, there was a higher overall incidence of Grade 3-5 AEs in study E3200 relative to study ML18147. Subject to a p-value boundary of 0.0116. Only patients with histologically documented ovarian, primary peritoneal, or fallopian tube carcinoma that had recurred mg/kg every 2 weeks (or 15 mg/kg every 3 weeks if used in combination with 1.25 mg/m2 topotecan on Days 1–5 every No bevaci- 1.13 (0.81, 1.57) 1.08 (0.80, 1.45) placebo) every 3 weeks until disease progression, treatment-limiting toxicity, or death. On documented disease included decreases in maternal and foetal body weights, an increased number of foetal resorptions and an increased 5 Paclitaxel 2 Patients with measurable disease at baseline. >6 months after platinum-based chemotherapy and who had not received chemotherapy in the recurrent setting and 3 weeks) in combination with chemotherapy and continued to receive bevacizumab until disease progression or zumab (11.9 vs.14.3 months; p=0.4825) (12.0 vs 15.0 months; p=0.6267) progression, patients who entered the optional open-label phase could receive open-label Bevacizumab together with incidence of specific gross and skeletal foetal malformations. Adverse foetal outcomes were observed at all tested FOLFOX-4 Oxaliplatin 85 mg/m IV 2 h Oxaliplatin on day 1 Advanced and/or metastatic renal cell cancer (mRCC) 6 2 Final overall survival analysis performed when 46.9% of the patients had died. who have not received prior therapy with bevacizumab or other VEGF inhibitors or VEGF receptor–targeted agents unacceptable toxicity, had a statistically significant improvement in PFS. The exploratory PFS and OS analyses by a wide-range of second line therapies. doses, of which the lowest dose resulted in average serum concentrations approximately 3 times larger than in humans or Leucovorin 200 mg/m IV 2 h Leucovorin on day 1 and 2 were included in the study. FOLFOX-4 + 5-Fluorouracil 400 mg/m2 IV bolus, 600 5-fluorouracil IV bolus/infusion, each on Bevacizumab in combination with interferon alfa-2a for the first-line treatment of advanced and/ or metastatic renal cell chemotherapy cohort (paclitaxel, topotecan and PLD) are summarized in Table 22. 1 Primary analysis was performed with a data cut-off date of 12 December 2012 and is considered the final Statistical analyses were performed independently for 1) patients who received capecitabine in combination with receiving 5 mg/kg every 2 weeks. Information on foetal malformations observed in the post marketing setting are cancer (Bo17705) Prespecified PFS analyses were conducted, all with a cut-off date of 29 September 2009. The results of these Bevacizumab mg/m2 IV 22 h days 1 and 2 prespecified analyses are as follows: A total of 484 patients with measurable disease were randomised 1:1 to either: analysis bevacizumab or placebo; 2) patients who received taxane-based or anthracycline-based chemotherapy in combination provided in section on Fertility, Pregnancy and Lactation and Undesirable Effects. 2 Table 22: Exploratory PFS and OS Analyses by Chemotherapy Cohort 2 Follow-up analysis was performed with a data cut-off date of 07 March 2014; all p-values are displayed for This was a phase III randomised double-blind trial conducted to evaluate the efficacy and safety of bevacizumab in Ÿ Ÿ Carboplatin (AUC4, Day 1) and gemcitabine (1000 mg/m on Days 1 and 8) and concurrent placebo every 3 weeks with bevacizumab or placebo. The primary endpoint of the study was PFS by investigator assessment. In addition, the 6 PHARMACEUTICAL PARTICULARS Placebo or 5 mg/kg IV 30-90 min Day 1, prior to FOLFOX-4, every 2 combination with interferon (IFN) alfa-2a versus IFN alfa-2a alone as first-line treatment in mRCC. The 649 randomised The protocol specified analysis of investigator-assessed PFS (without censoring for CA-125 progression or non- descriptive purpose only protocol therapy [NPT]) shows a stratified hazard ratio of 0.71 (95% CI: 0.61-0.83, 1-sided log-rank p-value for 6 and up to 10 cycles followed by placebo (every 3 weeks) alone until disease progression or unacceptable primary endpoint was also assessed by an independent review committee (IRC). 6.1 List of Excipients bevacizumab weeks patients (641 treated) had Karnofsky Performance Status (KPS) of ≥70%, no CNS metastases and adequate organ toxicity CT CT+BV function. Patients were nephrectomised for primary renal cell carcinoma. Bevacizumab 10 mg/kg was given every 2 <0.0001) when CPB15+ is compared with CPP, with a median PFS of 10.4 months in the CPP arm and 14.1 months Ÿ 2 The results of this study from the final protocol defined analyses for progression free survival and response rates for the Trehalose dihydrate 2 in the CPB15+ arm. Carboplatin (AUC4, Day 1) and gemcitabine (1000 mg/m on Days 1 and 8) and concurrent bevacizumab (15 mg/kg Glioblastoma XELOX Oxaliplatin 130 mg/m IV 2 h Oxaliplatin on day 1 weeks until disease progression. IFN alfa-2a was given up to 52 weeks or until disease progression at a recommended Day 1) every 3 weeks for 6 and up to 10 cycles followed by bevacizumab (15 mg/kg every 3 weeks) alone until Paclitaxel n=115 independently powered capecitabine cohort of Study AVF3694g are presented in Table 26 Results from an exploratory 2 Ÿ The primary analysis of investigator-assessed PFS (censoring for CA-125 progressions and NPT) shows a Mono-Sodium dihydrogen phosphate monohydrate or Capecitabine 1000 mg/m oral bid Capecitabine oral bid for 2 weeks starting dose of 9 MIU three times a week, allowing a dose reduction to 3 MIU three times a week in 2 steps. Patients disease progression or unacceptable toxicity The efficacy and safety of bevacizumab was evaluated in an open-label, multicenter, randomized, non-comparative overall survival analysis which include an additional 7 months of follow-up (approximately 46% of patients had died) are XELOX + (followed by 1 week off treatment) stratified hazard ratio of 0.62 (95% CI: 0.52-0.75, 1-sided log-rank p-value <0.0001) when CPB15+ is compared study of patients with previously treated glioblastoma. Patients received bevacizumab (10 mg/kg IV) alone or di-Sodium hydrogen phosphate anhydrous were stratified according to country and Motzer score and the treatment arms were shown to be well balanced for the Median PFS (months) 3.9 9.2 also presented. The percentage of patients who received bevacizumab in the open-label phase was 62.1% in the Bevacizumab prognostic factors. with CPP, with a median PFS of 12.0 months in the CPP arm and 18.2 months in the CPB15+ arm. The primary endpoint was progression-free survival based on investigator assessment using modified RECIST 1.0. bevacizumab plus irinotecan every 2 weeks until disease progression or until unacceptable toxicity. All patients Placebo or 7.5 mg/kg IV 30-90 min Day 1, prior to XELOX, q3 weeks Ÿ The analysis of PFS as determined by the independent review committee (censoring for NPT) shows a stratified Additional endpoints included objective response, duration of response, overall survival and safety. An independent capecitabine + placebo arm and 49.9% in the capecitabine + bevacizumab arm. Polysorbate 20 The primary endpoint was overall survival, with secondary endpoints for the trial including progression-free survival. received prior radiotherapy (completed at least 8 weeks prior to receiving bevacizumab) and temozolomide. Patients bevacizumab hazard ratio of 0.62 (95% CI: 0.50-0.77, 1-sided log-rank p-value <0.0001) when CPB15+ is compared with CPP, review of the primary endpoint was also conducted. Hazard ratio (95% CI) 0.47 [0.31, 0.72] a Ortho phosphoric acid The addition of bevacizumab to IFN-alpha-2a significantly increased PFS and objective tumour response rate. These with active brain hemorrhage were excluded. Of the 85 patients randomized to the bevacizumab arm, the median age Table 26: Efficacy Results for Study AVF3694g: – Capecitabine and Bevacizumab/Placebo with a median PFS of 13.1 in the CPP arm and 19.1 months in the CPB15+ arm. The results of this study are summarized in Table 19. Sodium hydroxide 5-Fluorouracil: IV bolus injection immediately after leucovorin results have been confirmed through an independent radiological review. However, the increase in the primary was 54 years, 32% were female, 81% were in first relapse, Karnofsky performance status was 90−100 for 45% and (Cap + Bevacizumab/Pl) endpoint of overall survival by 2 months was not significant (HR= 0.91). A high proportion of patients (approximately PFS subgroup analyses by disease stage and debulking status are summarized in Table 16. These results demonstrate Median OS (months) 13.2 22.4 70−80 for 55%. Water for injection robustness of the analysis of PFS as shown in Table 15. Table 19: Efficacy Results from Study AVF4095g Progression-free survivalb The primary efficacy parameter of the trial was the duration of progression-free survival. In this trial, there were two 63% IFN/placebo; 55% Bevacizumab/IFN) received a variety of non-specified post-trial anti-cancer therapies, The efficacy of bevacizumab was demonstrated using response assessment based on both WHO radiographic criteria 6.2 Incompatibilities primary objectives: to show that XELOX was non-inferior to FOLFOX-4 and to show that bevacizumab in combination including antineoplastic agents, which may have impacted the analysis of overall survival. Table 16: PFS1 Results by Disease Stage and Debulking Status from Study GOG-0218 Hazard ratio (95% CI) 0.64 [0.41, 0.99] with FOLFOX-4 or XELOX chemotherapy was superior to chemotherapy alone. Both co-primary objectives were met: Progression-free survival and by stable or decreasing corticosteroid use, which occurred in 25.9% (95% CI 17.0%, 36.1%) of the patients. Median No incompatibilities between bevacizumab and polyvinyl chloride and polyolefin bags have been observed. The efficacy results are presented in Table 14. duration of response was 4.2 months (95% CI 3.0, 5.7). Investigator assessment IRC assessment Ÿ Non-inferiority of the XELOX-containing arms compared with the FOLFOX-4-containing arms in the overall Randomised patients stage III optimally debulked disease2,3 Investigator Assessment IRC Assessment Topotecan n=120 6.3 Shelf Life comparison was demonstrated in terms of progression-free survival and overall survival in the eligible per-protocol Table 14: Efficacy Results for Trial BO17705 Radiologic assessment was based on MRI imaging (using T1 and T2/FLAIR). MRI does not necessarily distinguish CPP (n = 219) CPB15 (n = 204) CPB15+ (n = 216) Cap + Pl Cap + Bevacizum- Cap + Pl Cap + Bevacizum- Vial (unopened) population. Placebo + C/G Bevacizumab + Placebo + C/G Bevacizumab + between tumor, edema, and radiation necrosis. (n=206) ab (n=409) (n=206) ab (n=409) BIO17705 Median PFS (months) 2.1 6.2 24 months when stored under recommended storage conditions Ÿ Superiority of the bevacizumab-containing arms versus the chemotherapy alone arms in the overall comparison Median PFS (months) 12.4 14.3 17.5 (n=242) C/G (n=242) (n=242) C/G (n=242) In another single-arm, single institution trial, 56 patients with glioblastoma with documented disease progression after was demonstrated in terms of progression-free survival in the ITT population (Table 11). a b a receiving temozolomide and radiation therapy received bevacizumab 10 mg/kg IV every 2 weeks until disease Diluted medicinal product Placebo + IFN Bevacizumab + IFN 4 Not censored for NPT Hazard ratio (95% CI) 0.28 [0.18, 0.44] Median PFS (months) 5.7 8.6 6.2 9.8 Hazard Ratio (95% CI) 0.81 (0.62, 1.05) 0.66 (0.50, 0.86) progression or unacceptable toxicity. The median age was 54, 54% were male, 98% Caucasian, and 68% had a Chemical and physical in-use stability has been demonstrated for 24 hours at 25°C in sodium chloride 9 mg/mL (0.9%) Secondary PFS analyses, based on 'on-treatment'-based response assessments, confirmed the significantly superior Number of patients 322 327 clinical benefit for patients treated with bevacizumab (analyses shown in Table 11), consistent with the statistically 3 Median PFS (months) 8.4 12.4 8.6 12.3 Karnofsky Performance Status of 90−100. HR vs placebo arm (95% CI) 0.69 (0.56; 0.84) 0.68 (0.54; 0.86) solution for injection. From a microbiological point of view, the product should be used immediately. If not used Randomised patients with stage III suboptimally debulked disease Median OS (months) 13.3 13.8 immediately, in-use storage times and conditions are the responsibility of the user and would normally not be longer significant benefit observed in the pooled analysis. Progression-free survival The efficacy of bevacizumab was supported by an objective response rate of 19.6% (95% CI 10.9%, 31.3%). Median CPP (n = 253) CPB15 (n = 256) CPB15 + (n = 242) Hazard ratio (95% CI) 0.524 [0.425, 0.645] 0.480 [0.377, 0.613] than 24 hours at 25 ± 2°C, unless dilution has taken place in controlled and validated aseptic conditions. Table 11: Key Efficacy Results for the Superiority Analysis (ITT Population, Trial NO16966) Hazard ratio (95% CI) 1.07 [0.70, 1.63] duration of response was 3.9 months (95% CI 2.4, 17.4). p-value 0.0002 0.0011 Median (months) 5.4 10.2 p–value <0.0001 <0.0001 6.4 Special Precautions for Storage Median PFS (months) 10.1 10.9 13.9 Pediatric population – high grade glioma Endpoint (months) FOLFOX-4 or XELOX + FOLFOX-4 or XELOX + P-value b Bevacizumab should not be used after the expiry date shown on pack. Hazard ratio (95% CI) 0.63 (0.52, 0.75) (p<0.0001) 4 Censored for NPT Response rates (for patients with measurable disease) Placebo (n=701) Bevacizumab (n=699) Hazard Ratio (95% CI) 0.93 (0.77, 1.14) 0.78 (0.63, 0.96) PLD n=126 Anti-tumour activity was not observed in two earlier studies among a total of 30 children aged >3 years old with relapsed Store vials in a refrigerator at 2°C to 8°C. Objective response rate (%) in Patients with measurable disease Median PFS (months) 8.4 12.4 8.6 12.3 or progressive high-grade glioma when treated with bevacizumab and irinotecan (CPT-11). There is insufficient Primary endpoint Randomised patients with stage IV disease Cap + Pl (n=161) Cap + Bevacizumab (n=325) Do not freeze. Do not shake. Median PFS (months) 3.5 5.1 information to determine the safety and efficacy of bevacizumab in children with newly-diagnosed high-grade glioma. Number of patients 289 306 Hazard ratio (95% CI) 0.484 [0.388, 0.605] 0.451 [0.351, 0.580] Keep the vial in the outer carton in order to protect from light. Median PFS** 8.0 9.4 0.0023 CPP (n = 153) CPB15 (n = 165) CPB15 + (n = 165) Ÿ In a single-arm study (PBTC-022), 18 children with recurrent or progressive non-pontine high-grade glioma % pts with objective response 23.6 35.4 Response rate 12.8% 31.4% p–value <0.0001 <0.0001 Hazard ratio (95% CI) 0.53 [0.36, 0.77] (including 8 with glioblastoma [WHO Grade IV], 9 with anaplastic astrocytoma [Grade III] and 1 with anaplastic Keep out of reach and sight of children. Hazard ratio (97.5% CI)a 0.83 (0.72-0.95) Median PFS (months) 9.5 10.4 12.8 oligodendroglioma [Grade III]) were treated with bevacizumab (10 mg/kg) two weeks apart and then with The product doesn't contain any anti-microbial preservative; therefore, care must be taken to ensure sterility of the p<0.0001 Objective response rate p-value 0.0097 Secondary endpoints Hazard Ratio (95% CI)4 0.90 (0.70, 1.16) 0.64 (0.49, 0.82) Median OS (months) 14.1 13.7 bevacizumab in combination with CPT-11 (125-350 mg/m²) once every two weeks until progression. There prepared solution. Overall survival Investigator Assessment IRC Assessment were no objective (partial or complete) radiological responses (MacDonald criteria). Toxicity and adverse b 1 Investigator assessed GOG protocol-specified PFS analysis (neither censored for CA-125 progressions nor Overall survival 6.5 Nature and Contents of Container Median PFS (on treatment)** 7.9 10.4 <0.0001 Hazard ratio (95% CI) 0.91 [0.61, 1.35] reactions included arterial hypertension and fatigue as well as CNS ischaemia with acute neurological deficit. Median (months) 21.3 23.3 censored for NPT prior to disease progression) with data cut-off date of 25 February, 2010 Placebo+ C/G Bevacizumab + Placebo+ C/G Bevacizumab + Ÿ In a retrospective single institution series, 12 consecutive (2005 to 2008) children with relapsed or progressive BEVATAS 100: 4 mL solution in a vial (Type I glass) with a stopper (flurotec coated) containing 100 mg of bevacizumab. Hazard ratio (97.5% CI) 0.63 (0.52-0.75) 2 With gross residual disease. (n=242) C/G (n=242) (n=242) C/G (n=242) high-grade glioma (3 with WHO Grade IV, 9 with Grade III) were treated with bevacizumab (10 mg/kg) and HR (95% CI) 0.88 (0.69; 1.13) BEVATAS 400: 16 mL solution in a vial (Type I glass) with a stopper (flurotec coated) containing 400 mg of Hazard ratio (95% CI) 0.91 (0.76, 1.10) (p=0.3360) 3 3.7% of the overall randomised patient population had Stage IIIB disease. Cervical Cancer Overall response rate (invest. 