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Home , Abacavir, Dolutegravir

P1518054

Item Code With Serial Number in 2D format to be printed at printer’s end FUMARATE TABLETS FUMARATE and , DOLUTEGRAVIR,

HIGHLIGHTS OF PRESCRIBING INFORMATION suggestive of or pronounced hepatotoxicity. (5.1) approximately 160 HIV-1-infected pediatric subjects aged 4 weeks to less than 18 years, of which 46 treatment-experienced, INSTI-naïve Lamivudine: Studies in pregnant rats showed that lamivudine is transferred to the fetus through the placenta. Reproduction studies with These highlights do not include all the information needed to use DOLUTEGRAVIR, LAMIVUDINE and TENOFOVIR DISOPROXIL • Hepatotoxicity has been reported in patients receiving dolutegravir-containing regimens. Patients with underlying hepatitis B or C subjects aged 6 to less than 18 years have been enrolled [see Use in Specific Populations (8.4), Clinical Studies (14.2)]. orally administered lamivudine have been performed in rats and rabbits at doses producing plasma levels up to approximately 32 times the FUMARATE TABLETS safely and effectively. See full prescribing information for DOLUTEGRAVIR, LAMIVUDINE and TENOFOVIR may be at increased risk for worsening or development of transaminase elevations. Monitoring for hepatoxicity is recommended. The adverse reaction profile was similar to that for adults. Grade 2 ARs reported by more than one subject were decreased neutrophil count human exposure for a dose of 300 mg. No evidence of teratogenicity due to lamivudine was observed. Evidence of early embryolethality DISOPROXIL FUMARATE TABLETS. (5.2) (n = 3) and (n = 2). There were no Grade 3 or 4 drug-related ARs reported. No ARs led to discontinuation. was seen in the rabbit at exposure levels similar to those observed in humans, but there was no indication of this effect in the rat at plasma levels up to 32 times those in humans. DOLUTEGRAVIR, LAMIVUDINE and TENOFOVIR DISOPROXIL FUMARATE tablets, for oral use • Hypersensitivity reactions characterized by rash, constitutional findings, and sometimes organ dysfunction, including injury, The Grade 3 or 4 laboratory abnormalities reported in more than one subject were elevated total bilirubin (n = 3) and decreased neutrophil have been reported. Discontinue dolutegravir, lamivudine and tenofovir disoproxil fumarate tablets and other suspect agents count (n = 2). The changes in mean serum creatinine were similar to those observed in adults. Tenofovir Disoproxil Fumarate: Reproduction studies have been performed in rats and rabbits at doses up to 14 and 19 times the human WARNING: LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT EXACERBATIONS OF immediately if signs or symptoms of hypersensitivity reactions develop, as a delay in stopping treatment may result in a life- dose based on body surface area comparisons and revealed no evidence of impaired fertility or harm to the fetus due to tenofovir. Pancreatitis: Pancreatitis, which has been fatal in some cases, has been observed in antiretroviral nucleoside-experienced pediatric HEPATITIS B threatening reaction. (5.3) 8.2 Nursing Mothers See full prescribing information for complete boxed warning. • Pancreatitis: Use with caution in pediatric patients with a history of pancreatitis or other significant risk factors for pancreatitis. subjects receiving lamivudine alone or in combination with other antiretroviral agents. In an open-label dose-escalation trial (NUCA2002), • Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside Discontinue treatment as clinically appropriate. (5.4) 14 subjects (14%) developed pancreatitis while receiving monotherapy with lamivudine. Three of these subjects died of complications The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers not breastfeed their infants to avoid risking analogues. (5.1) • New onset or worsening renal impairment: Can include acute renal failure and Fanconi syndrome. Assess estimated creatinine of pancreatitis. In a second open-label trial (NUCA2005), 12 subjects (18%) developed pancreatitis. In Trial ACTG300, pancreatitis was postnatal transmission of HIV-1 infection. • Dolutegravir, lamivudine and tenofovir disoproxil fumarate tablets are not approved for the treatment of chronic hepatitis clearance before initiating treatment with dolutegravir, lamivudine and tenofovir disoproxil fumarate tablets. In patients at risk not observed in 236 subjects randomized to lamivudine plus . Pancreatitis was observed in 1 subject in this trial who received Because of both the potential for HIV-1 transmission and the potential for serious adverse reactions in nursing infants, instruct mothers B virus (HBV) infection. Severe acute exacerbations of hepatitis B have been reported in patients who are co-infected for renal dysfunction, assess estimated creatinine clearance, serum phosphorus, urine glucose and urine before initiating open-label lamivudine in combination with zidovudine and following discontinuation of monotherapy [see Warnings not to breastfeed. with HBV and human immunodeficiency virus (HIV-1) and have discontinued anti-hepatitis B therapy, including lamivudine treatment with dolutegravir, lamivudine and tenofovir disoproxil fumarate tablets and periodically during treatment. Avoid and Precautions (5.4)]. Dolutegravir and tenofovir disoproxil fumarate, two components of dolutegravir, lamivudine and tenofovir disoproxil fumarate tablets. administering dolutegravir, lamivudine and tenofovir disoproxil fumarate tablets with concurrent or recent use of nephrotoxic drugs. Tenofovir Disoproxil Fumarate: Clinical Trials in Adult Patients with HIV-1 Infection: More than 12,000 subjects have been treated with Monitor hepatic function closely in these patients and, if appropriate, initiate anti-hepatitis B treatment. (5.2) (5.5) tenofovir disoproxil fumarate alone or in combination with other antiretroviral medicinal products for periods of 28 days to 215 weeks in Studies in lactating rats and their offspring indicate that dolutegravir was present in rat milk. It is not known whether dolutegravir is • Hepatic decompensation, some fatal, has occurred in HIV-1/HCV co-infected patients receiving interferon and ribavirin-based clinical trials and expanded access programs. A total of 1,544 subjects have received tenofovir disoproxil fumarate 300 mg once daily in excreted in human breast milk. ------INDICATIONS AND USAGE------regimens. Monitor for treatment-associated toxicities. Discontinue dolutegravir, lamivudine and tenofovir disoproxil fumarate tablets clinical trials; over 11,000 subjects have received tenofovir disoproxil fumarate in expanded access programs. Lamivudine Dolutegravir, lamivudine and tenofovir disoproxil fumarate tablets, a combination of dolutegravir ( strand transfer inhibitor as medically appropriate and consider dose reduction or discontinuation of interferon alfa, ribavirin, or both. (5.6) • Administration of dolutegravir, lamivudine, and tenofovir disoproxil fumarate tablets is not recommended in patients receiving other The most common adverse reactions (incidence greater than or equal to 10%, Grades 2 to 4) identified from any of the 3 large controlled Lamivudine is excreted in human breast milk. [INSTI]), lamivudine, and tenofovir disoproxil fumarate (both nucleoside inhibitors), are indicated for use alone as a clinical trials include rash, diarrhea, , pain, , asthenia, and . complete regimen for the treatment of HIV-1 infection in adults and pediatric patients weighing 40 kg or greater. (1) products containing lamivudine, , tenofovir disoproxil fumarate, or (5.7). Do not administer in Tenofovir Disoproxil Fumarate combination with adefovir dipivoxil (HEPSERA). (5.2) Changes in Bone Mineral Density: In HIV-1 infected adult subjects in Study 903, there was a significantly greater mean percentage Limitations of Use: • Decreases in bone mineral density (BMD): Consider assessment of BMD in patients with a history of pathologic fracture or other risk decrease from baseline in BMD at the lumbar spine in subjects receiving tenofovir disoproxil fumarate + lamivudine + (-2.2% Samples of breast milk obtained from five HIV-1 infected mothers in the first post-partum week show that tenofovir is secreted in human milk • Dolutegravir, lamivudine and tenofovir disoproxil fumarate tablets alone are not recommended in patients with resistance-associated factors for osteoporosis or bone loss. (5.8) ± 3.9) compared with subjects receiving + lamivudine + efavirenz (-1.0% ± 4.6) through 144 weeks. Changes in BMD at integrase substitutions or clinically suspected integrase strand transfer inhibitor resistance because the dose of dolutegravir in • Redistribution/accumulation of body fat and immune reconstitution syndrome have been reported in patients treated with the hip were similar between the two treatment groups (-2.8% ± 3.5 in the tenofovir disoproxil fumarate group vs. -2.4% ± 4.5 in the 8.4 Pediatric Use combination antiretroviral therapy. (5.9, 5.10) stavudine group). In both groups, the majority of the reduction in BMD occurred in the first 24 to 48 weeks of the trial and this reduction dolutegravir, lamivudine and tenofovir disoproxil fumarate tablets is insufficient in these subpopulations. See the dolutegravir Dolutegravir, lamivudine and tenofovir disoproxil fumarate tablets should only be administered to patients with a body weight of at least was sustained through Week 144. Twenty-eight percent of tenofovir disoproxil fumarate-treated subjects vs. 21% of the stavudine- prescribing information. (1) ------ADVERSE REACTIONS------40 kg. treated subjects lost at least 5% of BMD at the spine or 7% of BMD at the hip. Clinically relevant fractures (excluding fingers and toes) ------DOSAGE AND ADMINISTRATION------• In adults subjects: The most common adverse reactions (in those receiving dolutegravir, lamivudine and tenofovir disoproxil were reported in 4 subjects in the tenofovir disoproxil fumarate group and 6 subjects in the stavudine group. In addition, there were 8.5 Geriatric Use fumarate) are , , and headache, nausea, nasal signs and symptoms, diarrhea, cough, rash, pain, depression, and • Recommended dose in adults and pediatric patients (12 years of age and older weighing at least 40 kg): One tablet once daily taken significant increases in biochemical markers of bone metabolism (serum bone-specific alkaline phosphatase, serum osteocalcin, serum C Clinical trials of dolutegravir, lamivudine, or tenofovir disoproxil fumarate did not include sufficient numbers of subjects aged 65 and older asthenia. (6.1) orally with or without food. (2.1) telopeptide, and urinary N telopeptide) and higher serum parathyroid hormone levels and 1,25 Vitamin D levels in the tenofovir disoproxil to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration of • In pediatric subjects: The most common adverse reactions (in those receiving lamivudine) are and cough. (6.1) • If dosing with certain UGT1A or CYP3A inducers, then the recommended dolutegravir dosage regimen is 50 mg twice daily. An fumarate group relative to the stavudine group; however, except for bone-specific alkaline phosphatase, these changes resulted in values dolutegravir, lamivudine and tenofovir disoproxil fumarate tablets in elderly patients reflecting the greater frequency of decreased hepatic, additional 50-mg dose of dolutegravir, separated by 12 hours from dolutegravir, lamivudine and tenofovir disoproxil fumarate To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or that remained within the normal range [see Warnings and Precautions (5.8)]. renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3)]. tablets, should be taken. (2.2) www.fda.gov/medwatch. 6.2 Postmarketing Experience • Because dolutegravir, lamivudine and tenofovir disoproxil fumarate tablets are a fixed-dose tablet and cannot be dose adjusted, 8.6 Patients with Impaired Renal Function ------DRUG INTERACTIONS------dolutegravir, lamivudine and tenofovir disoproxil fumarate tablets are not recommended in patients requiring dosage adjustment or In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postmarketing Dolutegravir, lamivudine and tenofovir disoproxil fumarate tablets are not recommended for patients with creatinine clearance less than patients with renal impairment. (2.3) Coadministration of dolutegravir, lamivudine, and tenofovir disoproxil fumarate tablets with other drugs can alter the concentration of use for each of the individual components of dolutegravir, lamivudine, and tenofovir disoproxil fumarate tablets. Because these reactions 50 mL per min because dolutegravir, lamivudine and tenofovir disoproxil fumarate tablets are a fixed-dose combination and the dosage other drugs and other drugs may alter the concentrations of dolutegravir, lamivudine, and tenofovir disoproxil fumarate tablets. The are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a of the individual components cannot be adjusted. If a dose reduction of lamivudine or tenofovir disoproxil fumarate, two components of ------DOSAGE FORMS AND STRENGTHS------potential drug-drug interactions must be considered prior to and during therapy. (4, 7, 12.3) causal relationship to drug exposure. dolutegravir, lamivudine and tenofovir disoproxil fumarate tablets, is required for patients with creatinine clearance less than 50 mL per Tablet: 50 mg of dolutegravir, 300 mg of lamivudine, and 300 mg of tenofovir disoproxil fumarate (3) ------USE IN SPECIFIC POPULATIONS------Dolutegravir min, then the individual components should be used [see Clinical Pharmacology (12.3)]. ------CONTRAINDICATIONS------• Nursing mothers: is not recommended due to the potential for HIV transmission. (8.2) Hepatobiliary Disorders: Acute liver failure, hepatotoxicity. 8.7 Patients with Impaired Hepatic Function • Previous hypersensitivity reaction to dolutegravir, lamivudine, or tenofovir disoproxil fumarate. (4) • Dolutegravir, lamivudine, and tenofovir disoproxil fumarate tablets are not recommended in patients with creatinine clearance less Musculoskeletal: arthralgia, . Dolutegravir • Coadministration with dofetilide. (4) than 50 mL per min. (8.6) Psychiatric: No clinically important pharmacokinetic differences between subjects with moderate hepatic impairment and matching healthy subjects ------WARNINGS AND PRECAUTIONS------See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Lamivudine were observed. No dosage adjustment is necessary for patients with mild to moderate hepatic impairment (Child-Pugh Score A or B). Body as a Whole: Redistribution/accumulation of body fat [see Warnings and Precautions (5.9)]. The effect of severe hepatic impairment (Child-Pugh Score C) on the of dolutegravir has not been studied. Therefore, • Lactic acidosis/severe hepatomegaly with steatosis: Discontinue treatment in patients who develop symptoms or laboratory findings Isuued: April 2018 Endocrine and Metabolic: Hyperglycemia. dolutegravir is not recommended for use in patients with severe hepatic impairment [see Clinical Pharmacology (12.3)]. General: Weakness. 10 OVERDOSAGE Hemic and Lymphatic: Anemia (including pure red cell aplasia and severe anemias progressing on therapy). FULL PRESCRIBING INFORMATION: CONTENTS* 7.5 Didanosine There is no known specific treatment for overdose with dolutegravir, lamivudine and tenofovir disoproxil fumarate tablets. If overdose 7.6 HIV-1 Protease Inhibitors Hepatic and Pancreatic: Lactic acidosis and hepatic steatosis [see Warnings and Precautions (5.1)], posttreatment exacerbations of occurs, the patient should be monitored and standard supportive treatment applied as required. FULL PRESCRIBING INFORMATION hepatitis B [see Warnings and Precautions (5.2)]. 7.7 Hepatitis C Antiviral Agents Dolutegravir WARNING: LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT EXACERBATIONS OF 7.8 Drugs Affecting Renal Function Hypersensitivity: Anaphylaxis, urticaria. As dolutegravir is highly bound to plasma , it is unlikely that it will be significantly removed by dialysis. HEPATITIS B 7.9 Sorbitol Musculoskeletal: Muscle weakness, CPK elevation, rhabdomyolysis. Lamivudine 1 INDICATIONS AND USAGE 8 USE IN SPECIFIC POPULATIONS Skin: Alopecia, pruritus. Because a negligible amount of lamivudine was removed via (4-hour) , continuous ambulatory , and 2 DOSAGE AND ADMINISTRATION 8.1 Tenofovir Disoproxil Fumarate automated peritoneal dialysis, it is not known if continuous hemodialysis would provide clinical benefit in a lamivudine overdose event. 2.1 Adults and Pediatric Patients Weighing 40 kg or Greater 8.2 Nursing Mothers Immune System Disorders: allergic reaction, including angioedema. 2.2 Dosage Recommendation with Certain Concomitant 8.4 Pediatric Use Metabolism and Nutrition Disorders: lactic acidosis, hypokalemia, hypophosphatemia. Tenofovir Disoproxil Fumarate 2.3 Not Recommended Due to Lack of Dosage Adjustment 8.5 Geriatric Use Respiratory, Thoracic, and Mediastinal Disorders: dyspnea. Limited clinical experience at doses higher than the therapeutic dose of tenofovir disoproxil fumarate 300 mg is available. In Study 901, 8.6 Patients with Impaired Renal Function Gastrointestinal Disorders: pancreatitis, increased amylase, . 600 mg tenofovir disoproxil fumarate was administered to 8 subjects orally for 28 days. No severe adverse reactions were reported. The 3 DOSAGE FORMS AND STRENGTHS 8.7 Patients with Impaired Hepatic Function Hepatobiliary Disorders: hepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT gamma GT). effects of higher doses are not known. 