Tenemine 300 mg, 200 mg FC tablet

TENEMINE is indicated in combination with other antiretroviral medicines (such as non-nucleoside reverse transcriptase inhibitors or protease inhibitors) for the treatment of HIV-1 infection in adults.

TENEMINE is indicated in combination with safer sex practices for pre-exposure prophylaxis (PrEP) in proven HIV-1 uninfected adults to reduce the risk of sexually acquired HIV-1 in adults at high risk, provided maximum treatment compliance can be monitored.

Posology Therapy should be initiated by a doctor experienced in the management of HIV infection.

Dosage in adults for treatment of HIV-1 infection The dose of TENEMINE is one tablet (containing 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate) once daily taken orally with or without food.

Dosage for Pre-Exposure Prophylaxis The dose of TENEMINE in HIV-1 uninfected adults is one tablet (containing 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate) once daily taken orally with or without food. Significantly increased medicine exposures occurred when emtricitabine or tenofovir disoproxil fumarate were administered to patients with moderate to severe renal impairment (see section 4.3).

Table 1 Dosage for HIV-1 infected adult patients with creatinine clearance u2265 50 (mL/min) Creatine Clearance (mL/min) 1 u2265 50 Recommended dosing interval Every 24 hours 1 Calculated using ideal (lean) body weight. Routine monitoring of calculated creatinine clearance and serum phosphorus should be performed in all individuals (see Section 4.3, 4.4 and Renal impairment).

Method of administration Oral administration. It is preferable that TENEMINE is taken with food. The film-coated tablet can be disintegrated in approximately 100 mL of water, orange juice or grape juice and taken immediately.

TENEMINE is contraindicated in patients with previously demonstrated hypersensitivity to any of the components of TENEMINE.

• Pregnancy and lactation.
• Creatinine CL < 60 mL/min when used for PrEP.
• Creatinine CL < 50 mL/min when used for treatment of HIV-1.
• TENEMINE should not be co-administered with other tenofovir-containing medicines, or with other emtricitabine-containing medicines.
• TENEMINE should not be administered with lamivudine-containing medicines due to similarities between emtricitabine and lamivudine.
• TENEMINE should not be used for Pre-Exposure Prophylaxis (PrEP) in individuals with unknown or positive HIV-1 status.
• TENEMINE should not be used for PrEP in individuals not fully committed to full treatment compliance.

WARNINGS: LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY WITH STEATOSIS, INCLUDING FATAL CASES, HAVE BEEN REPORTED WITH THE USE OF NUCLEOSIDE ANALOGUS ALONE OR IN COMBINATION WITH OTHER ANTIRETROVIRALS. TENEMINE IS NOT INDICATED FOR THE TREATMENT OF CHRONIC HEPATITIS B VIRUS (HBV) INFECTION AND THE SAFETY AND EFFICACY OF TENEMINE HAS NOT BEEN ESTABLISHED IN PATIENTS CO-INFECTED WITH HBV AND HIV. SEVERE ACUTE EXACERBATIONS OF HEPATITIS B HAVE BEEN REPORTED IN PATIENTS WHO HAVE DISCONTINUED TENEMINE. HEPATIC FUNCTION SHOULD BE MONITORED CLOSELY, WITH BOTH CLINICAL AND LABORATORY FOLLOW-UP, FOR AT LEAST SEVERAL MONTHS IN PATIENTS INFECTED WITH HBV WHO DISCONTINUE TENEMINE AND ARE CO-INFECTED WITH HIV AND HBV. IF APPROPRIATE, INITIATION OF ANTI-HEPATITIS B THERAPY MAY BE WARRANTED.

TENEMINE USED FOR PRE-EXPOSURE PROPHYLAXIS (PrEP) MUST ONLY BE PRESCRIBED TO INDIVIDUALS CONFIRMED TO BE HIV-NEGATIVE IMMEDIATELY PRIOR TO INITIATING AND PERIODICALLY (AT LEAST ONCE EVERY 3 MONTHS) DURING USE. RESISTANT HIV-1 VARIANTS HAVE BEEN IDENTIFIED WITH USE OF TENEMINE FOR PRE-EXPOSURE PROPHYLAXIS (PrEP) FOLLOWING UNDETECTED ACUTE HIV-1 INFECTION. DO NOT INITIATE TENEMINE FOR THE PRE-EXPOSURE PROPHYLAXIS (PrEP) INDICATION IF SIGNS OR SYMPTOMS OF ACUTE HIV-1 INFECTION ARE PRESENT, UNLESS NEGATIVE INFECTION STATUS IS CONFIRMED.

There are no study results demonstrating the effect of TENEMINE on clinical progression of HIV-1.

It is not recommended that TENEMINE be used as a component of a triple nucleoside regimen.

Individuals should be warned that full compliance with treatment is essential to the efficacy in preventing HIV-1 transmission and should be fully informed about the use of other preventative measures including barrier contraception (condoms). Individuals not fully committed or trusted to be treatment-compliant should not use TENEMINE for HIV-1 transmission prophylaxis.