49.2% 46.5% irinotecan (125 mg/m²) every 2 weeks. There were no complete responses and 2 partial responses (MacDonald bevacizumab. a 4 Relative to the control arm. % pts with objective 57.4% 78.5% 53.7% 74.8% assessment)** Interferon alfa-2a 9 MIU 3x/week GOG-0240 criteria). p-value 0.33 Pack of 1 vial b response Bevacizumab 10 mg/kg q2 wk Bo17707 (ICON7) The efficacy and safety of bevacizumab in combination with chemotherapy (paclitaxel and cisplatin or paclitaxel and In a randomized phase II study (BO25041) a total of 121 patients aged ≥ 3 years to <18 years with newly diagnosed 6.6 Special Precautions for Administration, Disposal and Other Handling Median overall survival* 19.9 21.2 0.0769 a 1000 mg/m2 oral twice daily for 14 days administered every 3 weeks BO17707 was a Phase III, two arm, multicentre, randomised, controlled, open-label study comparing the effect of p-value <0.0001 <0.0001 topotecan) in the treatment for patients with persistent, recurrent or metastatic carcinoma of the cervix was evaluated in supratentorial or infratentorial cerebellar or peduncular high-grade glioma (HGG) were treated with post-operative An exploratory multivariate Cox regression model using backward selection indicated that the following baseline b Stratified analysis included all progression and death events except those where non-protocol therapy Bevacizumab infusions should not be administered or mixed with dextrose or glucose solutions. Hazard ratio (97.5% CI) 0.89 (0.76-1.03) adding bevacizumab to carboplatin plus paclitaxel in patients with FIGO stage I or IIA (Grade 3 or clear cell histology Overall survival study GOG-0240, a randomised, four-arm, open label, multicenter phase III trial. radiation therapy (RT) and adjuvant temozolomide (T) with and without bevacizumab: 10 mg/kg every 2 weeks IV. prognostic factors were strongly associated with survival independent of treatment: gender, white blood cell count, only; n = 142), or FIGO stage IIB - IV (all Grades and all histological types, n = 1386) epithelial ovarian, fallopian tube or (NPT) was initiated prior to documented progression; data from those patients were censored at the last Do not administer as IV push or bolus. A total of 452 patients were randomised to receive either: The study did not meet its primary endpoint of demonstrating a significant improvement of EFS (Central Radiology * Overall survival analysis at clinical cut-off 31 January 2007 platelets, body weight loss in the 6 months prior to trial entry, number of metastatic sites, sum of longest diameter of primary peritoneal cancer following surgery (NCICTCAE v.3). Placebo + C/G (n = 242) Bevacizumab + C/G (n = 242) tumour assessment prior to starting NPT. It should be prepared by a healthcare professional using aseptic technique. Withdraw the necessary amount of target lesions, Motzer score. Adjustment for these baseline factors resulted in a treatment hazard ratio of 0.78 (95% CI Ÿ Paclitaxel 135 mg/m2 IV over 24 hours on Day 1 and cisplatin 50 mg/m2 IV on Day 2, every 3 weeks (q3w); or Review Committee (CRRC)-assessed) when bevacizumab was added to the RT/T arm compared with RT/T alone (HR ** Primary analysis at clinical cut-off 31 January 2006 Patients who had received prior therapy with bevacizumab or prior systemic anticancer therapy for ovarian cancer (e.g. 2 2 bevacizumab and dilute to the required administration volume with 0.9% sodium chloride solution. The concentration of a [0.63; 0.96], p=0.0219), indicating a 22% reduction in the risk of death for patients in the bevacizumab + IFN alfa-2a arm Median OS (months) 32.9 33.6 Ÿ Paclitaxel 175 mg/m IV over 3 hours on Day 1 and cisplatin 50 mg/m IV on Day 2 (q3w); or = 1.44; 95% CI: 0.90, 2.30). These results were consistent with those from various sensitivity analyses and in clinically An unstratified analysis of PFS (investigator assessed) was performed that did not censor for nonprotocol therapy prior relative to control arm 2 2 the final bevacizumab solution should be kept within the range of 1.4 to 16.5 mg/mL. compared to IFN alfa-2a arm. chemotherapy, monoclonal antibody therapy, tyrosine kinase inhibitor therapy, or hormonal therapy) or previous Ÿ Paclitaxel 175 mg/m IV over 3 hours on Day 1 and cisplatin 50 mg/m IV on Day 1 (q3w) relevant subgroups. The results for all secondary endpoints (investigator assessed EFS, and ORR and OS) were to disease progression. The results of these analyses were very similar to the primary PFS results. In the FOLFOX treatment subgroup, the median PFS was 8.6 months in placebo and 9.4 months in bevacizumab radiotherapy to the abdomen or pelvis were excluded from the study. Hazard Ratio (95% CI) 0.952 [0.771, 1.176] Ÿ Paclitaxel 135 mg/m2 IV over 24 hours on Day 1 and cisplatin 50 mg/m2 IV on Day 2 plus bevacizumab 15 Discard any unused portion left in a vial, as the product contains no preservatives. Parenteral drug products should be Ninety-seven (97) patients in the IFN alfa-2a arm and 131 patients in the bevacizumab arm reduced the dose of IFN consistent in showing no improvement associated with the addition of bevacizumab to the RT/T arm compared with the 5.2 Pharmacokinetic Properties inspected visually for particulate matter and discoloration prior to administration. treated patients, HR = 0.89, 97.5% CI = [0.73; 1.08]; p-value = 0.1871, the corresponding results in the XELOX alfa-2a from 9 MIU to either 6 or 3 MIU three times a week as pre-specified in the protocol. Dose-reduction of IFN alfa-2a A total of 1528 patients were randomised in equal proportions to the following two arms: mg/kg IV on Day 2 (q3w); or RT/T arm alone. 2 p-value 0.6479 2 2 treatment subgroup being 7.4 vs. 9.3 months, HR = 0.77, 97.5% CI = [0.63; 0.94]; p-value = 0.0026. • CP arm: Carboplatin (AUC 6) and paclitaxel (175 mg/m ) for 6 cycles of 3 weeks duration Ÿ Paclitaxel 175 mg/m IV over 3 hours on Day 1 and cisplatin 50 mg/m IV on Day 2 plus bevacizumab 15 mg/kg Information provided in this section is based on study conducted with BEVATAS. Manufactured and Marketed by: did not appear to affect the efficacy of the combination of bevacizumab and IFN alfa-2a based on PFS event free rates 2 The median overall survival was 20.3 months in placebo and 21.2 months in bevacizumab treated patients in the over time, as shown by a sub-group analysis. The 131 patients in the bevacizumab + IFN alfa-2a arm who reduced and • CPB7.5+ arm: Carboplatin (AUC 6) and paclitaxel (175 mg/m ) for 6 cycles of 3 weeks plus bevacizumab (7.5 PFS subgroup analyses depending on recurrence since last platinum therapy are summarized in Table 20. IV on Day 2 (q3w); or Addition of bevacizumab to RT/T did not demonstrate clinical benefit in study BO25041 in 60 evaluable children Pharmacokinetic (PK) profile of BEVATAS was evaluated in subset of patients during comparative, open-label, FOLFOX treatment subgroup, HR=0.94, 97.5% CI = [0.75; 1.16]; p-value = 0.4937, the corresponding results in the maintained the IFN alfa-2a dose at 6 or 3 MIU during the trial, exhibited at 6, 12 and 18 months PFS event free rates of mg/kg q3w) for up to 12 months (bevacizumab was started at cycle 2 of chemotherapy if treatment was initiated Ÿ Paclitaxel 175 mg/m2 IV over 3 hours on Day 1 and cisplatin 50 mg/m2 IV on Day 1 plus bevacizumab 15 mg/kg patients with newly diagnosed supratentorial or infratentorial cerebellar or peduncular highgrade glioma (HGG) (See randomized, multicenter phase III study in patients with unresectable or metastatic NSCLC. In each 21-day cycle, XELOX, treatment subgroup being 19.2 vs. 21.4 months, HR = 0.84, 97.5% CI = [0.68; 1.04]; p-value = 0.0698. 73, 52 and 21% respectively, as compared to 61, 43 and 17% in the total population of patients receiving bevacizumab + within 4 weeks of surgery or at cycle 1 if treatment was initiated more than 4 weeks after surgery). Table 20: Progression-free Survival by Time From Last Platinum Therapy to Recurrence IV on Day 1 (q3w) section 4.2 for information on paediatric use). patients were administered BEVATAS or Avastin as IV infusion at 7.5 mg/kg dose in combination with cisplatin and IFN alfa-2a. Ÿ Paclitaxel 175 mg/m2 IV over 3 hours on Day 1 and topotecan 0.75 mg/m2 IV over 30 minutes on days 1-3 (q3w) gemcitabine, for total four cycles. Serum samples were collected from 10 patients each from BEVATAS and Avastin arm ECOG E3200 The majority of patients included in the study were White (96%), the median age was 57 years in both treatment arms, 2 2 Metastatic breast cancer (mBC) Investigator Assessment Ÿ Paclitaxel 175 mg/m IV over 3 hours on Day 1 and topotecan 0.75 mg/m IV over 30 minutes on Days 1-3 plus during cycle 1. Descriptive statistics were used to report the PK parameters of BEVATAS and Avastin (Table 27). Plot No. 423/P/A, Sarkhej - Bavla Highway, AVF2938 25% of patients in each treatment arm were 65 years of age or over, and approximately 50% of patients had an ECOG Village - Moraiya, Taluka - Sanand, This was a phase III randomised, active-controlled, open-label trial investigating bevacizumab 10 mg/kg in combination PS of 1; 7% of patients in each treatment arm had an ECOG PS of 2. The majority of patients had EOC (87.7%) followed bevacizumab 15 mg/kg IV on Day 1 (q3w) Two large Phase III trials were designed to investigate the treatment effect of bevacizumab in combination with two with leucovorin with 5-fluorouracil bolus and then 5-fluorouracil infusional, with IV oxaliplatin (FOLFOX-4), This was a randomised, double-blind, phase II clinical trial investigating bevacizumab 10 mg/kg in a 2 weekly schedule Time from last platinum therapy to recurrence Placebo + C/G (n = 242) Bevacizumab + C/G (n = 242) individual chemotherapy agents, as measured by the primary endpoint of PFS. A clinically meaningful and statistically Table 27: Pharmacokinetic Parameters of BEVATAS in NSCLC patients (Cycle 1) District - Ahmedabad-382 213, INDIA. by PPC (6.9%) and FTC (3.7%) or a mixture of the three origins (1.7%). Most patients were FIGO Stage III (both 68%) Eligible patients had persistent, recurrent or metastatic squamous cell carcinoma, adenosquamous carcinoma, or administered on a 2-weekly schedule in previously-treated patients (second line) with advanced colorectal cancer. In with the same dose of bevacizumab in combination with 150 mg daily erlotinib, in patients with metastatic clear cell followed by FIGO Stage IV (13% and 14%), FIGO Stage II (10% and 11%) and FIGO Stage I (9% and 7%). The majority 6 - 12 months (n=202) significant improvement in PFS was observed in both trials. Prepared/revised in May 2017. the chemotherapy arms, the FOLFOX-4 regimen used the same doses and schedule as shown in Table 10 for trial RCC. A total of 104 patients were randomised to treatment in this trial, 53 to bevacizumab 10 mg/kg every 2 weeks plus adenocarcinoma of the cervix which was not amenable to curative treatment with surgery and/or radiation therapy and Mean ± SD (Untransformed data) of the patients in each treatment arm (74% and 71%) had poorly differentiated (Grade 3) primary tumours at baseline. Summarized below are PFS results for the individual chemotherapy agents included in the indication: Parameters (Units) NO16966. placebo and 51 to bevacizumab 10 mg/kg every 2 weeks plus erlotinib 150 mg daily. The analysis of the primary The incidence of each histologic sub-type of EOC was similar between the treatment arms; 69% of patients in each Median 8.0 11.0 who have not received prior therapy with bevacizumab or other VEGF inhibitors or VEGF receptor–targeted agents. BEVATAS (N=09) Avastin (N=10) endpoint showed no difference between the Bevacizumab + Placebo arm and the Bevacizumab + Erlotinib arm Ÿ The primary efficacy parameter of the trial was overall survival, defined as the time from randomisation to death from treatment arm had serous adenocarcinoma histologic type. The median age was 46.0 years (range: 20−83) in the Chemo alone group and 48.0 years (range: 22−85) in the Study E2100 (paclitaxel) (median PFS 8.5 versus 9.9 months). Seven patients in each arm had an objective response. The addition of erlotinib to Hazard ratio (95% CI) 0.41 (0.29 - 0.58) Ÿ Median PFS increase 5.6 months, HR 0.421 (p<0.0001, 95% CI 0.343; 0.516) AUC (μg*h/mL) 1805.912 ± 293.6909 2155.212 ± 577.5223 any cause. Eight hundred and twenty-nine patients were randomised (292 FOLFOX-4, 293 bevacizumab + FOLFOX-4 The primary endpoint was PFS as assessed by the investigator using RECIST. Chemo+Bevacizumab group; with 9.3% of patients in the Chemo alone group and 7.5% of patients in the Ÿ 0-480 and 244 bevacizumab monotherapy). The addition of bevacizumab to FOLFOX-4 resulted in a statistically significant bevacizumab did not result in an improvement in OS (HR = 1.764; p=0.1789), duration of objective response (6.7 vs 9.1 Study AVF3694g (capecitabine) months) or time to symptom progression (HR = 1.172; p=0.5076). >12 months (n=282) Chemo+Bevacizumab group over the age of 65 years. Ÿ prolongation of survival. Statistically significant improvements in progression-free survival and objective response rate The trial met its primary objective of PFS improvement. Compared to patients treated with chemotherapy (carboplatin Median PFS increase 2.9 months, HR 0.69 (p=0.0002, 95% CI 0.56; 0.84) Cmax (μg/mL) 29.038 ± 4.3307 35.790 ± 4.2238 and paclitaxel) alone in the front-line setting, patients who received bevacizumab at a dose of 7.5 mg/kg q3w in Of the 452 patients randomized at baseline, the majority of patients were white (80.0% in the Chemo alone group and were also observed (see Table 12). AVF0890 Median 9.7 12.4 Further details of each study and the results are provided below. combination with chemotherapy and continued to receive bevacizumab for up to 18 cycles had a statistically significant 75.3% in the Chemo+Bevacizumab group), had squamous cell carcinoma (67.1% in the Chemo alone group and Tmax (h)* 1.750 (1.500 – 2.000) 1.750 (1.500 – 2.000) Table 12: Efficacy Results for Trial E3200 This was a randomised phase II trial conducted to compare the efficacy and safety of bevacizumab versus placebo. A improvement in PFS. ECOG E2100 total of 116 patients were randomised to receive bevacizumab 3 mg/kg every 2 weeks (n=39), 10 mg/kg every 2 weeks; Hazard ratio (95% CI) 0.55 (0.41 – 0.73) 69.6% in the Chemo+Bevacizumab group), had persistent/recurrent disease (83.6% in the Chemo alone group and The results of this study are summarized in Table 17. 82.8% in the Chemo+Bevacizumab group), had 1-2 metastatic sites (72.0% in the Chemo alone group and 76.2% in the Trial E2100 was an open-label, randomised, active controlled, multicentre clinical trial evaluating bevacizumab in *Median value reported for T E3200 (n=37), or placebo (n=40). An interim analysis showed there was a significant prolongation of the time to progression of max disease in the 10 mg/kg group as compared with the placebo group (hazard ratio, 2.55; p <0.001). There was a small Chemo+ Bevacizumab group), had lymph node involvement (50.2% in the Chemo alone group and 56.4% in the combination with paclitaxel for locally recurrent or metastatic breast cancer in patients who had not previously received Mo22224 2 Information provided in this section is based on innovator data (Avastin, Roche/Genentech). FOLFOX-4 FOLFOX-4 + Bevacizumaba difference, of borderline significance, between the time to progression of disease in the 3 mg/kg group and that in the Table 17: Efficacy Results from Study BO17707 (ICON7) Chemo+ Bevacizumab group), and had a platinum free interval ≥6 months (72.5% in the Chemo alone group and chemotherapy for locally recurrent and metastatic disease. Patients were randomised to paclitaxel alone (90 mg/m IV placebo group (hazard ratio, 1.26; p=0.053). Four patients had objective (partial) response, and all of these had Study MO22224 evaluated the efficacy and safety of bevacizumab in combination with chemotherapy for platinum- 64.4% in the Chemo+ Bevacizumab group). over 1 hour once weekly for three out of four weeks) or in combination with bevacizumab (10 mg/kg IV infusion every The pharmacokinetic data for bevacizumab are available from ten clinical trials in patients with solid tumours. In all Progression-free survival clinical trials, bevacizumab was administered as an IV infusion. The rate of infusion was based on tolerability, with an Number of patients 292 293 received the 10 mg/kg dose bevacizumab; the ORR for the 10 mg/kg dose was 10%. resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer. This study was designed as an open- two weeks). Prior hormonal therapy for the treatment of metastatic disease was allowed. Adjuvant taxane therapy was label, randomized, two-arm Phase III evaluation of bevacizumab plus chemotherapy (CT+BV) versus chemotherapy The primary efficacy endpoint was overall survival. Secondary efficacy endpoints included progression-free survival initial infusion duration of 90 minutes. The pharmacokinetics of bevacizumab was linear at doses ranging from 1 to 10 Overall survival Epithelial ovarian, fallopian tube and primary peritoneal cancer CP (n = 764) CPB7.5+ (n =764) alone (CT). and objective response rate. Results from the primary analysis and the follow-up analysis are presented by allowed only if it was completed at least 12 months prior to trial entry. Of the 722 patients in the trial, the majority of mg/kg. patients had HER2-negative disease (90%), with a small number of patients with unknown (8%) or confirmed HER2- Front-line treatment of ovarian cancer 2 Bevacizumab Treatment and by Trial Treatment in Table 23 and Table 24, respectively. Distribution Median (months) 10.8 13.0 Median PFS (months) 16.9 19.3 A total of 361 patients were enrolled into this study and administered either chemotherapy (paclitaxel, topotecan, or positive status (2%), who had previously been treated with or were considered unsuitable for trastuzumab therapy. The safety and efficacy of bevacizumab in the front-line treatment of patients with epithelial ovarian, fallopian tube or pegylated liposomal doxorubicin (PLD) alone or in combination with bevacizumab: Hazard ratio [95% CI]2 0.86 [0.75; 0.98] (p-value = 0.0185) Table 23: Efficacy Results from Study GOG-0240 by Bevacizumab Treatment Furthermore, 65% of patients had received adjuvant chemotherapy including 19% prior taxanes and 49% prior The typical value for central volume (Vc) was 2.73L and 3.28L for female and male patients respectively, which is in the 95% CI 10.12 – 11.86 12.09 – 14.03 primary peritoneal cancer were studied in two phase III trials (GOG-0218 and BO17707) that evaluated the effect of the range that has been described for IgGs and other monoclonal antibodies. The typical value for peripheral volume (Vp) Ÿ anthracyclines. Patients with central nervous system metastases, including previously treated or resected brain addition of bevacizumab to carboplatin and paclitaxel compared to the chemotherapy regimen alone. 1 CT Arm (chemotherapy alone): was 1.69L and 2.35L for female and male patients respectively, when bevacizumab is co-administered with anti- b Objective Response Rate 2 Chemotherapy Chemotherapy + lesions, were excluded. Hazard ratio 0.751 (p=0.0012) Ÿ Paclitaxel 80 mg/m as a 1-hour IV infusion on Days 1, 8, 15, and 22 every 4 weeks. neoplastic agents. After correcting for body weight, male patients had a larger Vc (+20%) than female patients. GOG-0218 2 (n=225) Bevacizumab (n=227) CP (n = 277) CPB7.5+ (n = 272) Ÿ Topotecan 4 mg/m as a 30-minute IV infusion on Days 1, 8, and 15 every 4 weeks. In trial E2100, patients were treated until disease progression. In situations where early discontinuation of Progression-free survival 2 Metabolism The GOG-0218 study was a phase III multicentre, randomised, double-blind, placebo-controlled, three arm study Ÿ Alternatively, a 1.25 mg/m dose could be administered over 30 minutes on Days 1–5 every 3 weeks. chemotherapy was required, treatment with bevacizumab as a single agent continued until disease progression. The evaluating the effect of adding bevacizumab to an approved chemotherapy regimen (carboplatin and paclitaxel) in Ÿ 2 Median (months) 4.5 7.5 Response rate 54.9% 64.7% PLD 40 mg/m as a 1 mg/min IV infusion on Day 1 only every 4 weeks. After Cycle 1, the drug could be delivered Primary Endpoint patient characteristics were similar across the trial arms. The primary endpoint of this trial was progression free survival Assessment of bevacizumab metabolism in rabbits following a single IV dose of 125I-bevacizumab indicated that its patients with advanced (FIGO stages IIIB, IIIC and IV) epithelial ovarian, fallopian tube or primary peritoneal cancer. as a 1-hour infusion. metabolic profile was similar to that expected for a native IgG molecule which does not bind VEGF. The metabolism and (p-value = 0.0188) (PFS), based on trial investigators' assessment of disease progression. In addition, an independent review of the Hazard ratio 0.518 (p<0.0001) Patients who had received prior therapy with bevacizumab or prior systemic anticancer therapy for ovarian cancer (e.g. Ÿ CT+BV Arm (chemotherapy plus bevacizumab): Overall Survival – Primary analysis6 elimination of bevacizumab is similar to endogenous IgG i.e. primarily via proteolytic catabolism throughout the body, Ÿ primary endpoint was also conducted. The results of this trial are presented in Table 25. chemotherapy, monoclonal antibody therapy, tyrosine kinase inhibitor therapy, or hormonal therapy) or previous 3 The chosen chemotherapy was combined with bevacizumab 10 mg/kg IV every 2 weeks (or bevacizumab 15 including endothelial cells, and does not rely primarily on elimination through the kidneys and liver. Binding of the IgG to Objective response rate Overall Survival -QA-1554-01 mg/kg every 3 weeks if used in combination with topotecan 1.25 mg/m2 on Days 1–5 every 3 weeks). 1 the FcRn receptor results in protection from cellular metabolism and the long terminal half-life. radiotherapy to the abdomen or pelvis were excluded from the study. Median (months) 12.9 16.8 W A