4 CONTRAINDICATIONS 10 OVERDOSAGE Skin and Subcutaneous Tissue Disorders: rash. Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. Following a single 300 mg dose of 5 WARNINGS AND PRECAUTIONS 11 DESCRIPTION Musculoskeletal and Connective Tissue Disorders: rhabdomyolysis, osteomalacia (manifested as bone pain and which may contribute tenofovir disoproxil fumarate, a 4-hour hemodialysis session removed approximately 10% of the administered tenofovir dose. 5.1 Lactic Acidosis and Severe Hepatomegaly with Steatosis 12 CLINICAL PHARMACOLOGY to fractures), muscular weakness, myopathy. 11 DESCRIPTION 5.2 Patients with Hepatitis B Virus Co-infection 12.1 Mechanism of Action Renal and Urinary Disorders: acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, 5.3 Hypersensitivity Reactions Dolutegravir, lamivudine, and tenofovir disoproxil fumarate tablets 50 mg, 300 mg, and 300 mg is a fixed dose combination containing 12.2 Pharmacodynamics interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal insufficiency, increased creatinine, proteinuria, polyuria. 5.4 Pancreatitis dolutegravir, lamivudine, and tenofovir disoproxil fumarate in a film-coated tablet for oral use. 12.3 Pharmacokinetics General Disorders and Administration Site Conditions: asthenia. 5.5 New Onset or Worsening Renal Impairment 12.4 Microbiology Each film-coated tablet contains 50 mg dolutegravir (equivalent to 52.6 mg dolutegravir sodium) in one layer and 300 mg of lamivudine 5.6 Use with Interferon- and Ribavirin-Based Regimens The following adverse reactions, listed under the body system headings above, may occur as a consequence of proximal renal tubulopathy: USP, and 300 mg of tenofovir disoproxil fumarate (which is equivalent to 245 mg of tenofovir disoproxil) in the other layer. The tablets also 5.7 Related Products that are Not Recommended 13 NONCLINICAL TOXICOLOGY rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, hypophosphatemia. include the following inactive ingredients: croscarmellose sodium, ferric oxide, hypromellose, iron oxide black, iron oxide red, magnesium 5.8 Bone Effects 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 7 DRUG INTERACTIONS stearate, mannitol, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, povidone, sodium starch glycolate, sodium stearyl 5.9 Fat Redistribution 13.2 Animal Toxicology and/or Pharmacology fumarate, talc and titanium dioxide. 5.10 Immune Reconstitution Syndrome 7.1 Effect of Dolutegravir on the Pharmacokinetics of Other Agents 14 CLINICAL STUDIES Dolutegravir: The chemical name of dolutegravir sodium is sodium (4R,12aS)-9-{[(2,4-difluorophenyl)methyl]carbamoyl}-4-methyl-6,8- 6 ADVERSE REACTIONS In vitro, dolutegravir inhibited the renal organic cation transporters, OCT2 (IC50 = 1.93 microM) and multidrug and toxin extrusion dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1’,2’:4,5]pyrazino[2,1-b][1,3]oxazin-7-olate. The molecular formula is C H F N NaO and the 14.1 Adult Subjects transporter (MATE) 1 (IC = 6.34 microM). In vivo, dolutegravir inhibits tubular secretion of creatinine by inhibiting OCT2 and potentially 20 18 2 3 5 6.1 Clinical Trials Experience 50 molecular weight is 441.36 g per mol. It has the following structural formula: 14.2 Pediatric Subjects MATE1. Dolutegravir may increase plasma concentrations of drugs eliminated via OCT2 or MATE1 (dofetilide and metformin, Table 5) [see 6.2 Postmarketing Experience 16 HOW SUPPLIED/STORAGE AND HANDLING Contraindications (4), Drug Interactions (7.3)]. ONa O CH3 7 DRUG INTERACTIONS 17 PATIENT COUNSELING INFORMATION In vitro, dolutegravir inhibited the basolateral renal transporters, organic anion transporter (OAT) 1 (IC50 = 2.12 microM) and OAT3 (IC50 7.1 Effect of Dolutegravir on the Pharmacokinetics of Other Agents = 1.97 microM). However, in vivo, dolutegravir did not alter the plasma concentrations of tenofovir or para-amino hippurate, substrates F F O *Sections or subsections omitted from the full prescribing information are not listed. 7.2 Effect of Other Agents on the Pharmacokinetics of Dolutegravir of OAT1 and OAT3. N 7.3 Established and Other Potentially Significant Drug Interactions H In vitro, dolutegravir did not inhibit (IC greater than 50 microM) the following: (CYP)1A2, CYP2A6, CYP2B6, CYP2C8, 7.4 Drugs without Clinically Significant Interactions with Dolutegravir 50 CYP2C9, CYP2C19, CYP2D6, CYP3A, uridine diphosphate (UDP)-glucuronosyl transferase 1A1 (UGT1A1), UGT2B7, P-glycoprotein (P- N N gp), breast cancer resistance protein (BCRP), bile salt export pump (BSEP), organic anion transporter polypeptide (OATP)1B1, OATP1B3, O OCT1, multidrug resistance protein (MRP)2, or MRP4. In vitro, dolutegravir did not induce CYP1A2, CYP2B6, or CYP3A4. Based on these H FULL PRESCRIBING INFORMATION 5.9 Fat Redistribution data and the results of drug interaction trials, dolutegravir is not expected to affect the pharmacokinetics of drugs that are substrates of O Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, these enzymes or transporters. Dolutegravir sodium is a white to light yellow powder and is practically insoluble in methanol and water at 20° to 25°C. WARNING: LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT EXACERBATIONS OF facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The HEPATITIS B 7.2 Effect of Other Agents on the Pharmacokinetics of Dolutegravir Lamivudine: The chemical name of lamivudine is (2R,cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one. mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established. Lamivudine is the (-) enantiomer of a dideoxy analogue of cytidine. Lamivudine has also been referred to as (-)2′,3′-dideoxy, 3′-thiacytidine. Lactic Acidosis and Severe Hepatomegaly with Steatosis: Lactic acidosis and severe hepatomegaly with steatosis, including fatal Dolutegravir is metabolized by UGT1A1 with some contribution from CYP3A. Dolutegravir is also a substrate of UGT1A3, UGT1A9, BCRP, 5.10 Immune Reconstitution Syndrome It has a molecular formula of C8H11N3O3S and a molecular weight of 229.3 g per mol. It has the following structural formula: cases, have been reported with the use of nucleoside analogues and other antiretrovirals. Discontinue dolutegravir, lamivudine and P-gp in vitro. Drugs that induce those enzymes and transporters may decrease dolutegravir plasma concentration and reduce the and tenofovir disoproxil fumarate tablets if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including dolutegravir, therapeutic effect of dolutegravir. occur [see Warnings and Precautions (5.1)]. lamivudine and tenofovir disoproxil fumarate tablets. During the initial phase of combination antiretroviral treatment, patients whose Coadministration of dolutegravir and other drugs that inhibit these enzymes may increase dolutegravir plasma concentration. immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such asMycobacterium Exacerbations of Hepatitis B: Dolutegravir, lamivudine and tenofovir disoproxil fumarate tablets are not approved for the treatment avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation significantly reduced plasma concentrations of dolutegravir, but the effect of etravirine was mitigated by coadministration of of chronic hepatitis B virus (HBV) infection. Severe acute exacerbations of hepatitis B have been reported in patients who are and treatment. /ritonavir or /ritonavir, and is expected to be mitigated by /ritonavir (Table 5) [see Drug Interactions (7.3), co-infected with HBV and human immunodeficiency virus (HIV-1) and have discontinued anti-hepatitis B therapy, including Clinical Pharmacology (12.3)]. lamivudine or tenofovir disoproxil fumarate. Hepatic function should be monitored closely with both clinical and laboratory follow- Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the In vitro, dolutegravir was not a substrate of OATP1B1 or OATP1B3. up for at least several months in patients who discontinue dolutegravir, lamivudine and tenofovir disoproxil fumarate tablets and setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of treatment. are co-infected with HIV-1 and HBV. If appropriate, initiation of anti-hepatitis B therapy may be warranted [see Warnings and 6 ADVERSE REACTIONS 7.3 Established and Other Potentially Significant Drug Interactions Precautions (5.2)]. The following serious adverse drug reactions are discussed in other sections of the labeling: There were no drug-drug interaction trials conducted with the dolutegravir, lamivudine, and tenofovir disoproxil fumarate fixed-dose combination tablets. 1 INDICATIONS AND USAGE • Lactic Acidosis and Severe Hepatomegaly with Steatosis [see Boxed Warning, Warnings and Precautions (5.1)]. Table 5 provides clinical recommendations as a result of drug interactions with dolutegravir. These recommendations are based on either • Effects on Serum Liver Biochemistries in Patients with Hepatitis B or C Co-infection [see Warnings and Precautions (5.2)]. Dolutegravir, lamivudine and tenofovir disoproxil fumarate tablets are indicated for use alone as a complete regimen for the treatment of drug interaction trials or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or Lamivudine USP is a white to off-white solid and is soluble in water. • Severe Acute Exacerbation of Hepatitis [see Boxed Warning, Warnings and Precautions (5.2)]. human immunodeficiency virus type 1 (HIV-1) infection in adults and pediatric patients weighing 40 kg or greater. loss of efficacy.[See Clinical Pharmacology (12.3).] • Hypersensitivity Reactions [see Warnings and Precautions (5.3)]. Tenofovir disoproxil fumarate: Tenofovir disoproxil fumarate (a prodrug of tenofovir) is a fumaric acid salt of bis- Limitation of Use: • Pancreatitis [see Warnings and Precautions (5.4)]. Table 5. Established and Other Potentially Significant Drug Interactions for Dolutegravir: Alterations in Dose or Regimen May Be isopropoxycarbonyloxymethyl ester derivative of tenofovir. In vivo tenofovir disoproxil fumarate is converted to tenofovir, an acyclic • Dolutegravir, lamivudine and tenofovir disoproxil fumarate tablets alone are not recommended in patients with resistance-associated • New Onset or Worsening Renal Impairment [see Warnings and Precautions (5.5)]. Recommended Based on Drug Interaction Trials or Predicted Interactions nucleoside phosphonate (nucleotide) analog of adenosine 5’-monophosphate. Tenofovir exhibits activity against HIV-1 reverse integrase substitutions or clinically suspected integrase strand transfer inhibitor resistance because the dose of dolutegravir in • Hepatic Decompensation in Patients Co-infected with HIV-1 and Hepatitis C [see Warnings and Precautions (5.6)]. transcriptase. Effect on dolutegravir, lamivudine and tenofovir disoproxil fumarate tablets is insufficient in these subpopulations. See the dolutegravir • Bone Effects of Tenofovir Disoproxil Fumarate [see Warnings and Precautions (5.8)]. Concomitant Drug The chemical name of tenofovir disoproxil fumarate is 9-[(R)-2-[[bis[[(isopropoxycarbonyl)oxy]methoxy]phosphinyl]methoxy]propyl] Concentration of prescribing information. • Fat Redistribution [see Warnings and Precautions (5.9)]. Class: Clinical Comment adenine fumarate (1:1). It has a molecular formula of C H N O P • C H O and a molecular weight of 635.52. It has the following Dolutegravir and/or 19 30 5 10 4 4 4 • Immune Reconstitution Syndrome [see Warnings and Precautions (5.10)]. Drug Name structural formula: 2 DOSAGE AND ADMINISTRATION Concomitant Drug 6.1 Clinical Trials Experience NH2 2.1 Adults and Pediatric Patients Weighing 40 kg (88 lbs) or Greater HIV-1 Antiviral Agents Dolutegravir, lamivudine and tenofovir disoproxil fumarate tablets are a fixed-dose combination product containing 50 mg of dolutegravir, Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot N Use of dolutegravir, lamivudine, and tenofovir N 300 mg of lamivudine, and 300 mg of tenofovir disoproxil fumarate. The recommended dosage regimen of dolutegravir, lamivudine and be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Non-nucleoside reverse transcriptase disoproxil fumarate tablets with etravirine without tenofovir disoproxil fumarate tablets in adults and pediatric patients weighing 40 kg (88 lbs) or greater is one tablet once daily orally with Dolutegravir, Lamivudine, Tenofovir Disoproxil Fumarate inhibitor: ↓Dolutegravir coadministration of atazanavir/ritonavir, darunavir/ N O or without food. Etravirinea N O Serious Dolutegravir Hypersensitivity Reactions: In clinical trials, hypersensitivity reactions have occurred with dolutegravir, a component ritonavir, or lopinavir/ritonavir is not recommended. 2.2 Dosage Recommendation with Certain Concomitant Medications of dolutegravir, lamivudine, and tenofovir disoproxil fumarate tablets [see Warnings and Precautions (5.3)]. These hypersensitivity O P O O O H CO2H Adjust dolutegravir dose to 50 mg twice daily. An reactions have been characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury. The dolutegravir dose (50 mg) in dolutegravir, lamivudine and tenofovir disoproxil fumarate tablets is insufficient when coadministered with Non-nucleoside reverse transcriptase additional 50-mg dose of dolutegravir should be O O CC medications listed in Table 1 that may decrease dolutegravir concentrations; the following dolutegravir dosage regimen is recommended. inhibitor: CH O Treatment-Naïve Subjects: In SINGLE, 833 adult subjects were randomized and received at least one dose of either dolutegravir 50 mg with ↓Dolutegravir taken, separated by 12 hours from dolutegravir, 3 HO2C H Table 1. Dosing Recommendations for Dolutegravir, Lamivudine and Tenofovir Disoproxil Fumarate Tablets with Coadministered fixed-dose sulfate and lamivudine once daily (n = 414) or fixed-dose efavirenz/emtricitabine/tenofovir disoproxil fumarate once Efavirenza lamivudine, and tenofovir disoproxil fumarate Medications daily (n = 419) (study treatment was blinded through Week 96 and open-label from Week 96 through Week 144). Through 144 weeks, the tablets. O rate of adverse events leading to discontinuation was 4% in subjects receiving dolutegravir + fixed-dose abacavir sulfate and lamivudine Tenofovir disoproxil fumarate is a white to off-white, crystalline powder freely soluble in N,N-dimethylformamide, soluble in methanol, Avoid coadministration with dolutegravir, Coadministered Drug Dosing Recommendation and 14% in subjects receiving fixed-dose efavirenz/emtricitabine/tenofovir disoproxil fumarate once daily. Non-nucleoside reverse transcriptase sparingly soluble in acetone, slightly soluble in acetonitrile, insoluble in methylene chloride. lamivudine, and tenofovir disoproxil fumarate tablets inhibitor: ↓Dolutegravir Efavirenz, /ritonavir, /ritonavir, The recommended dolutegravir dosage regimen is 50 mg twice Treatment‑emergent adverse reactions (ARs) of moderate to severe intensity observed in at least 2% of subjects in either treatment arm because there are insufficient data to make dosing 12 CLINICAL PHARMACOLOGY carbamazepine, or rifampin daily. An additional dolutegravir 50-mg tablet, separated by 12 of SINGLE are provided in Table 2. recommendations. 12.1 Mechanism of Action hours from dolutegravir, lamivudine and tenofovir disoproxil Table 2. Treatment‑Emergent Adverse Drug Reactions of at Least Moderate Intensity (Grades 2 to 4) and at Least 2% Frequency in fumarate tablets, should be taken. Adjust dolutegravir dose to 50 mg twice daily. An Dolutegravir, lamivudine, and tenofovir disoproxil fumarate are HIV-1 antiviral agents [see Microbiology (12.4)]. Treatment‑Naïve Subjects in SINGLE (Week 144 Analysis) Protease inhibitor: additional 50-mg dose of dolutegravir should be 12.2 Pharmacodynamics 2.3 Not Recommended Due to Lack of Dosage Adjustment Efavirenz/Emtricitabine/Tenofovir Fosamprenavir/ritonavira ↓Dolutegravir taken, separated by 12 hours from dolutegravir, Dolutegravir + Abacavir Sulfate and a Disoproxil Fumarate Tipranavir/ritonavir lamivudine, and tenofovir disoproxil fumarate Dolutegravir Because dolutegravir, lamivudine and tenofovir disoproxil fumarate tablets are a fixed-dose combination tablets and cannot be dose Adverse Reaction Lamivudine Once Daily Once Daily tablets. adjusted, dolutegravir, lamivudine and tenofovir disoproxil fumarate tablets are not recommended in patients requiring dosage adjustment (n = 414) Effects on Electrocardiogram: A thorough QT trial has been conducted for dolutegravir. Neither the effects of lamivudine nor tenofovir or patients with renal impairment (estimated creatinine clearance below 50 mL/min). (n = 419) Other Agents disoproxil fumarate as single entities or the combination of dolutegravir, lamivudine and tenofovir disoproxil fumarate on the QT interval have been evaluated. 