N O V A R T I S

Zometa® Treatment of Hypercalcemia of Malignancy (HCM)

COMPOSITION One vial contains 4 mg zoledronic acid (anhydrous), corresponding to 4.264 mg zoledronic acid monohydrate

PHARMACEUTICAL FORM Powder and solvent for solution for infusion

INDICATIONS Treatment of Hypercalcemia of Malignancy (HCM)

DOSAGE AND ADMINISTRATION

Dosage Adults and elderly patients The recommended dose in HCM (albumin-corrected serum calcium ≥ 12.0 mg/dl or 3.0 mmol/l) is 4 mg reconstituted and further diluted Zometa solution for infusion (diluted with 50 ml 0.9% sodium chloride or 5% glucose solution), given as a single 15-minute intravenous infusion (see instructions for preparation of the infusion solution under Other information).

The hydration status of patients must be assessed prior to administration of Zometa, and an infusion of fluids should be given based on the patient’s clinical condition.

Dosage during retreatment Experience of retreatment in patients with a renewed increase in serum calcium is limited (and this limited experience has only been gathered for the 8 mg dose; see properties/action). At least 7-10 days* should elapse before retreatment (*:statement in accordance with study protocol). Serum creatinine should be determined in such patients prior to retreatment (see Precaution under Restrictions on use).

Dosage in patients with renal insufficiency

Studies performed to date show that no adjustment of dosage or infusion time is required in patients with mild or moderate renal impairment (serum creatinine < 400 µmol/l or <4.5 mg/dl).

Dosage in patients with hepatic insufficiency As only limited clinical data are available on the treatment of patients with severe hepatic insufficiency, no specific recommendations can be made for such patients.

CONTRAINDICATIONS Zometa powder for solution for infusion is contraindicated in patients with clinically significant hypersensitivity to zoledronic acid, other bisphosphonates or any of the excipients in the formulation of Zometa.

SPECIAL WARNINGS AND PRECAUTIONS FOR USE

Together with serum creatinine, serum levels of calcium, phosphate and magnesium should be carefully monitored after initiating Zometa therapy.

Following thyroid surgery, patients may be particularly susceptible to hypocalcaemia as a result of relative hypoparathyroidism.

Bisphosphonates have been associated with reports of renal dysfunction. In view of possible serum creatinine level elevations and the lack of data in patients with severe renal impairment (serum creatinine < 400 µmol/l or <4.5 mg/dl), the use of Zometa cannot be recommended in these patients unless the benefits outweight the risks.

In any patients requiring repeated administration of Zometa, serum creatinine should be evaluated prior to each dose. Patients with evidence of renal function deterioration should be appropriately evaluated and consideration should be given as to whether the potential benefit outweighs the possible risk.

As only limited clinical data are available in patients with severe hepatic insufficiency, no specific recommendations can be made for these patients.

The safety and efficacy of Zometa in paediatric patients have not been established.

PREGNANCY/LACTATION Pregnancy category C

PREGNANCY In animal reproduction studies, teratogenic effects were observed in rats. In rabbits, there was no teratogenicity or fetotoxicity, but maternal toxicity was observed.

As there is no experience in humans as regards the use of Zometa during pregnancy and lactation, Zometa should not be used during pregnancy unless the benefits to the mother outweight the risk to the fetus.

LACTATION Not only are bisphosphonates poorly absorbed from the gastrointestinal tract, but bisphosphonates are present in milk as bisphosphonate-calcium complexes, which are very likely to be unabsorbable. Since no experience is available, caution is to be exercised when administering Zometa to breast-feeding women.

EFFECTS ON ABILITY TO DRIVE AND USE MACHINE No empirical data are available concerning the effects on the ability to drive or use machines.

ADVERSE EFFECTS

In clinical studies in patients with HCM, the overall safety profile was similar for all 3 treatment groups (4 mg and 8 mg zoledronic acid, 90 mg pamidronate) as regards the nature and severity of adverse effects.

In most cases no specific treatment is required and the symptoms subside after a few hours or days.

The following adverse effects have occurred in clinical studies of zoledronic acid in HCM. They are listed according to their frequency and described as follows: Very common : > 10%; common : > 1% - < 10% ;occasional: > 0.1% - < 1%; rare : > 0.01% - < 0.1 %; very rare : < 0.001% (including isolated reports)

Common: A rise in body temperature (approx. 10%), occasionally with flu-like symptoms such as fever, chills, and bone or muscle ache.

Occasional: Chest pain, dysgeusia, thirst.

Circulatory and lymphatic system Occasional: Pacytopenia, thrombocytopenia.

Central nervous system Occasional: Confusion, headache.

Gastrointestinal tract Occasional to common, depending on the dosage: Nausea and vomiting (less than 8 mg: 3%).

Skin Rare: Erythromatous rash. Occasional: Pruritus.

Local reactions Occasional: reactions at the site of injection: redness and swelling.

Muscoskeletal system, connective tissue and bones Occasional: skeletal pain, fatigue, arthralgia.

Cardiovascular system Occasional: Bradycardia

Sensory organs Occasional: conjunctivitis (0-1%, depending on the dose).

Kidneys Common: grade 3 (NCI Common Toxicity Criteria [CTC] elevations of serum creatinine were seen in 2.4% of patients treated with 4 mg Zometa and in 3.1% of patients treated with 8 mg Zometa.

Isolated cases: There have been some reports of impaired renal function, but a causal relationship has not been established.

Respiratory system Administration of bisphosphonates has been associated with bronchospastic reactions in acetylsalicylic acid-sensitive asthmatic patients.