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Reason for Revision: Add more indications, safety profile and dosage & administrations, Refer CC no. 51318 Artwork No.: AW-QA-1554-01 Product Name : Bevatas - Domestic - insert Insert size : 800 x 300 mm Supersedes No.: NA Folded size : ~200 x ~37.5 mm Prepared by Approved by Authorised by GSM of paper : 40 ± 5 gsm Department PPMC Packing Regulatory Marketing Medical QA QA Type of paper: Bible (FP) Services No. of colours: 1 Signature Colours: Black Nos. of fold : 5 Date 24.05.17 Name Designation For the use of an Oncologist or Hospital only Pegfilgrastim has reduced renal clearance and prolonged persistence in vivo as compared to filgrastim.

INDICATIONS Pegylated Recombinant Human Granulocyte Colony Stimulating Factor Pegfilgrastim is indicated to decrease the incidence of infection, Pegfilgrastim Injection 6 mg as manifested by febrile neutropenia, in patients with non myeloid malignancies receiving myelosuppressive anti-cancer DECSRIPTION AND COMPOSITION drugs associated with a clinically significant incidence of febrile Pegfilgrastim is a covalent conjugate of recombinant methionyl neutropenia. human G-CSF (filgrastim) and monomethoxypolyethylene Step 5 glycol. Filgrastim is a water soluble 175 amino acid protein with DOSE AND METHOD OF ADMINISTRATION Immediately dispose the a molecular weight of approximately 19 kilodaltons. Filgrastim is The recommended dosage of pegfilgrastim is a single syringe using suitable obtained from the bacterial fermentation of a strain of subcutaneous injection of 6 mg administered by subcutaneous container Escherichia coli transformed with a genetically engineered route once per chemotherapy cycle. Pegfilgrastim should not be plasmid containing the human G-CSF gene. To produce administered in the period between 14 days before and 24 CONTRAINDICATIONS pegfilgrastim, a 20 kDa monomethoxypolyethylene glycol hours after administration of cytotoxic chemotherapy. The 6 mg Do not administer pegfilgrastim to patients with a history of molecule is covalently bound to the N-terminal methionyl fixed-dose formulation should not be used in infants, children serious allergic reaction to pegfilgrastim or filgrastim or patients residue of filgrastim. The average molecular weight of and smaller adolescents weighing less than 45 kg. No dosing with known history of E Coli derived proteins. pegfilgrastim is approximately 39 kDa. adjustment is necessary for renal dysfunction. Pegfilgrastim should be visually inspected for discoloration and particulate WARNINGS Each 0.6 mL of prefilled syringe contains: 6 mg of Pegylated matter and if found, should not be administered. General Recombinant Human G-CSF The safety and efficacy of pegfilgrastim for peripheral blood progenitor cell (PBPC) mobilization has not been evaluated. Each Syringe contains 6 mg Pegfilgrastim (based on protein Pegfilgrastim should not be used for PBPC mobilization. weight) in a sterile, clear, colorless, preservative-free solution. The pH of the solution is 4.0 Splenic Rupture Contents Pegasta 6 mg/0.6 mL Splenic rupture, including fatal cases, has been reported Pegfilgrastim 6 mg following the administration of pegfilgrastim and its parent Glacial Acetic Acid 0.35 mg compound, filgrastim. Patients receiving pegfilgrastim who Sorbitol 30.0 mg report left upper abdominal and / or shoulder tip pain should be Polysorbate 20 0.024 mg evaluated for an enlarged spleen or splenic rupture. Sodium Hydroxide 0.034 mg Step 1 Water for injection (qs) 0.6 mL Remove the needle shield by Acute Respiratory Distress Syndrome (ARDS) pulling it straight off the syringe Acute Respiratory Distress Syndrome (ARDS) has been DOSAGE FORM If needed, adjust the dose reported in patients receiving pegfilgrastim, and is postulated to Solution for Injection (6 mg per 0.6 mL in single use prefilled be secondary to an influx of neutrophils to sites of inflammation syringe) in the lungs. Neutropenic patients receiving pegfilgrastim who develop fever, lung infiltrates or respiratory distress should be PRECLINICAL PHARMACOLOGY evaluated for the possibility of ARDS. In the event that ARDS The relative potency of Pegfilgrastim was assessed in an in-vivo occurs, pegfilgrastim should be discontinued and/or withheld bioassay using neutropenic mice, and compared with the until resolution of ARDS and patients should receive reference standard. In this test both the test and reference drug appropriate medical management for this condition. were found comparable and equipotent. Pharmacokinetic studies were done in non-neutropenic rat and compared with Allergic reaction the reference standard. The half-lives of the product were Allergic reactions to pegfilgrastim, including anaphylaxis, skin comparable to that of the reference standard. Step 2 rash and urticaria have been reported in post marketing experience. If a serious allergic reaction occurs, appropriate Acute toxicity studies were conducted in rats and mice by Inject subcutaneously using the syringe body therapy should be administered with close patient follow-up administering i.v. and s.c. single doses of 1000, 5000 and 10000 over several days. Pegfilgrastim should be permanently mcg/Kg of Pegfilgrastim. The animals were observed for discontinued in patients with serious allergic reaction. mortality, clinical signs and gross organ examinations. There was no death or any other adverse effect in the animals at all the PFS Sickle Cell Disease dose levels. In repeat dose sub acute toxicity studies in rats, Severe sickle cell crises have been associated with the use of mice and rabbits a dose of 100, 500 and 1000 mcg/Kg was with needle guard before use pegfilgrastim in patients with sickle cell disease. Severe sickle administered for a period of 28 days by s.c. and i.v. routes. The cell crises, in some cases resulting in death, have also been animals were examined for body weight changes, food associated with filgrastim, the parent compound of consumption, blood chemistry and histopathological pegfilgrastim. Only physician qualified by specialized training or examination of body organs. There was no abnormality experience in the treatment of patients with sickle cell disorders detected in any of the parameters in the animals. Pegfilgrastim should prescribe Pegfilgrastim should be used with caution in Step 3 was well tolerated in low, medium and high dose levels. patients with sickle cell disease, and only after careful Remove the syringe from the consideration of the potential risks and benefits. CLINICAL PHARMACOKINETIC PROPERTIES injection site, keeping your The pharmacokinetics of pegfilgrastim is nonlinear in cancer finger on the plunger rod... patients and clearance decreases with increase in the doses. PRECAUTIONS Neutrophil receptor binding is an important component of the Use with chemotherapy and / or radiation therapy clearance of pegfilgrastim and serum clearance is directly Pegfilgrastim should not be administered in the period between related to the number of neutrophils. The concentration of 14 days before and 24 hours after administration of cytotoxic pegfilgrastim declines rapidly at the onset of neutrophil recovery chemotherapy because of the potential for an increase in that follows myelosuppression chemotherapy. Additionally, sensitivity of rapidly dividing myeloid cells to cytotoxic patients with higher body weights experience higher systemic chemotherapy. The use of pegfilgrastim has not been studied in exposure of pegfilgrastim after receiving a dose normalized for patients receiving chemotherapy associated with delayed body weight. A large variability in the pharmacokinetics of myelosuppression (e.g. , ). The pegfilgrastim has been observed in cancer patients. The half life administration of pegfilgrastim concomitantly with 5-fluorouracil of pegfilgrastim ranges from 15 to 80 hours after subcutaneous Step 4 or other has not been evaluated in patients. injection. ...Then, with the same hand, Administration of pegfilgrastim at 0, 1 and 3 days before 5- activate safety device orienting fluorouracil results in increased mortality in mice: administration CLINICAL PHARMACODYANAMIC PROPERTIES it downwards and away from of pegfilgrastim 24 hours after 5-fluorouracil did not adversely Pegfilgrastim is a pegylated recombinant human granulocyte yourself and others, by firmly affect survival. The use of pegfilgrastim has not been studied in colony stimulating factor that acts on hematopoietic cells by pushing the plunger rod patients receiving radiation therapy. binding to specific cell surface receptor thereby stimulating The protective sleeve will proliferation, differentiation, commitment and end cell function automatically cover the needle Potential for tumour growth stimulating effects on activation. Studies on cellular proliferation, receptor binding and PFS An audible "click" indicates malignant cells neutrophil function demonstrate that pegfilgrastim has with needle guard that the system has been The granulocyte colony stimulating factor (G-CSF) receptor mechanism of action similar to its patent drug filgrastim. after use properly activated through which pegfilgrastim and filgrastim act has been found

Front Reason for Revision: Add instructions to use Artwork No.: AW-QA-469-02 Supersedes No.:AW-QA-469-01 Prepared by Approved by Authorised by Packing Department PPMC Regulatory Marketing Medical QA QA (FP) Services

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Date Name Designation Product Name : Pegasta 6 mg/0.6 mL- Domestic - Pack Insert No. of Col. : 1 Type of Paper / Board : Maplitho Size : 195 x 210 (mm) Colour Shade No. : Black GSM of Paper : Not less than 60 GSM No. of fold : 5 Finishing of Paper / Board : Fold size : ~27 mm X ~65 mm on tumor cell lines. The possibility that pegfilgrastim acts as a Cytopenias resulting from an antibody response to exogenous growth factor for any tumor type, including myeloid growth factors have been reported on rare occasions in patients malignancies and myelodysplasia, disease for which treated with other recombinant growth factors. There is a pegfilgrastim is not approved, cannot be excluded. theoretical possibility that an antibody directed against pegfilgrastim may cross-react with endogenous G-CSF, Laboratory Monitoring resulting in immune-mediated neutropenia, but this has not To assess the patient's hematologic status and ability to tolerate been observed in clinical studies of pegfilgrastim. Myelosuppressive chemotherapy, a complete blood count and platelet count should be obtained before chemotherapy is The experimental data obtained from post marketing administered. Regular monitoring of hematocrit value and surveillance study showed that none of the patients were platelet count is recommended. observed to develop any immunogenic response according to the specified screening cut point criteria. It was concluded that Carcinogenesis, Mutagenesis & Impairment of Fertility in this study none of the patients showed anti-peg GCSF No mutagenesis studies were conducted with pegfilgrastim. antibody development against pegfilgrastim. The carcinogenic potential of pegfilgrastim has not been OVERDOSE evaluated in long-term animal studies. In toxicity studies of 6 Single subcutaneous doses of 300 mcg/kg have been months duration in rats given once weekly subcutaneous administered to healthy volunteers and patients with non-small injections of upto 1000 mcg/Kg of pegfilgrastim, no cell lung cancer without serious adverse effects. These patients precancerous or cancerous lesions were noted. When experienced a mean maximum ANC of 55x109/L, with a administered once weekly via subcutaneous injections to male corresponding mean maximum WBC of 67x109/L. The absolute and female rats at dose upto 1000 mcg/Kg prior to, during maximum ANC observed was 96x109/L wit a corresponding mating, reproductive performance, fertility and sperm absolute maximum WBC observed of 120x109/L. The duration assessment parameters were not affected. of leukocytosis ranged from 6 to 13 days. Leukopheresis should be considered in the management of symptomatic individuals. USE IN SPECIAL POPULATIONS Pregnancy Pregnancy Category C INCOMPATIBILITIES There are no adequate and well-controlled studies in pregnant This medicinal product must not be mixed with other medicinal woman. Pegfilgrastim should be used during pregnancy only if products, particularly with sodium chloride solutions. (Normal potential benefit to the mother justifies the potential risk to the Saline 0.9% NaCl or half saline or 5% DNS- Dextrose Normal fetus. Saline)

Nursing Mothers SHELF LIFE: 24 Months It is not know whether pegfilgrastim is secreted in human milk. Caution should be exercised when administered to a nursing PACKING INFORMATION woman. Pegasta is supplied in a 0.6 mL single dose prefilled syringe containing 6 mg Pegfilgrastim. Each prefilled syringe is placed Pediatric Use in a plastic trough and packed in a carton along with a package Safety and effectiveness of pegfilgrastim in pediatric patients insert. have not been established. The 6 mg fixed-dose formulation should not be used in infants, children and smaller adolescents STORAGE AND HANDLING INSTRUCTION weighing less than 45 kg. Store refrigerated between 2 °C to 8 °C (36 °F to 46 °F) in the carton to protected from light. Do not shake. The preparation Geriatric Use should not be allowed to freeze. Keep out of reach and sight of No overall differences in safety or effectiveness were observed children. between patients aged 65 and older and younger patients.

Renal Impairment Pegfilgrastim dose adjustment in patients with renal dysfunction is not necessary.

DRUG INTERACTIONS No formal drug interaction studies between pegfilgrastim and other drugs have been performed. Drugs such as lithium may potentiate the release of neutrophils; patients receiving pegfilgrastim and lithium should have more frequent monitoring of neutrophil counts. Increased hematopoietic activity of the bone marrow in reponse to growth factor therapy may result in transient positive bone-imaging changes. Consider these finding when interpreting bone-imaging results.

UNDESIRABLE EFFECTS The most common adverse reactions that are bone pain and pain in extremity were reported more in patients treated with pegfilgrastim as compared to placebo treated patients. The other common undesirable effects includes vomiting, headache, anemia, constipation, fatigue, diarrhea, general weakness, mucositis, neutropenia, fever, body pain, taste alteration, alopecia, anorexia, skeletal pain, asthenia, pyrexia, dyspepsia, myalgias, insomnia, abdominal pain, arthralgias, peripheral edema, dizziness, granulocytopenia, stomatitis and neutropenic fever. Leukocytosis (WBC counts > 100x109/L) is observed in less than 1% of patients with non-myeloid malignancies receiving pegfilgrastim. Leukocytosis is not associated with any adverse effects.

Immunogenicity The incidence of antibody development in patients receiving pegfilgrastim has not been adequately determined. While Manufactured & Marketed by: available data suggest that a small proportion of patients developed binding antibodies to filgrastim of pegfilgrastim, the nature and specificity of these antibodies has not been adequately studied. Plot No. 423/P/A, Sarkhej - Bavla Highway,