3 DOSAGE FORMS AND STRENGTHS Psychiatric Coadministration is contraindicated with dolutegravir Dofetilide ↑Dofetilide In a randomized, placebo-controlled, cross-over trial, 42 healthy subjects received single-dose oral administrations of placebo, Dolutegravir, lamivudine and tenofovir disoproxil fumarate are available as tablets. Each tablet contains 50 mg of dolutegravir (equivalent Insomnia 3% 3% [see Contraindications (4)]. to 52.6 mg of dolutegravir sodium), 300 mg of lamivudine, and 300 mg of tenofovir disoproxil fumarate (which is equivalent to 245 mg dolutegravir 250 mg suspension (exposures approximately 3-fold of the 50 mg once-daily dose at steady state), and moxifloxacin Depression 1% 2% Adjust dolutegravir dose to 50 mg twice daily. An of tenofovir disoproxil). Tablets are pink colored, oval, biconvex, film-coated debossed with ‘N33’ on one side and plain on the other side. 400 mg (active control) in random sequence. After baseline and placebo adjustment, the maximum mean QTc change based on Fridericia additional 50-mg dose of dolutegravir should be correction method (QTcF) for dolutegravir was 2.4 msec (1-sided 95% upper CI: 4.9 msec). Dolutegravir did not prolong the QTc interval Abnormal dreams <1% 2% a 4 CONTRAINDICATIONS Carbamazepine ↓Dolutegravir taken, separated by 12 hours from dolutegravir, over 24 hours’ post-dose. Nervous System lamivudine, and tenofovir disoproxil fumarate Dolutegravir, lamivudine and tenofovir disoproxil fumarate tablets are contraindicated in patients: tablets. Effects on Renal Function: The effect of dolutegravir on renal function was evaluated in an open-label, randomized, 3-arm, parallel, with prior hypersensitivity reaction to dolutegravir [see Warnings and Precautions (5.3)], lamivudine, or tenofovir disoproxil Dizziness <1% 5% placebo-controlled trial in healthy subjects (n = 37) who received dolutegravir 50 mg once daily (n = 12), dolutegravir 50 mg twice daily • Oxcarbazepine Avoid coadministration with dolutegravir, fumarate. (n = 13), or placebo once daily (n = 12) for 14 days. A decrease in creatinine clearance, as determined by 24-hour urine collection, was Headache 2% 2% Phenytoin lamivudine, and tenofovir disoproxil fumarate tablets • receiving dofetilide due to the potential for increased dofetilide plasma concentrations and the risk for serious and/or life-threatening observed with both doses of dolutegravir after 14 days of treatment in subjects who received 50 mg once daily (9% decrease) and 50 mg Phenobarbital ↓Dolutegravir because there are insufficient data to make dosing events with concomitant use of dolutegravir [see Drug Interactions (7)]. Gastrointestinal twice daily (13% decrease). Neither dose of dolutegravir had a significant effect on the actual glomerular filtration rate (determined by St. John’s wort recommendations. the clearance of probe drug, iohexol) or effective renal plasma flow (determined by the clearance of probe drug, para-amino hippurate) Nausea <1% 3% 5 WARNINGS AND PRECAUTIONS (Hypericum perforatum) compared with the placebo. 5.1 Lactic Acidosis and Severe Hepatomegaly with Steatosis Diarrhea <1% 2% Medications containing polyvalent Administer dolutegravir, lamivudine, and tenofovir 12.3 Pharmacokinetics Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues General Disorders cations (e.g., Mg or Al): disoproxil fumarate tablets 2 hours before or 6 a ↓Dolutegravir Pharmacokinetics in Aduts and other antiretrovirals. See full prescribing information for lamivudine and tenofovir disoproxil fumarate. Treatment with dolutegravir, Cation-containing antacids or laxatives hours after taking medications containing polyvalent Fatigue 2% 2% lamivudine, and tenofovir disoproxil fumarate tablets should be suspended in any patient who develops clinical or laboratory findings Sucralfate Buffered medications cations. Dolutegravir, Lamivudine and Tenofovir Disoproxil Fumarate Tablets suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked Skin and Subcutaneous Tissue Administer dolutegravir, lamivudine, and tenofovir Dolutegravir, lamivudine and tenofovir disoproxil fumarate from the combination tablets (50 mg/300 mg/300 mg) were comparable to transaminase elevations). a disoproxil fumarate tablets 2 hours before or 6 that from TIVICAY tablets of ViiV USA (containing dolutegravir 50 mg), EPIVIR tablets of ViiV USA (containing lamivudine 300 mg), and Rash <1% 6% Oral calcium or iron supplements, hours after taking supplements containing calcium VIREAD tablets of Gilead Sciences, Inc. USA (containing tenofovir disoproxil fumarate 300 mg), respectively, when single doses were 5.2 Patients with Hepatitis B Virus Co-infection including multivitamins containing ↓Dolutegravir Ear and Labyrinth or iron. Alternatively, dolutegravir and supplements administered to healthy subjects under fasted and fed conditions. calcium or irona It is recommended that all patients with HIV-1 be tested for the presence of chronic HBV before initiating antiretroviral therapy. containing calcium or iron can be taken together Dolutegravir, lamivudine, and tenofovir disoproxil fumarate tablets are not approved for the treatment of chronic HBV infection, and the Vertigo 0 2% Dolutegravir: Following oral administration of dolutegravir, peak plasma concentrations were observed 2 to 3 hours postdose. With with food. once-daily dosing, pharmacokinetic steady state is achieved within approximately 5 days with average accumulation ratios for AUC, C , safety and efficacy of dolutegravir, lamivudine, and tenofovir disoproxil fumarate tablets have not been established in patients coinfected a Includes pooled terms: rash, rash generalized, rash macular, rash maculo-papular, rash pruritic, and drug eruption. max with HBV and HIV-1. With concomitant use, limit the total daily dose and C24 h ranging from 1.2 to 1.5. Dolutegravir is a P-glycoprotein substrate in vitro. The absolute of dolutegravir has not Treatment-Experienced Subjects: SAILING is an international, double-blind trial in INSTI-naïve, antiretroviral treatment-experienced adult of metformin to 1,000 mg either when starting been established. Dolutegravir is highly bound (greater than or equal to 98.9%) to human plasma proteins based on in vivo data and Dolutegravir, lamivudine, and tenofovir disoproxil fumarate tablets should not be administered with HEPSERA® (adefovir dipivoxil) [see subjects. Subjects were randomized and received either dolutegravir 50 mg once daily or 400 mg twice daily with investigator- metformin or dolutegravir, lamivudine, and tenofovir binding is independent of plasma concentration of dolutegravir. The apparent volume of distribution (Vd/F) following 50-mg once-daily Drug Interactions (7.8)]. selected background regimen consisting of up to 2 agents, including at least one fully active agent. At 48 weeks, the rate of adverse events disoproxil fumarate tablets. When stopping administration is estimated at 17.4 L based on a population pharmacokinetic analysis. Effects on Serum Liver Biochemistries: Hepatic adverse events have been reported in patients receiving a dolutegravir-containing regimen. leading to discontinuation was consistent with that seen in the overall treatment-naïve patient population. See full prescribing information dolutegravir, lamivudine, and tenofovir disoproxil 14 Metformin ↑Metformin Dolutegravir is primarily metabolized via UGT1A1 with some contribution from CYP3A. After a single oral dose of [ C] dolutegravir, 53% Patients with underlying hepatitis B or C may be at increased risk for worsening or development of transaminase elevations with use for dolutegravir. fumarate tablets, the metformin dose may require of the total oral dose is excreted unchanged in the feces. Thirty-one percent of the total oral dose is excreted in the urine, represented of dolutegravir, lamivudine, and tenofovir disoproxil fumarate tablets [see Adverse Reactions (6.1)]. See full prescribing information The ADRs observed in the subset of subjects who received dolutegravir + fixed-dose abacavir sulfate and lamivudine were generally an adjustment. Monitoring of blood glucose when by an ether glucuronide of dolutegravir (18.9% of total dose), a metabolite formed by oxidation at the benzylic carbon (3.0% of total for dolutegravir. In some cases the elevations in transaminases were consistent with immune reconstitution syndrome or hepatitis B consistent with those seen in the overall treatment-naïve patient population. initiating concomitant use and after withdrawal of dose), and its hydrolytic N-dealkylation product (3.6% of total dose). Renal elimination of unchanged drug was less than 1% of the dose. reactivation particularly in the setting where anti-hepatitis therapy was withdrawn. Cases of hepatic toxicity, including elevated serum dolutegravir, lamivudine, and tenofovir disoproxil Dolutegravir has a terminal half-life of approximately 14 hours and an apparent clearance (CL/F) of 1.0 L per hour based on population Less Common Adverse Reactions Observed in Treatment-Naïve and Treatment-Experienced Trials: The following ARs occurred in less than liver biochemistries, hepatitis, and acute liver failure have been reported in patients receiving a dolutegravir-containing regimen without fumarate tablets is recommended. pharmacokinetic analyses. pre-existing hepatic disease or other identifiable risk factors. Drug-induced liver injury leading to liver transplant has been reported with 2% of treatment-naïve or treatment-experienced subjects receiving dolutegravir in a combination regimen in any one trial. These events TRIUMEQ (abacavir, dolutegravir, and lamivudine). Monitoring for hepatotoxicity is recommended. have been included because of their seriousness and assessment of potential causal relationship. Adjust dolutegravir dose to 50 mg twice daily. An The pharmacokinetic properties of dolutegravir have been evaluated in healthy adult subjects and HIV-1-infected adult subjects. Exposure additional 50-mg dose of dolutegravir should be to dolutegravir was generally similar between healthy subjects and HIV-1-infected subjects. Posttreatment Exacerbations of Hepatitis: Clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation Gastrointestinal Disorders: Abdominal pain, abdominal discomfort, flatulence, upper abdominal pain, . Rifampina ↓Dolutegravir taken, separated by 12 hours from dolutegravir, Table 6. Dolutegravir Steady-State Pharmacokinetic Parameter Estimates in HIV-1-Infected Adults of lamivudine or tenofovir disoproxil fumarate. See full prescribing information for lamivudine and tenofovir disoproxil fumarate. Patients Hepatobiliary Disorders: Hepatitis. lamivudine, and tenofovir disoproxil fumarate should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. Musculoskeletal Disorders: Myositis. tablets. Parameter 50 mg Once Daily Geometric Mean (%CV) Emergence of Lamivudine-Resistant HBV: Safety and efficacy of lamivudine have not been established for treatment of chronic hepatitis B Psychiatric Disorders: Suicidal ideation, attempt, behavior, or completion. These events were observed primarily in subjects with a pre- a See Clinical Pharmacology (12.3) Table 8 or Table 9 for magnitude of interaction. AUC (mcg•h/mL) 53.6 (27) in subjects dually infected with HIV-1 and HBV. Emergence of hepatitis B virus variants associated with resistance to lamivudine has also (0-24) been reported in HIV-1-infected subjects who have received lamivudine-containing antiretroviral regimens in the presence of concurrent existing history of depression or other psychiatric illness. 7.4 Drugs without Clinically Significant Interactions with Dolutegravir Cmax (mcg/mL) 3.67 (20) infection with hepatitis B virus. See full prescribing information for lamivudine. Renal and Urinary Disorders: Renal impairment. Based on drug interaction trial results, the following drugs can be coadministered with dolutegravir without a dose adjustment: atazanavir/ Cmin (mcg/mL) 1.11 (46) 5.3 Hypersensitivity Reactions Skin and Subcutaneous Tissue Disorders: Pruritus. ritonavir, darunavir/ritonavir, daclatasvir, elbasvir/grazoprevir, , midazolam, omeprazole, oral contraceptives containing norgestimate and ethinyl estradiol, prednisone, rifabutin, , sofosbuvir/velpatasvir, and tenofovir [see Clinical Pharmacology Cerebrospinal Fluid (CSF): In 11 treatment-naïve subjects on dolutegravir 50 mg daily plus abacavir/lamivudine, the median dolutegravir Hypersensitivity reactions have been reported and were characterized by rash, constitutional findings, and sometimes organ dysfunction, Laboratory Abnormalities: Treatment-Naïve Subjects: Selected laboratory abnormalities (Grades 2 to 4) with a worsening grade from (12.3)]. concentration in CSF was 18 ng per mL (range: 4 ng per mL to 23.2 ng per mL) 2 to 6 hours postdose after 2 weeks of treatment. The including liver injury. The events were reported in less than 1% of subjects receiving dolutegravir in Phase 3 clinical trials. Discontinue baseline and representing the worst-grade toxicity in at least 2% of subjects in SINGLE are presented in Table 3. The mean change from clinical relevance of this finding has not been established. dolutegravir, lamivudine, and tenofovir disoproxil fumarate tablets and other suspect agents immediately if signs or symptoms of baseline observed for selected lipid values is presented in Table 4. 7.5 Didanosine Lamivudine: Following oral administration, lamivudine is rapidly absorbed and extensively distributed. After multiple dose oral hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general , fatigue, Coadministration of dolutegravir, lamivudine and tenofovir disoproxil fumarate tablets and didanosine should be undertaken with caution Table 3. Selected Laboratory Abnormalities (Grades 2 to 4) in Treatment‑Naïve Subjects in SINGLE (Week 144 Analysis) administration of lamivudine 300 mg once daily for 7 days to 60 healthy subjects, steady-state C (C ) was 2.04 ± 0.54 mcg per muscle or joint aches, blisters or peeling of the skin, oral blisters or lesions, conjunctivitis, facial edema, hepatitis, , and patients receiving this combination should be monitored closely for didanosine-associated adverse reactions. Didanosine should be max max,ss mL (mean ±SD) and the 24 hour steady state AUC (AUC ) was 8.87 ± 1.83 mcg•hour per mL. Binding to plasma protein is low. angioedema, difficulty breathing). Clinical status, including liver aminotransferases, should be monitored and appropriate therapy initiated. Dolutegravir + Abacavir Sulfate and Efavirenz/Emtricitabine/ discontinued in patients who develop didanosine-associated adverse reactions. 24,ss Delay in stopping treatment with dolutegravir, lamivudine, and tenofovir disoproxil fumarate tablets or other suspect agents after the onset Laboratory Abnormality Lamivudine Once Daily Tenofovir Disoproxil Fumarate Approximately 70% of an intravenous dose of lamivudine is recovered as unchanged drug in the urine. Metabolism of lamivudine is a When tenofovir disoproxil fumarate was administered with didanosine, C and AUC of didanosine increased significantly [see Clinical of hypersensitivity may result in a life-threatening reaction. (n = 414) Once Daily (n = 419) max minor route of elimination. In humans, the only known metabolite is the trans sulfoxide metabolite (approximately 5% of an oral dose after Pharmacology (12.3)]. The mechanism of this interaction is unknown. Higher didanosine concentrations could potentiate didanosine- 12 hours). In most single-dose trials in HIV-1-infected subjects, HBV-infected subjects, or healthy subjects with serum sampling for 24 5.4 Pancreatitis ALT associated adverse reactions, including pancreatitis and neuropathy. Suppression of CD4+ cell counts has been observed in patients hours after dosing, the observed mean elimination half-life (t½) ranged from 5 to 7 hours. In HIV-1-infected subjects, total clearance was In pediatric patients with a history of prior antiretroviral nucleoside exposure, a history of pancreatitis, or other significant risk factors for Grade 2 (>2.5 to 5.0 x ULN) 3% 5% receiving tenofovir disoproxil fumarate with didanosine 400 mg daily. 398.5 ± 69.1 mL per min (mean ± SD). the development of pancreatitis, dolutegravir, lamivudine, and tenofovir disoproxil fumarate tablets should be used with caution. Treatment In patients weighing greater than 60 kg, the didanosine dose should be reduced to 250 mg once daily when it is coadministered with Tenofovir Disoproxil Fumarate: The pharmacokinetic properties of tenofovir disoproxil fumarate are summarized in Table 7. Following oral with dolutegravir, lamivudine, and tenofovir disoproxil fumarate tablets should be stopped immediately if clinical signs, symptoms, or Grade 3 to 4 (>5.0 x ULN) 1% <1% dolutegravir, lamivudine and tenofovir disoproxil fumarate tablets. Data are not available to recommend a dose adjustment of didanosine administration of tenofovir disoproxil fumarate, maximum tenofovir serum concentrations are achieved in 1.0 ± 0.4 hour. Less than 0.7% laboratory abnormalities suggestive of pancreatitis occur [see Adverse Reactions (6.1)]. AST for adult of pediatric patients weighing less than 60 kg. When coadministered, dolutegravir, lamivudine and tenofovir disoproxil fumarate of tenofovir binds to human plasma proteins in vitro and the binding is independent of concentration over the range of 0.01 to 25 mcg/mL. tablets and didanosine EC may be taken under fasted conditions or with a light meal (less than 400 kcal, 20% fat). 5.5 New Onset or Worsening Renal Impairment Grade 2 (>2.5 to 5.0 x ULN) 3% 4% Approximately 70 to 80% of the intravenous dose of tenofovir is recovered as unchanged drug in the urine. Tenofovir is eliminated by a Because dose interval adjustment requirement for tenofovir disoproxil fumarate for patients with CrCL below 50 mL/min and dose 7.6 HIV-1 Protease Inhibitors combination of glomerular filtration and active tubular secretion. Following a single oral dose of tenofovir disoproxil fumarate, the terminal Grade 3 to 4 (>5.0 x ULN) 1% 3% elimination half-life of tenofovir is approximately 17 hours. adjustments of lamivudine cannot be achieved with dolutegravir, lamivudine, and tenofovir disoproxil fumarate tablets, patients with Tenofovir disoproxil fumarate decreases the AUC and C of atazanavir [see Clinical Pharmacology (12.3)]. When coadministered with min a estimated creatinine clearance below 50 mL/min should not receive dolutegravir, lamivudine, and tenofovir disoproxil fumarate tablets. Creatine kinase dolutegravir, lamivudine and tenofovir disoproxil fumarate tablets, it is recommended that atazanavir 300 mg is given with ritonavir Table 7. Single Dose Pharmacokinetic Parameters for Tenofovir in Adults 100 mg. Dolutegravir, lamivudine and tenofovir disoproxil fumarate tablets should not be coadministered with atazanavir without ritonavir. Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has Grade 2 (6.0 to 9.9 x ULN) 5% 3% Tenofovir been reported with the use of tenofovir disoproxil fumarate [see Adverse Reactions (6.2)]. Lopinavir/ritonavir, atazanavir coadministered with ritonavir, and darunavir coadministered with ritonavir have been shown to increase Grade 3 to 4 (≥10.0 x ULN) 7% 8% Fasted Oral Bioavailabilityb (%) 25 (NC to 45.0) It is recommended that estimated creatinine clearance be assessed in all patients prior to initiating therapy and as clinically appropriate tenofovir concentrations [see Clinical Pharmacology (12.3)]. Tenofovir disoproxil fumarate is a substrate of P-glycoprotein (Pgp) and during therapy with dolutegravir, lamivudine, and tenofovir disoproxil fumarate tablets. In patients at risk of renal dysfunction, including Hyperglycemia breast cancer resistance protein (BCRP) transporters. When tenofovir disoproxil fumarate is coadministered with an inhibitor of these Plasma Terminal Elimination Half-Lifeb (hr) 17 (12.0 to 25.7) patients who have previously experienced renal events while receiving adefovir dipivoxil (HEPSERA), it is recommended that estimated transporters, an increase in absorption may be observed. Patients receiving dolutegravir, lamivudine and tenofovir disoproxil fumarate Grade 2 (126 to 250 mg/dL) 9% 6% C c (mcg/mL) 0.30±0.09 creatinine clearance, serum phosphorus, urine glucose, and urine protein be assessed prior to initiation of dolutegravir, lamivudine, and tablets concomitantly with lopinavir/ritonavir, ritonavir-boosted atazanavir, or ritonavir-boosted darunavir should be monitored for max tenofovir disoproxil fumarate tablets and periodically during dolutegravir, lamivudine, and tenofovir disoproxil fumarate tablets therapy. Grade 3 (>250 mg/dL) 2% <1% tenofovir disoproxil fumarate-associated adverse reactions. Dolutegravir, lamivudine and tenofovir disoproxil fumarate tablets should be AUCc (mcg·hr/mL) 2.29±0.69 discontinued in patients who develop tenofovir disoproxil fumarate-associated adverse reactions. Dolutegravir, lamivudine, and tenofovir disoproxil fumarate tablets should be avoided with concurrent or recent use of a nephrotoxic agent Lipase CL/Fc (mL/min) 1043±115 7.7 Hepatitis C Antiviral Agents (e.g., high-dose or multiple non-steroidal anti-inflammatory drugs (NSAIDs) [see Drug Interactions (7.8)]. Cases of acute renal failure Grade 2 (>1.5 to 3.0 x ULN) 11% 11% c CLrenal (mL/min) 243±33 after initiation of high-dose or multiple NSAIDs have been reported in HIV-infected patients with risk factors for renal dysfunction who Coadministration of dolutegravir, lamivudine and tenofovir disoproxil fumarate tablets and sofosbuvir/velpatasvir (EPCLUSA) or ledipasvir/ Grade 3 to 4 (>3.0 ULN) 5% 4% a. NC=Not calculated appeared stable on tenofovir DF. Some patients required hospitalization and renal replacement therapy. Alternatives to NSAIDs should be sofosbuvir (HARVONI) has been shown to increase tenofovir exposure [see Clinical Pharmacology (12.3)]. b. Median (range) considered, if needed, in patients at risk for renal dysfunction. Total neutrophils In patients receiving dolutegravir, lamivudine and tenofovir disoproxil fumarate tablets concomitantly with sofosbuvir/velpatasvir, monitor c. Mean (± SD) Persistent or worsening bone pain, pain in extremities, fractures and/or muscular pain or weakness may be manifestations of proximal Grade 2 (0.75 to 0.99 x 109) 4% 5% for adverse reactions associated with tenofovir disoproxil fumarate. renal tubulopathy and should prompt an evaluation of renal function in at-risk patients. Effects of Food on Oral Absorption of Dolutegravir, lamivudine and tenofovir disoproxil fumarate: The effect of food on dolutegravir, Grade 3 to 4 (<0.75 x 109) 3% 3% In patients receiving dolutegravir, lamivudine and tenofovir disoproxil fumarate tablets concomitantly with ledipasvir/sofosbuvir without lamivudine and tenofovir disoproxil fumarate tablets has not been evaluated. Based on cross trial comparisons, the pharmacokinetics of 5.6 Use with Interferon- and Ribavirin-Based Regimens ULN = Upper limit of normal. an HIV-1 protease inhibitor/ritonavir or an HIV-1 protease inhibitor/ combination, monitor for adverse reactions associated with dolutegravir, lamivudine, and tenofovir is not anticipated to be significantly affected by food, hence dolutegravir, lamivudine, and tenofovir Patients receiving interferon alfa with or without ribavirin and dolutegravir, lamivudine, and tenofovir disoproxil fumarate tablets should be tenofovir disoproxil fumarate. disoproxil fumarate tablets can be administered with or without food. Table 4. Mean Change from Baseline in Fasted Lipid Values in Treatment‑Naïve Subjects in SINGLE (Week 144 Analysisa) closely monitored for treatment associated toxicities, especially hepatic decompensation. See full prescribing information for lamivudine. In patients receiving dolutegravir, lamivudine and tenofovir disoproxil fumarate tablets concomitantly with ledipasvir/sofosbuvir and an Specific Populations Discontinuation of dolutegravir, lamivudine, and tenofovir disoproxil fumarate tablets should be considered as medically appropriate. Dose HIV-1 protease inhibitor/ritonavir or an HIV-1 protease inhibitor/cobicistat combination, consider an alternative HCV or antiretroviral Dolutegravir + Abacavir Sulfate and Efavirenz/Emtricitabine/Tenofovir Patients with Hepatic Impairment: Dolutegravir: Dolutegravir is primarily metabolized and eliminated by the liver. In a trial comparing 8 reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if worsening clinical toxicities are observed, therapy, as the safety of increased tenofovir concentrations in this setting has not been established. If coadministration is necessary, Lipid Lamivudine Once Daily Disoproxil Fumarate Once Daily subjects with moderate hepatic impairment (Child-Pugh Score B) with 8 matched healthy controls, exposure of dolutegravir from a single including hepatic decompensation (e.g., Child Pugh greater than 6) (see full prescribing information for interferon and ribavirin). monitor for adverse reactions associated with tenofovir disoproxil fumarate. (n = 414) (n = 419) 50 mg dose was similar between the 2 groups. The effect of severe hepatic impairment (Child-Pugh Score C) on the pharmacokinetics of 5.7 Related Products that are Not Recommended Cholesterol (mg/dL) 24.0 26.7 7.8 Drugs Affecting Renal Function dolutegravir has not been studied. Dolutegravir, lamivudine, and tenofovir disoproxil fumarate tablets contains fixed doses of an INSTI (dolutegravir) and 2 nucleoside HDL cholesterol (mg/dL) 5.4 7.2 Since tenofovir is primarily eliminated by the kidneys [see Clinical Pharmacology (12.3)], coadministration of dolutegravir, lamivudine and HBV/HCV Co-infected Patients: Dolutegravir: Population analyses using pooled pharmacokinetic data from adult trials indicated no analogue reverse transcriptase inhibitors (lamivudine and tenofovir disoproxil fumarate); concomitant administration of dolutegravir, tenofovir disoproxil fumarate tablets with drugs that reduce renal function or compete for active tubular secretion may increase serum clinically relevant effect of HCV co-infection on the pharmacokinetics of dolutegravir. There were limited data on HBV co-infection. lamivudine, and tenofovir disoproxil fumarate tablets with other products containing lamivudine, emtricitabine, tenofovir disoproxil LDL cholesterol (mg/dL) 16.0 14.6 concentrations of tenofovir and/or increase the concentrations of other renally eliminated drugs. Some examples include, but are not Lamivudine: The pharmacokinetic properties of lamivudine have been determined in adults with impaired hepatic function. Pharmacokinetic fumarate, or tenofovir alafenamide is not recommended. limited to, adefovir dipivoxil, cidofovir, acyclovir, valacyclovir, ganciclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high- Triglycerides (mg/dL) 13.6 31.9 parameters were not altered by diminishing hepatic function. Safety and efficacy of lamivudine have not been established in the presence dose or multiple NSAIDs [see Warnings and Precautions (5.5)]. 5.8 Bone Effects of Tenofovir Disoproxil Fumarate a Subjects on lipid-lowering agents at baseline were excluded from these analyses (dolutegravir + fixed-dose abacavir sulfate and of decompensated . 7.9 Sorbitol Bone Mineral Density: In clinical trials in HIV-1 infected adults, tenofovir disoproxil fumarate was associated with slightly greater decreases lamivudine n = 30 and fixed-dose efavirenz/emtricitabine/tenofovir disoproxil fumarate n = 27). Seventy-two subjects initiated a lipid- Tenofovir Disoproxil Fumarate: The pharmacokinetics of tenofovir following a 300 mg single dose of tenofovir disoproxil fumarate have in bone mineral density (BMD) and increases in biochemical markers of bone metabolism, suggesting increased bone turnover relative lowering agent post-baseline; their last fasted on-treatment values (prior to starting the agent) were used regardless if they discontinued Coadministration of single doses of lamividine and sorbitol resulted in a sorbitol dose-dependent reduction in lamivudine exposures. been studied in non-HIV infected subjects with moderate to severe hepatic impairment. There were no substantial alterations in tenofovir to comparators. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in subjects receiving tenofovir disoproxil the agent (dolutegravir + fixed-dose abacavir sulfate and lamivudine n = 36 and fixed-dose efavirenz/emtricitabine/tenofovir disoproxil When possible, avoid use of sorbitol-containing medicines with lamivudine [see Clinical Pharmacology (12.3)]. pharmacokinetics in subjects with hepatic impairment compared with unimpaired subjects. No change in tenofovir disoproxil fumarate fumarate. fumarate n = 36). 8 USE IN SPECIFIC POPULATIONS dosing is required in patients with hepatic impairment. Clinical trials evaluating tenofovir disoproxil fumarate in pediatric and adolescent subjects were conducted. Under normal circumstances, Treatment-Experienced Subjects: Laboratory abnormalities observed in SAILING were generally similar compared with observations seen 8.1 Pregnancy Patients with Renal Impairment: Because dolutegravir, lamivudine and tenofovir disoproxil fumarate tablets are a fixed-dose tablet and BMD increases rapidly in pediatric patients. In HIV-1 infected subjects aged 2 years to less than 18 years, bone effects were similar to in the treatment-naïve trials. cannot be dose adjusted, dolutegravir, lamivudine and tenofovir disoproxil fumarate tablets are not recommended in patients requiring those observed in adult subjects and suggest increased bone turnover. Total body BMD gain was less in the tenofovir disoproxil fumarate- Hepatitis B and/or Hepatitis C Virus Co-infection: In Phase 3 trials, subjects with hepatitis B and/or C virus co-infection were permitted to Pregnancy Category C. There are no adequate and well controlled trials in pregnant women. Reproduction studies with the components dosage adjustment or patients with renal impairment [see Dosage and Administration (2.3)]. treated HIV-1 infected pediatric subjects as compared to the control groups. Similar trends were observed in chronic hepatitis B infected enroll provided that baseline liver chemistry tests did not exceed 5 times the upper limit of normal. Overall, the safety profile in subjects of dolutegravir, lamivudine and tenofovir disoproxil fumarate tablets have been performed in animals (see Dolutegravir, Abacavir, and adolescent subjects aged 12 years to less than 18 years. In all pediatric trials, skeletal growth (height) appeared to be unaffected. For more Lamivudine sections below). Animal reproduction studies are not always predictive of human response. Dolutegravir, lamivudine and Gender: There are no significant or clinically relevant gender differences in the pharmacokinetics of the individual components (dolutegravir, with hepatitis B and/or C virus co-infection was similar to that observed in subjects without hepatitis B or C co-infection, although the rates lamivudine or tenofovir disoproxil fumarate) based on the available information that was analyzed for each of the individual components. information, consult the tenofovir disoproxil fumarate prescribing information. of AST and ALT abnormalities were higher in the subgroup with hepatitis B and/or C virus co-infection for all treatment groups. Grades 2 to tenofovir disoproxil fumarate tablets should be used during pregnancy only if the potential benefit outweigh the risks. The effects of tenofovir disoproxil fumarate-associated changes in BMD and biochemical markers on long-term bone health and future 4 ALT abnormalities in hepatitis B and/or C co-infected compared with HIV mono-infected subjects receiving dolutegravir were observed Animal Data Race: Dolutegravir and Lamivudine: There are no significant or clinically relevant racial differences in the pharmacokinetics of dolutegravir fracture risk are unknown. Assessment of BMD should be considered for adults and pediatric patients who have a history of pathologic in 18% vs. 3% with the 50 mg once-daily dose and 13% vs. 8% with the 50 mg twice-daily dose. Liver chemistry elevations consistent or lamivudine based on the available information that was analyzed for each of the individual components. Dolutegravir: Reproduction studies performed in rats and rabbits at doses up to 50 times the human dose of 50 mg once daily have bone fracture or other risk factors for osteoporosis or bone loss. Although the effect of supplementation with calcium and vitamin D was with immune reconstitution syndrome were observed in some subjects with hepatitis B and/or C at the start of therapy with dolutegravir, revealed no evidence of impaired fertility or harm to the fetus due to dolutegravir. Tenofovir Disoproxil Fumarate: There were insufficient numbers from racial and ethnic groups other than Caucasian to adequately not studied, such supplementation may be beneficial for all patients. If bone abnormalities are suspected then appropriate consultation particularly in the setting where anti-hepatitis therapy was withdrawn [see Warnings and Precautions (5.2)]. determine potential pharmacokinetic differences among these populations. Oral administration of dolutegravir to pregnant rats at doses up to 1,000 mg per kg daily, approximately 50 times the 50-mg once- should be obtained. Changes in Serum Creatinine: Dolutegravir has been shown to increase serum creatinine due to inhibition of tubular secretion of creatinine daily human clinical exposure based on AUC, from days 6 to 17 of gestation did not elicit maternal toxicity, developmental toxicity, or Geriatric Patients: Dolutegravir: Population pharmacokinetic analysis indicated age had no clinically relevant effect on the pharmacokinetics Mineralization Defects: Cases of osteomalacia associated with proximal renal tubulopathy, manifested as bone pain or pain in extremities and without affecting renal glomerular function [see Clinical Pharmacology (12.2)]. Increases in serum creatinine occurred within the first teratogenicity. of dolutegravir. which may contribute to fractures, have been reported in association with the use of tenofovir disoproxil fumarate [see Adverse Reactions 4 weeks of treatment and remained stable through 96 weeks. In treatment-naïve subjects, a mean change from baseline of 0.15 mg per Lamivudine and Tenofovir Disoproxil Fumarate: The pharmacokinetics of lamivudine or tenofovir disoproxil fumarate have not been (6.2)]. Arthralgias and muscle pain or weakness have also been reported in cases of proximal renal tubulopathy. Hypophosphatemia and dL (range: -0.32 mg per dL to 0.65 mg per dL) was observed after 96 weeks of treatment. Creatinine increases were comparable by Oral administration of dolutegravir to pregnant rabbits at doses up to 1,000 mg per kg daily, approximately 0.74 times the 50-mg once- studied in subjects older than 65 years. osteomalacia secondary to proximal renal tubulopathy should be considered in patients at risk of renal dysfunction who present with background NRTIs and were similar in treatment-experienced subjects. daily human clinical exposure based on AUC, from days 6 to 18 of gestation did not elicit developmental toxicity or teratogenicity. In rabbits, maternal toxicity (decreased food consumption, scant/no feces/urine, suppressed body weight gain) was observed at 1,000 mg persistent or worsening bone or muscle symptoms while receiving products containing tenofovir disoproxil fumarate [see Warnings and Clinical Trials Experience in Pediatric Subjects: IMPAACT P1093 is an ongoing multicenter, open-label, non-comparative trial of Pediatric Patients: Dolutegravir, lamivudine and tenofovir disoproxil fumarate tablets should not be administered to pediatric patients Precautions (5.5)]. per kg. weighing less than 40 kg (88 lbs).

