COMPOSITION
Each tablet contains:
Tenofovir Disoproxil Fumarate 300 mg
Emtricitabine 200mg

PHARMACOLOGY
TENMAC-EM is a fixed-dose combination of antiviral drugs emtricitabine and tenofovir disoproxil fumarate. Tenofovir disoproxil fumarate is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. Tenofovir disoproxil fumarate requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate. Tenofovir diphosphate inhibits the activity of HIV-1 reverse transcriptase by competing with the natural substrate deoxyadenosine 5`-triphosphate and, after incorporation into DNA, by DNA chain termination. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases alpha and beta, and mitochondrial DNA polymerase gamma.

Emtricitabine works by inhibiting reverse transcriptase, the enzyme that copies HIV RNA into new viral DNA. Emtricitabine is a synthetic nucleoside analogue of cytidine. It is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate, which is responsible for the inhibition of HIV-1 reverse transcriptase. It competes with the natural substrate deoxycytidine 5'-triphosphate and incorporates into nascent viral DNA, resulting in early chain termination. Therefore emtricitabine inhibits the activity of HIV-1 reverse transcriptase (RT) both by competing with the natural substrate deoxycytidine 5'-triphosphate and by its incorporation into viral DNA. By inhibiting HIV-1 reverse transcriptase, emtricitabine can help to lower the amount of HIV, or "viral load", in a patient's body and can indirectly increase the number of immune system cells (called T cells or CD4+ T-cells). Both of these changes are associated with healthier immune systems and decreased likelihood of serious illness.

PHARMACOKINETICS
Emtricitabine: Following oral administration of emtricitabine tablets, emtricitabine is rapidly absorbed with peak plasma concentrations occurring at 1–2 hours post-dose. Less than 4% of emtricitabine binds to human plasma proteins in vitro and the binding is independent of concentration over the range of 0.02–200 μg/mL. Following administration of radiolabelled emtricitabine, approximately 86% is recovered in the urine and 13% is recovered as metabolites. The metabolites of emtricitabine include 3′-sulfoxide diastereomers and their glucuronic acid conjugate. Emtricitabine is eliminated by a combination of glomerular filtration and active tubular secretion. Following a single oral dose of
emtricitabine, the plasma emtricitabine half-life is approximately 10 hours.

Tenofovir Disoproxil Fumarate: The pharmacokinetic properties of tenofovir disoproxil fumarate are summarized in Table 6. Following oral administration of Tenofovir Disoproxil Fumarate:, maximum tenofovir serum concentrations are achieved in 1.0 ± 0.4 hour. Less than 0.7% of tenofovir binds to human plasma proteins in vitro and the binding is independent of concentration over the range of 0.01–25 μg/mL. Approximately 70–80% of the intravenous dose of tenofovir is recovered as unchanged drug in the urine. Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion. Following a single oral dose of Tenofovir Disoproxil Fumarate:, the terminal elimination half-life of tenofovir is approximately 17 hours.

INDICATIONS

TENMAC-EM is a combination of Tenofovir Disoproxil Fumarate & Emtricitabine, both nucleoside analog HIV-1 reverse transcriptase inhibitors.

TENMAC-EM is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients 12 years of age and older.

TENMAC-EM is indicated in combination with safer sex practices for pre-exposure prophylaxis (PrEP) to reduce the
risk of sexually acquired HIV-1 in adults at high risk.

DOSAGE AND ADMINISTRATION:
Treatment of HIV-1 Infection
• Recommended dose in adults and pediatric patients (12 years of age and older and weighing greater than or equal to 35 kg): One tablet once daily taken orally with or without food.
• Recommended dose in renally impaired HIV-1 infected adult patients: Creatinine clearance 30-49 mL/min: 1 tablet every 48 hours. CrCl below 30 mL/min or hemodialysis: Do not use TENMAC- EM.
Pre-exposure Prophylaxis
• Recommended dose in HIV-1 uninfected adults: One tablet once daily taken orally with or without food.
• Recommended dose in renally impaired HIV-uninfected individuals: Do not use TRUVADA in HIV- uninfected individuals if CrCl is below 60 mL/min. If a decrease in CrCl is observed in uninfected individuals while using TENMAC-EM for PrEP, evaluate potential causes and re-assess potential risks and benefits of continued use.

CONTRAINDICATIONS:
Do not use TENMAC-EM for pre-exposure prophylaxis in individuals with unknown or positive HIV-1 status. TENMAC-EM should be used in HIV-infected patients only in combination with other antiretroviral agents.