Village - Moraiya, Taluka - Sanand, -QA-469-02 W

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Back PRESCRIBING INFORMATION: For the use of an Oncologist or a Overall response (CR+PR) rate identified from best response rate (BOR) were 35.4% ● If the docetaxel lipid suspension initial diluted solution or final dilution for intravenous Gastrointestinal disorders: diarrhoea, nausea and vomiting Hospital or a Laboratory. (95% CI, 21.9 - 48.9%) for test treatment and 26.3% (95% CI, 6.5 - 46.1%) for reference infusion appeared to have particulate matter, the same should be discarded. General disorders: asthenia, mucosal inflammation, pain and pyrexia treatment. The point estimate and 95% CI of difference between two treatments for overall Investigations: increased gamma-glutamyl transferase DOCEAQUALIP response (CR+PR) was found 9.1% and (-35.7 - 53.9%) respectively. Disease control rate ● Use within 8 hours of reconstitution Musculoskeletal and connective tissue disorders: back pain (DOCETAXEL LIPID SUSPENSION FOR INJECTION 20 MG/80 MG VIAL) (CR+PR+SD) identified from BOR was observed to be 81.3% (95% CI, 70.2 -92.3%) for Respiratory, thoracic and mediastinal disorders: dyspnoea and pleural test treatment and 89.5% (95% CI, 75.7 - 103.3%) for reference treatment. The point CONTRAINDICATIONS effusion COMPOSITION estimate and 95% CI of difference between two treatments for disease control rate Polysorbate based Docetaxel Injection containing ethanol has been contraindicated in Skin and subcutaneous tissue disorders: alopecia and pruritus DOCEAQUALIP 20 (CR+PR+SD) was found to be 8.2% and (-10.8 - 27.3%) respectively. patients with a hypersensitivity (anaphylactic/anaphylactoid reactions) to polysorbate 80. DOCETAXEL LIPID SUSPENSION FOR INJECTION 20 mg/vial However, docetaxel lipid suspension is not contraindicated in patients with hypersensitivity to DRUG INTERACTIONS Each vial contains: All the vital parameters were also within acceptable range during the study in both the polysorbate 80. Docetaxel is contraindicated in patients who have a history of severe Docetaxel is a CYP3A4 substrate. In vitro studies have shown that the Docetaxel Anhydrous USP 20 mg treatment groups. The total number of post-dose AEs observed in the study was 510. hypersensitivity reactions to docetaxel. Severe reactions, including anaphylaxis, have metabolism of docetaxel may be modified by the concomitant 3 Excipients: Q.S. The breakdown by treatment group is as follows: 123 AEs were reported by 91.30% occurred. Docetaxel should not be used in patients with neutrophil counts of <1500 cells/mm . administration of compounds that induce, inhibit, or are metabolized by (n=21) of the 23 patients under the reference arm and 387 AEs were reported by 93.88% CYP3A4. DOCEAQUALIP 80 (n=46) of the 49 patients under the test arm. Overall, the investigational drugs were found WARNINGS AND PRECAUTIONS DOCETAXEL LIPID SUSPENSION FOR INJECTION 80 mg/vial to be well tolerated by cancer patients, even as a multiple dose administration. Majority of Toxic Deaths: The incidence of treatment-related mortality associated with Docetaxel In vivo studies showed that the exposure of docetaxel increased 2.2-fold Each vial contains: the post-dose AEs were resolved without any sequel despite the fact patients were not therapy is increased in patients with abnormal liver function, in patients receiving higher when it was coadministered with ketoconazole, a potent inhibitor of Docetaxel Anhydrous USP 80 mg pre-medicated with corticosteroids or anti-allergic treatment in docetaxel lipid suspension doses of Docetaxel. Patients should be closed monitored for liver dysfunction. CYP3A4. Protease inhibitors, particularly ritonavir, may increase the Excipients: Q.S. treatment group. exposure of docetaxel. Concomitant use of Docetaxel and drugs that Hepatic Impairment: The incidence of treatment-related mortality associated with inhibit CYP3A4 may increase exposure to docetaxel and should be DESCRIPTION INDICATIONS Docetaxel therapy is increased in patients with abnormal liver function. Patients with avoided. In patients receiving treatment with Docetaxel, close monitoring Docetaxel is an antineoplastic agent belonging to the taxoid family. It is prepared by Docetaxel lipid suspension for injection is indicated for: combined abnormalities of transaminases and alkaline phosphatase should not be treated for toxicity and a Docetaxel dose reduction could be considered if semi-synthesis beginning with a precursor extracted from the renewable needle biomass ● For the treatment of patients with advanced gastric adenocarcinoma with Docetaxel. Patients treated with docetaxel lipid suspension should be closed systemic administration of a potent CYP3A4 inhibitor cannot be avoided. of yew plants. The chemical name for docetaxel is (2R,3S)-N-carboxy-3-phenylisoserine, ● For the induction treatment of patients with inoperable locally advanced squamous cell monitored for hepatic impairment. N-tert-butyl ester, 13-ester with 5β-20-epoxy-l,2α,4,7β,10β,13α hexahydroxytax-11-en-9- carcinoma of the head and neck USE IN SPECIFIC POPULATIONS one 4-acetate 2-benzoate. Docetaxel has the following structural formula: ● For the treatment of patients with androgen independent (hormone refractory) Hematologic Effects: Perform frequent peripheral blood cell counts on all patients Pregnancy Docetaxel can cause fetal harm when administered to a pregnant woman. Docetaxel HO H O metastatic prostate cancer receiving Docetaxel lipid suspension. Patients should not be retreated with subsequent H C OH cycles of Docetaxel until neutrophils recover to a level >1500 cells/mm3 and platelets caused embryo-fetal toxicities including intrauterine mortality when administered to 3 CH H ● For the treatment of patients with locally advanced or metastatic breast cancer after H OH 3 recover to a level > 100,000 cells/mm3. A 25% reduction in the dose of Docetaxel is pregnant rats and rabbits during the period of organogenesis. O CH3 failure of prior chemotherapy recommended during subsequent cycles following severe neutropenia (<500 cells/mm3) CH H ● For the treatment of patients with non-small cell lung cancer CH NH H H 3 There are no adequate and well-controlled studies in pregnant women using Docetaxel. H C 3 O lasting 7 days or more, febrile neutropenia, or a grade 4 infection in a Docetaxel cycle. 3 HO H O If Docetaxel is used during pregnancy, or if the patient becomes pregnant while receiving H C O DOSAGE AND ADMINISTRATION 3 O O H this drug, the patient should be apprised of the potential hazard to the fetus. O O O Docetaxel lipid suspension for injection is a sterile lyophilized powder containing 20 Hypersensitivity Reactions: Patients should be observed closely for hypersensitivity CH reactions, especially during the first and second infusions. Severe hypersensitivity Women of childbearing potential should be advised to avoid becoming pregnant during 3 mg/vial Docetaxel (anhydrous). Each 20 mg vial is first reconstituted by adding 9 ml of therapy with Docetaxel. sterile water to yield 2 mg/ml of docetaxel lipid suspension. Similarly, 80 mg vial is first reactions require immediate discontinuation of the Docetaxel infusion and aggressive Nursing Mothers reconstituted by adding 36 ml of sterile water to yield 2 mg/ml of docetaxel lipid therapy. Patients with a history of severe hypersensitivity reactions should not be rechallenged with Docetaxel Injection. It is not known whether docetaxel is excreted in human milk. Because many drugs are Docetaxel is a white to almost-white powder with an empirical formula of C H NO , and suspension. The reconstituted suspension can further be diluted with 5% dextrose excreted in human milk, and because of the potential for serious adverse reactions in 43 53 14 Injection IP or 0.9% sodium chloride Injection IP prior to administration. Dosage and a molecular weight of 807.88. It is highly lipophilic and practically insoluble in water. Fluid Retention: Severe fluid retention has been reported following conventional nursing infants from Docetaxel, a decision should be made whether to discontinue nursing procedure of administration can vary based on the cancer types as following. polysorbate based Docetaxel therapy. Only one patient had fluid retention without or to discontinue the drug, taking into account the importance of the drug to the mother. This formulation is a sterile lyophilized powder containing Soy phosphatidylcholine and premedication in docetaxel lipid suspension group. However, patients should be closely Pediatric Use Gastric adenocarcinoma Sodium Cholesteryl Sulfate with 20 mg Docetaxel (anhydrous) per vial. Each 20 mg vial is monitored and treated based on the severity of fluid retention. The efficacy of docetaxel lipid suspension in pediatric patients as monotherapy or in first reconstituted by adding 9 ml of sterile water to yield 2 mg/ml of docetaxel lipid For gastric adenocarcinoma, the recommended dose of docetaxel lipid suspension is 75 combination has not been established. mg/m2 as a 1 hour intravenous infusion, followed by cisplatin 75 mg/m2, as a 1 to 3 hour suspension. Similarly, 80 mg vial is first reconstituted by adding 36 ml of sterile water to : Treatment-related acute myeloid leukemia (AML) or Hepatic Impairment intravenous infusion (both on day 1 only), followed by fluorouracil 750 mg/m2 per day given yield 2 mg/ml of docetaxel lipid suspension. The reconstituted suspension can further be myelodysplasia has occurred in patients with polysorbate based Docetaxel Injection given Patients with bilirubin >ULN should not receive Docetaxel. Also, patients with AST and/or as a 24-hour continuous intravenous infusion for 5 days, starting at the end of the cisplatin diluted with 5% dextrose Injection IP or 0.9% sodium chloride Injection IP prior to anthracyclines and/or cyclophosphamide, including use in adjuvant therapy for breast ALT >1.5 x ULN concomitant with alkaline phosphatase >2.5 x ULN should not receive administration. infusion. Treatment is repeated every three weeks. Patients must receive premedication cancer. AML has occurred who received Docetaxel, doxorubicin and cyclophosphamide in Docetaxel. with antiemetics and appropriate hydration for cisplatin administration. the clinical studies. CLINICAL PHARMACOLOGY Head and Neck Cancer CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY Mechanism of Action Induction chemotherapy followed by radiotherapy Cutaneous Reactions Carcinogenicity studies with docetaxel have not been performed. Docetaxel is an antineoplastic agent that acts by disrupting the microtubular network in For the induction treatment of locally advanced inoperable squamous cell carcinoma of Localized erythema of the extremities with edema followed by desquamation has been cells that is essential for mitotic and interphase cellular functions. Docetaxel binds to free the head and neck (SCCHN), the recommended dose of docetaxel lipid suspension is 75 Docetaxel was clastogenic in the in vitro chromosome aberration test in CHO-K1 cells and 2 2 observed with polysorbate based Docetaxel Injection. In case of severe skin toxicity with tubulin and promotes the assembly of tubulin into stable while mg/m as a 1 hour intravenous infusion followed by cisplatin 75 mg/m intravenously over docetaxel lipid suspension is observed, an adjustment in dosage is recommended. The in the in vivo micronucleus test in mice administered doses of 0.39 to 1.56 mg/kg(about 2 simultaneously inhibiting their disassembly. This leads to the production of 1 hour, on day one, followed by fluorouracil as a continuous intravenous infusion at 750 discontinuation rate due to skin toxicity was 1.6% for metastatic breast cancer patients. 1/60th to 1/15th the recommended human dose on a mg/m basis). bundles without normal function and to the stabilization of microtubules, which results in mg/m2 per day for five days. This regimen is administered every 3 weeks for 4 cycles. the inhibition of mitosis in cells. Docetaxel's binding to microtubules does not alter the Following chemotherapy, patients should receive radiotherapy. Neurologic Reactions Docetaxel was not mutagenic in the Ames test or the CHO/HGPRT gene mutation assays. number of protofilaments in the bound microtubules, a feature which differs from most Induction chemotherapy followed by chemoradiotherapy Severe neurosensory symptoms (e.g. paresthesia, dysesthesia, pain) were observed with spindle poisons currently in clinical use. For the induction treatment of patients with locally advanced (unresectable, low surgical polysorbate based Docetaxel Injection in 5.5% of metastatic breast cancer patients, and Docetaxel did not reduce fertility in rats when administered in multiple intravenous doses th 2 cure, or organ preservation) SCCHN, the recommended dose of docetaxel lipid resulted in treatment discontinuation in 6.1%. When these symptoms occur with docetaxel of up to 0.3 mg/kg (about 1/50 the recommended human dose on a mg/m basis), but 2 Pharmacokinetics suspension is 75 mg/m as a 1 hour intravenous infusion on day 1, followed by cisplatin lipid suspension, dosage must be adjusted. If symptoms persist, treatment should be decreased testicular weights were reported. This correlates with findings of a10-cycle 2 In vitro drug interaction studies conducted by investigators have shown that Docetaxel is 100 mg/m administered as a 30-minute to 3 hour infusion, followed by fluorouracil 1000 discontinued. toxicity study (dosing once every 21 days for 6 months) in rats and dogs in which testicular metabolized by the CYP3A4 isoenzyme, and its metabolism may be modified by the mg/m2/day as a continuous infusion from day 1 to day 4. This regimen is administered atrophy or degeneration was observed at intravenous doses of 5 mg/kg in rats and 0.375 rd th 2 concomitant administration of compounds that induce, inhibit, or are metabolized by every 3 weeks for 3 cycles. Following chemotherapy, patients should receive ADVERSE EFFECTS mg/kg in dogs (about 1/3 and 1/15 the recommended human dose on a mg/m basis, CYP3A4. chemo-radiotherapy. The most serious adverse reactions from Docetaxel are: respectively). An increased frequency of dosing in rats produced similar effects at lower Prostate cancer dose levels by polysorbate based Docetaxel. The effects can be expected with docetaxel An open label, balanced, randomized, two periods, two treatment, two sequences, For hormone-refractory metastatic prostate cancer, the recommended dose of docetaxel Toxic Deaths lipid suspension. crossover, multicentric study was conducted to evaluate safety and pharmacokinetic lipid suspension is 75 mg/m2 every 3 weeks as a 1 hour intravenous infusion. Prednisone Polysorbate based Docetaxel administered at 100 mg/m2 was associated with deaths comparison of intravenous infusion of docetaxel lipid suspension (test) and polysorbate 5 mg orally twice daily is administered continuously. considered possibly or probably related to treatment in 2.0% of metastatic breast cancer NON CLINICAL TOXICOLOGICAL STUDIES based Docetaxel Injection Concentrate (reference), innovator's product in advanced solid Breast cancer patients, both previously treated and untreated, with normal baseline liver function and in A subchronic 28 day intravenous toxicity study was conducted by five consecutive day’s tumor patients. For locally advanced or metastatic breast cancer after failure of prior chemotherapy, the 11.5% of patients with various tumor types who had abnormal baseline liver function (AST administration of docetaxel lipid suspension in Swiss Albino mice at 5 mg/kg, 10 mg/kg or recommended dose of docetaxel lipid suspension is 75 mg/m2 administered intravenously 15 mg/kg. The results showed in no haematological abnormalities related to the treatment 2 and/or ALT >1.5 times ULN together with AP >2.5 times ULN). Among patients dosed at 60 All patients were dosed at 75 mg/m intravenously, over 1 hour once every three weeks. In over 1 hour every 3 weeks for maximum of 6 cycles. mg/m2, mortality related to treatment occurred in 0.6% of patients with normal liver in all groups. Biochemical analysis revealed no abnormalities at 5 and 10 mg/kg dose but Period I patients were dosed with test or reference on the first day of the chemotherapy Non-small cell lung cancer function, and in 3 of 7 patients with abnormal liver function. Approximately half of these elevated levels of Alanine Aminotransferase and Alkaline Phosphatase was observed at cycle (day 1) of the study as per the randomization schedule. In Period II patients were For treatment after failure of prior platinum-based chemotherapy, the recommended dose deaths occurred during the first cycle. Sepsis accounted for the majority of the deaths. the highest dose (15 mg/kg). Gross and histopathological changes were observed in male crossed over to either test or reference drug (patients on test product to be crossed over is 75 mg/m2 administered intravenously over 1 hour every 3 weeks. Cautions should be taken when treating patients with docetaxel lipid suspension and and female animals from different dose levels. Mortalities (2/6 male and 1/6 female) were to reference product and vice-versa) on the first day of the next chemotherapy cycle (day For chemotherapy-naïve patients, the recommended dose is 75 mg/m2 administered medical condition should be regularly monitored. noted in animals treated with highest dose (15 mg/kg) of the docetaxel lipid suspension. 22) as per randomization schedule. The pharmacokinetics evaluations were done by intravenously over 1 hour immediately followed by cisplatin 75 mg/m2 over 30-60 minutes Hepatotoxicity Similar subchronic 28 day intravenous toxicity study was conducted in rats by five collecting whole blood samples from patients (both test and reference product) prior to every 3 weeks. Similar to polysorbate based Docetaxel Injection, the docetaxel lipid suspension should consecutive day's administration of docetaxel lipid suspension at 0 mg/kg, 0.312 mg/kg, each dose and over a period of 72-hour after each dose. The study revealed about 40% not be given to patients with bilirubin > upper limit of normal (ULN), or to patients with AST 0.625 mg/kg and 1.25 mg/kg. The results showed no mortalities or haematological higher C and similar AUC values compared to the reference product. The safety profile abnormalities related to the treatment in all groups. Gross and histopathological max Preparation Guide for Use of Docetaxel Lipid Suspension and/or ALT >1.5 x ULN concomitant with alkaline phosphatase >2.5 x ULN. Patients with examination showed effect only at highest dose level (1.25 mg/kg) whereas, no effect on of docetaxel lipid suspension was similar to that of polysorbate based Docetaxel Injection. Initial dilution elevations of bilirubin or abnormalities of transaminase concurrent with alkaline the organs was observed at 0.312 mg/kg and 0.625 mg/kg dose levels. The docetaxel lipid suspension available as lyophilized powder in a vial should be reconstituted phosphatase are at increased risk for the development of grade 4 neutropenia, febrile CLINICAL STUDIES using Sterile Water for Injection (WFI). Initial dilution should be prepared as follows: neutropenia, infections, severe thrombocytopenia, severe stomatitis/ severe skin toxicity, OVERDOSAGE ● Add 9 ml of Sterile WFI to vial of Doceaqualip 20 to yield a preparation containing and toxic death. Patients with isolated elevations of transaminase >1.5 x ULN also had a There is no known antidote for docetaxel overdosage. In case of overdosage, the patient Locally Advanced or Metastatic Breast Cancer higher rate of febrile neutropenia grade 4. Bilirubin, AST or ALT, and alkaline phosphatase 2mg/ml. For vial of Doceaqualip 80, add 36 ml of Sterile WFI to the vial to yield a should be kept in a specialized unit where vital functions can be closely monitored. An open label, randomized, multiple-dose, parallel study to evaluate the safety and values should be obtained prior to each cycle of Docetaxel therapy. preparation containing 2 mg/ml. Anticipated complications of overdosage include: bone marrow suppression, peripheral efficacy of docetaxel lipid suspension (test) and Polysorbate based Docetaxel (reference) Neutropenia neurotoxicity, and mucositis. Patients should receive therapeutic G-CSF as soon as was conducted in patients with locally advanced or metastatic breast cancer after failure Neutropenia (<2000 neutrophils/mm3) occurs in virtually all patients given 60 mg/m2 to ● Immediately after the addition of WFI, shake the vial vigorously for 60 seconds to completely possible after discovery of overdose. Other appropriate symptomatic measures should be to prior chemotherapy. 100 mg/m2 of polysorbate based Docetaxel and grade 4 neutropenia (<500 cells/mm3) disperse the material. Keep the vial aside for 15 min to complete the constitution. Inspect taken, as needed. visually for any particulate matter and shake until complete desperation. occurs in 85% of patients given 100 mg/m2 and 75% of patients given 60 mg/m2. Patients were randomized to receive either test (n=49) or reference (n=23) at a ratio of 2:1, Frequent monitoring of blood counts is, therefore, essential so that dose can be adjusted stratified by Eastern Cooperative Oncology Group (ECOG) performance status (0, or 1-2). STORAGE 2 Final Dilution for Infusion when treated with docetaxel lipid suspension. Docetaxel should not be administered to Each drug was administered by IV infusion over 1 hour at a dose of 75 mg/m . Patients 3 Store at 2-8°C. Do not freeze. Protect from light. Keep out of reach of children. ● Aseptically withdraw the required amount of initial diluted docetaxel lipid suspension (2 mg patients with neutrophils <1500 cells/mm . were treated every 21 days (a treatment cycle) in the absence of disease progression or Fluid Retention docetaxel / ml) with a calibrated syringe and inject into a 250 /500 ml infusion bag or bottle PACKAGING INFORMATION unacceptable toxicity. The primary objective of this study was to compare the overall Severe fluid retention has been reported following polysorbate 80 based Docetaxel response rate (complete or partial response) and to evaluate the efficacy of test versus of 5% Dextrose Injection IP or 0.9% sodium chloride Injection IP solution to produce a final Available as 20 mg and 80 mg in single vials individually packed in a carton. concentration of 0.3 to 0.74 mg/ml. therapy in earlier studies. Even though this was not observed in greater number of reference products in patients. The secondary objective was to evaluate the safety of the Patients treated with docetaxel lipid suspension without premedication but such condition Manufactured by: patients who are exposed to the test or reference products. A point estimate and a ● Mix the infusion thoroughly by manual rotation. should be monitored by medical Investigators. two-sided 95% confidence interval were computed for the primary efficacy endpoint, INTAS PHARMACEUTICALS LTD. response rates (CR+PR) from best overall response of the two treatment groups and their ● As with all parenteral products, docetaxel lipid suspension should be inspected visually In clinical trial, commonly observed adverse reactions with docetaxel lipid suspension are Matoda-382 210, Dist.: Ahmedabad. INDIA difference. A point estimate and a two-sided 95% confidence interval (CI) were computed as following: for the secondary efficacy endpoint, disease control rate (CR+PR+SD) from best overall for particulate matter or discoloration prior to administration whenever the solution and 10 0328 1 676522 container permitted. Blood and lymphatic system disorders: anaemia, febrile neutropenia, leucopenia and response of the two treatment groups and their difference. neutropenia INP010