A/s: 480 x 680 mm Black

Product Name Component Item Code Date & Time Dolutegravir, Lamivudine and Tenofovir Disoproxil Fumarate Tablets Leaflet P1518054 26.04.2018 & 12.15 pm Country Version No. Reason Of Issue Reviewed / Approved by USA - APL 03 Submission Team Leader Ramesh Sajja Dimensions (mm) Colours

Sitaram 480 x 680 mm Initiator No Of Colours: 01

Artist Sree Designers Pharma Code: 18054 Dotted lines and pink colored text not be printed

Additional Information: Supersedes Code: P1512976

Vittalbala 18054 Table 10.DrugInteractions:ChangesinPharmacokineticParametersforTenofovir oral contraceptives,ribavirin,orsofosbuvir. betweentenofovir disoproxilfumarate andefavirenz,methadone,,No clinicallysignificantdruginteractions have beenobserved coated capsulesaloneunderfastedconditions(Table 11).Themechanismofthisinteractionisunknown. administered with tenofovirdisoproxil fumarate, systemic exposures of didanosinewere similar tothose seen withthe400mgenteric- fumarate withdidanosinesignificantlyincreasestheC results inchangesthepharmacokineticsofdidanosinethatmaybeclinicalsignificance.Concomitantdosingtenofovirdisoproxil disoproxil fumarateonthepharmacokineticsofcoadministereddrug.Coadministrationtenofovirwithdidanosine drugs. Tables 10and11summarizepharmacokineticeffectsofcoadministereddrugontenofovirpharmacokinetics effectsoftenofovir Tenofovir disoproxilfumaratehasbeenevaluatedinhealthyvolunteerscombinationwithotherantiretroviralandpotential concomitant products islow. and theknowneliminationpathwayoftenofovir, thepotentialforCYP-mediatedinteractionsinvolvingtenofovirwith othermedicinal Based onthe resultsof (6%) but statistically significant reduction inmetabolism of CYP1Asubstrate wasobserved. vitro Tenofovir DisoproxilFumarate: higher dosesofTMP/SMXsuchasthoseusedintreatPCP. were notalteredbycoadministrationwithlamivudine.Thereisnoinformationregardingtheeffectonlamivudinepharmacokineticsof lamivudine oralclearance, and adecrease of 30%±36%inlamivudinerenalclearance. The pharmacokinetic properties of TMPandSMX Effect ofOtherAgentsonthePharmacokineticsLamivudine: (MATE1), MATE2-K, organiccationtransporter1(OCT1),OCT2,orOCT3. polypeptide 1B1/3(OATP1B1/3), breastcancerresistance protein (BCRP),P-glycoprotein(P-gp),multidrugandtoxinextrusion1 is not expected to affect the pharmacokinetics of drugs that are substrates of the following transporters: organic anion transporter d c b a of TMP/SMXwithlamivudineresultedinanincrease43%±23%(meanSD)AUC once adayfor5dayswithconcomitantadministrationoflamivudine300mgthefifthdoseincrossoverdesign.Coadministration label, randomized,crossovertrial.Eachsubjectreceivedtreatmentwithasingle300mgdoseoflamivudineandTMP160mg/SMX800 Trimethoprim/Sulfamethoxazole C dose-dependent decreasesof20%,39%,and44%intheAUC a singledoseof3.2grams,10.2or13.4gramssorbitolinsolution.Coadministrationlamivudinewithresulted sequence, 4-period,crossovertrial.Eachsubjectreceivedasingle300mgdoseoflamivudineoralsolutionaloneorcoadministeredwith Sorbitol (Excipient): were coadministeredaspartofamulti-drugregimentoHIV-1/HCV co-infectedsubjects whenribavirinandlamivudine(n=18),stavudine10),orzidovudine6) HCV virologicsuppression)interactionwasobserved activemetaboliteconcentrations)orpharmacodynamic(e.g.,lossofHIV-1/(e.g., plasmaconcentrationsorintracellulartriphosphorylated Ribavirin subjects Alfa Interferon is unlikelytoaffectthedispositionandeliminationoflamivudine. play asignificantroleintheabsorptionoflamivudine.Therefore, coadministrationofdrugsthatareinhibitorstheseeffluxtransporters Lamivudine isasubstrateofP-gpandBCRP;however, consideringitsabsolutebioavailability(87%),itisunlikelythat thesetransporters not consideredclinicallysignificantasnodoseadjustmentoflamivudineisneeded. Trimethoprim (an inhibitor of these drug transporters) has been shown toincrease lamivudine plasma concentrations. This interaction is Effect ofLamivudineonthePharmacokineticsOtherAgents Lamivudine: c b a Table ofEffectCoadministeredDrugsonthePharmacokineticsDolutegravir 9.Summary a Table ofEffectDolutegravironthePharmacokineticsCoadministeredDrugs 8.Summary in Section7.3 Dosing recommendations as a result of established and other potentially significant drug-drug interactions with dolutegravir are provided clinically significantdruginteractionsareexpectedbetweendolutegravirandlamivudine. no drug interaction trials havebeen conducted using the combination of dolutegravir, lamivudine, and tenofovir disoproxil fumarate. No The druginteractiontrialsdescribedwereconductedwithdolutegravir, lamivudine,and/ortenofovirdisoproxilfumarateassingleentities; Assessment ofDrugInteractions: receiving once-dailydosesoftenofovirdisoproxilfumarate300mg. in thesepediatricsubjectsreceivingoraldailydosesoftenofovirdisoproxilfumarate300mgwassimilartoexposuresachievedadults than 18 years). Mean ± SD C Tenofovir DisoproxilFumarate: been established. Dolutegravir andLamivudine: Reyataz (atazanavir)PrescribingInformation Subjects receivedtenofovirdisoproxilfumarate300mgoncedaily. The numberofsubjectsrepresentsthemaximumthatwereevaluated. Comparison isrifampintakenwithdolutegravir50mgtwicedailycompareddaily. The numberofsubjectsrepresentsthemaximumthatwereevaluated. Increase = Comparison isrifampintakenwithdolutegravir50mgtwicedailycomparedoncedaily. Prezista (darunavir)PrescribingInformation Rifabutin Rifampin Rifampin Prednisone Omeprazole Multivitamin (One-A-Day) Ferrous fumarate324mg Ferrous fumarate324mg Ferrous fumarate324mg Daclatasvir Carbamazepine Calcium carbonate1,200mg Calcium carbonate1,200mg Calcium carbonate1,200mg Antacid (MAALOX) Antacid (MAALOX) Tipranavir/ritonavir Tenofovir Rilpivirine Lopinavir/ritonavir Fosamprenavir/ritonavir Etravirine +lopinavir/ritonavir Etravirine +darunavir/ritonavir Etravirine 50 mg/200mgoncedaily Elbasvir/grazoprevir Efavirenz Darunavir/ritonavir Atazanavir/ritonavir Atazanavir 100mgoncedaily Velpatasvir Tenofovir disoproxilfumarate Metabolite (GS-331007) 400 mgoncedaily Sofosbuvir Rilpivirine Norelgestromin Midazolam Methadone Metformin Metformin 200mgoncedaily Grazoprevir Ethinyl estradiol 50 mgoncedaily Elbasvir Daclatasvir Ritonavir Tipranavir/ Tacrolimus Velpatasvir Sofosbuvir/ Velpatasvir Sofosbuvir/ Velpatasvir Sofosbuvir/ Velpatasvir Sofosbuvir/ Velpatasvir Sofosbuvir/ Velpatasvir Sofosbuvir/ Sofosbuvir Ritonavir / Ritonavir Lopinavir/ Ledipasvir/ Sofosbuvir Ledipasvir/ Sofosbuvir Ledipasvir/ Sofosbuvir Ledipasvir/ Sofosbuvir Ledipasvir/ Sofosbuvir Ritonavir Darunavir/ Ritonavir Atazanavir/ Atazanavir max Coadministered Drug(s)and oflamivudine. Coadministered Drug(s)and Coadministered Drug 300 mgoncedaily 600 mgoncedaily 600 mgoncedaily 60 mgoncedailywithtaper 40 mgoncedaily simultaneous administration 2 hafterdolutegravir (fed) simultaneous administration (fasted) simultaneous administration 60 mgoncedaily 300 mgtwicedaily 2 hafterdolutegravir (fed) simultaneous administration (fasted) simultaneous administration 2 hafterdolutegravir simultaneous administration 500 mg/200mgtwicedaily 300 mgoncedaily 25 mgoncedaily 400 mg/100mgtwicedaily 700 mg/100mgtwicedaily twice daily 200 mg+400mg/100 twice daily 200 mg+600mg/100 200 mgtwicedaily 600 mgoncedaily 600 mg/100mgtwicedaily 300 mg/100mgoncedaily 400 mgoncedaily 300 mgoncedaily 25 mgoncedaily 0.25 mg 3 mg 16 to150mg 500 mgtwicedaily 500 mgtwicedaily 0.035 mg 60 mgoncedaily drug metabolismmediatedbyanyofthefollowinghumanCYPisoforms:CYP3A4,CYP2D6,CYP2C9,orCYP2E1.However, asmall : [see Warnings andPrecautions(5.6)] In vitro c r d b a c ↑ K

q p o n m l Dose(s)

; Decrease= [see DrugInteractions(7)] : Dose(s) There was no significant pharmacokinetic interaction between lamivudine and interferon alfainatrialof 19 healthymale There wasnosignificantpharmacokineticinteractionbetweenlamivudineandinterferon data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine. However, data indicate ribavirin reduces phosphorylation no pharmacokinetic

Lamivudine andsorbitolsolutionswerecoadministered to 16healthyadultsubjectsinanopen-label,randomized j i h e,g e,f

↓ ; NoEffect= max

Steady-statepharmacokineticsoftenofovirwereevaluatedin8HIV-1 infectedpediatricsubjects(12toless At concentrations substantially higher (~300-fold) than those observed Atconcentrationssubstantiallyhigher(~300-fold)thanthoseobserved and AUC The pharmacokineticsofthecombinationdolutegravirandlamivudineinpediatricsubjectshavenot : 750/200 twicedaily 500/100 twicedaily 400/100 twicedaily 300/100 twicedaily 400/100 oncedaily 400/100 oncedaily 400/100 oncedaily 400/100 oncedaily 400/100 oncedaily 400/100 oncedaily 300/100 oncedaily Lamivudine andTMP/SMXwerecoadministeredto14HIV-1-positive subjectsinasingle-center, open- 90/400 oncedaily 90/400 oncedaily 90/400 oncedaily 90/400 oncedaily 0.05 mg/kgtwice

Coadministered 400 singledose 800 threetimes 1000/100 twice daily ×14days 400 oncedaily daily ×7days daily x7days Dolutegravir (23 doses) Drug (mg) single dose single dose × 14days × 14days x 10days x 10days x 14days x 10days twice daily twice daily twice daily twice daily once daily once daily once daily once daily once daily once daily once daily Dose of Dose of tau 50 mg 50 mg 50 mg 50 mg 50 mg 25 mg 50 mg 50 mg 50 mg 50 mg 50 mg 50 mg 50 mg ⇔ . are 0.38 ± 0.13 mcg/mL and 3.39 ± 1.22 mcg•hr/mL, respectively. Tenofovir exposure achieved Dolutegravir single dose single dose single dose single dose single dose single dose single dose single dose single dose single dose single dose ; NC=NotCalculated twice daily twice daily once daily once daily once daily once daily once daily once daily once daily once daily once daily once daily once daily once daily once daily once daily once daily once daily Dose of 50 mg 30 mg 50 mg 50 mg 50 mg 50 mg 50 mg 50 mg 30 mg 30 mg 30 mg 50 mg 50 mg 50 mg 50 mg 50 mg 50 mg 50 mg 50 mg 50 mg 50 mg 50 mg 50 mg 50 mg 50 mg 50 mg 50 mg 50 mg 50 mg . max andAUCofdidanosine.Whendidanosine250mgenteric-coatedcapsuleswere 15 15 24 15 24 16 15 10 11 12 15 12 12 20 22 21 30 24 24 15 29 24 16 35 24 29 14 15 23 24 13 12 12 33 n N a a : Basedon (0-24) 16 11 11 12 12 16 10 11 11 12 11 11 12 16 16 14 15 16 15 12 16 12 12 15 12 12 Lamivudine isasubstrateofMATE1, MATE2-K, andOCT2 , 14%,32%,and36%intheAUC 9 8 9 n c % ChangeofTenofovir PharmacokineticParameters ( ( ( ( ( ( ( ( ( ( ( ( ( ( (0.97 to1.23) (0.99 to1.22) (0.82 to0.97) (0.94 to1.06) (1.91 to2.33) (1.53 to1.81) (0.91 to1.08) (0.84 to1.25) ↑ ↑ ( ( ( ( ( in vitro ↓ ↓ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ (0.86, 1.02) (0.93, 1.10) (0.80, 0.98) (0.44, 0.93) (0.89, 1.05) ↑ ↑ ↓ ↑ ↑ 53to 56to 46to 32to 39to 33to 25to 45to 43to 51to 25to 54to 37to 20to Geometric MeanRatio(90%CI)ofPharmacokinetic 1to 8to 3to 8to 8to Parameters ofCoadministeredDrugwith/without 0.94 1.09 1.01 0.88 1.10 0.89 1.00 2.11 1.66 0.64 0.99 0.97 1.03 ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↓ ↓ ↑ ↑ ↑ ↑ ↑ ↑ ↑ C C (1.06 to1.21) (0.94 to1.07) (0.63 to0.92) (1.02 to1.13) (0.78 to1.00) (0.43 to0.54) (0.51 to0.73) (0.83 to0.97) (1.25 to1.42) (1.40 to1.59) (0.98 to1.37) (1.03 to1.37) (0.49 to0.65) (0.99 to1.14) (0.75 to1.11) (0.54 to0.77) (0.81 to1.21) (0.84 to1.26) (0.35 to0.52) (1.07 to1.57) (0.61 to0.73) (0.78 to1.29) (0.83 to1.38) (0.50 to0.81) (0.69 to0.98) (0.23 to0.33) (0.50 to0.57) (0.87 to1.08) ⇔ ⇔ _ 38 23 13 46 44 36 77 55 55 25 61 32 79 64 47 14 24 34 14 max max (1.05, 1.40) studyresults,lamivudineattherapeuticdrugexposures ↑ ↑ ↑ ↑ ↑ ↑ ↑ Geometric MeanRatio(90%CI)ofDolutegravir ↓ ↓ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ 27) 104) 45) 104) 33) 42) 20) 29) 13) 54) 55) 47) 66) 68) 72) 39) 74) 58) 51) 1.13 1.00 0.76 1.07 0.88 0.48 1.22 0.61 0.89 1.34 1.50 1.16 1.18 0.57 1.06 0.92 0.65 0.99 1.03 0.43 1.29 0.67 1.00 1.07 0.63 0.82 0.28 0.54 0.97 C Pharmacokinetic Parameterswith/without max a inthePresenceofCoadministeredDrug Dolutegravir NoEffect=1.00 [see Warnings andPrecautions(5.6)] Coadministered Drugs ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( (1.01 to1.24) (0.98 to1.16) (0.91 to1.04) (0.79 to1.15) (0.91 to1.06) (2.25 to2.66) (1.65 to1.93) (0.96 to1.11) (0.83 to1.15) ↑ ↑ ( ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ (0.84, 0.98) (0.97, 1.01) (0.85, 0.99) (0.67, 0.97) (0.93, 1.04) ( ↓ 77to No Effect=1.00 29to ↓ 34to 34to 29to 68to 33to 24to 25to 59to 31to 42to 10to 30to 21to 6to (1.05 to1.19) (0.91 to1.04) (0.54 to0.78) (1.02 to1.20) (0.69 to0.81) (0.26 to0.34) (0.35 to0.54) (0.72 to0.85) (1.50 to1.74) (1.80 to2.03) (0.82 to1.10) (1.15 to1.53) (0.38 to0.55) (1.03 to1.20) (0.78 to1.20) (0.55 to0.81) (0.77 to1.15) (0.81 to1.20) (0.38 to0.56) (1.11 to1.59) (0.48 to0.55) (0.72 to1.23) (0.84 to1.43) (0.47 to0.80) (0.62 to0.90) (0.22 to0.32) (0.38 to0.44) (0.91 to1.11) 9to (1.00, 1.34) 0.91 1.12 0.99 0.92 1.06 0.98 0.95 0.98 2.45 1.79 0.81 1.03 0.98 0.98 AUC ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ AUC ↑ ↓ ( ⇔ ⇔ ⇔ ⇔ ∞ 40 40 35 81 39 30 32 65 40 98 50 35 22 37 24 2 2 ) in vivo , and28%,52%,55%inthe 0.95 1.33 0.46 1.11 0.97 0.67 0.95 0.98 0.46 1.33 0.51 0.94 1.09 0.61 0.74 0.26 0.41 1.01 1.12 0.97 0.65 1.11 0.75 0.29 1.16 0.43 0.78 1.62 1.91 AUC ↑ ↑ ∞ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ 10) 123) , adecreaseof29%±13%in 42) 5) 45) 46) 42) 94) 44) 36) 38) 71) 50) 59) 35) 45) 28)

, tenofovirdidnotinhibit in vitro ( ( ( ( ↑ ↑ ↑ ( ( ( ( ( ( ( ( ( ( ( ( (1.04 to1.35) (1.07 to1.38) (0.85 to1.03) (0.91 to1.07) (0.93 to1.11) (0.88 to1.29) ↑ ( ( ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ (0.57 to0.87) (1.01 to1.48) (0.23 to0.34) (1.06 to1.28) (0.75 to1.21) (0.56 to0.82) (0.74 to1.13) (0.81 to1.23) (0.36 to0.54) (1.25 to1.68) (0.24 to0.31) (0.68 to1.19) (0.81 to1.42) (0.47 to0.80) (0.58 to0.85) (0.21 to0.31) (0.21 to0.27) (0.82 to1.04) (1.15 to1.30) (0.85 to1.05) (0.41 to0.63) (1.13 to1.45) (0.52 to0.76) (0.09 to0.16) (0.18 to0.34) (0.56 to0.69) (1.97 to2.47) (2.52 to3.11) (0.82, 0.94) (0.97, 1.01) (0.79, 0.93) (0.93, 1.03) 105to 132to 100to ↑ ↓ 74to (0.95, 1.36) 16to 37to 49to 38to 19to 21to 15to 61to 76to 39to 45to 31to C 1to 2to C ↑ ↑ ↑ τ 0.88 1.19 0.99 1.21 0.93 0.99 0.86 1.02 0.98 1.06 ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ orC τ C ↑ NA 1.22 0.94 0.51 1.28 0.63 0.12 1.14 0.25 0.62 2.21 2.80 0.70 1.22 0.28 1.17 0.95 0.68 0.92 1.00 0.44 1.45 0.27 0.90 1.08 0.61 0.70 0.26 0.24 0.92 121 115 163 orC ⇔ ⇔ ⇔ experiments b _ _ _ 14 70 84 45 52 39 23 51 91 59 47 37 29 22

min (90%CI) 7 . ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ ↑ 24 27) 17) 110)