Biochemical changes Frequently, the reduction in renal calcium excretion is accompanied by a fall in serum phosphate levels not requiring treatment (3.5%). Common: Asymptomatic hypocalcaemia (6%). Occasional: Hypomagnesaemia.

INTERACTIONS In clinical studies, Zometa has been administered concomitantly with commonly used anticancer agents, diuretics, antibiotics and analgesics without clinically apparent interactions occurring. Zoledronic acid shows no appreciable binding to plasma proteins and does not inhibit human P450 enzymes in vitro (see “pharmacokinetics properties”), but no formal clinical interaction studies have been performed. Caution is advised when bisphosphonates are administered with aminoglycosides, since both agents may have an additive effect, resulting in a lower serum calcium level for longer periods than required. Attention should be paid to the possibility of hypomagnesaemia developing during treatment.

OVERDOSE

There has been no experience of acute intoxication with Zometa. Patients who have received doses higher than those recommended should be carefully monitored. Clinically significant hypocalcemia should be reserved with an infusion of calcium gluconate.

PHARMACOLOGICAL PROPERTIES

Pharmacodynamics Pharmacotherapeutic group: Bisphosphonates, ATC code: M05 BA 08

Zoledronic acid is a bisphosphonates which acts specifically on bone. It inhibits bone resorption caused by increased osteoclastic activity. The selective action of bisphosphonates on bone tissue is based on their high affinity for mineralized bone.

The molecular mechanism of action is still unclear. In long-term animal studies, zoledronic acid inhibits bone resorption without adversely affecting the formation, mineralization or mechanical properties of bone.

Clinical Studies Clinical studies with pamidronate demonstrated that in tumour –induced hypercalcaemia, zoledronic acid brings about a decrease in serum calcium and in urinary calcium excretion.

Complete response rate after 10 days are 88.4% with 4 mg and 86.7 % with 8 mg Zometa and 69.7% for pamidronate. There was no significant difference between two doses of Zometa as regards effect, but the difference between Zometa and pamidronate was statistically significant. The frequency of hypocalcaemia was somewhat higher with the 8 mg dose.

In half of all cases, elevated serum calcium can be lowered to within the normal range within 4 days by a single infusion of Zometa. The median time to recurrence of hypercalcaemia was 30- 40 days with Zometa and 20-22 days with pamidronate.

The response rate (complete response) in patients retreated due to a renewed rise in corrected serum calcium (>2.9 mmol/l) was about 52%. This parameter was only studied with the 8 mg dose. There are thus no data allowing comparison with the 4 mg dose and the question of whether or not the 8 mg dose is superior to in this respect therefore remains open.

Pharmacokinetic properties

Distribution Over the first 24 hours, 44 + 18% of the administered dose is recovered in the urine, while the remainder is principally bound to bone tissue.

Zoledronic acid shows no affinity for blood cells, and plasma protein binding is low (approx. 22%) and independent of concentration of zoledronic acid.

Increasing the infusion time for 5 to 15 minutes causes a 30% decrease in zoledronic acid concentration at the end of the infusion, but has no effect on the AUC.

As with other bisphosphonates, the between-patient variability of the pharmacokinetic parameters of zoledronic acid is high.

Metabolism Zoledronic acid does not inhibit human P450 enzymes in vitro and is not metabolized. It is excreted unchanged via the kidney. It is slowly released from the bone tissue back into the systemic circulation and is eliminated via the kidney with a half-life (t1/2 γ) of at least 167 hour. The total body clearance is 5.6 + 2.5 l/h, independent of dose, and unaffected by gender, age, race, or body weight.

Elimination Intravenously administered zoledronic acid is eliminated in two stages : rapid biphasic elimination from the systemic circulation, with half-lives of 0.23 hours (1/2 β) and 1.75 hours (1/2 α), followed by a long elimination phase.

In animal studies, < 3% of the administered dose was recovered in the faeces.

Pharmacokinetics in special clinical situations

Patients with hypercalcaemia There are no pharmacokinetic data on zoledronic acid in patients with hepatic insufficiency. Zoledronic acid does not inhibit human P450 enzymes in vitro and is not metabolized. In animal studies <3% of the administered dose was recovered in the faeces. This suggests that liver function plays no relevant role in the pharmacokinetics of zoledronic acid.

Patients with renal insufficiency Studies have not been performed in patients with severe renal insufficiency.

EXCIPIENTS Zometa vial : Manitol, sodium citrate Solvent ampoule : Water for injections

INCOMPATIBILITIES Studies with glass bottles, as well as several types of infusion bags and infusion lines made from polyvinylchloride, polyethylene and polypropylene (prefilled with 0.9% w/v sodium chloride solution or 5% w/v glucose solution), showed no incompatibility with Zometa.

To avoid potential incompatibilities, Zometa reconstituted solution is to be diluted with 0.9% w/v sodium chloride solution or 5% w/v glucose solution.

Zometa reconstituted solutions must not be mixed with calcium-containing solutions such as Ringer’s solution.

STORAGE Do not store above 30°C

Keep out of the reach and sight of children

HARUS DENGAN RESEP DOKTER

PACKAGE QUANTITIES AND REGISTRATION NUMBER Zometa 4 mg powder for solution is supplied as packs containing 1 vial and 1 ampoule of water for injections, respectively.

Reg. No……….

Manufactured by Novartis Pharma AG, Basle, Switzerland Imported by PT Novartis Biochemie, Citeureup, Bogor, Indonesia