Note: PIL should be in flat form

File Name : 10 0328 1 676522-DOCEAQUALIP-PIL Size : 160 x 270 (mm) Front Side Colour : Pantone Black Date : 06/07/17, 20/07/17 PRESCRIBING INFORMATION: For the use of an Oncologist or a Overall response (CR+PR) rate identified from best response rate (BOR) were 35.4% ● If the docetaxel lipid suspension initial diluted solution or final dilution for intravenous Gastrointestinal disorders: diarrhoea, nausea and vomiting Hospital or a Laboratory. (95% CI, 21.9 - 48.9%) for test treatment and 26.3% (95% CI, 6.5 - 46.1%) for reference infusion appeared to have particulate matter, the same should be discarded. General disorders: asthenia, mucosal inflammation, pain and pyrexia treatment. The point estimate and 95% CI of difference between two treatments for overall Investigations: increased gamma-glutamyl transferase DOCEAQUALIP response (CR+PR) was found 9.1% and (-35.7 - 53.9%) respectively. Disease control rate ● Use within 8 hours of reconstitution Musculoskeletal and connective tissue disorders: back pain (DOCETAXEL LIPID SUSPENSION FOR INJECTION 20 MG/80 MG VIAL) (CR+PR+SD) identified from BOR was observed to be 81.3% (95% CI, 70.2 -92.3%) for Respiratory, thoracic and mediastinal disorders: dyspnoea and pleural test treatment and 89.5% (95% CI, 75.7 - 103.3%) for reference treatment. The point CONTRAINDICATIONS effusion COMPOSITION estimate and 95% CI of difference between two treatments for disease control rate Polysorbate based Docetaxel Injection containing ethanol has been contraindicated in Skin and subcutaneous tissue disorders: alopecia and pruritus DOCEAQUALIP 20 (CR+PR+SD) was found to be 8.2% and (-10.8 - 27.3%) respectively. patients with a hypersensitivity (anaphylactic/anaphylactoid reactions) to polysorbate 80. DOCETAXEL LIPID SUSPENSION FOR INJECTION 20 mg/vial However, docetaxel lipid suspension is not contraindicated in patients with hypersensitivity to DRUG INTERACTIONS Each vial contains: All the vital parameters were also within acceptable range during the study in both the polysorbate 80. Docetaxel is contraindicated in patients who have a history of severe Docetaxel is a CYP3A4 substrate. In vitro studies have shown that the Docetaxel Anhydrous USP 20 mg treatment groups. The total number of post-dose AEs observed in the study was 510. hypersensitivity reactions to docetaxel. Severe reactions, including anaphylaxis, have metabolism of docetaxel may be modified by the concomitant 3 Excipients: Q.S. The breakdown by treatment group is as follows: 123 AEs were reported by 91.30% occurred. Docetaxel should not be used in patients with neutrophil counts of <1500 cells/mm . administration of compounds that induce, inhibit, or are metabolized by (n=21) of the 23 patients under the reference arm and 387 AEs were reported by 93.88% CYP3A4. DOCEAQUALIP 80 (n=46) of the 49 patients under the test arm. Overall, the investigational drugs were found WARNINGS AND PRECAUTIONS DOCETAXEL LIPID SUSPENSION FOR INJECTION 80 mg/vial to be well tolerated by cancer patients, even as a multiple dose administration. Majority of Toxic Deaths: The incidence of treatment-related mortality associated with Docetaxel In vivo studies showed that the exposure of docetaxel increased 2.2-fold Each vial contains: the post-dose AEs were resolved without any sequel despite the fact patients were not therapy is increased in patients with abnormal liver function, in patients receiving higher when it was coadministered with ketoconazole, a potent inhibitor of Docetaxel Anhydrous USP 80 mg pre-medicated with corticosteroids or anti-allergic treatment in docetaxel lipid suspension doses of Docetaxel. Patients should be closed monitored for liver dysfunction. CYP3A4. Protease inhibitors, particularly ritonavir, may increase the Excipients: Q.S. treatment group. exposure of docetaxel. Concomitant use of Docetaxel and drugs that Hepatic Impairment: The incidence of treatment-related mortality associated with inhibit CYP3A4 may increase exposure to docetaxel and should be DESCRIPTION INDICATIONS Docetaxel therapy is increased in patients with abnormal liver function. Patients with avoided. In patients receiving treatment with Docetaxel, close monitoring Docetaxel is an antineoplastic agent belonging to the taxoid family. It is prepared by Docetaxel lipid suspension for injection is indicated for: combined abnormalities of transaminases and alkaline phosphatase should not be treated for toxicity and a Docetaxel dose reduction could be considered if semi-synthesis beginning with a precursor extracted from the renewable needle biomass ● For the treatment of patients with advanced gastric adenocarcinoma with Docetaxel. Patients treated with docetaxel lipid suspension should be closed systemic administration of a potent CYP3A4 inhibitor cannot be avoided. of yew plants. The chemical name for docetaxel is (2R,3S)-N-carboxy-3-phenylisoserine, ● For the induction treatment of patients with inoperable locally advanced squamous cell monitored for hepatic impairment. N-tert-butyl ester, 13-ester with 5β-20-epoxy-l,2α,4,7β,10β,13α hexahydroxytax-11-en-9- carcinoma of the head and neck USE IN SPECIFIC POPULATIONS one 4-acetate 2-benzoate. Docetaxel has the following structural formula: ● For the treatment of patients with androgen independent (hormone refractory) Hematologic Effects: Perform frequent peripheral blood cell counts on all patients Pregnancy metastatic prostate cancer receiving Docetaxel lipid suspension. Patients should not be retreated with subsequent Docetaxel can cause fetal harm when administered to a pregnant woman. Docetaxel 3 ● For the treatment of patients with locally advanced or metastatic breast cancer after cycles of Docetaxel until neutrophils recover to a level >1500 cells/mm and platelets caused embryo-fetal toxicities including intrauterine mortality when administered to 3 failure of prior chemotherapy recover to a level > 100,000 cells/mm . A 25% reduction in the dose of Docetaxel is pregnant rats and rabbits during the period of organogenesis. 3 ● For the treatment of patients with non-small cell lung cancer recommended during subsequent cycles following severe neutropenia (<500 cells/mm ) lasting 7 days or more, febrile neutropenia, or a grade 4 infection in a Docetaxel cycle. There are no adequate and well-controlled studies in pregnant women using Docetaxel. If Docetaxel is used during pregnancy, or if the patient becomes pregnant while receiving DOSAGE AND ADMINISTRATION this drug, the patient should be apprised of the potential hazard to the fetus. Docetaxel lipid suspension for injection is a sterile lyophilized powder containing 20 Hypersensitivity Reactions: Patients should be observed closely for hypersensitivity Women of childbearing potential should be advised to avoid becoming pregnant during mg/vial Docetaxel (anhydrous). Each 20 mg vial is first reconstituted by adding 9 ml of reactions, especially during the first and second infusions. Severe hypersensitivity therapy with Docetaxel. sterile water to yield 2 mg/ml of docetaxel lipid suspension. Similarly, 80 mg vial is first reactions require immediate discontinuation of the Docetaxel infusion and aggressive therapy. Patients with a history of severe hypersensitivity reactions should not be Nursing Mothers reconstituted by adding 36 ml of sterile water to yield 2 mg/ml of docetaxel lipid It is not known whether docetaxel is excreted in human milk. Because many drugs are suspension. The reconstituted suspension can further be diluted with 5% dextrose rechallenged with Docetaxel Injection. Docetaxel is a white to almost-white powder with an empirical formula of C43H53NO14, and excreted in human milk, and because of the potential for serious adverse reactions in Injection IP or 0.9% sodium chloride Injection IP prior to administration. Dosage and a molecular weight of 807.88. It is highly lipophilic and practically insoluble in water. Fluid Retention: Severe fluid retention has been reported following conventional nursing infants from Docetaxel, a decision should be made whether to discontinue nursing procedure of administration can vary based on the cancer types as following. polysorbate based Docetaxel therapy. Only one patient had fluid retention without or to discontinue the drug, taking into account the importance of the drug to the mother. This formulation is a sterile lyophilized powder containing Soy phosphatidylcholine and premedication in docetaxel lipid suspension group. However, patients should be closely Pediatric Use Gastric adenocarcinoma Sodium Cholesteryl Sulfate with 20 mg Docetaxel (anhydrous) per vial. Each 20 mg vial is monitored and treated based on the severity of fluid retention. The efficacy of docetaxel lipid suspension in pediatric patients as monotherapy or in first reconstituted by adding 9 ml of sterile water to yield 2 mg/ml of docetaxel lipid For gastric adenocarcinoma, the recommended dose of docetaxel lipid suspension is 75 combination has not been established. mg/m2 as a 1 hour intravenous infusion, followed by cisplatin 75 mg/m2, as a 1 to 3 hour suspension. Similarly, 80 mg vial is first reconstituted by adding 36 ml of sterile water to Acute Myeloid Leukemia: Treatment-related acute myeloid leukemia (AML) or Hepatic Impairment intravenous infusion (both on day 1 only), followed by fluorouracil 750 mg/m2 per day given yield 2 mg/ml of docetaxel lipid suspension. The reconstituted suspension can further be myelodysplasia has occurred in patients with polysorbate based Docetaxel Injection given Patients with bilirubin >ULN should not receive Docetaxel. Also, patients with AST and/or as a 24-hour continuous intravenous infusion for 5 days, starting at the end of the cisplatin diluted with 5% dextrose Injection IP or 0.9% sodium chloride Injection IP prior to anthracyclines and/or cyclophosphamide, including use in adjuvant therapy for breast ALT >1.5 x ULN concomitant with alkaline phosphatase >2.5 x ULN should not receive administration. infusion. Treatment is repeated every three weeks. Patients must receive premedication cancer. AML has occurred who received Docetaxel, doxorubicin and cyclophosphamide in Docetaxel. with antiemetics and appropriate hydration for cisplatin administration. the clinical studies. CLINICAL PHARMACOLOGY Head and Neck Cancer CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY Mechanism of Action Induction chemotherapy followed by radiotherapy Cutaneous Reactions Carcinogenicity studies with docetaxel have not been performed. Docetaxel is an antineoplastic agent that acts by disrupting the microtubular network in For the induction treatment of locally advanced inoperable squamous cell carcinoma of Localized erythema of the extremities with edema followed by desquamation has been cells that is essential for mitotic and interphase cellular functions. Docetaxel binds to free the head and neck (SCCHN), the recommended dose of docetaxel lipid suspension is 75 Docetaxel was clastogenic in the in vitro chromosome aberration test in CHO-K1 cells and 2 2 observed with polysorbate based Docetaxel Injection. In case of severe skin toxicity with tubulin and promotes the assembly of tubulin into stable microtubules while mg/m as a 1 hour intravenous infusion followed by cisplatin 75 mg/m intravenously over docetaxel lipid suspension is observed, an adjustment in dosage is recommended. The in the in vivo micronucleus test in mice administered doses of 0.39 to 1.56 mg/kg(about 2 simultaneously inhibiting their disassembly. This leads to the production of microtubule 1 hour, on day one, followed by fluorouracil as a continuous intravenous infusion at 750 discontinuation rate due to skin toxicity was 1.6% for metastatic breast cancer patients. 1/60th to 1/15th the recommended human dose on a mg/m basis). bundles without normal function and to the stabilization of microtubules, which results in mg/m2 per day for five days. This regimen is administered every 3 weeks for 4 cycles. the inhibition of mitosis in cells. Docetaxel's binding to microtubules does not alter the Following chemotherapy, patients should receive radiotherapy. Neurologic Reactions Docetaxel was not mutagenic in the Ames test or the CHO/HGPRT gene mutation assays. number of protofilaments in the bound microtubules, a feature which differs from most Induction chemotherapy followed by chemoradiotherapy Severe neurosensory symptoms (e.g. paresthesia, dysesthesia, pain) were observed with spindle poisons currently in clinical use. For the induction treatment of patients with locally advanced (unresectable, low surgical polysorbate based Docetaxel Injection in 5.5% of metastatic breast cancer patients, and Docetaxel did not reduce fertility in rats when administered in multiple intravenous doses th 2 cure, or organ preservation) SCCHN, the recommended dose of docetaxel lipid resulted in treatment discontinuation in 6.1%. When these symptoms occur with docetaxel of up to 0.3 mg/kg (about 1/50 the recommended human dose on a mg/m basis), but 2 Pharmacokinetics suspension is 75 mg/m as a 1 hour intravenous infusion on day 1, followed by cisplatin lipid suspension, dosage must be adjusted. If symptoms persist, treatment should be decreased testicular weights were reported. This correlates with findings of a10-cycle 2 In vitro drug interaction studies conducted by investigators have shown that Docetaxel is 100 mg/m administered as a 30-minute to 3 hour infusion, followed by fluorouracil 1000 discontinued. toxicity study (dosing once every 21 days for 6 months) in rats and dogs in which testicular metabolized by the CYP3A4 isoenzyme, and its metabolism may be modified by the mg/m2/day as a continuous infusion from day 1 to day 4. This regimen is administered atrophy or degeneration was observed at intravenous doses of 5 mg/kg in rats and 0.375 rd th 2 concomitant administration of compounds that induce, inhibit, or are metabolized by every 3 weeks for 3 cycles. Following chemotherapy, patients should receive ADVERSE EFFECTS mg/kg in dogs (about 1/3 and 1/15 the recommended human dose on a mg/m basis, CYP3A4. chemo-radiotherapy. The most serious adverse reactions from Docetaxel are: respectively). An increased frequency of dosing in rats produced similar effects at lower Prostate cancer dose levels by polysorbate based Docetaxel. The effects can be expected with docetaxel An open label, balanced, randomized, two periods, two treatment, two sequences, For hormone-refractory metastatic prostate cancer, the recommended dose of docetaxel Toxic Deaths lipid suspension. crossover, multicentric study was conducted to evaluate safety and pharmacokinetic lipid suspension is 75 mg/m2 every 3 weeks as a 1 hour intravenous infusion. Prednisone Polysorbate based Docetaxel administered at 100 mg/m2 was associated with deaths comparison of intravenous infusion of docetaxel lipid suspension (test) and polysorbate 5 mg orally twice daily is administered continuously. considered possibly or probably related to treatment in 2.0% of metastatic breast cancer NON CLINICAL TOXICOLOGICAL STUDIES based Docetaxel Injection Concentrate (reference), innovator's product in advanced solid Breast cancer patients, both previously treated and untreated, with normal baseline liver function and in A subchronic 28 day intravenous toxicity study was conducted by five consecutive day’s tumor patients. For locally advanced or metastatic breast cancer after failure of prior chemotherapy, the 11.5% of patients with various tumor types who had abnormal baseline liver function (AST administration of docetaxel lipid suspension in Swiss Albino mice at 5 mg/kg, 10 mg/kg or recommended dose of docetaxel lipid suspension is 75 mg/m2 administered intravenously 15 mg/kg. The results showed in no haematological abnormalities related to the treatment 2 and/or ALT >1.5 times ULN together with AP >2.5 times ULN). Among patients dosed at 60 All patients were dosed at 75 mg/m intravenously, over 1 hour once every three weeks. In over 1 hour every 3 weeks for maximum of 6 cycles. mg/m2, mortality related to treatment occurred in 0.6% of patients with normal liver in all groups. Biochemical analysis revealed no abnormalities at 5 and 10 mg/kg dose but Period I patients were dosed with test or reference on the first day of the chemotherapy Non-small cell lung cancer function, and in 3 of 7 patients with abnormal liver function. Approximately half of these elevated levels of Alanine Aminotransferase and Alkaline Phosphatase was observed at cycle (day 1) of the study as per the randomization schedule. In Period II patients were For treatment after failure of prior platinum-based chemotherapy, the recommended dose deaths occurred during the first cycle. Sepsis accounted for the majority of the deaths. the highest dose (15 mg/kg). Gross and histopathological changes were observed in male crossed over to either test or reference drug (patients on test product to be crossed over is 75 mg/m2 administered intravenously over 1 hour every 3 weeks. Cautions should be taken when treating patients with docetaxel lipid suspension and and female animals from different dose levels. Mortalities (2/6 male and 1/6 female) were to reference product and vice-versa) on the first day of the next chemotherapy cycle (day For chemotherapy-naïve patients, the recommended dose is 75 mg/m2 administered medical condition should be regularly monitored. noted in animals treated with highest dose (15 mg/kg) of the docetaxel lipid suspension. 22) as per randomization schedule. The pharmacokinetics evaluations were done by intravenously over 1 hour immediately followed by cisplatin 75 mg/m2 over 30-60 minutes Hepatotoxicity Similar subchronic 28 day intravenous toxicity study was conducted in rats by five collecting whole blood samples from patients (both test and reference product) prior to every 3 weeks. Similar to polysorbate based Docetaxel Injection, the docetaxel lipid suspension should consecutive day's administration of docetaxel lipid suspension at 0 mg/kg, 0.312 mg/kg, each dose and over a period of 72-hour after each dose. The study revealed about 40% not be given to patients with bilirubin > upper limit of normal (ULN), or to patients with AST 0.625 mg/kg and 1.25 mg/kg. The results showed no mortalities or haematological higher C and similar AUC values compared to the reference product. The safety profile abnormalities related to the treatment in all groups. Gross and histopathological max Preparation Guide for Use of Docetaxel Lipid Suspension and/or ALT >1.5 x ULN concomitant with alkaline phosphatase >2.5 x ULN. Patients with examination showed effect only at highest dose level (1.25 mg/kg) whereas, no effect on of docetaxel lipid suspension was similar to that of polysorbate based Docetaxel Injection. Initial dilution elevations of bilirubin or abnormalities of transaminase concurrent with alkaline the organs was observed at 0.312 mg/kg and 0.625 mg/kg dose levels. The docetaxel lipid suspension available as lyophilized powder in a vial should be reconstituted phosphatase are at increased risk for the development of grade 4 neutropenia, febrile CLINICAL STUDIES using Sterile Water for Injection (WFI). Initial dilution should be prepared as follows: neutropenia, infections, severe thrombocytopenia, severe stomatitis/ severe skin toxicity, OVERDOSAGE ● Add 9 ml of Sterile WFI to vial of Doceaqualip 20 to yield a preparation containing and toxic death. Patients with isolated elevations of transaminase >1.5 x ULN also had a There is no known antidote for docetaxel overdosage. In case of overdosage, the patient Locally Advanced or Metastatic Breast Cancer higher rate of febrile neutropenia grade 4. Bilirubin, AST or ALT, and alkaline phosphatase 2mg/ml. For vial of Doceaqualip 80, add 36 ml of Sterile WFI to the vial to yield a should be kept in a specialized unit where vital functions can be closely monitored. An open label, randomized, multiple-dose, parallel study to evaluate the safety and values should be obtained prior to each cycle of Docetaxel therapy. preparation containing 2 mg/ml. Anticipated complications of overdosage include: bone marrow suppression, peripheral efficacy of docetaxel lipid suspension (test) and Polysorbate based Docetaxel (reference) Neutropenia neurotoxicity, and mucositis. Patients should receive therapeutic G-CSF as soon as was conducted in patients with locally advanced or metastatic breast cancer after failure Neutropenia (<2000 neutrophils/mm3) occurs in virtually all patients given 60 mg/m2 to ● Immediately after the addition of WFI, shake the vial vigorously for 60 seconds to completely possible after discovery of overdose. Other appropriate symptomatic measures should be to prior chemotherapy. 100 mg/m2 of polysorbate based Docetaxel and grade 4 neutropenia (<500 cells/mm3) disperse the material. Keep the vial aside for 15 min to complete the constitution. Inspect taken, as needed. visually for any particulate matter and shake until complete desperation. occurs in 85% of patients given 100 mg/m2 and 75% of patients given 60 mg/m2. Patients were randomized to receive either test (n=49) or reference (n=23) at a ratio of 2:1, Frequent monitoring of blood counts is, therefore, essential so that dose can be adjusted stratified by Eastern Cooperative Oncology Group (ECOG) performance status (0, or 1-2). STORAGE 2 Final Dilution for Infusion when treated with docetaxel lipid suspension. Docetaxel should not be administered to Each drug was administered by IV infusion over 1 hour at a dose of 75 mg/m . Patients 3 Store at 2-8°C. Do not freeze. Protect from light. Keep out of reach of children. ● Aseptically withdraw the required amount of initial diluted docetaxel lipid suspension (2 mg patients with neutrophils <1500 cells/mm . were treated every 21 days (a treatment cycle) in the absence of disease progression or Fluid Retention docetaxel / ml) with a calibrated syringe and inject into a 250 /500 ml infusion bag or bottle PACKAGING INFORMATION unacceptable toxicity. The primary objective of this study was to compare the overall Severe fluid retention has been reported following polysorbate 80 based Docetaxel response rate (complete or partial response) and to evaluate the efficacy of test versus of 5% Dextrose Injection IP or 0.9% sodium chloride Injection IP solution to produce a final Available as 20 mg and 80 mg in single vials individually packed in a carton. concentration of 0.3 to 0.74 mg/ml. therapy in earlier studies. Even though this was not observed in greater number of reference products in patients. The secondary objective was to evaluate the safety of the Patients treated with docetaxel lipid suspension without premedication but such condition Manufactured by: patients who are exposed to the test or reference products. A point estimate and a ● Mix the infusion thoroughly by manual rotation. should be monitored by medical Investigators. two-sided 95% confidence interval were computed for the primary efficacy endpoint, INTAS PHARMACEUTICALS LTD. response rates (CR+PR) from best overall response of the two treatment groups and their ● As with all parenteral products, docetaxel lipid suspension should be inspected visually In clinical trial, commonly observed adverse reactions with docetaxel lipid suspension are Matoda-382 210, Dist.: Ahmedabad. INDIA difference. A point estimate and a two-sided 95% confidence interval (CI) were computed as following: for the secondary efficacy endpoint, disease control rate (CR+PR+SD) from best overall for particulate matter or discoloration prior to administration whenever the solution and 10 0328 1 676522 container permitted. Blood and lymphatic system disorders: anaemia, febrile neutropenia, leucopenia and response of the two treatment groups and their difference. neutropenia INP010

