(Tenofovir Disoproxil Fumarate, Lamivudine & Emtricitabine Tablets)

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(and dosage form):
TENMAC-LEF (tablets)

Each tablet contains:
Tenofovir Disoproxil Fumarate 300 mg
Lamivudine 300 mg
Efavirenz 600mg

Tenofovir disoproxil fumarate
Tenofovir disoproxil fumarate is an antiviral drug.

The pharmacokinetics of tenofovir disoproxil fumarate have been evaluated in healthy volunteers and HIV-1 infected individuals. Tenofovir pharmacokinetics are similar between these populations.

Tenofovir is a water soluble diester prodrug of the active ingredient tenofovir. The oral bioavailability of tenofovir from Tenofovir in fasted subjects is approximately 25%. Following oral administration of a single dose of Tenofovir 300 mg to HIV-1 infected subjects in the fasted state, maximum serum concentrations (Cmax) are achieved in 1.0 ± 0.4 hrs. Cmax and AUC values are 0.30 ± 0.09 μg/mL and 2.29 ± 0.69 μg·hr/mL, respectively. The pharmacokinetics of tenofovir are dose proportional over a Tenofovir dose range of 75 to 600 mg and are not affected by repeated dosing.

In vitro binding of tenofovir to human plasma or serum proteins is less than 0.7 and 7.2%, respectively, over the tenofovir concentration range 0.01 to 25 μg/mL. The volume of distribution at steady-state is 1.3 ± 0.6 L/kg and 1.2 ± 0.4 L/kg, following intravenous administration of tenofovir 1.0 mg/kg and 3.0 mg/kg.
Metabolism and Elimination
In vitro studies indicate that neither tenofovir disoproxil nor tenofovir are substrates of CYP enzymes. Following IV administration of tenofovir, approximately 70–80% of the dose is recovered in the urine as unchanged tenofovir within 72 hours of dosing. Following single dose, oral administration of Tenofovir, the terminal elimination half-life of tenofovir is approximately 17 hours. After multiple oral doses of Tenofovir 300 mg once daily (under fed conditions), 32 ± 10% of the administered dose is recovered in urine over 24 hours. Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion. There may be competition for elimination with other compounds that are also renally eliminated.

Lamivudine is a selective inhibitor of HIV-1 and HIV-2 replication in vitro, including zidovudine-resistant clinical isolates of the human immunodeficiency virus (HIV). Lamivudine is metabolised intracellularly to the active 5'- triphosphate which inhibits the RNA-and DNA-dependant activities of HIV reverse transcriptase by termination of the viral DNA chain. Lamivudine does not interfere with cellular deoxynucleotide metabolism and has little effect on mammalian cell and mitochondrial DNA content. In vitro, lamivudine demonstrates low cytotoxicity to peripheral blood lymphocytes, to established lymphocyte and monocyte-macrophage cell lines, and to a variety of bone marrow
progenitor cells. In vitro, lamivudine therefore has a high therapeutic index. Reduced in-vitro sensitivity to lamivudine has been reported for HIV isolated from patients who have received lamivudine therapy before.
Lamivudine has been shown to act additively or synergistically with other anti-HIV agents, particularly zidovudine, inhibiting the replication of HIV in cell culture. In vitro studies indicate that zidovudine-resistant virus isolates can become zidovudine-sensitive when they acquire resistance to lamivudine.

Efavirenz is a non-nucleoside reverse transcriptase (RT) inhibitor of HIV-1. Efavirenz activity is mediated predominantly by non-competitive inhibition of HIV-1 reverse transcriptase(RT). HIV-2 RT and human cellular DNA polymerases α, β, γ, and σ are not inhibited by efavirenz.

Pharmacokinetics in adults:

Following oral administration, lamivudine is well absorbed with bioavailability of approximately 80%. The mean time (Tmax) to maximum serum concentration (Cmax) is about an hour. At therapeutic dose levels of 4 mg/kg/day (as two 12- hourly doses), Cmaxis in the order of 1-1.5 micrograms/mL.
The mean volume of distribution from intravenous studies has been reported as 1.3 L/kg and the mean terminal half-life of elimination as 5 to 7 hours. The mean systemic clearance of lamivudine is approximately 0.32 L/kg/h, with predominantly renal clearance of more than 70% via active tubular secretion, but little hepatic metabolism, at less than 10 L. The intracellular half-life of the lamivudine triphosphate active metabolite is prolonged, averaging over 10 hours in peripheral blood lymphocytes. A delay in Tmax, and reduction in Cmax have been observed when co-administered with food, but no dose adjustment is needed, as lamivudine bioavailability is not altered. Lamivudine displays limited binding to albumin and exhibits linear pharmacokinetics over the therapeutic dose range. Co-administration of zidovudine results in a 13% increase in zidovudine exposure and a 28% increase in peak plasma levels. No dosage adjustments are necessary, as this is not considered to be of significance to patient safety. Limited data shows lamivudine penetrates the central nervous system and reaches the cerebrospinal fluid (CSF). The true extent of penetration or relationship with any clinical efficacy is unknown.
Pharmacokinetics in children:
In general, lamivudine pharmacokinetics in paediatric patients are similar to adults. However, absolute bioavailability is reduced to approximately 65%, in paediatric patients, with an increased clearance of 0.52 L/kg/hr.
There are limited pharmacokinetic data for patients <3 months of age.

Efavirenz: In HIV-1 infected subjects time-to-peak plasma concentrations were approximately 3–5 hours and steady- state plasma concentrations were reached in 6–10 days. In 35 HIV-1 infected subjects receiving efavirenz 600 mg once daily, steady-state Cmax was 12.9 ± 3.7 μM (mean ± SD), Cmin was 5.6 ± 3.2 μM, and AUC was 184 ± 73 μM•hr. Efavirenz is highly bound (approximately 99.5–99.75%) to human plasma proteins, predominantly albumin. Following administration of 14C-labeled efavirenz, 14–34% of the dose was recovered in the urine (mostly as metabolites) and 16–61% was recovered in feces (mostly as parent drug). In vitro studies suggest CYP3A and CYP2B6 are the major isozymes responsible for efavirenz metabolism. Efavirenz has been shown to induce CYP enzymes, resulting in induction of its own metabolism. Efavirenz has a terminal half-life of 52–76 hours after single doses and 40–55 hours after multiple doses

TENMAC-LEF is indicated as part of antiretroviral combination therapy for treatment of HIV infected adults and children.

Hypersensitivity to any of the ingredients.

Patients receiving Lamivudine, Tenofovir disoproxil fumarate and other antiretroviral agents may continue to develop opportunistic infections and other complications of HIV infection. Patients should therefore remain under close supervision by medical practitioners experienced in the treatment of patients with HIV-associated diseases.
Current antiretroviral therapy, including Lamivudine, has not been proven to prevent the risk of transmission of HIV to others through sexual contact or blood contamination. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of lamivudine alone or in combination, in the treatment of HIV infection.

Zidovudine plasma levels are not significantly altered when co-administered with lamivudine (see Pharmacokinetics).
An interaction with trimethoprim, a constituent of co-trimoxazole. causes a 40% increase in lamivudine plasma concentrations at therapeutic doses. This does not require dose adjustment unless the patient also has renal impairment.
Administration of co-trimoxazole with the Lamivudine/zidovudine combinations in patients with renal impairment should be carefully assessed. lamivudine may inhibit the intracellular phosphorylation of zalcitabine when the two medicinal products are used concurrently. Lamivudine is therefore not recommended to be used in combination with zalcitabine.

Safety in pregnancy and lactation has not been established.

Adults and adolescents more than 12 years of age:
The recommended dose of TENMAC-LEF is one tablet daily.
Children >3 months to 12 years of age:
The recommended dose is 4 mg/kg twice daily up to a maximum of 300 mg daily.

Children <3 months of age:
There are limited data to propose specific dosage recommendations
TENMAC-LEF can be taken with or without food.

Tenofovir disoproxil fumarate
The following adverse reactions have been identified during use of Tenofovir disoproxil fumarate. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune System Disorders allergic reaction, including angioedema Metabolism and Nutrition Disorders lactic acidosis, hypokalemia, hypophosphatemia Respiratory, Thoracic, and Mediastinal Disorders dyspnea Gastrointestinal Disorders pancreatitis, increased amylase, abdominal pain Hepatobiliary Disorders hepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT gamma GT) Skin and Subcutaneous Tissue Disorders rash Musculoskeletal and Connective Tissue Disorders rhabdomyolysis, osteomalacia (manifested as bone pain and which may contribute to fractures), muscular weakness, myopathy Renal and Urinary Disorders acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal insufficiency, increased creatinine, proteinuria, polyuria General Disorders and Administration Site Conditions asthenia The following adverse reactions, listed under the body system headings above, may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, hypophosphatemia.