79) 92) 51) 143) 59) 48) 30) 66) 126) 197) 70) 57) 57) 36) 30) in vitro. 24

in

Disoproxil Fumarate Table 11.DrugInteractions:ChangesinPharmacokineticParametersforCoadministeredthePresenceofTenofovir abacavir, didanosine(bufferedtablets),emtricitabine,entecavir, andlamivudine. withtenofovir disoproxilfumarate: No effectonthepharmacokineticparametersoffollowingcoadministereddrugswasobserved r q p velpatasvir). o n m l k j i h g f similar results. e Evidence ofrenaltoxicitywasnotedin4animalspecies.Increasesserumcreatinine,BUN,glycosuria,proteinuria,phosphaturia, is unknown. of tenofovir. Inrats and dogs, the bonetoxicity manifested as reduced bone mineral density. The mechanism(s)underlying bone toxicity inmonkeysappearedtobereversibleupondosereductionordiscontinuation was diagnosedasosteomalacia.Osteomalaciaobserved inhumanscausedbonetoxicity.at exposures(basedonAUCs)greaterthanorequalto6-foldthoseobserved Inmonkeysthebonetoxicity Tenofovir DisoproxilFumarate: AnimalToxicology and/orPharmacology 13.2 however, analterationoftheestrouscycleinfemalerats. comparisons for 28 days prior to mating and to female rats for 15 days prior to mating through day seven of gestation. There was, area disoproxil fumaratewasadministeredtomaleratsatadoseequivalent10timesthehumanbasedonbodysurface Tenofovir DisoproxilFumarate: 300 mg(respectively). associated withexposuresapproximately44or112times(respectively)higherthantheinhumansatdosesof50mgand Impairment ofFertility: administered tomalemice. vitro Tenofovir DisoproxilFumarate: micronucleus test,inaratbonemarrowcytogeneticassay, andinanassayforunscheduledDNAsynthesisratliver. human lymphocytes.Lamivudinewasnotmutagenicinamicrobialmutagenicityassay, inan Lamivudine: vivo Mutagenesis: carcinogenic inhumansatthetherapeuticdose. findingsatexposuresupto5timesthatobserved At thehighdoseinfemalemice,liveradenomaswereincreasedatexposures16timesthathumans.Inrats,studywasnegativefor inhumansatthetherapeuticdoseforHIV-1exposures uptoapproximately16times(mice)and5(rats)thoseobserved infection. Tenofovir DisoproxilFumarate: exposures upto12times(mice)and57(rats)thehumanatrecommendeddoseof300mg. Lamivudine: respectively, thanthoseinhumansattherecommendeddoseof50mgtwicedaily. atthehighestdosetested,resultingindolutegravirAUCexposures10timesand15highermalesfemales, were observed than thoseinhumansattherecommendeddoseof50mgtwicedaily. Inrats,noincreasesintheincidenceofdrug-relatedneoplasms atthehighestdosestested,resultingindolutegravirAUCexposuresapproximately14timeshigher drug-related neoplasmswereobserved doses of upto 500 mgper kg, and rats were administered doses of up to50 mg perkg. In mice, no significant increases inthe incidence of Carcinogenesis: 13.1 13 c b a Table 12.HIV-1 RNAResponseatWeek 24byBaselineTenofovir DisoproxilFumarateSusceptibility(Intent-To-Treat) therapy. Table 12summarizestheHIV-1 RNAresponsebybaselinetenofovirdisoproxilfumaratesusceptibility. demonstrated a correlation between baseline susceptibility to tenofovirdisoproxil fumarate and response totenofovirdisoproxil fumarate Studies 902and907PhenotypicAnalyses: durable throughWeek 48. the abacavir/emtricitabine/lamivudineresistance-associatedM184Vsubstitution.HIV-1 RNAresponsesamongthesesubjectswere In theprotocoldefinedanalyses,virologicresponsetotenofovirdisoproxilfumaratewasnotreducedinsubjectswithHIV-1 thatexpressed virus expressedaY115Fsubstitution(N=3),Q151M2),orT69insertion4),allofwhomhadreducedresponse. associated substitutions(N=8)hadreducedresponsetotenofovirdisoproxilfumarate.Limiteddataareavailableforsubjectswhose responses totenofovirdisoproxilfumaratetherapy. SubjectswhosevirusexpressedanL74Vsubstitutionwithoutzidovudineresistance were stillimprovedcomparedwithplacebo.ThepresenceoftheD67N,K70R,T215Y/F, orK219Q/E/Nsubstitutiondidnotappeartoaffect L210W reversetranscriptasesubstitutionshowedreducedresponsestotenofovirdisoproxilfumaratetherapy;however, theseresponses treated subjectswhoseHIV-1 expressedthreeormorezidovudineresistance-associatedsubstitutionsthatincludedeithertheM41L andappearedtodependonthetypenumberofspecificsubstitutions. K219Q/E/N) wereobserved Tenofovir disoproxilfumarate- of tenofovirdisoproxil fumarate to pre-existing zidovudine resistance-associated substitutions (M41L, D67N, K70R, L210W, T215Y/F, or outcome. Becauseofthelargenumberpotentialcomparisons,statisticaltestingwasnotconducted.Varyingdegreescross-resistance analyseswereconductedtoevaluatetheeffectofspecificsubstitutionsandsubstitutionalpatternsonvirologic Several exploratory overall trialresults. HIV-1 isolatesexpressing at leastoneNRTI substitution.Virologicresponsesforsubjectsinthegenotypesubstudyweresimilarto treatment-experienced subjectsparticipatinginStudies902and907.Intheseclinicaltrials,94%oftheparticipantsevaluatedhadbaseline The virologicresponsetotenofovirdisoproxilfumaratetherapyhasbeenevaluated with respect to baselineviral genotype (N=222)in the developmentofK65RsubstitutioninHIV-1 reversetranscriptasegene. greater than1.4-fold(median2.7-fold)reducedsusceptibilitytotenofovir. Genotypicanalysisofthebaselineandfailureisolatesshowed compared toPlacebo+SBT),14/304(5%)ofthetenofovirdisoproxilfumarate-treated StudyconductedwithTRUVADA (emtricitabine/tenofovirDF)+dolutegravircoadministeredwithHARVONI. Aptivus(tipranavir)PrescribingInformation. StudyconductedwithATRIPLA coadministeredwithSOVALDI Comparisonbasedonexposureswhenadministeredasatazanavir/ritonavir+emtricitabine/tenofovirDF. Study conductedwithCOMPLERA(emtricitabine/rilpivirine/tenofovirDF)coadministeredHARVONI. Aptivus (tipranavir)PrescribingInformation. Administeredasraltegravir+emtricitabine/tenofovirDF. StudyconductedwithCOMPLERA(emtricitabine/rilpivirine/tenofovirDF)coadministeredEPCLUSA(sofosbuvir/velpatasvir). StudyconductedwithSTRIBILD(/cobicistat/emtricitabine/tenofovirDF)coadministeredEPCLUSA(sofosbuvir/ StudyconductedwithATRIPLA (efavirenz/emtricitabine/tenofovirDF)coadministeredwithEPCLUSA(sofosbuvir/velpatasvir). Comparison basedonexposureswhenadministeredasatazanavir/ritonavir+emtricitabine/tenofovirDF. 373 kcal,8.2gfat In HIV-infected subjects,additionoftenofovirDFtoatazanavir300mgplusritonavir100mg,resultedinAUCandC Average HIV-1 RNAchangefrombaselinethroughWeek 24(DAVG Tenofovir susceptibilitywasdeterminedbyrecombinantphenotypicAntivirogramassay(Virco). Videx (didanosine)ECPrescribingInformation.Subjectsreceiveddidanosineenteric-coatedcapsules. Increase = Study conductedwithATRIPLA (efavirenz/emtricitabine/tenofovirDF)coadministeredwithHARVONI. Comparison basedonexposureswhenadministeredasdarunavir/ritonavir+emtricitabine/tenofovirDF. Compared withdidanosine(enteric-coated)400mgadministeredaloneunderfastingconditions. Prezista (darunavir)PrescribingInformation Reyataz (atazanavir)PrescribingInformation. Fold changeinsusceptibilityfromwild-type. Comparisonbasedonexposureswhenadministeredasdarunavir/ritonavir+emtricitabine/tenofovirDF. Data generatedfromsimultaneous dosing withHARVONI (ledipasvir/sofosbuvir). Staggered administration (12hoursapart)provide Increases inAUCandC Darunavir Atazanavir Atazanavir Abacavir Coadministered Drug Tipranavir Tacrolimus Ritonavir Saquinavir Ritonavir Lopinavir Lamivudine Indinavir Entecavir Emtricitabine Didanosine 50 rodentmicronucleusassay. valuesoflamivudinewere60nM(range:20to70nM),353040903 max bacterial mutagenicitytest(Amestest).Inan Carcinogenesis, Mutagenesis,ImpairmentofFertility NONCLINICAL TOXICOLOGY Baseline Tenofovir DisoproxilFumarateSusceptibility andAUCofdidanosine.Whendidanosine250mgenteric-coatedcapsuleswereadministeredwithtenofovirdisoproxilfumarate, 50 valuesof0.5nM(0.21ngpermL)to2.1(0.85inperipheralbloodmononuclearcells(PBMCs)andMT-4 cells. d i b b ↑ Lamivudine-resistantvariantsofHIV-1 havebeenselectedincellculture.Genotypicanalysisshowedthattheresistance TheantiviralactivityoflamivudineagainstHIV-1 wasassessedinanumberofcelllinesincludingmonocytesandPBMCs Lamivudineisasyntheticnucleosideanalogue.Intracellularly, toitsactive5 lamivudineisphosphorylated LamivudinewasmutagenicinanL5178Ymouselymphomaassayandclastogenicacytogeneticusingcultured Long-term carcinogenicity studies with lamivudine in mice and rats showed no evidence of carcinogenic potential at

e Cross-resistance has been observed amongnucleosidereversetranscriptaseinhibitors(NRTIs).Cross-resistance hasbeenobserved Lamivudine-resistantHIV-1

; Decrease=

Dolutegravir:

Dolutegravir: γ .

Dolutegravir: ‑1 clinical isolates with median EC

Dolutegravir:

Dolutegravir andLamivudine: min ↓ fumarate andalightmeal 250 once,simultaneously

Dose ofCoadministered Dolutegravirwasnotgenotoxicinthebacterialreversemutationassay, mouselymphomaassay, orinthe with tenofovirdisoproxil arenotexpectedtobeclinicallyrelevant;hencenodoseadjustmentsrequiredwhentenofovirDFand Dolutegravir: 200 oncedaily×7days ; NoEffect= 800 threetimesdaily× 1000/100 twicedaily× 0.05 mg/kgtwicedaily > 3and > 1and 400/100 twicedaily× 300/100 oncedaily× Saquinavir/Ritonavir Atazanavir/Ritonavir Tipranavir/Ritonavir Tipranavir/Ritonavir 750/200 twicedaily 500/100 twicedaily Darunavir/Ritonavir Two-year carcinogenicity studiesinmiceandratswereconductedwithdolutegravir. Micewereadministered 300/100 oncedaily Lopinavir/Ritonavir 1 mgoncedailyx Long-term oralcarcinogenicity studiesoftenofovirdisoproxilfumarateinmiceandratswerecarriedoutat Cross-resistance amongcertainreversetranscriptaseinhibitorshasbeenrecognized.TheK65RandK70E 150 twicedaily× Tenofovir disoproxilfumaratewasmutagenicinthe 400 oncedaily× The antiviral activity of tenofovir against laboratory and clinical isolates of HIV-1 The antiviral activity of tenofovir against laboratory was assessed in

HIV-1 isolateswithreducedsusceptibilitytotenofovirhavebeenselectedincellculture.Theseviruses There werenoeffectsonfertility, developmentwhentenofovir orearlyembryonic matingperformance Tenofovir disoproxilfumarateisanacyclicnucleosidephosphonatediesteranalogofadenosine Tenofovir andtenofovirdisoproxilfumarateadministeredintoxicologystudiestorats,dogs,monkeys > 4 < 1

The singleINSTI-resistancesubstitutionsT66K,I151L,andS153Yconferredagreaterthan2-fold Dolutegravir: (23 doses) Drug (mg) 300 once x 7days 42 days 14 days 14 days 14 days 10 days 7 days 7 days Dolutegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand ≤ ≤ 4 3 50 ⇔ Dolutegravir-resistant viruseswereselectedincellculturestartingfromdifferentwild-typeHIV-1 valueswereintherangeof0.003to15microM(1=0.23mcgpermL).Themedian ; NA=NotApplicable

Phenotypic analysisofbaselineHIV-1 fromtreatment-experiencedsubjects(N=100) Dolutegravir exhibited antiviral activity against laboratory strains of wild-type HIV-1Dolutegravir exhibited antiviral activity against laboratory with in vivo f 50 valuesrangedfrom1.6μMto5.5μM). Dolutegravirorlamivudinedidnotaffectmalefemalefertilityinratsatdoses 50 values of 0.18 nM (n =3, range: 0.09 to 0.5 nM), 0.08 nM (n mouse micronucleusassay, tenofovirdisoproxilfumaratewasnegativewhen 10 34 20 22 21 32 24 15 12 28 17 33 12 N 8 b Neitherdolutegravirnorlamivudinewereantagonistictoalltestedanti-HIV ® (sofosbuvir). 24 ) inlog 50 valuesagainst3HIV-2 clinicalisolatesinPBMCassaysranged ( ( ( ( ( ( ( ( ( ( ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↑ ↓ ↓ 27to 34to 30to % ChangeofCoadministeredDrugPharmacokinetic 50to 1to 16to 26to 6to 32to 6to 10 ↓ ↓ ↓ ↑ ↓ ↓ ↑ ↓ ↓ ↑ copies/mL. C ⇔ ⇔ ⇔ ⇔ ⇔ ⇔ 20 28 21 12 11 17 22 24 11 16 max ↑ ↑ ↑ ↓ ↓ ↑ g ↑ ↓ ↓ ↓ 26) 41) 42) 14) 12) 12) in vitro 5) 4) 6) 7) Change inHIV-1 RNA 50 mouse lymphomaassayandnegativeinan Parameters valuesagainstHIV-2 isolates(n=4)ranged in vitro ( ( ( ( ( ( ( ↓ ↑ ↑ ↓ ↓ ↓ ↓ -0.56 (49) -0.74 (35) 30to 12to 11to -0.12 (9) 50 42to 15to 25to 5to 50 -0.3 (7) valuesof2.7nMand12.6nM. ↑ ↓ value of 0.52 nM in a viral integrase ↓ ↓ ↑ ↑ AUC ↓ ⇔ ⇔ ⇔ ⇔ ⇔ ⇔ ⇔ ⇔ ⇔ 29 25 25 18 13 21 cell transformation assay, in a rat 9 a 50 g ↑ (90%CI) ↓ ↑ ↑ h c 50 ↓ ↓ ↓ valuesrangedfrom0.5μMto 54) 19) 48) 15) (50%effectiveconcentration) 3) 3) 9) c (N) α , min β valuesofatazanavir , andmitochondrial ( ( ( ( ( ( ( ↓ ↓ ↓ ↑ ↑ ↓ ↑ ( 46to 48to 30to 23to 12to 10to = 5, range: 0.05 ↓ a 3to 22to0) ′ ↑ ↓ ↓ ↓ ↓ ↑ ↑ ↑ -triphosphate C NA NA ⇔ ⇔ ⇔ ⇔ ⇔ ⇔ 47 23 40 12 21 23 20 24 min ↑ ↑ ↓ ↓ ↑ ↑ ↑ h c 46) 10) 32) 10) 76) 29) 69) in in