Note: PIL should be in flat form

File Name : 10 0328 1 676522-DOCEAQUALIP-PIL Size : 160 x 270 (mm) Back Side Colour : Pantone Black Date : 06/07/17, 20/07/17 For the use of an Oncologist or a Hospital or a Laboratory disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have patients who received Paclitaxel lipid suspension at 80 mg/m2. However, none of the patients ing experience, diffuse edema, thickening, and sclerosing of the skin have included any anthracycline unless clinically contraindicated. receiving 175 mg/m2 of Paclitaxel lipid suspension or paclitaxel every 3 weeks experienced any been reported following paclitaxel administration. paclitaxel has been • For the adjuvant treatment of node-positive breast cancer administered sequentially to peripheral neuropathy. reported to exacerbate signs and symptoms of scleroderma. PACLIAQUALIP standard doxorubicin-containing combination chemotherapy. Hepatic Reports of asthenia and malaise have been received as part of the continuing (PACLITAXEL LIPID SUSPENSION FOR INJECTION) • For the treatment of advanced carcinoma of the ovary. As first-line therapy, it is indicated in There is limited evidence that the myelotoxicity of paclitaxel may be exacerbated in patients with surveillance of paclitaxel safety. combination with cisplatin. serum total bilirubin >2 times ULN. Extreme caution should be exercised when administering Conjunctivitis, increased lacrimation, anorexia, confusional state, photopsia, COMPOSITION • For the first-line treatment of non-small cell lung cancer in patients who are not candidates for paclitaxel to such patients. visual floaters, vertigo, and increase in blood creatinine have been reported. PACLIAQUALIP 30 potentially curative surgery and/or radiation therapy, in combination with cisplatin. Injection Site Reaction In the clinical trial, the incidence of pyrexia in Paclitaxel lipid suspension 175 PACLITAXEL LIPID SUSPENSION FOR INJECTION 30 mg/vial • For the second-line treatment of AIDS-related Kaposi’s sarcoma. Injection site reactions, including reactions secondary to extravasation may occur in patients mg/m2 Q3W, 80 mg/m2 QW and paclitaxel 175 mg/m2 Q3W arms was 14.58%, Each vial contains: Preparation Guide for Use of Paclitaxel Lipid Suspension being treated with Paclitaxel lipid suspension. A specific treatment for extravasation reactions is 13.33% and 7.41% respectively. Paclitaxel IP...... 30 mg Paclitaxel lipid suspension is supplied as a sterile lyophilized powder for reconstitution before use. unknown at this time. Given the possibility of extravasation, it is advisable to closely monitor the The incidence of urinary tract infections in Paclitaxel lipid suspension 175 Excipients: ...... Q.S. AVOID ERRORS, READ ENTIRE PREPARATION INSTRUCTIONS PRIOR TO RECONSTITUTION. infusion site for possible infiltration during drug administration. mg/m2 Q3W,80 mg/m2 QW and paclitaxel 175 mg/m2 Q3W arms was 25%, Aseptic technique must be strictly observed in all handling of Paclitaxel lipid suspension. Carcinogenesis, Mutagenesis, Impairment of Fertility 17.78% and 11.11% respectively. Description Slowly inject 24 mL of Sterile Water for Injection, IP, over a period of 1 - 2 minute to each Paclitaxel The carcinogenic potential of paclitaxel lipid suspension has not been studied. Accidental Exposure: Paclitaxel is a natural product with antitumor activity. It is obtained via a lipid suspension vial to yield a preparation containing 1 mg/mL of Paclitaxel. It has been reported that paclitaxel is clastogenic in vitro (chromosome aberrations in human Upon inhalation, dyspnea, chest pain, burning eyes, sore throat, and nausea semi-synthetic process from Taxus baccata. The chemical name for paclitaxel Once the injection is complete, allow the vial to sit for a minimum of 15 minutes to ensure proper lymphocytes) and in vivo (micronucleus test in mice). Paclitaxel was not mutagenic in the Ames have been reported. Following topical exposure, events have included is 5β,20-Epoxy-1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-one 4,10-diace- wetting of the lyophilized cake/powder. test or the CHO/HGPRT gene mutation assay. tingling, burning, and redness. tate 2-benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine. Paclitaxel has the following Gently shake and/or swirl the vial slowly for at least 2 minutes until complete dispersion of any Administration of paclitaxel prior to and during mating produced impairment of fertility in male and In the clinical trial, commonly observed adverse reactions with paclitaxel lipid suspension were as structural formula: cake/powder occurs. Avoid generation of foam, if any. female rats at doses equal to or greater than 1 mg/kg/day (about 0.04 the daily maximum following: Paclitaxel lipid suspension forms a whitish-translucent suspension. Visually inspect the vial for recommended human dose on a mg/m² basis). At this dose, to or greater than 1 mg/kg/day (about Blood and lymphatic system disorders: anemia, leucopenia and neutropenia particulate matter. Do not use material if there is any evidence of precipitation or foreign matter. 0.04 the daily maximum recommended human dose on a mg/m² basis). At this dose, paclitaxel Gastrointestinal disorders: diarrhea, nausea and vomiting Withdraw the appropriate dose of Paclitaxel from the Paclitaxel lipid suspension vial into sterile caused reduced fertility and reproductive indices, and increased embryo- and fetotoxicity. General disorders: urinary tract infections, pyrexia and chills syringe using an 18-gauge needle. Remove the needle from syringe filled with Paclitaxel lipid Adverse effects Musculoskeletal and connective tissue disorders: back pain, peripheral neuropathy suspension and replace with the 5-micron filter needle supplied with each vial. The most serious adverse reactions from Paclitaxel lipid suspension were alopecia, neutropenia, Respiratory, thoracic and mediastinal disorders: cough Inject the syringe contents through the 5-micron filter needle, into the appropriate amount of 5% back pain, anemia and urinary tract infections. Skin and subcutaneous tissue disorders: alopecia Dextrose Injection so to achieve a final concentration between 0.3 mg/mL and 0.5 mg/mL prior to Hematologic Drug Interactions Paclitaxel is a white to off-white crystalline powder with the empirical formula administration. Neutropenia, the most important hematologic toxicity of paclitaxel, is dose and schedule The metabolism of paclitaxel is catalyzed by cytochrome P450 isoenzymes CYP2C8 and

C47H51NO14 and a molecular weight of 853.9. It is highly lipophilic, insoluble in water, Mix the infusion thoroughly by manual rotation. dependent and is generally rapidly reversible. CYP3A4. Caution should be exercised when administering paclitaxel concomitantly with known and melts at around 216–217°C. As with all parenteral products, Paclitaxel Lipid Suspension should be inspected visually for In the clinical trial, the incidence of neutropenia with Paclitaxel lipid suspension 175 mg/m2 substrates or inhibitors of the cytochrome P450 isoenzymes CTP2C8 and CYP3A4. Caution The Paclitaxel Lipid Suspension formulation is a sterile lyophilized powder containing Soy particulate matter or discoloration prior to administration. Q3W,80 mg/m2 QW and paclitaxel 175 mg/m2 Q3W arms was 31.25%, 44.44% and 7.41% should be exercised when paclitaxel is concomitantly administered with known substrates (e.g., phosphatidylcholine and Sodium Cholesteryl Sulphate with 30 mg Paclitaxel per vial. Each 30 mg THE USE OF AN IN-LINE FILTER IS NOT RECOMMENDED DURING INFUSION. respectively. The incidence of anemia with Paclitaxel lipid suspension 175 mg/m2 Q3W,80 mg/m2 midazolam, buspirone, felodipine, lovastatin, eletriptan, sildenafil, simvastatin, and triazolam), vial is first reconstituted by adding 24 ml of sterile water to yield 1 mg/ml of Paclitaxel lipid Any unused material must be discarded. QW and paclitaxel 175 mg/m2 Q3W arms was 16.67%, 44.44% and 18.52% respectively. The inhibitors (e.g., atazanavir, clarithromycin, indinavir, etaconazole, ketoconazole, nefazodone, suspension. The reconstituted suspension can further be diluted with 5% dextrose Injection IP Use within 8 hours of reconstitution/dilution. incidence of thrombocytopenia in Paclitaxel lipid suspension 175 mg/m2 Q3W and 80 mg/m2 QW nelfinavir, ritonavir, saquinavir, and telithromycin), and inducers (e.g., rifampin and carbamaze- prior to administration. Dosage and Administration arms was 10.42%, and 2.22% respectively. pine) of CYP3A4. Clinical Pharmacology Dosage and procedure of administration can vary based on the cancer types as following. Hypersensitivity Reactions (HSRs): Caution should also be exercised when paclitaxel is concomitantly administered with known Mechanism of Action 1. After failure of initial chemotherapy for metastatic disease or relapse within 6 months of No routine premedication prior to Paclitaxel lipid suspension administration is necessary for substrates (e.g., repaglinide and rosiglitazone), inhibitors (e.g., gemfibrozil), and inducers (e.g., Paclitaxel is a novel antimicrotubule agent that promotes the assembly of microtubules from adjuvant chemotherapy, paclitaxel at a dose of 175 mg/m2 administered intravenously over 3 prevention of Infusion related reaction (IRRs). Clinical signs and symptoms indicative of an IRR rifampin) of CYP2C8. tubulin dimers and stabilizes microtubules by preventing depolymerization. This stability results in hours every 3 weeks has been shown to be effective. may include flushing, tachycardia, hypertension or hypotension, rash or hives, fever with chills, Potential interactions between paclitaxel, a substrate of CYP3A4, and protease inhibitors the inhibition of the normal dynamic reorganization of the microtubule network that is essential for vital 2. For the adjuvant treatment of node-positive breast cancer, the recommended regimen is rigors, hypoxia or dyspnea, as well as back, flank, chest, or abdominal pain. These reactions may (ritonavir, saquinavir, indinavir, and nelfinavir), which are substrates and/or inhibitors of CYP3A4, interphase and mitotic cellular functions. In addition, paclitaxel induces abnormal arrays or “bundles” paclitaxel, at a dose of 175 mg/m2 intravenously over 3 hours every 3 weeks for 4 courses be transient. When such signs and symptoms are observed, the infusion should be interrupted have not been evaluated in clinical trials. of microtubules throughout the and multiple asters of microtubules during mitosis. administered sequentially to doxorubicin-containing combination chemotherapy. The clinical and supportive care administrated immediately according to the institution’s protocol for treating Plasma levels of doxorubicin (and its active metabolite doxorubicinol) may be increased when Pharmacokinetics trial used 4 courses of doxorubicin and cyclophosphamide. such events. paclitaxel and doxorubicin are used in combination. An open label, balanced, randomized, 2-period, 2-treatment, 2-sequence, and 2-way crossover 3. For previously untreated patients with carcinoma of the ovary, one of the following None of the patients receiving 175 mg/m2 of Paclitaxel lipid suspension every 3 weeks Use in Specific Populations study was conducted to evaluate safety and pharmacokinetic comparison of intravenous infusion recommended regimens may be given every 3 weeks. experienced any hypersensitivity reactions. Pregnancy of Paclitaxel lipid suspension and Taxol in patients with metastatic breast cancer. a. Paclitaxel administered intravenously over 3 hours at a dose of 175 mg/m2 followed by Cardiovascular: Paclitaxel can cause fetal harm when administered to a pregnant woman. Paclitaxel lipid 16 patients were dosed at 175 mg/m2 intravenously, over 3 hours once every three weeks. In cisplatin at a dose of 75 mg/m2; or Treatment with Paclitaxel lipid suspension may result in significant cardiovascular events possibly suspension has not been tested in pregnant patients. It has been reported that administration of Period I, patients were dosed with test or reference product on the first day of the chemotherapy b. Paclitaxel administered intravenously over 24 hours at a dose of 135 mg/m2 followed by related to single-agent paclitaxel may occur in approximately 1% of all patients as was observed paclitaxel during the period of organogenesis to rabbits at doses of 3 mg/kg/day (about 0.2 the cycle (day 1) of the study as per the randomization schedule. In Period II, patients were crossed cisplatin at a dose of 75 mg/m2 by Paclitaxel injection. These events may include syncope, rhythm abnormalities, hypertension, daily maximum recommended human dose on a mg/m² basis) caused embryo- and fetotoxicity, over to either test or reference product (patients on test product to be crossed over to reference 4. For patients with non-small cell lung carcinoma, the recommended regimen, given every 3 and venous thrombosis. as indicated by intrauterine mortality, increased resorptions, and increased fetal deaths. Maternal product and vice-versa) on the first day of the next chemotherapy cycle (day 22) as per weeks, is paclitaxel administered intravenously over 24 hours at a dose of 135 mg/m2 followed It has been reported that in patients treated with Paclitaxel, the Electrocardiogram (ECG) toxicity was also observed at this dose. No teratogenic effects were observed at 1 mg/kg/day randomization schedule. The pharmacokinetics evaluations were done by collecting whole blood by cisplatin, 75 mg/m2. abnormalities were common among patients at baseline. ECG abnormalities did not usually result (about 1/15 the daily maximum recommended human dose on a mg/m² basis); teratogenic samples from patients (both test and reference product) prior to each dose and over a period of 5. For patients with AIDS-related Kaposi’s sarcoma, paclitaxel administered at a dose of 135 in symptoms, were not dose-limiting, and required no intervention. potential could not be assessed at higher doses due to extensive fetal mortality. 2 2 51-hour after each dose. The log transformed Test/Reference ratios for Cmax and AUC0-t were mg/m given intravenously over 3 hours every 3 weeks or at a dose of 100 mg/m given Cases of myocardial infarction have been reported with paclitaxel. Congestive heart failure, There are no adequate and well-controlled studies in pregnant women. If paclitaxel is used during about 29.5% and 44.8% respectively. The safety profile of paclitaxel lipid suspension was similar intravenously over 3 hours every 2 weeks is recommended (dose intensity 45 to 50 including cardiac dysfunction and reduction of left ventricular ejection fraction or ventricular pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be to that of Taxol. mg/m2/week). failure, has been reported typically in patients who have received other chemotherapy, notably apprised of the potential hazard to the fetus. Women of child- bearing potential should be advised Clinical Studies Contraindications anthracyclines. to avoid becoming pregnant. Locally Advanced or Metastatic Breast Cancer Paclitaxel lipid suspension is contraindicated in patients who have a history of hypersensitivity Atrial fibrillation and supraventricular tachycardia have been reported. Nursing Mothers An open label, randomized, multiple dose, parallel study was conducted in locally advanced or reactions to paclitaxel. Respiratory It is not known whether the drug is excreted in human milk. It has been reported that following metastatic breast cancer patients after failure of prior chemotherapy. Paclitaxel lipid suspension should not be used in patients with solid tumors who have baseline Interstitial pneumonia, lung fibrosis, and pulmonary embolism have been reported with paclitaxel. intravenous administration of carbon 14-labeled paclitaxel to rats on days 9 to 10 postpartum, Females, ≥ 18 years and ≤ 65 years of age, with histopathologically/ cytologically confirmed neutrophil counts of <1,500 cells/mm³ or in patients with AIDS-related Kaposi’s sarcoma with Radiation pneumonitis may occur in patients receiving concurrent radiotherapy. Pleural effusion concentrations of radioactivity in milk were higher than in plasma and declined in parallel with the breast cancer, having locally advanced or metastatic breast cancer after failure of prior baseline neutrophil counts of <1,000 cells/mm³. and respiratory distress have been reported. plasma concentrations. Because many drugs are excreted in human milk and because of the chemotherapy, having Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2, Warnings and Precautions In the clinical trial, the incidence of cough in Paclitaxel lipid suspension 175 mg/m2 Q3W,80 mg/m2 potential for serious adverse reactions in nursing infants, it is recommended that nursing be having adequate bone marrow, renal and hepatic function, having at least one measurable lesion Patients who have severe hypersensitivity reactions to paclitaxel should not be rechallenged with QW and paclitaxel 175 mg/m2 Q3W arms was 4.17%, 22.22% and 7.41% respectively. discontinued when receiving paclitaxel therapy. as per the Response Evaluation Criteria In Solid Tumors 1.1 (RECIST 1.1), having life expectancy the drug. Anaphylaxis and severe hypersensitivity reactions characterized by dyspnea and Neurologic Pediatric Use of at least 6 months were randomized to receive either Paclitaxel lipid suspension or Taxol®. hypotension requiring treatment, angioedema, and generalized urticaria have occurred in 2 to 4% In clinical trial of Paclitaxel lipid suspension, peripheral neuropathy was reported in 3 patients who The safety and effectiveness of paclitaxel in pediatric patients have not been established. 120 patients with locally advanced or metastatic breast cancer, after failure of prior chemotherapy, of patients receiving paclitaxel in clinical trials. were receiving Paclitaxel lipid suspension at 80 mg/m2. However, none of the patients receiving Geriatric Use were randomized in the ratio 2:2:1 (PLS every three weeks: PLS weekly: Taxol® every three Bone marrow suppression (primarily neutropenia) is dose-dependent and is the dose-limiting 175 mg/m2 of Paclitaxel lipid suspension every 3 weeks experienced any peripheral neuropathy. No specific studies with Paclitaxel lipid suspension was conducted. In most studies reported, weeks) and enrolled into the study. toxicity. Paclitaxel should not be administered to patients with baseline neutrophil counts of less These patients were also not pre-medicated with corticosteroids. severe myelosuppression was more frequent in elderly patients; in some studies, severe Patients were administered Paclitaxel lipid suspension (n= 48) or Taxol® (n= 27) at 175 mg/m2 as than 1,500 cells/mm³ (<1,000 cells/mm³ for patients with KS). Frequent monitoring of blood counts Hepatic neuropathy was more common in elderly patients. Estimates of efficacy appeared similar in per randomization schedule, by IV infusion for 3 hours in each cycle of 21 days in Arm A and Arm should be conducted during paclitaxel treatment. Patients should not be retreated with No relationship was observed between liver function abnormalities and either dose or schedule of elderly patients and in younger patients; however, comparative efficacy cannot be determined C respectively. Each patient received maximum of 6 cycles of Paclitaxel lipid suspension or subsequent cycles of paclitaxel until neutrophils recover to a level >1,500 cells/mm³ (>1,000 paclitaxel administration. Prolonged exposure to paclitaxel was not associated with cumulative with confidence due to the small number of elderly patients studied. Taxol®. In Arm B, patients were administered weekly with Paclitaxel lipid suspension at the dose cells/mm³ for patients with KS) and platelets recover to a level >100,000 cells/mm³. hepatic toxicity. Non Clinical Toxicological Studies of 80 mg/m2 (n= 45) for 18 weeks. Patients in the Paclitaxel lipid suspension groups (Arm A and Severe conduction abnormalities have been reported in <1% of patients during paclitaxel therapy Hepatic necrosis and hepatic encephalopathy leading to death have been reported. A sub chronic 28 days’ intravenous toxicity study was conducted by five consecutive days’ Arm B) were not premedicated whereas patients treated with Taxol® were pre-medicated as per and in some cases requiring pacemaker placement. If patients develop significant conduction Renal administration of paclitaxel lipid suspension in Swiss Albino mice at 5 mg/kg, 10 mg/kg or 15 the prescribing information. abnormalities during paclitaxel infusion, appropriate therapy should be administered and Patients with gynecological cancers treated with paclitaxel and cisplatin may increase the risk of mg/kg. The results showed in no hematological abnormalities related to the treatment in all Each drug, Paclitaxel lipid suspension (Arm A, 175 mg/m2 / Arm B, 80 mg/m2) or Taxol® (Arm C, continuous cardiac monitoring should be performed during subsequent therapy with paclitaxel. renal failure with the combination therapy of paclitaxel and cisplatin in gynecological cancers as groups. 175 mg/m2) was administered by IV infusion over 3 hours. Disease status and tumor response Hematology compared to cisplatin alone. Biochemical analysis revealed no abnormalities at 5 and 10 mg/kg dose but elevated levels of (CT Scan/MRI) was assessed after every 2 cycles of treatment using RECIST 1.1 guidelines Paclitaxel lipid suspension therapy should not be administered to patients with baseline neutrophil Gastrointestinal (GI) Alanine Aminotransferase and Alkaline Phosphatase was observed at the highest dose (15 through cycle 6 (including confirmation of response if required). Independent evaluation (blinded counts of less than 1,500 cells/mm³. In order to monitor the occurrence of myelotoxicity, it is Intestinal obstruction, intestinal perforation, pancreatitis, ischemic colitis, dehydration, mg/kg). Gross and histopathological changes were observed in male and female animals at 10 reading) of the images acquired in clinical trial was done by Central Imaging Facility. recommended that frequent peripheral blood cell counts be performed on all patients receiving esophagitis, constipation, and ascites have been reported with paclitaxel. Neutropenic and 15 mg/kg. Mortalities (1/6 males and 1/6 females) were noted in animals treated with highest The primary efficacy evaluation was based on the overall response rate (CR + PR), defined as the Paclitaxel lipid suspension. enterocolitis (typhlitis), despite the co-administration of filgrastim, was observed in patients dose (15 mg/kg) of the paclitaxel lipid suspension. The results were consistent with Taxol where proportion of patients whose best overall response was complete response (CR) or partial As reported earlier, patients should not be retreated with subsequent cycles of Paclitaxel lipid treated with paclitaxel alone and in combination with other chemotherapeutic agents. the maximum tolerated dose of Taxol in mice was determined to be over 12.5 mg/kg. response (PR) after receiving study treatment with Paclitaxel lipid suspension or Taxol®. The suspension until neutrophils recover to a level >1,500 cells/mm³ and platelets recover to a level In the clinical trial, the incidence of diarrhea in Paclitaxel lipid suspension 175 mg/m2 Q3W and 80 Overdosage secondary efficacy endpoint was based on the disease control rate (DCR=CR + PR + SD), >100,000 cells/mm³. In the case of severe neutropenia (<500 cells/mm³ for 7 days or more) during mg/m2 QW and paclitaxel 175 mg/m2 Q3W arms was 2.08%, 8.88% and 3.7% respectively. The There is no known antidote for paclitaxel overdosage. The primary anticipated complications of defined as the proportion of patients whose best overall response was complete response (CR) a course of therapy, a 20% reduction in dose for subsequent courses of Paclitaxel lipid incidence of nausea in Paclitaxel lipid suspension 175 mg/m2 Q3W, 80 mg/m2 QW and paclitaxel overdosage would consist of bone marrow suppression, peripheral neurotoxicity, and mucositis. or partial response (PR) or stable disease (SD). suspension therapy is recommended. 175 mg/m2 Q3W arms was 4.16%, 6.66% and 3.7% respectively. The incidence of vomiting in Storage A point estimate and a two-sided 95% confidence interval (CI) were computed for the secondary In patients with advanced HIV disease and poor-risk AIDS-related Kaposi’s sarcoma, the Paclitaxel lipid suspension 175 mg/m2 Q3W and 80 mg/m2 QW arms was 6.25%, and 11.11% Store at 2 -8°C. Do not freeze. Protect from light. Keep out of reach of children. efficacy endpoint, disease control rate (CR+PR+SD) from best overall response of the two recommended dose of Paclitaxel lipid suspension for this disease, can be initiated and repeated respectively. Packaging information treatment groups and their difference. if the neutrophil count is at least 1,000 cells/mm³. Injection Site Reaction Available as 30 mg in single vial individually packed in a carton. The overall response rate (CR + PR) was 36.4% (95% CI, 22.1- 50.6%) for Paclitaxel lipid Hypersensitivity Reactions Injection site reactions, including reactions secondary to extravasation, reported with paclitaxel Include 5-micron filter needle and package insert. suspension treatment- [Arm A (175 mg/m2)] administered every 3 weeks, 46.5% (95% CI, 31.6- No routine premedication prior to Paclitaxel lipid suspension administration is necessary for are usually mild and consist of erythema, tenderness, skin discoloration, or swelling at the MANUFACTURED BY: 61.4%) for Paclitaxel lipid suspension treatment- [Arm B (80 mg/m2)] administered every week prevention of Infusion related reaction (IRRs). However, patients with a history of severe injection site. These reactions have been observed more frequently with the 24-hour infusion than and 20.8% (95% CI, 4.6- 37.1%) for Taxol® treatment- [Arm C (175 mg/m2)] administered every 3 hypersensitivity reactions to paclitaxel should not be treated with paclitaxel lipid suspension. with the 3-hour infusion. INTAS PHARMACEUTICALS LTD. weeks. The disease control rates were 86.4%, 88.4% and 83.3% for Arm A, Arm B and Arm C Minor symptoms such as flushing, skin reactions, dyspnea, hypotension, or tachycardia do not More severe events such as phlebitis, cellulitis, induration, skin exfoliation, necrosis, and fibrosis Plot No. 5 to 14, Pharmez-382 213, respectively. require interruption of therapy. However, severe reactions, such as hypotension requiring have been reported with paclitaxel. In some cases, the onset of the injection site reaction either Near Village Matoda, Ta: Sanand, Dist: Ahmedabad. A total of 450 adverse events (AEs) reported in 97 patients during the course of the trial. 157 AEs treatment, dyspnea requiring bronchodilators, angioedema, or generalized urticaria require occurred during a prolonged infusion or was delayed by a week to 10 days. occurred to patients under Paclitaxel lipid suspension Arm A (n=48), 239 AEs occurred to patients immediate discontinuation of paclitaxel and aggressive symptomatic therapy. Patients who have In the clinical trial, the incidence of chills in Paclitaxel lipid suspension 175 mg/m2 Q3W, 80 mg/m2 51 4024 0 722423 under Paclitaxel lipid suspension Arm B (n=45) and 54 AEs occurred to patients under Paclitaxel developed severe hypersensitivity reactions should not be rechallenged with paclitaxel. QW and paclitaxel 175 mg/m2 Q3W arms was 52.08%, 40% and 7.41% respectively. Arm C (n=27). The Paclitaxel lipid suspension treated patients were not given any pre-medication Cardiovascular Other Clinical Events including corticosteroids. The AEs related to Paclitaxel lipid suspension Arm A, Paclitaxel lipid Hypotension, bradycardia, and hypertension have been observed during administration of In clinical trials of paclitaxel, alopecia was observed in almost all (87%) of the patients. Transient suspension Arm B and Taxol® Arm C were 68.75%, 68.89% and 48.15% respectively. In both paclitaxel, but generally do not require treatment. Occasionally paclitaxel infusions must be skin changes due to paclitaxel related hypersensitivity reactions have been observed, but no Paclitaxel lipid suspension and Taxol® treatment groups one or more Grade 3 or 4 treatment-relat- interrupted or discontinued because of initial or recurrent hypertension. Frequent vital sign other skin toxicities were significantly associated with paclitaxel administration. ed adverse events were observed. The percentage of patients reporting serious Grade 4 AEs in monitoring, particularly during the first hour of paclitaxel infusion, is recommended. Continuous In the clinical trial, the incidence of alopecia in Paclitaxel lipid suspension 175 mg/m2 Q3W,80 Arm A, Arm B and Arm C were 6.25%, 11.11% and 7.41% respectively. cardiac monitoring is not required except for patients with serious conduction abnormalities. Use mg/m2 QW and paclitaxel 175 mg/m2 Q3W arms was 29.17%, 33.33% and 33.33% respectively. Overall, the investigational drugs were found to be well tolerated. Majority of the post-dose AEs of paclitaxel lipid suspension in combination with doxorubicin for treatment of metastatic breast In clinical trials of paclitaxel, edema was reported in 21% of all patients (17% of those without resolved without any sequelae despite the fact patients were not pre-medicated with cancer, monitoring of cardiac function is recommended. baseline edema); only 1% had severe edema and none of these patients required treatment corticosteroids or anti-allergic treatment in paclitaxel lipid suspension treatment groups. Nervous System discontinuation. Edema was most commonly focal and disease-related. Edema was observed in Indications Peripheral neuropathy is frequent with paclitaxel, the development of severe symptomatology is 5% of all courses for patients with normal baseline and did not increase with time on study. Paclitaxel lipid suspension for injection is indicated for: unusual and requires a dose reduction of 20% for all subsequent courses of treatment cycle. Skin abnormalities related to radiation recall as well as maculopapular rash, pruritus, • For the treatment of breast cancer after failure of combination chemotherapy for metastatic In the clinical trial of Paclitaxel lipid suspension, peripheral neuropathy was reported in 3 (6.66%) Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported. In postmarket-

