1 Name of Medicine
Tenofovir disoproxil succinate/ emtricitabine.
2 Qualitative and Quantitative Composition
Each film-coated tablet contains 300.6 mg tenofovir disoproxil succinate which is equivalent to 245 mg of tenofovir disoproxil and 200 mg emtricitabine.
Tenofovir disoproxil succinate is a white to off-white crystalline powder. Emtricitabine is a white to off-white crystalline powder.
Excipients with known effect. Lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.
3 Pharmaceutical Form
The tablets are blue, capsule-shaped, film-coated and plain on both sides.
4 Clinical Particulars
4.9 Overdose
There is no known antidote for tenofovir disoproxil fumarate and emtricitabine. If overdose occurs the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary.
Tenofovir disoproxil fumarate. Clinical experience of doses higher than the therapeutic dose of tenofovir disoproxil fumarate is available from two studies. In one study, intravenous tenofovir, equivalent to 16.7 mg/kg/day of tenofovir disoproxil fumarate, was administered daily for 7 days. In the second study, 600 mg of tenofovir disoproxil fumarate was administered to patients orally for 28 days. No unexpected or severe adverse reactions were reported in either study. The effects of higher doses are not known.
Tenofovir is efficiently removed by haemodialysis with an extraction coefficient of approximately 54%. Following a single 300 mg dose of tenofovir disoproxil fumarate, a four-hour haemodialysis session removed approximately 10% of the administered tenofovir dose.
Emtricitabine. Limited clinical experience is available at doses higher than the therapeutic dose of emtricitabine. In once clinical pharmacology study, single doses of emtricitabine 1200 mg were administered to 11 patients. No severe adverse reactions were reported. The effects of higher doses are not known.
Haemodialysis treatment removes approximately 30% of the emtricitabine dose over a 3-hour dialysis period starting within 1.5 hours of emtricitabine dosing (blood flow rate of 400 mL/min and a dialysate flow rate of 600 mL/min). It is not known whether emtricitabine can be removed by peritoneal dialysis.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia) and 0800 764 766 (New Zealand).
5 Pharmacological Properties
Tenofovir/Emtricitabine Sandoz 301/200 tablet contains 200 mg of emtricitabine with 300.6 mg of tenofovir disoproxil succinate salt as compared to the innovator product which contained 300 mg tenofovir disoproxil fumarate salt. All clinical data in this product information (including Pharmacokinetic, Pharmacodynamic, and Clinical Trial data) relevant to tenofovir are based on tenofovir disoproxil fumarate.
5.3 Preclinical Safety Data
Tenofovir and tenofovir disoproxil fumarate administered in toxicology studies to rats, dogs and monkeys at exposures (based on AUCs) greater than or equal to 6-fold those observed in humans caused bone toxicity. In monkeys the bone toxicity was diagnosed as osteomalacia. Osteomalacia observed in monkeys appeared to be reversible upon dose reduction or discontinuation of tenofovir. In rats and dogs, the bone toxicity manifested as reduced bone mineral density. The mechanism(s) underlying bone toxicity is unknown.
Evidence of renal toxicity was noted in 4 animal species. Increases in serum creatinine, BUN, glycosuria, proteinuria, phosphaturia and/or calciuria and decreases in serum phosphate were observed to varying degrees in these animals. These toxicities were noted at exposures (based on AUCs) 2-20 times higher than those observed in humans. The relationship of the renal abnormalities, particularly the phosphaturia, to the bone toxicity is not known.
Carcinogenicity. No carcinogenicity studies have been conducted with tenofovir disoproxil fumarate and emtricitabine in combination. In a long-term carcinogenicity study conducted in mice with tenofovir disoproxil (as fumarate) there was a low incidence of duodenal tumours with the highest dose of 600 mg/kg/day. These were associated with a high incidence of duodenal mucosal hyperplasia, which was also observed with a dose of 300 mg/kg/day. These findings may be related to high local drug concentrations in the gastro-intestinal tract, likely to result in much higher exposure margins than that based on the AUC. At therapeutic doses the risk of these duodenal effects occurring in humans is likely to be low. The systemic drug exposure (AUC) with the 600 mg/kg/day dose was approximately 15 times the human exposure at the therapeutic dose of 300 mg/day. No tumourigenic response was observed in rats treated with doses of up to 300 mg/kg/day (5 times the human systemic exposure at the therapeutic dose based on AUC).
In long-term oral carcinogenicity studies conducted with emtricitabine, no drug-related increases in tumour incidence were found in mice at doses up to 750 mg/kg/day (32 times the human systemic exposure (AUC) at the therapeutic dose of 200 mg/day) or in rats at doses up to 600 mg/kg/day (38 times the human systemic exposure at the therapeutic dose).
Genotoxicity. Tenofovir disoproxil fumarate was mutagenic in an in vitro mouse L5178Y lymphoma cell assay (tk locus) and in an ex vivo assay for unscheduled DNA synthesis in rat hepatocytes, but it was negative in in vitro bacterial assays for gene mutation and an in vivo mouse micronucleus test for chromosomal damage. Emtricitabine was not mutagenic in bacteria or mouse lymphoma cell assays in vitro nor clastogenic in the mouse micronucleus test in vivo.
6 Pharmaceutical Particulars
6.7 Physicochemical Properties
Chemical structure. Tenofovir disoproxil succinate. The chemical name of tenofovir disoproxil succinate is (R)-(((1-(6-amino-9H-purin-9-yl) propan-2-yloxy) methyl) phosphoryl) bis(oxy)bis(methylene) isopropyl dicarbonate succinate. It has a molecular formula of C19H30N5O10P.C4H6O4 and a molecular weight of 637.53. It has the following structural formula:
https://stagingapi.mims.com/au/public/v2/images/fullchemgif/CSTEDISU.gif Emtricitabine. The chemical name of emtricitabine is 5-fluoro-1-(2R,5S)-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl] cytosine. Emtricitabine is the (-) enantiomer of a thio analog of cytidine, which differs from other cytidine analogs in that it has a fluorine in the 5-position.
It has a molecular formula of C8H10FN3O3S and a molecular weight of 247.24. It has the following structural formula:
https://stagingapi.mims.com/au/public/v2/images/fullchemgif/CSEMTRIC.gif CAS number. Tenofovir disoproxil succinate CAS registry number: 1637632-97-3.
Emtricitabine CAS registry number: 143491-57-0.
The partition coefficient (log p) for tenofovir disoproxil is 1.25 and the pKa is 3.75.
Emtricitabine has a solubility of approximately 112 mg/mL in water at 25°C. The partition coefficient (log p) for emtricitabine is -0.43 and the pKa is 2.65.
7 Medicine Schedule (Poisons Standard)
S4 - Prescription only medicine.
Summary Table of Changes
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