The adjusted mean changes in CD4+ cell counts from baseline were 378 Treatment differences were maintained across baseline characteristics including baseline viral load, CD4+ 12.3%). in thefixed-doseefavirenz/emtricitabine/tenofovirdisoproxilfumarategroup,withatreatmentdifferenceof7.4%and95%CI(2.5%, d c during theanalysiswindow. b a Keep thebottletightlyclosed.Dispenseonlyinoriginalcontainer. Protectfrommoisture. Store below30°C. HDPE bottlesof90withdesiccant,inductionsealandchild-resistantcapNDC59651-062-90 HDPE bottlesof30withdesiccant,inductionsealandchild-resistantcapNDC59651-062-30 coated tabletsdebossedwith‘N33’ononesideandplaintheotheraresuppliedasfollows Dolutegravir, HOWSUPPLIED/STORAGEANDHANDLING 16 ineachdifferentagegroupevaluated. observed than in those who had received solution formulation(s) at any time (52% [29/56] and 54% [30/56]), respectively. These differences were Week 96washigherinsubjects whohadreceivedtabletformulationsoflamivudineandabacavir(75%[458/610]72%[434/601]) Analyses byformulationdemonstratedtheproportionofsubjectswithHIV-1 RNAoflessthan80copiespermLatrandomizationand (or missing). d the protocol. load valueofgreaterthanorequalto80copiespermL,subjectswhohadaswitchinbackgroundregimenthatwasnotpermittedby c b a 144 weeks. Theadjusteddifferencebetweentreatmentarmsand95%CIwas46.9cellspermm abacavir sulfateandlamivudine332 cellspermm Table 13.VirologicOutcomesofRandomizedTreatment inSINGLEat144 Weeks (SnapshotAlgorithm) Week 144(open-label-phaseanalysiswhichfollowedtheWeek 96double-blindphase)outcomesforSINGLEareprovidedinTable 13. characteristics weresimilarbetweentreatmentgroups. and thatthecauselong-termhealtheffectsoftheseconditionsarenotknownatthistime Fat Redistribution: Precautions (5.8)] tablets shouldnotbeadministeredincombinationwithadefovirdipivoxil(HEPSERA) fumarate, ortenofoviralafenamide Coadministration concurrent orrecentuseofanephrotoxicagent(e.g.,high-dosemultipleNSAIDs) with theuseoftenofovirdisoproxilfumarate.Dolutegravir, lamivudine,andtenofovirdisoproxilfumaratetabletsshouldbeavoidedwith Renal Impairment: and Precautions(5.4)] receiving combinationantiretroviraltherapyforHIV Inform patientswithHIV [see Warnings andPrecautions(5.2)]. lamivudine ortenofovirdisoproxilfumaratewerediscontinued.Advisepatientstodiscussanychangesinregimenwiththeirphysician Advise patientsco‑infectedwithHIV testingbeforeandduringtherapy to havelaboratory development oftransaminaseelevationswithusedolutegravir, lamivudine,andtenofovirdisoproxilfumaratetabletsadvisepatients Patients Warnings andPrecautions(5.1)] fumarate tablets,cancausearare,butseriousconditioncalledlacticacidosiswithliverenlargement(hepatomegaly) Lactic St. John’s wort patients toreporttheirhealthcareprovidertheuseofanyotherprescriptionornonprescriptionmedicationherbalproducts,including Drug Interactions: Advise thepatienttoreadFDA-approvedlabeling(PatientInformation). PATIENT COUNSELINGINFORMATION 17 was 4.6log These 46 subjects had a mean age of 12 years (range: 6 to 17), were 54% female and 52% black. At baseline, mean plasma HIV-1 RNA to lessthan12years).Allsubjectsreceivedaweight-baseddoseofdolutegravir. were stratified byage, enrolling adolescents first(Cohort 1:aged 12to less than18years) andthen younger children (Cohort2A: aged6 tolerability, andefficacyofdolutegravirincombinationtreatmentregimensHIV-1-infected infants,children,andadolescents.Subjects Dolutegravir: PediatricSubjects 14.2 background regimenhadHIV Week 48,71%ofsubjectsrandomized to dolutegravirplusbackgroundregimenversus64%ofsubjectsrandomizedraltegravir In SAILING,therewere715subjects included intheefficacyandsafetyanalyses (seefullprescribing informationfordolutegravir).At Treatment-Experienced (adjusted forpre-specifiedstratificationfactors:baselineHIV C (AIDS),32%hadHIV-1 RNAgreaterthan100,000copiespermL,and53%hadCD4+cellcountless350cellsmm 35 years,16%female,32%non-white,7%hadhepatitisCco-infection(hepatitisBviruswasexcluded),4%wereCDCClass sulfate and lamivudine or fixed-dose efavirenz/emtricitabine/tenofovir disoproxil fumarate. At baseline, the median age of subjects was In SINGLE, 833 subjects were randomized and received at least 1 dose of either dolutegravir 50 mg once daily with fixed-dose abacavir Treatment-Naïve Subjects AdultSubjects 14.1 14 the phosphaturia,tobonetoxicityisnotknown. inhumans.Therelationshipoftherenal abnormalities,particularly exposures (basedonAUCs)2to20timeshigherthanthoseobserved degrees in these animals. These toxicities were noted at to varying and/or calciuria and decreases in serum phosphate were observed taking nucleosideanalogmedicinesforalongtime. You • • Dolutegravir, lamivudineandtenofovirdisoproxilfumaratetabletscancauseserioussideeffects,including What isthemostimportantinformationIshouldknowaboutdolutegravir, lamivudineandtenofovirdisoproxilfumaratetablets? medical conditionoryourtreatment. get arefill.Theremaybenewinformation.Thisinformationdoesnottaketheplaceoftalkingwithyourhealthcareproviderabout Read thisPatientInformationbeforeyoustarttakingdolutegravir, lamivudineandtenofovirdisoproxilfumaratetabletseachtimeyou and keepthebottletightlyclosed.Donotremovedesiccant. Instruct patientstostoredolutegravir, lamivudineandtenofovir disoproxilfumaratetabletsintheoriginalpackage,protectfrommoisture, double theirnextdoseortakemorethantheprescribeddose. of thetimefornextdose,theyshouldbeinstructedtoskipmisseddoseandgobackregularschedule.Patientsnot Instruct patientsthatiftheymissadose,shouldtakeitassoonremember. Iftheydonotrememberuntilitiswithin4hours worsens. Instruct patientstoinformtheirphysicianorpharmacistiftheydevelopanyunusualsymptom,knownsymptompersists reread iteachtimetheprescriptionisrenewed. Instruct patientstoreadthePatientInformationbeforestartingdolutegravir, lamivudineandtenofovirdisoproxilfumaratetabletsto because HIV-1 canbepassedtothebabyinbreastmilk. tablets canbepassedtoyourbabyinbreastmilkandwhetheritcouldharmbaby. MotherswithHIV-1 shouldnotbreastfeed Female patientsshouldbeadvisednottobreastfeedbecauseitisknownifdolutegravir, lamivudineandtenofovirdisoproxilfumarate vaginal secretions,orblood. Advise patientstoalwayspracticesafersexbyusingalatexorpolyurethanecondomlowerthechanceofsexualcontactwithsemen, Advise patientsnottosharepersonalitemsthatcanhavebloodorbodyfluidsonthem,liketoothbrushesandrazorblades. Advise patientsnottore-useorshareneedlesotherinjectionequipment. Advise patientstoavoiddoingthingsthatcanspreadHIV-1 infectiontoothers. Advise patientstotakeallHIVmedicationsexactlyasprescribed. Advise patientstoremainunderthecareofaphysicianwhenusingdolutegravir, lamivudineandtenofovirdisoproxilfumaratetablets. decreases inplasmaHIVRNAhavebeenassociatedwithareducedriskofprogressiontoAIDSanddeath. under thecareofaphysicianwhenusingdolutegravir, lamivudineandtenofovirdisoproxilfumaratetablets.Informpatientsthatsustained patients may continue toexperience illnesses associated with HIV-1 infection, including opportunistic infections. Patients should remain Information aboutHIV-1 Infection; Dolutegravir, lamivudineandtenofovirdisoproxilfumaratetabletsarenotacureforHIV-1 infectionand their healthcareproviderimmediatelyofanysymptomsinfection immune response,enablingthebodytofightinfectionsthatmayhavebeenpresentwithnoobvioussymptoms.Advisepatientsinform infections mayoccursoonafteranti-HIVtreatmentisstarted.Itbelievedthatthesesymptomsareduetoanimprovementinthebody’s Immune Reconstitution Syndrome: ofpathologicbonefractureoratriskforosteopenia monitoring shouldbeconsideredinpatientswhohaveahistory Bone Effects: Risk count increasefrombaselinetoWeek 24was209cellspermm The medianCD4+cellcountincreasefrombaselinetoWeek 48was84cellspermm less than40kgweight-band.AtWeek 48,63%(12/19)ofthesubjectsinCohort1weighingatleast40kgwerevirologicallysuppressed. 50 copies per mL) at Week 24 was achieved in 75% (18/24) of subjects weighing at least 40 kg and 55% (6/11) of subjects in the 30 to (14/23). Virologicoutcomeswerealsoevaluatedbasedonbodyweight.Acrossbothcohorts,virologicsuppression(HIV-1 RNAlessthan 61% (14/23),respectively. AtWeek 48,theproportionofsubjectsfromCohort1withHIV-1 RNAlessthan50copiespermLwas61% At Week 24,theproportionofsubjectswithHIV-1 RNA less than50copiespermLinCohort1and2Awas70%(16/23) C.Mostsubjectshadpreviouslyusedatleast1NNRTIof category (50%)or1PI(70%). to 44%).Overall,39%hadbaselineplasmaHIV-1 RNAgreaterthan50,000copiespermLand33%hadaCDCHIVclinicalclassification Table 15.VirologicOutcomeofRandomizedTreatment atWeek 96 virologic responsesinthetwotreatmentarmswerecomparableacrossbaselinecharacteristicsforgenderandage. The proportion of subjects with HIV-1 RNAof less than 80 copies per mL through 96weeks is shown in Table 15. The differences between subjects inthetwice-dailycohortwerevirologicallysuppressed,comparedwith71%ofonce-dailycohort. not arequirementforparticipation:atbaselineRandomization3(followingminimumof36weekstwice-dailytreatment),75% drug, foranadditional96weeks.Ofthe1,206originalARROWsubjects,669participatedinRandomization3.Virologicsuppressionwas the safetyandefficacyofonce-dailydosingwithtwice-dailylamivudineabacavir, incombinationwithathirdantiretroviral a minimumof36weeksontreatment,subjectsweregiventheoptiontoparticipateinRandomization3ARROWtrial,comparing first-line regimencontaininglamivudineandabacavir, dosedtwicedailyaccordingto World HealthOrganizationrecommendations.After infection inpediatricsubjects.HIV ARROW (COL105677)wasa5-yearrandomized,multicentertrialwhichevaluatedmultipleaspectsofclinicalmanagementHIV-1 Once-Daily Dosing Table ClinicalEndpoint(DiseaseProgressionorDeath) 14.NumberofSubjects(%)ReachingaPrimary monotherapy. ResultsaresummarizedinTable 14. duration ontrialwas10.1monthsforthesubjectsreceivinglamivudinepluszidovudineand9.2didanosine to 1,555cellspermm cells permm weeks to14years),58%werefemale,and86%non-white.ThemeanbaselineCD4+cellcountwas868cellspermm to 56daysofantiretroviraltherapy)pediatricsubjectswereenrolledinthese2treatmentarms.Themedianagewas2.7years(range:6 lamivudine pluszidovudinewithdidanosinemonotherapy. Atotalof471symptomatic,HIV-1-infected therapy-naive(lessthanorequal Lamivudine: Includes subjectswhodiscontinuedduetoanadverseeventordeathatanytimepointifthisresultedinnovirologicdataontreatment Other includesreasonssuchaswithdrewconsent,losstofollow-up,moved,andprotocoldeviation. Adjusted forpre-specifiedstratificationfactors. Includes subjectswhodiscontinuedduetolackorlossofefficacyforreasonsotherthananadverseeventdeath,andhadaviral Otherincludesreasonssuchaswithdrewconsent,losstofollow-up,etc.andthelastavailableHIV-1 RNAlessthan80copiespermL The primary endpointwasassessedatWeekThe primary 48andthevirologicsuccessratewas88%ingroupreceivingdolutegravir81% Race Gender Plasma viralload(copies/mL) Proportion (%)ofSubjectswithHIV Reasons No virologicdata Virologic nonresponse Missing dataduringwindowbutonstudy HIV Discontinued studyforotherreasons Discontinued due toadverse event ordeath No virologicdata HIV-1 RNA HIV-1 RNA<80copies/mL Analyses were based on the last observed viralloaddatawithintheWeekAnalyses werebasedonthelastobserved 96window. Predicted difference(95%CI)ofresponserateis-4.5%(-11%to2%)atWeek 96. HIV-1 diseaseprogressionordeath(total) African-American/African Heritage/Other White Female Male >100,000 < study Missing data during windowbuton reasons Discontinued study/study drug for other adverse eventordeath Discontinued study/study drug due to suppressed Discontinued forotherreasonswhilenot Discontinued forlackofefficacy Data inwindownot<50copies/mL Treatment difference may ‑1 RNA<50 Death C CDC ClinicalCategory systemdeterioration Central nervous Physical growthfailure of 100,000 CLINICAL STUDIES provider rightawayifyougetanyofthefollowingsymptomsthatcouldbesignslacticacidosis: liver (steatosis). cases these seriousliver problems can lead todeath.Your livermaybecome large (hepatomegaly) and youmaydevelop fat in your Serious liver problems and tenofovir disoproxil fumaratetablets.Lacticacidosisisaseriousmedicalemergencythatcancause death. Build-up Acidosis/Hepatomegaly: Pancreatitis: • • • • • • • with be 10 c copiespermL,medianCD4+cellcountwas639cellsmm > 3 more Decreases in bone mineral density have been observed withtheuseoftenofovirdisoproxilfumarate.Bonemineraldensity Decreasesinbonemineraldensityhavebeenobserved IMPAACT P1093isaPhase1/2,48-week,multicenter, open-labeltrialtoevaluatethepharmacokineticparameters,safety, andrange:0to4,650cellspermm Clinical EndpointTrial: 80 copies/mL Lamivudine Hepatitis of [see Contraindications(4),DrugInteractions(7)] stomach painwithnauseaandvomiting trouble breathing unusual (notnormal)musclepain weakortired feel very light-colored stools(bowelmovements) dark or“tea-colored”urine yellow (jaundice) your skinorthewhitepartofeyesturns

copies/mL an . Outcome Endpoint with likely Informpatientsthatredistributionoraccumulationofbodyfatmayoccurinreceivingantiretroviraltherapy Dolutegravir, lamivudine,andtenofovirdisoproxilfumaratetabletsmayinteractwithotherdrugs;therefore,advise Renalimpairment,includingcasesofacuterenalfailureandFanconisyndrome,hasbeenreportedinassociation Adviseparentsorguardianstomonitorpediatricpatientsforsignsandsymptomsofpancreatitis acid 3 forsubjectsagedover5years)andthemeanbaselineplasmaHIV-1 RNAwas5.0log . Call yourhealthcareproviderrightawayifyougetanyofthefollowingsignsorsymptomsliverproblems: Other a ‑1/HCV co-infectionthathepaticdecompensation(somefatal)hasoccurredinHIV B to in b and or c b get your ‑1 RNAlessthan50copiespermL(treatmentdifferenceand95%CI:7.4%[0.7%,14.2%]). can happen in people who take dolutegravir, lamivudine and tenofovir disoproxil fumarate tablets. In some C Products: Tenofovir InformpatientsthatsomeHIVmedicines,includingdolutegravir, lamivudine,andtenofovirdisoproxil lactic . Dolutegravir, LamivudineandTenofovir DisoproxilFumarateTablets Co-infection: blood ‑1-infected, treatment-naïvesubjectsaged3monthsto17yearswereenrolledandtreatedwitha In some patients with advanced HIV infection, signs and symptoms of inflammation from previous [see Warnings andPrecautions (5.7)] ACTG300wasamulticenter, randomized,double-blindtrialthatprovidedforcomparisonof ‑1 andHBVthatworseningofliverdiseasehasoccurredinsomecaseswhentreatmentwith ‑1 RNA<50 copies/mLbyBaselineCategory d acidosis (lactic Do notusewithotherproductscontaininglamivudine,emtricitabine,tenofovirdisoproxil Disoproxil Patients withunderlyinghepatitisBorCmaybeatincreasedriskforworsening acidosis). or 3 Dolutegravir +AbacavirSulfateand forsubjectsagedlessthanorequalto5years;mean:419cellspermm 1 and interferon alfawithorwithoutribavirin ‑1 andinterferon serious [see Warnings andPrecautions(5.2)] Lamivudine plusZidovudine Fumarate 3 Lamivudine plusAbacavir forthefixed-doseefavirenz/emtricitabine/tenofovir disoproxil fumarategroupat Lamivudine OnceDaily Patient Information Lactic acidosis can happen in some people who take dolutegravir, lamivudine Twice-Daily Dosing liver ‑1 RNA,andbaselineCD4+cellcount). 15 (6.4%) 3 (n =333) (n =236) (n =414) 2 (0.8%) 2 (0.8%) 4 (1.7%) 7 (3.0%) . Tablets . problems 28% 70% 71% 72% 69% 72% 69% 73% 12% 18% 10% 71% 1% 0% 1% 2% 4% 3% 3% 4% [see Warnings andPrecautions (5.10)] a (ARROWRandomization3) • • • • • • 50 cells per mm 3 (range:9to1,700),andmedianCD4+%was23%1% . Dolutegravir, lamivudineandtenofovirdisoproxilfumarate if 8.3% (95%CI:2.0%,14.6%) mg/300 stomach area pain, aching,ortendernessontherightsideofyour nausea loss ofappetiteforseveraldaysorlonger have afastorirregularheartbeat feel dizzyorlight-headed feel cold,especiallyinyourarmsandlegs you are mg/300 [see Warnings andPrecautions(5.5)] [see Warnings andPrecautions (5.5)] 3 inCohort1.For2A,themedianCD4+cell female, 3 in the group receiving dolutegravir + . mg [see Warnings andPrecautions(5.9)] 3 very (15.6 cellspermm arepink colored, oval, biconvex, film- [see Warnings andPrecautions(5.6)]. Efavirenz, Emtricitabine,and Lamivudine plusAbacavir overweight cell count, age, gender, and race. Once-Daily Dosing d . Tenofovir DF 10 Didanosine 37 (15.7%) Once Daily ‑1/HCV co-infectedpatients 11 (4.7%) 12 (5.1%) copiespermL.Themedian (n =336) (n =235) (n =419) 8 (3.4%) 6 (2.6%) : <1% <1% 31% 67% <1% 47% 71% 48% 66% 61% 64% 13% 14% 30% 63% 1% 3% 7% 3% 4% (obese), 3 Call yourhealthcare , 78.2 cellspermm [see BoxedWarning, [see Warnings and 3 [see Warnings 3 (mean:1,060 or . . andrange:0 have fixed-dose 3