Front Side

File Name : 722423 - PacliAqualip 30 30 mg (Ind) PIL Size : 160 x 270 (mm) Front Side Colour : Pantone Black Date : 19*11*19, 23*12*19 For the use of an Oncologist or a Hospital or a Laboratory disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have patients who received Paclitaxel lipid suspension at 80 mg/m2. However, none of the patients ing experience, diffuse edema, thickening, and sclerosing of the skin have included any anthracycline unless clinically contraindicated. receiving 175 mg/m2 of Paclitaxel lipid suspension or paclitaxel every 3 weeks experienced any been reported following paclitaxel administration. paclitaxel has been • For the adjuvant treatment of node-positive breast cancer administered sequentially to peripheral neuropathy. reported to exacerbate signs and symptoms of scleroderma. PACLIAQUALIP standard doxorubicin-containing combination chemotherapy. Hepatic Reports of asthenia and malaise have been received as part of the continuing (PACLITAXEL LIPID SUSPENSION FOR INJECTION) • For the treatment of advanced carcinoma of the ovary. As first-line therapy, it is indicated in There is limited evidence that the myelotoxicity of paclitaxel may be exacerbated in patients with surveillance of paclitaxel safety. combination with cisplatin. serum total bilirubin >2 times ULN. Extreme caution should be exercised when administering Conjunctivitis, increased lacrimation, anorexia, confusional state, photopsia, COMPOSITION • For the first-line treatment of non-small cell lung cancer in patients who are not candidates for paclitaxel to such patients. visual floaters, vertigo, and increase in blood creatinine have been reported. PACLIAQUALIP 30 potentially curative surgery and/or radiation therapy, in combination with cisplatin. Injection Site Reaction In the clinical trial, the incidence of pyrexia in Paclitaxel lipid suspension 175 PACLITAXEL LIPID SUSPENSION FOR INJECTION 30 mg/vial • For the second-line treatment of AIDS-related Kaposi’s sarcoma. Injection site reactions, including reactions secondary to extravasation may occur in patients mg/m2 Q3W, 80 mg/m2 QW and paclitaxel 175 mg/m2 Q3W arms was 14.58%, Each vial contains: Preparation Guide for Use of Paclitaxel Lipid Suspension being treated with Paclitaxel lipid suspension. A specific treatment for extravasation reactions is 13.33% and 7.41% respectively. Paclitaxel IP...... 30 mg Paclitaxel lipid suspension is supplied as a sterile lyophilized powder for reconstitution before use. unknown at this time. Given the possibility of extravasation, it is advisable to closely monitor the The incidence of urinary tract infections in Paclitaxel lipid suspension 175 Excipients: ...... Q.S. AVOID ERRORS, READ ENTIRE PREPARATION INSTRUCTIONS PRIOR TO RECONSTITUTION. infusion site for possible infiltration during drug administration. mg/m2 Q3W,80 mg/m2 QW and paclitaxel 175 mg/m2 Q3W arms was 25%, Aseptic technique must be strictly observed in all handling of Paclitaxel lipid suspension. Carcinogenesis, Mutagenesis, Impairment of Fertility 17.78% and 11.11% respectively. Description Slowly inject 24 mL of Sterile Water for Injection, IP, over a period of 1 - 2 minute to each Paclitaxel The carcinogenic potential of paclitaxel lipid suspension has not been studied. Accidental Exposure: Paclitaxel is a natural product with antitumor activity. It is obtained via a lipid suspension vial to yield a preparation containing 1 mg/mL of Paclitaxel. It has been reported that paclitaxel is clastogenic in vitro (chromosome aberrations in human Upon inhalation, dyspnea, chest pain, burning eyes, sore throat, and nausea semi-synthetic process from Taxus baccata. The chemical name for paclitaxel Once the injection is complete, allow the vial to sit for a minimum of 15 minutes to ensure proper lymphocytes) and in vivo (micronucleus test in mice). Paclitaxel was not mutagenic in the Ames have been reported. Following topical exposure, events have included is 5β,20-Epoxy-1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-one 4,10-diace- wetting of the lyophilized cake/powder. test or the CHO/HGPRT gene mutation assay. tingling, burning, and redness. tate 2-benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine. Paclitaxel has the following Gently shake and/or swirl the vial slowly for at least 2 minutes until complete dispersion of any Administration of paclitaxel prior to and during mating produced impairment of fertility in male and In the clinical trial, commonly observed adverse reactions with paclitaxel lipid suspension were as structural formula: cake/powder occurs. Avoid generation of foam, if any. female rats at doses equal to or greater than 1 mg/kg/day (about 0.04 the daily maximum following: Paclitaxel lipid suspension forms a whitish-translucent suspension. Visually inspect the vial for recommended human dose on a mg/m² basis). At this dose, to or greater than 1 mg/kg/day (about Blood and lymphatic system disorders: anemia, leucopenia and neutropenia particulate matter. Do not use material if there is any evidence of precipitation or foreign matter. 0.04 the daily maximum recommended human dose on a mg/m² basis). At this dose, paclitaxel Gastrointestinal disorders: diarrhea, nausea and vomiting Withdraw the appropriate dose of Paclitaxel from the Paclitaxel lipid suspension vial into sterile caused reduced fertility and reproductive indices, and increased embryo- and fetotoxicity. General disorders: urinary tract infections, pyrexia and chills syringe using an 18-gauge needle. Remove the needle from syringe filled with Paclitaxel lipid Adverse effects Musculoskeletal and connective tissue disorders: back pain, peripheral neuropathy suspension and replace with the 5-micron filter needle supplied with each vial. The most serious adverse reactions from Paclitaxel lipid suspension were alopecia, neutropenia, Respiratory, thoracic and mediastinal disorders: cough Inject the syringe contents through the 5-micron filter needle, into the appropriate amount of 5% back pain, anemia and urinary tract infections. Skin and subcutaneous tissue disorders: alopecia Dextrose Injection so to achieve a final concentration between 0.3 mg/mL and 0.5 mg/mL prior to Hematologic Drug Interactions Paclitaxel is a white to off-white crystalline powder with the empirical formula administration. Neutropenia, the most important hematologic toxicity of paclitaxel, is dose and schedule The metabolism of paclitaxel is catalyzed by cytochrome P450 isoenzymes CYP2C8 and