PRECAUTIONS AND WARNING:
• Recommended dose in renally impaired HIV-uninfected individuals: Do not use TENMAC-EM in HIV-uninfected individuals if CrCl is below 60 mL/min. If a decrease in CrCl is observed in uninfected individuals while using TENMAC-EM for PrEP, evaluate potential causes and re-assess potential risks and benefits of continued use.
• New onset or worsening renal impairment: Can include acute renal failure and Fanconi syndrome. Assess creatinine clearance (CrCl) before initiating treatment with TENMAC-EM. Monitor CrCl and serum phosphorus in patients at risk. Avoid administering TENMAC-EM with concurrent or recent use of nephrotoxic drugs.
• Coadministration with Other Products: Do not use with drugs containing emtricitabine or tenofovir disoproxil fumarate including efavirenz + emtricitabine + tenofovir disoproxil fumarate, emtricitabine+rilpivirine+tenofovir, emtricitabine, tenofovir Disoproxil Fumarate; or with drugs containing lamivudine. Do not administer in combination with adefovir dipivoxil,.
• Decreases in bone mineral density (BMD): Consider assessment of BMD in patients with a history of pathologic fracture or other risk factors for osteoporosis or bone loss.
• Redistribution/accumulation of body fat: Observed in patients receiving antiretroviral therapy.
• Immune reconstitution syndrome: May necessitate further evaluation and treatment.
• Triple nucleoside-only regimens: Early virologic failure has been reported in HIV-infected patients. Monitor carefully and consider treatment modification.
• Comprehensive management to reduce the risk of acquiring HIV-1: Use as part of a comprehensive prevention strategy including other prevention measures; strictly adhere to dosing schedule.
• Management to reduce the risk of acquiring HIV-1 drug resistance: Prior to initiating TENMAC-EM for PrEP - if clinical symptoms consistent with acute viral infection are present and recent (<1 month) exposures are suspected, delay starting PrEP for at least one month and reconfirm negative HIV-1 status or use a test approved by the FDA as an aid in the diagnosis of HIV-1 infection, including acute or primary HIV-1 infection.

While using TENMAC-EM for PrEP - HIV-1 screening tests should be repeated at least every 3 months.
Lactic Acidosis/Severe Hepatomegaly with Steatosis
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs such as TENMAC-EM alone or in combination with other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogs such as TENMAC-EM to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with TENMAC-EM should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

Patients with HIV and Hepatitis B Virus Coinfection It is recommended that all patients with HIV be tested for the presence of hepatitis B virus (HBV) before initiating antiretroviral therapy. TENMAC-EM is not indicated for the treatment of chronic HBV infection and the safety and
efficacy of TENMAC-EM have not been established in patients coinfected with HBV and HIV. Severe acute exacerbations of hepatitis B have been reported in patients after the discontinuation of emtricitabine (200 mg) and tenofovir disoproxil fumarate. Hepatic function should be closely monitored with both clinical and laboratory follow-up for at least several months in patients who discontinue TENMAC-EM and are coinfected with HIV and HBV. If appropriate, initiation of anti-hepatitis B therapy may be warranted.
Renal Impairment
Emtricitabine and tenofovir are principally eliminated by the kidney. Dosing interval adjustment of TENMAC-EM is recommended in all patients with creatinine clearance 30 –49 mL/min,. TENMAC-EM should not be administered to patients with creatine clearance < 30 mL/min or patients requiring hemodialysis. Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported in association with the use of tenofovir. The majority of these cases occurred in patients with underlying systemic or renal disease, or in patients taking nephrotoxic agents, however, some cases occurred in patients without identified risk factors. TENMAC-EM should be avoided with concurrent or recent use of a nephrotoxic agent. Patients at risk for, or with a history of, renal dysfunction and patients receiving concomitant nephrotoxic agents should be carefully monitored for changes in serum creatinine and phosphorus.
Fat Redistribution
Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance”have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including tenofovir. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis), which may necessitate further evaluation and treatment.

Nursing mothers:
Women infected with HIV-1 should be instructed not to breast feed.
Paediatric Use
Safety and effectiveness in paediatric patients have not been established.
Geriatric Use
Clinical studies of emtricitabine (200 mg) or tenofovir did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for the elderly patients should be cautious, keeping in mind the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

SIDE EFFECTS:
In HIV1 infected patients, the most common adverse reactions (incidence greater than or equal to 10%) are diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. In HIV-1 uninfected individuals in PrEP trials, adverse reactions that were reported by more than 2% of TENMAC-EM subjects and more frequently than by placebo subjects were headache, abdominal pain and weight decreased.

DRUG INTERACTIONS
Didanosine: Tenofovir disoproxil fumarate increases didanosine concentrations. Use with caution and monitor for evidence of didanosine toxicity (e.g., pancreatitis, neuropathy) when coadministered. Consider dose reductions or discontinuations of didanosine if warranted.

Atazanavir: Coadministration decreases atazanavir concentrations and increases tenofovir concentrations. Use atazanavir with TENMAC-EM only with ritonavir; monitor for evidence of tenofovir toxicity.

Lopinavir/ritonavir: Coadministration increases tenofovir concentrations. Monitor for evidence of tenofovir toxicity.

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

Emtricitabine: Limited clinical experience is available at doses higher than the therapeutic dose of Emtricitabine. In one clinical pharmacology trial, single doses of emtricitabine 1200 mg were administered to 11 subjects. No severe
adverse reactions were reported.
Hemodialysis 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.
Tenofovir Disoproxil Fumarate: Limited clinical experience at doses higher than the therapeutic dose of Tenofovir
Disoproxil Fumarate 300 mg is available. In one trial, 600 mg tenofovir disoproxil fumarate was administered to 8 subjects orally for 28 days, and no severe adverse reactions were reported. The effects of higher doses are not known.
Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. Following a single 300 mg dose of Tenofovir Disoproxil Fumarate, a four-hour hemodialysis session removed approximately 10% of the administered tenofovir dose.

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

SHELF LIFE:
24 months from the date of manufacturing

STORAGE:.
Keep in a dry place at a temperature below 30°C.