The following side-effects have been reported during therapy of HIV disease with Lamivudine alone, and in combination with other anti-retrovirals.
Gastro-intestinal disorders:
Pancreatitis, upper abdominal pain, nausea; vomiting and diarrhoea have been reported.
Blood and lymphatic system disorders:
Neutropenia, thrombocytopenia and anaemia have occurred.
Skin and appendages disorders:
Alopecia has been reported.

Central and Peripheral Nervous system disorders:
Peripheral neuropathy, paraesthesia, and headache have been reported.

Musculo-skeletal system disorders:
Arthralgia, muscle disorders including less frequently, rhabdomyolysis have been reported.

Body as a whole:
Malaise, fatigue and fever have occurred.

Hypersensitivity reactions:
Skin rash.

Changes in laboratory test parameters:
Transient rises in serum liver enzymes (AST; ALT) and rises in serum amylase have been reported.

Special precautions:
Lamivudine should be used with caution in patients with advanced cirrhotic liver disease due to chronic Hepatitis B infection, as there is a small risk of rebound hepatitis post treatment.

Pancreatitis has been observed in some patients receiving Lamivudine. However it is unclear whether this is due to Lamivudine or to underlying HIV disease. Pancreatitis must be considered whenever a patient develops abdominal pain, nausea, vomiting or elevated biochemical markers. Discontinue use of Lamivudine until diagnosis of pancreatitis is excluded.

Lactic acidosis/severe hepatomegaly with steatosis:
Long-term use of Lamivudine can result in potentially fatal lactic acidosis. Symptomatic hyperlactacaemia and lactic
acidosis are uncommon. Clinical features are non-specific, and include nausea, vomiting, abdominal pain, dyspnoea,
fatigue and weight loss. Suspicious biochemical features include mild raised transaminases, raised lactate
dehydrogenase (LDH) and/or creatine kinase.
In patients with suspicious symptoms or biochemistry. measure the venous lactate level (normal <2 mmol/L), and
respond as follows:
Lactate 2 - 5 mmol/L: monitor regularly, and be alert for clinical signs.
Lactate 5 - 10 mmol/L without symptoms: monitor closely.
Lactate 5 - 10 mmol/L with symptoms: STOP all therapy. Exclude other causes (e.g. sepsis, uraemia. diabetic
ketoacidosis, thyrotoxicosis, lymphoma).
Lactate 5 - 10 mmol/L: STOP all therapy (80% mortality in case studies).
Diagnosis of lactic acidosis is confirmed by demonstrating metabolic acidosis with an increased anion gap and raised
lactate level. Therapy should be stopped in any acidotic patient with raised lactate level.
Blood for lactate assays should be heparinised and stored on ice.
After recovery, NRTI's should be avoided. Seek expert advice on medicine selection. The above lactate values may not
be applicable to paediatric patients.
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of
Lamivudine alone or in combination, in the treatment of HIV infection. Most cases were women.
Caution should be exercised when administering Lamivudine to patients with known risk factors for liver disease.
Treatment with Lamivudine should be suspended in any patient who develops clinical or laboratory findings suggestive
of lactic acidosis or hepatotoxicity.

Opportunistic infections:
Patients receiving Lamivudine may continue to develop opportunistic infections and other complications of HIV infection, and therefore they should remain under close observation by medical practitioners experienced in the treatment of patients with associated HIV disease.
The risk of HIV transmission to others:
Patients should be advised that current antiretroviral therapy, including Lamivudine, has not been proven to prevent the risk of transmission of HIV to others through sexual contact or blood contamination. Appropriate precautions should continue to be employed.

Patients with moderate to severe renal impairment:
In patients with moderate to severe renal impairment, the terminal half-life of lamivudine is increased due to decreased
clearance. The dose should therefore be adjusted

If overdose occurs the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as

TENMAC-LEF tablets are Light blue color, elongated, biconvex, uncoated tablet, having a break line on one side of each

Store below 30oC. Protect from light.

24 months from the date of manufacturing

HDPE Bottle pack of 30 tablets and packed in a unit carton along with package insert.

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