C47H51NO14 and a molecular weight of 853.9. It is highly lipophilic, insoluble in water, Mix the infusion thoroughly by manual rotation. dependent and is generally rapidly reversible. CYP3A4. Caution should be exercised when administering paclitaxel concomitantly with known and melts at around 216–217°C. As with all parenteral products, Paclitaxel Lipid Suspension should be inspected visually for In the clinical trial, the incidence of neutropenia with Paclitaxel lipid suspension 175 mg/m2 substrates or inhibitors of the cytochrome P450 isoenzymes CTP2C8 and CYP3A4. Caution The Paclitaxel Lipid Suspension formulation is a sterile lyophilized powder containing Soy particulate matter or discoloration prior to administration. Q3W,80 mg/m2 QW and paclitaxel 175 mg/m2 Q3W arms was 31.25%, 44.44% and 7.41% should be exercised when paclitaxel is concomitantly administered with known substrates (e.g., phosphatidylcholine and Sodium Cholesteryl Sulphate with 30 mg Paclitaxel per vial. Each 30 mg THE USE OF AN IN-LINE FILTER IS NOT RECOMMENDED DURING INFUSION. respectively. The incidence of anemia with Paclitaxel lipid suspension 175 mg/m2 Q3W,80 mg/m2 midazolam, buspirone, felodipine, lovastatin, eletriptan, sildenafil, simvastatin, and triazolam), vial is first reconstituted by adding 24 ml of sterile water to yield 1 mg/ml of Paclitaxel lipid Any unused material must be discarded. QW and paclitaxel 175 mg/m2 Q3W arms was 16.67%, 44.44% and 18.52% respectively. The inhibitors (e.g., atazanavir, clarithromycin, indinavir, etaconazole, ketoconazole, nefazodone, suspension. The reconstituted suspension can further be diluted with 5% dextrose Injection IP Use within 8 hours of reconstitution/dilution. incidence of thrombocytopenia in Paclitaxel lipid suspension 175 mg/m2 Q3W and 80 mg/m2 QW nelfinavir, ritonavir, saquinavir, and telithromycin), and inducers (e.g., rifampin and carbamaze- prior to administration. Dosage and Administration arms was 10.42%, and 2.22% respectively. pine) of CYP3A4. Clinical Pharmacology Dosage and procedure of administration can vary based on the cancer types as following. Hypersensitivity Reactions (HSRs): Caution should also be exercised when paclitaxel is concomitantly administered with known Mechanism of Action 1. After failure of initial chemotherapy for metastatic disease or relapse within 6 months of No routine premedication prior to Paclitaxel lipid suspension administration is necessary for substrates (e.g., repaglinide and rosiglitazone), inhibitors (e.g., gemfibrozil), and inducers (e.g., Paclitaxel is a novel antimicrotubule agent that promotes the assembly of microtubules from adjuvant chemotherapy, paclitaxel at a dose of 175 mg/m2 administered intravenously over 3 prevention of Infusion related reaction (IRRs). Clinical signs and symptoms indicative of an IRR rifampin) of CYP2C8. tubulin dimers and stabilizes microtubules by preventing depolymerization. This stability results in hours every 3 weeks has been shown to be effective. may include flushing, tachycardia, hypertension or hypotension, rash or hives, fever with chills, Potential interactions between paclitaxel, a substrate of CYP3A4, and protease inhibitors the inhibition of the normal dynamic reorganization of the microtubule network that is essential for vital 2. For the adjuvant treatment of node-positive breast cancer, the recommended regimen is rigors, hypoxia or dyspnea, as well as back, flank, chest, or abdominal pain. These reactions may (ritonavir, saquinavir, indinavir, and nelfinavir), which are substrates and/or inhibitors of CYP3A4, interphase and mitotic cellular functions. In addition, paclitaxel induces abnormal arrays or “bundles” paclitaxel, at a dose of 175 mg/m2 intravenously over 3 hours every 3 weeks for 4 courses be transient. When such signs and symptoms are observed, the infusion should be interrupted have not been evaluated in clinical trials. of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis. administered sequentially to doxorubicin-containing combination chemotherapy. The clinical and supportive care administrated immediately according to the institution’s protocol for treating Plasma levels of doxorubicin (and its active metabolite doxorubicinol) may be increased when Pharmacokinetics trial used 4 courses of doxorubicin and cyclophosphamide. such events. paclitaxel and doxorubicin are used in combination. An open label, balanced, randomized, 2-period, 2-treatment, 2-sequence, and 2-way crossover 3. For previously untreated patients with carcinoma of the ovary, one of the following None of the patients receiving 175 mg/m2 of Paclitaxel lipid suspension every 3 weeks Use in Specific Populations study was conducted to evaluate safety and pharmacokinetic comparison of intravenous infusion recommended regimens may be given every 3 weeks. experienced any hypersensitivity reactions. Pregnancy of Paclitaxel lipid suspension and Taxol in patients with metastatic breast cancer. a. Paclitaxel administered intravenously over 3 hours at a dose of 175 mg/m2 followed by Cardiovascular: Paclitaxel can cause fetal harm when administered to a pregnant woman. Paclitaxel lipid 16 patients were dosed at 175 mg/m2 intravenously, over 3 hours once every three weeks. In cisplatin at a dose of 75 mg/m2; or Treatment with Paclitaxel lipid suspension may result in significant cardiovascular events possibly suspension has not been tested in pregnant patients. It has been reported that administration of Period I, patients were dosed with test or reference product on the first day of the chemotherapy b. Paclitaxel administered intravenously over 24 hours at a dose of 135 mg/m2 followed by related to single-agent paclitaxel may occur in approximately 1% of all patients as was observed paclitaxel during the period of organogenesis to rabbits at doses of 3 mg/kg/day (about 0.2 the cycle (day 1) of the study as per the randomization schedule. In Period II, patients were crossed cisplatin at a dose of 75 mg/m2 by Paclitaxel injection. These events may include syncope, rhythm abnormalities, hypertension, daily maximum recommended human dose on a mg/m² basis) caused embryo- and fetotoxicity, over to either test or reference product (patients on test product to be crossed over to reference 4. For patients with non-small cell lung carcinoma, the recommended regimen, given every 3 and venous thrombosis. as indicated by intrauterine mortality, increased resorptions, and increased fetal deaths. Maternal product and vice-versa) on the first day of the next chemotherapy cycle (day 22) as per weeks, is paclitaxel administered intravenously over 24 hours at a dose of 135 mg/m2 followed It has been reported that in patients treated with Paclitaxel, the Electrocardiogram (ECG) toxicity was also observed at this dose. No teratogenic effects were observed at 1 mg/kg/day randomization schedule. The pharmacokinetics evaluations were done by collecting whole blood by cisplatin, 75 mg/m2. abnormalities were common among patients at baseline. ECG abnormalities did not usually result (about 1/15 the daily maximum recommended human dose on a mg/m² basis); teratogenic samples from patients (both test and reference product) prior to each dose and over a period of 5. For patients with AIDS-related Kaposi’s sarcoma, paclitaxel administered at a dose of 135 in symptoms, were not dose-limiting, and required no intervention. potential could not be assessed at higher doses due to extensive fetal mortality. 2 2 51-hour after each dose. The log transformed Test/Reference ratios for Cmax and AUC0-t were mg/m given intravenously over 3 hours every 3 weeks or at a dose of 100 mg/m given Cases of myocardial infarction have been reported with paclitaxel. Congestive heart failure, There are no adequate and well-controlled studies in pregnant women. If paclitaxel is used during about 29.5% and 44.8% respectively. The safety profile of paclitaxel lipid suspension was similar intravenously over 3 hours every 2 weeks is recommended (dose intensity 45 to 50 including cardiac dysfunction and reduction of left ventricular ejection fraction or ventricular pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be to that of Taxol. mg/m2/week). failure, has been reported typically in patients who have received other chemotherapy, notably apprised of the potential hazard to the fetus. Women of child- bearing potential should be advised Clinical Studies Contraindications anthracyclines. to avoid becoming pregnant. Locally Advanced or Metastatic Breast Cancer Paclitaxel lipid suspension is contraindicated in patients who have a history of hypersensitivity Atrial fibrillation and supraventricular tachycardia have been reported. Nursing Mothers An open label, randomized, multiple dose, parallel study was conducted in locally advanced or reactions to paclitaxel. Respiratory It is not known whether the drug is excreted in human milk. It has been reported that following metastatic breast cancer patients after failure of prior chemotherapy. Paclitaxel lipid suspension should not be used in patients with solid tumors who have baseline Interstitial pneumonia, lung fibrosis, and pulmonary embolism have been reported with paclitaxel. intravenous administration of carbon 14-labeled paclitaxel to rats on days 9 to 10 postpartum, Females, ≥ 18 years and ≤ 65 years of age, with histopathologically/ cytologically confirmed neutrophil counts of <1,500 cells/mm³ or in patients with AIDS-related Kaposi’s sarcoma with Radiation pneumonitis may occur in patients receiving concurrent radiotherapy. Pleural effusion concentrations of radioactivity in milk were higher than in plasma and declined in parallel with the breast cancer, having locally advanced or metastatic breast cancer after failure of prior baseline neutrophil counts of <1,000 cells/mm³. and respiratory distress have been reported. plasma concentrations. Because many drugs are excreted in human milk and because of the chemotherapy, having Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2, Warnings and Precautions In the clinical trial, the incidence of cough in Paclitaxel lipid suspension 175 mg/m2 Q3W,80 mg/m2 potential for serious adverse reactions in nursing infants, it is recommended that nursing be having adequate bone marrow, renal and hepatic function, having at least one measurable lesion Patients who have severe hypersensitivity reactions to paclitaxel should not be rechallenged with QW and paclitaxel 175 mg/m2 Q3W arms was 4.17%, 22.22% and 7.41% respectively. discontinued when receiving paclitaxel therapy. as per the Response Evaluation Criteria In Solid Tumors 1.1 (RECIST 1.1), having life expectancy the drug. Anaphylaxis and severe hypersensitivity reactions characterized by dyspnea and Neurologic Pediatric Use of at least 6 months were randomized to receive either Paclitaxel lipid suspension or Taxol®. hypotension requiring treatment, angioedema, and generalized urticaria have occurred in 2 to 4% In clinical trial of Paclitaxel lipid suspension, peripheral neuropathy was reported in 3 patients who The safety and effectiveness of paclitaxel in pediatric patients have not been established. 120 patients with locally advanced or metastatic breast cancer, after failure of prior chemotherapy, of patients receiving paclitaxel in clinical trials. were receiving Paclitaxel lipid suspension at 80 mg/m2. However, none of the patients receiving Geriatric Use were randomized in the ratio 2:2:1 (PLS every three weeks: PLS weekly: Taxol® every three Bone marrow suppression (primarily neutropenia) is dose-dependent and is the dose-limiting 175 mg/m2 of Paclitaxel lipid suspension every 3 weeks experienced any peripheral neuropathy. No specific studies with Paclitaxel lipid suspension was conducted. In most studies reported, weeks) and enrolled into the study. toxicity. Paclitaxel should not be administered to patients with baseline neutrophil counts of less These patients were also not pre-medicated with corticosteroids. severe myelosuppression was more frequent in elderly patients; in some studies, severe Patients were administered Paclitaxel lipid suspension (n= 48) or Taxol® (n= 27) at 175 mg/m2 as than 1,500 cells/mm³ (<1,000 cells/mm³ for patients with KS). Frequent monitoring of blood counts Hepatic neuropathy was more common in elderly patients. Estimates of efficacy appeared similar in per randomization schedule, by IV infusion for 3 hours in each cycle of 21 days in Arm A and Arm should be conducted during paclitaxel treatment. Patients should not be retreated with No relationship was observed between liver function abnormalities and either dose or schedule of elderly patients and in younger patients; however, comparative efficacy cannot be determined C respectively. Each patient received maximum of 6 cycles of Paclitaxel lipid suspension or subsequent cycles of paclitaxel until neutrophils recover to a level >1,500 cells/mm³ (>1,000 paclitaxel administration. Prolonged exposure to paclitaxel was not associated with cumulative with confidence due to the small number of elderly patients studied. Taxol®. In Arm B, patients were administered weekly with Paclitaxel lipid suspension at the dose cells/mm³ for patients with KS) and platelets recover to a level >100,000 cells/mm³. hepatic toxicity. Non Clinical Toxicological Studies of 80 mg/m2 (n= 45) for 18 weeks. Patients in the Paclitaxel lipid suspension groups (Arm A and Severe conduction abnormalities have been reported in <1% of patients during paclitaxel therapy Hepatic necrosis and hepatic encephalopathy leading to death have been reported. A sub chronic 28 days’ intravenous toxicity study was conducted by five consecutive days’ Arm B) were not premedicated whereas patients treated with Taxol® were pre-medicated as per and in some cases requiring pacemaker placement. If patients develop significant conduction Renal administration of paclitaxel lipid suspension in Swiss Albino mice at 5 mg/kg, 10 mg/kg or 15 the prescribing information. abnormalities during paclitaxel infusion, appropriate therapy should be administered and Patients with gynecological cancers treated with paclitaxel and cisplatin may increase the risk of mg/kg. The results showed in no hematological abnormalities related to the treatment in all Each drug, Paclitaxel lipid suspension (Arm A, 175 mg/m2 / Arm B, 80 mg/m2) or Taxol® (Arm C, continuous cardiac monitoring should be performed during subsequent therapy with paclitaxel. renal failure with the combination therapy of paclitaxel and cisplatin in gynecological cancers as groups. 175 mg/m2) was administered by IV infusion over 3 hours. Disease status and tumor response Hematology compared to cisplatin alone. Biochemical analysis revealed no abnormalities at 5 and 10 mg/kg dose but elevated levels of (CT Scan/MRI) was assessed after every 2 cycles of treatment using RECIST 1.1 guidelines Paclitaxel lipid suspension therapy should not be administered to patients with baseline neutrophil Gastrointestinal (GI) Alanine Aminotransferase and Alkaline Phosphatase was observed at the highest dose (15 through cycle 6 (including confirmation of response if required). Independent evaluation (blinded counts of less than 1,500 cells/mm³. In order to monitor the occurrence of myelotoxicity, it is Intestinal obstruction, intestinal perforation, pancreatitis, ischemic colitis, dehydration, mg/kg). Gross and histopathological changes were observed in male and female animals at 10 reading) of the images acquired in clinical trial was done by Central Imaging Facility. recommended that frequent peripheral blood cell counts be performed on all patients receiving esophagitis, constipation, and ascites have been reported with paclitaxel. Neutropenic and 15 mg/kg. Mortalities (1/6 males and 1/6 females) were noted in animals treated with highest The primary efficacy evaluation was based on the overall response rate (CR + PR), defined as the Paclitaxel lipid suspension. enterocolitis (typhlitis), despite the co-administration of filgrastim, was observed in patients dose (15 mg/kg) of the paclitaxel lipid suspension. The results were consistent with Taxol where proportion of patients whose best overall response was complete response (CR) or partial As reported earlier, patients should not be retreated with subsequent cycles of Paclitaxel lipid treated with paclitaxel alone and in combination with other chemotherapeutic agents. the maximum tolerated dose of Taxol in mice was determined to be over 12.5 mg/kg. response (PR) after receiving study treatment with Paclitaxel lipid suspension or Taxol®. The suspension until neutrophils recover to a level >1,500 cells/mm³ and platelets recover to a level In the clinical trial, the incidence of diarrhea in Paclitaxel lipid suspension 175 mg/m2 Q3W and 80 Overdosage secondary efficacy endpoint was based on the disease control rate (DCR=CR + PR + SD), >100,000 cells/mm³. In the case of severe neutropenia (<500 cells/mm³ for 7 days or more) during mg/m2 QW and paclitaxel 175 mg/m2 Q3W arms was 2.08%, 8.88% and 3.7% respectively. The There is no known antidote for paclitaxel overdosage. The primary anticipated complications of defined as the proportion of patients whose best overall response was complete response (CR) a course of therapy, a 20% reduction in dose for subsequent courses of Paclitaxel lipid incidence of nausea in Paclitaxel lipid suspension 175 mg/m2 Q3W, 80 mg/m2 QW and paclitaxel overdosage would consist of bone marrow suppression, peripheral neurotoxicity, and mucositis. or partial response (PR) or stable disease (SD). suspension therapy is recommended. 175 mg/m2 Q3W arms was 4.16%, 6.66% and 3.7% respectively. The incidence of vomiting in Storage A point estimate and a two-sided 95% confidence interval (CI) were computed for the secondary In patients with advanced HIV disease and poor-risk AIDS-related Kaposi’s sarcoma, the Paclitaxel lipid suspension 175 mg/m2 Q3W and 80 mg/m2 QW arms was 6.25%, and 11.11% Store at 2 -8°C. Do not freeze. Protect from light. Keep out of reach of children. efficacy endpoint, disease control rate (CR+PR+SD) from best overall response of the two recommended dose of Paclitaxel lipid suspension for this disease, can be initiated and repeated respectively. Packaging information treatment groups and their difference. if the neutrophil count is at least 1,000 cells/mm³. Injection Site Reaction Available as 30 mg in single vial individually packed in a carton. The overall response rate (CR + PR) was 36.4% (95% CI, 22.1- 50.6%) for Paclitaxel lipid Hypersensitivity Reactions Injection site reactions, including reactions secondary to extravasation, reported with paclitaxel Include 5-micron filter needle and package insert. suspension treatment- [Arm A (175 mg/m2)] administered every 3 weeks, 46.5% (95% CI, 31.6- No routine premedication prior to Paclitaxel lipid suspension administration is necessary for are usually mild and consist of erythema, tenderness, skin discoloration, or swelling at the MANUFACTURED BY: 61.4%) for Paclitaxel lipid suspension treatment- [Arm B (80 mg/m2)] administered every week prevention of Infusion related reaction (IRRs). However, patients with a history of severe injection site. These reactions have been observed more frequently with the 24-hour infusion than and 20.8% (95% CI, 4.6- 37.1%) for Taxol® treatment- [Arm C (175 mg/m2)] administered every 3 hypersensitivity reactions to paclitaxel should not be treated with paclitaxel lipid suspension. with the 3-hour infusion. INTAS PHARMACEUTICALS LTD. weeks. The disease control rates were 86.4%, 88.4% and 83.3% for Arm A, Arm B and Arm C Minor symptoms such as flushing, skin reactions, dyspnea, hypotension, or tachycardia do not More severe events such as phlebitis, cellulitis, induration, skin exfoliation, necrosis, and fibrosis Plot No. 5 to 14, Pharmez-382 213, respectively. require interruption of therapy. However, severe reactions, such as hypotension requiring have been reported with paclitaxel. In some cases, the onset of the injection site reaction either Near Village Matoda, Ta: Sanand, Dist: Ahmedabad. A total of 450 adverse events (AEs) reported in 97 patients during the course of the trial. 157 AEs treatment, dyspnea requiring bronchodilators, angioedema, or generalized urticaria require occurred during a prolonged infusion or was delayed by a week to 10 days. occurred to patients under Paclitaxel lipid suspension Arm A (n=48), 239 AEs occurred to patients immediate discontinuation of paclitaxel and aggressive symptomatic therapy. Patients who have In the clinical trial, the incidence of chills in Paclitaxel lipid suspension 175 mg/m2 Q3W, 80 mg/m2 51 4024 0 722423 under Paclitaxel lipid suspension Arm B (n=45) and 54 AEs occurred to patients under Paclitaxel developed severe hypersensitivity reactions should not be rechallenged with paclitaxel. QW and paclitaxel 175 mg/m2 Q3W arms was 52.08%, 40% and 7.41% respectively. Arm C (n=27). The Paclitaxel lipid suspension treated patients were not given any pre-medication Cardiovascular Other Clinical Events including corticosteroids. The AEs related to Paclitaxel lipid suspension Arm A, Paclitaxel lipid Hypotension, bradycardia, and hypertension have been observed during administration of In clinical trials of paclitaxel, alopecia was observed in almost all (87%) of the patients. Transient suspension Arm B and Taxol® Arm C were 68.75%, 68.89% and 48.15% respectively. In both paclitaxel, but generally do not require treatment. Occasionally paclitaxel infusions must be skin changes due to paclitaxel related hypersensitivity reactions have been observed, but no Paclitaxel lipid suspension and Taxol® treatment groups one or more Grade 3 or 4 treatment-relat- interrupted or discontinued because of initial or recurrent hypertension. Frequent vital sign other skin toxicities were significantly associated with paclitaxel administration. ed adverse events were observed. The percentage of patients reporting serious Grade 4 AEs in monitoring, particularly during the first hour of paclitaxel infusion, is recommended. Continuous In the clinical trial, the incidence of alopecia in Paclitaxel lipid suspension 175 mg/m2 Q3W,80 Arm A, Arm B and Arm C were 6.25%, 11.11% and 7.41% respectively. cardiac monitoring is not required except for patients with serious conduction abnormalities. Use mg/m2 QW and paclitaxel 175 mg/m2 Q3W arms was 29.17%, 33.33% and 33.33% respectively. Overall, the investigational drugs were found to be well tolerated. Majority of the post-dose AEs of paclitaxel lipid suspension in combination with doxorubicin for treatment of metastatic breast In clinical trials of paclitaxel, edema was reported in 21% of all patients (17% of those without resolved without any sequelae despite the fact patients were not pre-medicated with cancer, monitoring of cardiac function is recommended. baseline edema); only 1% had severe edema and none of these patients required treatment corticosteroids or anti-allergic treatment in paclitaxel lipid suspension treatment groups. Nervous System discontinuation. Edema was most commonly focal and disease-related. Edema was observed in Indications Peripheral neuropathy is frequent with paclitaxel, the development of severe symptomatology is 5% of all courses for patients with normal baseline and did not increase with time on study. Paclitaxel lipid suspension for injection is indicated for: unusual and requires a dose reduction of 20% for all subsequent courses of treatment cycle. Skin abnormalities related to radiation recall as well as maculopapular rash, pruritus, • For the treatment of breast cancer after failure of combination chemotherapy for metastatic In the clinical trial of Paclitaxel lipid suspension, peripheral neuropathy was reported in 3 (6.66%) Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported. In postmarket- INP010

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File Name : 722423 - PacliAqualip 30 30 mg (Ind) PIL Size : 160 x 270 (mm) Back Side Colour : Pantone Black Date : 19*11*19, 23*12*19