Patients with HIV-1 harbouring mutations: TENEMINE should be avoided in antiretroviral-experienced patients with HIV-1 harbouring the K65R mutation (see section 5.1).

Lactic acidosis/severe hepatomegaly with steatosis: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues such as TENEMINE alone or in combination with other antiretrovirals. This is caused by mitochondrial dysfunction. 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 analogues such as TENEMINE 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 TENEMINE 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). Clinical features are non-specific, and include nausea, vomiting, abdominal pain, dyspnoea, fatigue and weight loss. In patients with suspicious symptoms or biochemistry, measure the venous lactate level (normal < 2 mmol/L) and the serum bicarbonate and respond as follows:

• Lactate 2 to 5 mmol/L with minimum symptoms: Switch to medicines that are less likely to cause lactic acidosis.
• Lactate 5 to 10 mmol/L with symptoms and/or with reduced standard bicarbonate: Stop TENEMINE and change treatment option. Once lactate has settled, use medicines that are less likely to cause lactic acidosis. Exclude other causes (e.g. sepsis, uraemia, diabetic ketoacidosis, thyrotoxicosis and hyperthyroidism).
• Lactate > 10 mmol/L: STOP all therapy (80 % mortality).

The above lactate values may not be applicable to paediatric patients. Caution should be exercised when administering TENEMINE to patients with known risk factors for liver disease.

Treatment with TENEMINE should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity.

Pancreatitis: Pancreatitis has been observed in some patients receiving TENEMINE. Pancreatitis must be considered whenever a patient develops abdominal pain, nausea, vomiting or elevated biochemical markers. Discontinue use of TENEMINE until diagnosis of pancreatitis is excluded.

Liver disease: Use of TENEMINE can result in hepatomegaly due to non-alcoholic fatty liver disease (hepatic steatosis). The safety and efficacy of TENEMINE has not been established in patients with significant underlying liver disorders/diseases. Patients with pre-existing liver dysfunction, including chronic active hepatitis, have an increased frequency of liver function abnormalities during combination antiretroviral therapy and should be monitored. If there is evidence of worsening liver disease in such patients, temporary or permanent discontinuation of treatment must be considered.

Mitochondrial dysfunction: Nucleoside and nucleotide analogues such as TENEMINE have been demonstrated in vitro and in vivo to cause a variable degree of mitochondrial damage. There have been reports of mitochondrial dysfunction in HIV negative infants exposed in utero and/or post-natally to nucleoside analogues. Apart from lactic acidosis / hyperlactataemia (see above), other manifestations of mitochondrial dysfunction include haematological disorders (anaemia, neutropenia), and peripheral neuropathy. Some late-onset neurological disorders have been reported (hypertonia, convulsion, abnormal behaviour). It is not known whether the neurological disorders are transient or permanent. Any foetus exposed in utero to nucleoside and nucleotide analogues, even HIV negative infants/children, should have clinical and laboratory follow-up and should be fully investigated for possible mitochondrial dysfunction in case of relevant signs and symptoms.

Patients with HIV and Hepatitis B or C Virus co-infection: Patients with chronic hepatitis B or C and treated with antiretroviral therapy such as TENEMINE, are at an increased risk for severe and potentially fatal hepatic adverse reactions. Patients co-infected with HBV to discontinue TENEMINE, should be closely monitored with both clinical and laboratory follow-up after stopping treatment. Medical practitioners should refer to current HIV treatment guidelines for the optimal management of HIV infection in patients co-infected with hepatitis B virus (HBV). TENEMINE is not indicated for the treatment of chronic HBV infection and the safety and efficacy of TENEMINE have not been established in patients co-infected with HBV and HIV. In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant package inserts for these medicines. In patients with advanced liver disease or cirrhosis, treatment discontinuation is not recommended since post-treatment exacerbation of hepatitis may lead to hepatic decompensation. Discontinuation of TENEMINE therapy in patients co-infected with HIV and HBV may be associated with severe, acute exacerbations of hepatitis which may lead to liver decompensation and liver failure. It is recommended that all patients with HIV be tested for the presence of chronic hepatitis B virus (HBV) before initiating TENEMINE therapy. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are co-infected with HIV and HBV and discontinue TENEMINE. If appropriate, initiation of anti-hepatitis B therapy may be warranted.

Renal impairment: TENEMINE is principally eliminated by the kidney. 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 disoproxil fumarate (see section 4.3). It is recommended that creatinine clearance be calculated in all patients prior to initiating therapy and as clinically appropriate during therapy with TENEMINE. Routine monitoring of calculated creatinine clearance and serum phosphorus should be performed in patients at risk for renal impairment (see section 4.3). TENEMINE should be avoided with concurrent or recent use of a nephrotoxic medicine. TENEMINE should not be administered to patients with creatinine clearance below 50 mL/min or patients requiring haemodialysis or for pre-exposure prophylaxis in patients with creatinine clearance below 60 mL/min (see section 4.3). If a decrease in creatinine clearance is observed in uninfected individuals while using TENEMINE for PrEP, evaluate potential causes and re-assess potential risks and benefits of continued use (see section 4.3).