; these been . 3 )

Dolutegravir, lamivudineandtenofovirdisoproxilfumaratetabletsmayreducetheamountofHIVinyourblood(called“viralload”). • tablets contain3prescriptionmedicines,dolutegravir, lamivudineandtenofovirdisoproxilfumarate. HIV-1 isthevirusthatcausesAcquiredImmuneDeficiencySyndrome(AIDS).Dolutegravir, lamivudineandtenofovirdisoproxilfumarate treat HumanImmunodeficiencyVirustype1(HIV-1) infectioninadultsandchildrenwhoweigh88pounds(40kg)ormore. Dolutegravir, lamivudine and tenofovir disoproxil fumarate tablets are a prescription medicine that is used alone as a complete regimen to What aredolutegravir, lamivudineandtenofovirdisoproxilfumaratetablets? • • • • • • Issued: April2018 Hyderabad-500 038,India Aurobindo PharmaLimited Manufactured by: East Windsor, NJ08520 279 Princeton-HightstownRoad Aurobindo PharmaUSA,Inc. Distributed by: This PatientInformationhasbeenapprovedbytheU.S.FoodandDrugAdministration. The brandslistedaretrademarksoftheirrespectiveowners. titanium dioxide. cellulose,polyethyleneglycol,polyvinylalcohol,povidone,sodiumstarch fumarate,talcand microcrystalline glycolate,sodiumstearyl Inactive ingredients: Active ingredient: What aretheingredientsindolutegravir, lamivudineandtenofovirdisoproxilfumaratetablets? For moreinformation,callAurobindoPharmaUSA,Inc.at1-866-850-2876. dolutegravir, lamivudineandtenofovirdisoproxilfumaratetabletsthatiswrittenforhealthprofessionals. would likemoreinformation,talkwithyourhealthcareprovider. You canaskyourhealthcareproviderorpharmacistforinformationabout This leafletsummarizesthemostimportantinformationaboutdolutegravir, lamivudineandtenofovirdisoproxilfumaratetablets.Ifyou tenofovir disoproxilfumaratetabletstootherpeople,eveniftheyhavethesamesymptomsyouhave.Theymayharmthem. and tenofovirdisoproxilfumaratetabletsforaconditionwhichtheywerenotprescribed.Dogivedolutegravir, lamivudineand Medicines aresometimesprescribedforpurposesotherthanthoselistedinaPatientInformationleaflet.Donotusedolutegravir, lamivudine General informationaboutthesafeandeffectiveuseofdolutegravir, lamivudineandtenofovirdisoproxilfumaratetablets. Keep dolutegravir, lamivudineandtenofovirdisoproxilfumaratetabletsallmedicinesoutofthereachchildren. • • • How shouldIstoredolutegravir, lamivudineandtenofovirdisoproxilfumaratetablets? Call yourdoctorformedicaladviceaboutsideeffects.You mayreportsideeffectstoFDAat1-800-FDA-1088. These arenotallthepossiblesideeffectsofdolutegravir, lamivudineandtenofovirdisoproxilfumaratetablets. Tell yourhealthcareprovideraboutanysideeffectthatbothersyouordoesnotgoaway. cough. The The mostcommonsideeffectsofdolutegravir, lamivudineandtenofovirdisoproxilfumaratetablesinclude: • • • • tenofovir disoproxilfumaratetabletstoyourchildiftheirsymptomsandbloodtestresultsshowthatmayhavepancreatitis. area Call • • • • • • • Callyourhealthcareproviderrightawayifyoudevelopanyofthefollowingsignsorsymptomsliverproblems • ° • • Dolutegravir, lamivudineandtenofovirdisoproxilfumaratetabletscancauseserioussideeffectsincluding: What arethepossiblesideeffectsofdolutegravir, lamivudineandtenofovirdisoproxilfumaratetablets? • • • • • • • • How shouldItakedolutegravir, lamivudineandtenofovirdisoproxilfumaratetablets? • • • • • • • • • • • • • • • • • • Tell yourhealthcareproviderifyoutake: • • • • • You shouldnottakedolutegravir, lamivudineandtenofovirdisoproxilfumaratetabletsifyoualsotake: other medicines. provider. Your healthcareprovidercantellyouifitissafetotakedolutegravir, lamivudineandtenofovirdisoproxilfumaratetabletswith with dolutegravir, lamivudineandtenofovirdisoproxilfumaratetablets.Donotstarttakinganewmedicinewithouttellingyourhealthcare it toyourhealthcareproviderandpharmacist.You canaskyourhealthcareproviderorpharmacistforalistofmedicinesthatinteract Some medicinesinteractwithdolutegravir, lamivudineandtenofovirdisoproxilfumaratetablets.Keepalistofyourmedicinesshow supplements. Tell • • • • • • Before youtakedolutegravir, lamivudineandtenofovirdisoproxilfumaratetablets,tellyourhealthcareproviderifyou: What shouldItellmyhealthcareproviderbeforetakingdolutegravir, lamivudineandtenofovirdisoproxilfumaratetablets? • • Do nottakedolutegravir, lamivudineandtenofovirdisoproxilfumaratetabletsifyou: Who shouldnottakedolutegravir, lamivudineandtenofovirdisoproxilfumaratetablets? Ask yourhealthcareproviderifyouhaveanyquestionsabouthowtopreventpassingHIVotherpeople. • • • Avoid doingthingsthatcanspreadHIV-1 infectiontoothers. medicines tocontrolHIV-1 infectionanddecreaseHIV-related illnesses. Dolutegravir, 88 poundsorinchildrenwhohavereceivedcertaintypesofmedicineforHIV-1 infection. It isnotknownifdolutegravir, lamivudineandtenofovir disoproxil fumarate tablets aresafe and effective in children who weighless than This mayreduceyourriskofdeathorinfectionsthatcanhappenwhenimmunesystemisweak(opportunisticinfections). which helpfightoffotherinfections.ReducingtheamountofHIVandincreasingCD4(T)cellcountmayimproveyourimmunesystem. Dolutegravir, lamivudineandtenofovirdisoproxilfumaratetabletsmayalsohelptoincreasethenumberofCD4(T)cellsinyourblood your most your pain, resistance todolutegravir, lamivudine,ortenofovirdisoproxilfumarate. Dolutegravir, lamivudineandtenofovirdisoproxilfumaratetabletsarenotforusebythemselvesinpeoplewhohaveorhad with orwithoutribavirin,tellyourhealthcareproviderifyouhaveanynewsymptoms. with or without ribavirin. If you are taking dolutegravir,interferon lamivudine and tenofovir disoproxil fumarate tablets and interferon infected withbothHIV-1 andhepatitisCviruswhoaretakingantiretroviralmedicinesalsobeingtreatedforwith Use treatment withdolutegravir, lamivudineandtenofovirdisoproxilfumaratetabletsbecomehardertotreat(resistant). Resistant HepatitisBVirus(HBV). disease canbeseriousandmayleadtodeath. disoproxil fumaratetablets.A“flare-up”iswhenyourHBVinfectionsuddenlyreturnsinaworsewaythanbefore. Worsening liver and hepatitisBvirus(HBV)infection,yourHBVmaygetworse(flare-up)ifyoustoptakingdolutegravir, lamivudineandtenofovir Worsening Keep thebottletightlyclosed.Donotremovedesiccant. Keep dolutegravir, lamivudineandtenofovirdisoproxilfumaratetabletsintheoriginalcontainer. Store dolutegravir, lamivudineandtenofovirdisoproxilfumaratetabletsbelow30°C(86°F). disoproxil fumaratetablets. healthcare providerrightawayifyoustarthavingnewsymptomsaftertakingdolutegravir, lamivudine and tenofovir immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your Changes inyourimmunesystem(ImmuneReconstitutionSyndrome) face mayalsohappen.Theexactcauseandlong-termhealtheffectsoftheseproblemsarenotknown. the upperbackandneck(“buffalohump”),breast,aroundmiddleofyourbody(trunk).Lossfatfromlegs,arms, Changes tests tocheckyourbones. problems includebonepain,softeningorthinning(whichmayleadtofractures).Your healthcareprovidermayneedtodoadditional Bone problems lamivudine andtenofovirdisoproxilfumaratetablets. problems,yourhealthcareprovidermayneedtodobloodtestscheckkidneysduringtreatmentwithdolutegravir, tenofovir disoproxilfumaratetablets.Ifyouhavehadkidneyproblemsinthepastorneedtotakeanothermedicine that cancause New lamivudine ifthey: Risk may dobloodteststocheckyourliver. ofliverdiseaseorotherriskfactors.Yourincluding liverfailure,havealsohappenedinpeoplewithoutahistory healthcareprovider in certainlivertestsduringtreatmentwithdolutegravir, lamivudineandtenofovirdisoproxilfumaratetablets.Liverproblems, Liver problems. right awayifyoudeveloparashwithanyofthefollowingsignsorsymptoms: disoproxil fumarate tablets. Allergic reactions tablets?” See nearest hospitalemergencyroomrightaway. If youtaketoomanydolutegravir, lamivudine and tenofovirdisoproxil fumarate tablets, call yourhealthcare provider orgotothe virus maybecomehardertotreat.Whenyoursupplystartsrunlow, getmorefromyourhealthcareproviderorpharmacy. Do notrunoutofdolutegravir, lamivudineandtenofovirdisoproxilfumaratetablets.Thevirusinyourbloodmayincreasethe Dolutegravir, lamivudineandtenofovirdisoproxilfumaratetabletsmaybetakenwithorwithoutfood. Stay underthecareofahealthcareproviderduringtreatmentwithdolutegravir, lamivudineandtenofovirdisoproxilfumaratetablets. take 2dosesatthesametimeormorethanwhatyourhealthcareprovidertellsyoutotake. If youmissadoseofdolutegravir, lamivudineandtenofovirdisoproxilfumaratetablets,takeitassoonyouremember. Donot will informyouifneedtotaketheextradolutegravirdose tablets isonetableteachday. forcertainpopulations.Your Anextradoseofdolutegravironlymaybenecessary healthcareprovider For adultsandchildrenweighing40kg(88lbs)ormore,theusualdoseofdolutegravir, lamivudineandtenofovirdisoproxilfumarate Take tablets?” See sofosbuvir withvelpatasvir ledipasvir withsofosbuvir lopinavir withritonavir darunavir atazanavir didanosine St. John’s wort( rifampin a medicinethatcontainsmetformin orribavirin medicines usedtotreathepatitisvirusinfections,suchasinterferon tenofovir disoproxilfumaratetabletsshouldbetakenatleast2hoursbeforeor6afteryoutakethesemedicines. dolutegravir, dolutegravir, lamivudineandtenofovirdisoproxilfumaratetabletsiftakenwithfood.Otherwise, lamivudineand iron or calcium supplements taken by mouth. Supplements containing calcium or iron may be taken at the same time with any othermedicinetotreatHIV anti-seizure medicines: medicines. lamivudine andtenofovirdisoproxilfumaratetabletsshouldbetakenatleast2hoursbeforeor6afteryoutakethese antacids, laxatives, or othermedicines that contain aluminum, magnesium, sucralfate, or buffered medicines. Dolutegravir, adefovir tenofovir emtricitabine lamivudine abacavir • tablets. are breastfeedingorplantobreastfeed. harm yourunbornbaby. Tell yourhealthcareproviderifyoubecomepregnant. are pregnantorplantobecomepregnant.Itisnotknownifdolutegravir, lamivudineandtenofovirdisoproxilfumaratetabletswill have anyothermedicalcondition. have boneproblems. have kidneyproblems. have hadliverproblems,includinghepatitisBorCinfection. tablets. end of this Patient Information leaflet for a complete list of ingredients in dolutegravir, lamivudine and tenofovir disoproxil fumarate are allergictodolutegraviroranyoftheingredientsindolutegravir, lamivudineandtenofovirdisoproxilfumaratetablets.Seethe take dofetilide chance ofsexualcontactwithanybodyfluidssuchassemen,vaginalsecretions,orblood. Do nothaveanykindofsexwithoutprotection.Alwayspractice safer sexbyusingalat • • • • • • healthcare healthcare • • • • • “What common “What with dolutegravir, of or with tablets. any neworunusualsymptomsyoumayhaveafterstoptakingdolutegravir, lamivudineandtenofovirdisoproxilfumarate check yourhealthoftenanddobloodtestsregularlyforseveralmonthstoliver. Tell yourhealthcareproviderabout If youstoptakingdolutegravir, lamivudineandtenofovirdisoproxilfumaratetablets,yourhealthcareproviderwillneedto Do not stop dolutegravir, lamivudine and tenofovir disoproxil fumarate tablets without first talking to your healthcare provider. healthcare providerbeforeyourdolutegravir, lamivudineandtenofovirdisoproxilfumaratetabletsareallgone. Do notrunoutofdolutegravir, lamivudineandtenofovirdisoproxilfumaratetablets.Refillyourprescriptionortalkto pain, aching,ortendernessontherightsideofyourstomacharea loss ofappetite nausea orvomiting light-colored stools(bowelmovements) dark or“tea-colored”urine your skinorthewhitepartofeyesturnsyellow(jaundice) develop arashwithanyofthefollowingsignsorsymptoms: carbamazepine phenobarbital phenytoin oxcarbazepine provider aboutthebestwaytofeedyourbaby. you shouldnotbreastfeedifhaveHIV-1 becauseoftheriskpassingHIV-1 toyourbaby. Talk withyourhealthcare inflammation lamivudine worse in

interferon depression pain diarrhea nausea trouble sleeping past have takennucleosideanaloguemedicinesinthe or is of blisters orsoresinmouth muscle orjointaches tiredness generally illfeeling fever is body dolutegravir sodium,lamivudine,tenofovirdisoproxilfumarate. without the side the hepatitis provider provider kidney croscarmellose sodium,ferricoxide,hypromellose,ironoxideblack,red,magnesiumstearate,mannitol, Hypericum perforatum can happeninsomepeoplewhotakedolutegravir, lamivudineandtenofovirdisoproxilfumaratetablets.Bone People with a history ofhepatitisBorCvirusmayhaveanincreasedriskdevelopingnewworseningchanges People withahistory fat most most . Callyourhealthcareproviderrightawayifyoudeveloparashwithdolutegravir, lamivudineandtenofovir lamivudine effects and can and nausea of problems, important important B about right tenofovir happen the ribavirin-based virus of Stop pancreas dolutegravir, away the ‑1 and and in taking in medicines information including information people disoproxil tenofovir vomiting. if people IfyouhaveHIV-1 andhepatitisB,theBviruscanchange(mutate)duringyour your ) Do dolutegravir, (pancreatitis). regimens. who not child who lamivudine kidney disoproxil you fumarate Your healthcare provider may tell you to stop giving dolutegravir, lamivudine and breastfeed I I have • • • • take should develops should take, failure, Worsening ofliverdiseasethathascauseddeathhappenedinpeople generallynotfeelingwell HIV-1 lamivudine HIV-1 Childrenmaybeatriskfordevelopingpancreatitisduringtreatmentwith weakness cough tiredness including prescriptionandover-the-counter medicines,vitamins,orherbal fumarate and know tablets know if signs infection. medicines. you tenofovir can happeninsomepeoplewhotakedolutegravir, lamivudineand about about • • • • • • do take and and tablets

not cureHIVinfectionorAIDS. dolutegravir, dolutegravir, symptoms dolutegravir, IfyouhaveHIV-1 (HumanImmunodeficiencyVirustype1) tenofovir problems breathing swelling ofthemouth,face,lips,ortongue redness orswellingoftheeyes blisters orpeelingoftheskin have otherriskfactorsforpancreatitis ofpancreatitis have ahistory disoproxil can happenwhenyoustarttakingHIV-1 medicines.Your These changesmayincludeanincreasedamountoffatin exactly disoproxil of as fumarate lamivudine lamivudine pancreatitis lamivudine your healthcare fumarate tables • • • and and and including in tenofovir tenofovir tenofovir You mustkeeptakingHIV-1 tablets rash nasal signsandsymptoms headache provider children severe and disoproxil disoproxil disoproxil tells include get upper : you medical fever to stomach- fumarate fumarate fumarate take help and it. P1518054