TENEMINE is a fixed-dose combination of emtricitabine and tenofovir disoproxil fumarate. TENEMINE should not be co-administered with other medicines containing emtricitabine or tenofovir (see section 4.3). Due to similarities between emtricitabine and lamivudine, TENEMINE should not be co-administered with other medicines containing lamivudine, including lamivudine and zidovudine co-formulation, lamivudine for HIV, lamivudine for HBV, abacavir sulfate and lamivudine co-formulation or abacavir sulfate, lamivudine and zidovudine co-formulation (see section 4.3). Co-administration of didanosine buffered tablet formulation with TENEMINE should be under fasted conditions (see section 4.5). Co-administration of TENEMINE and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse events. Didanosine should be discontinued in patients who develop didanosine-associated adverse events (see section 4.8). Patients receiving atazanavir and lopinavir/ritonavir and TENEMINE should be monitored for TENEMINE-associated adverse events. TENEMINE should be discontinued in patients who develop TENEMINE-associated adverse events (see section 4.8). Tenofovir decreases the AUC and C min of atazanavir. When co-administered with TENEMINE, it is recommended that atazanavir 300 mg is given with ritonavir 100 mg. Atazanavir without ritonavir should not be co-administered with TENEMINE. Since emtricitabine and tenofovir are primarily eliminated by the kidneys, co-administration of TENEMINE with medicines that reduce renal function or compete for active tubular secretion may increase serum concentrations of emtricitabine, tenofovir, and/or other renally eliminated medicines (see section 4.5). Some examples include, but are not limited to adefovir dipivoxil, cidofovir, aciclovir, valaciclovir, ganciclovir and valganciclovir.

The safety of TENEMINE in pregnancy and lactation has not been established (see section 4.3). Women of childbearing potential / Contraception in males and females A reliable method of contraception should be used to avoid pregnancy while taking TENEMINE.

Pregnancy There are no adequate and well-controlled studies in pregnant women. TENEMINE should not be used in pregnancy (see section 4.3).

Breastfeeding Nursing Mothers: HIV-infected mothers should not breastfeed their infants, to avoid risking postnatal transmission of HIV. Studies in rats have demonstrated that tenofovir is secreted in milk. It is not known whether tenofovir is excreted in human milk. It is not known whether emtricitabine is excreted in human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving TENEMINE.

Fertility No human data on the effect of emtricitabine/tenofovir disoproxil are available. Animal studies do not indicate harmful effects of emtricitabine or tenofovir disoproxil on fertility.

No studies on the effects of TENEMINE on the ability to drive and use machines have been performed. However, patients should be informed that dizziness has been reported during treatment with both emtricitabine and tenofovir disoproxil fumarate.

Side effects have been reported for Emtricitabine and Tenofovir Disoproxil Fumarate:

Blood and lymphatic system disorders: Frequent: Neutropenia. Less frequent: Anaemia.

Immune system disorders: Frequent: Allergic reaction.

Metabolism and nutrition disorders: Frequent: Hypertriglyceridaemia, hyperglycaemia, hypophosphataemia. Less frequent: Lactic acidosis, hypokalaemia.

Psychiatric disorders: Frequent: Abnormal dreams, insomnia.

Nervous system disorders: Frequent: Dizziness, headache.

Respiratory, thoracic and mediastinal disorders: Less frequent: Dyspnoea.

Gastrointestinal disorders: Frequent: Diarrhoea, nausea, vomiting, flatulence, dyspepsia, abdominal pain, lipase elevation, amylase elevation. Less frequent: Pancreatitis.

Hepatobiliary disorders: Frequent: Hyperbilirubinaemia, increased liver enzymes (including increased AST, increased ALT and/or gamma GT). Less frequent: Hepatitis, hepatic steatosis.

Skin and subcutaneous tissue disorders: Frequent: Rash event, (rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, pustular rash and skin discolouration). Less frequent: Angiodema.

Musculoskeletal, connective tissue and bone disorders: Frequent: Creatine kinase elevation, bone mineral density decreased. Less frequent: Myopathy, osteomalacia (manifested as bone pain and infrequently contributing to fractures), rhabdomyolysis, muscular weakness.

Renal and urinary disorders: Less frequent: Increased creatinine, renal insufficiency, renal failure (acute and chronic), Fanconi syndrome, proximal renal tubulopathy, nephrogenic diabetes insipidus, proteinuria, acute tubular necrosis, polyuria, interstitial nephritis (including acute cases).

General disorders and administration site conditions: Frequent: Pain, asthenia.

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

Emtricitabine: 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.

Tenofovir disoproxil fumarate: Tenofovir is poorly removed by haemodialysis. Following a single 300 mg dose of tenofovir DF, a four-hour haemodialysis session removed only approximately 10 % of the administered tenofovir dose.