Prepetam 300mg. 245mg. 200mg Tablet

Treatment of HIV-1 Infections

• PREPETAM is indicated in combination with other antiretroviral agents (example; non-nucleoside reverse transcriptase inhibitors or protease inhibitors) for the treatment of HIV-1 infection in adults.

Pre-Exposure Prophylaxis (PrEP):

• PREPETAM 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

Dosage in adults for treatment of HIV-1 infection

The dose of PREPETAM is one tablet (containing 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate) once daily.

Dosage for Pre-Exposure Prophylaxis (PrEP)

The dose of PREPETAM in HIV-1 uninfected adults is one tablet (containing 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate) once daily.

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).

Creatinine Clearance (mL/min) a u2265 50

Recommended Dosing Interval Every 24 hours

a 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 and section 4.4)

Method of administration

Oral use. It is recommended that PREPETAM be swallowed whole with water. PREPETAM can usually be taken with food or without food.

• Hypersensitivity to the tenofovir, emtricitabine or to any of the excipients listed in section 6.1.
• Pregnancy and lactation.
• Creatinine CL < 60 mL/min when used for PrEP.
• Creatinine CL < 50 mL/min when used for treatment of HIV-1.
• PREPETAM should not be co-administered with other tenofovir-containing, or emtricitabine-containing products. PREPETAM should not be administered with lamivudine-containing products due to similarities between emtricitabine and lamivudine.
• PREPETAM should not be used for Pre-Exposure Prophylaxis (PrEP) in individuals with unknown or positive HIV-1 status.
• PREPETAM should not be used for PrEP in individuals not fully committed to full treatment compliance.

WARNING

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination with other antiretrovirals (see section 4.4).

PREPETAM is not indicated for the treatment of chronic hepatitis B virus (HBV) infection and the safety and efficacy of PREPETAM 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 PREPETAM. 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 the combination tablet. If appropriate, initiation of anti-hepatitis b therapy may be warranted (see section 4.4).

PREPETAM used for pre-exposure prophylaxis (PrEP) indication 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 PREPETAM for a pre-exposure prophylaxis (PrEP) indication following undetected acute HIV-1 infection. Do not initiate PREPETAM for a pre-exposure prophylaxis (PrEP) indication if signs or symptoms of acute HIV-1 infection are present unless negative infection status is confirmed (see section 4.4).

There are no study results demonstrating the effect of PREPETAM on clinical progression of HIV-1. It is not recommended that PREPETAM be used as a component of a triple nucleoside regime. 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 PREPETAM for HIV-1 transmission prophylaxis.

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 PREPETAM 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 PREPETAM 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 PREPETAM 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 PREPETAM 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 PREPETAM to patients with known risk factors for liver disease. Treatment with PREPETAM 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 PREPETAM. Pancreatitis must be considered whenever a patient develops abdominal pain, nausea, vomiting or elevated biochemical markers. Discontinue use of PREPETAM until diagnosis of pancreatitis is excluded.

Liver disease

Use of PREPETAM can result in hepatomegaly due to non-alcoholic fatty liver disease (hepatic steatosis). The safety and efficacy of PREPETAM 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 PREPETAM 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-natal, 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 PREPETAM, are at an increased risk for severe and potentially fatal hepatic adverse reactions. Patients co-infected with HBV to discontinue PREPETAM, 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). PREPETAM is not indicated for the treatment of chronic HBV infection and the safety and efficacy of PREPETAM 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 PREPETAM 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 PREPETAM 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 PREPETAM. If appropriate, initiation of anti-hepatitis B therapy may be warranted.

Renal impairment

PREPETAM 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 PREPETAM. Routine monitoring of calculated creatinine clearance and serum phosphorus should be performed in patients at risk for renal impairment (see section 4.3). PREPETAM should be avoided with concurrent or recent use of a nephrotoxic agent. PREPETAM 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 PREPETAM for PrEP, evaluate potential causes and re-assess potential risks and benefits of continued use (see section 4.3).

PREPETAM is a fixed-dose combination of emtricitabine and tenofovir disoproxil fumarate. PREPETAM should not be co-administered with other medicines containing emtricitabine or tenofovir (see section 4.3).

Due to similarities between emtricitabine and lamivudine, PREPETAM 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 PREPETAM should be under fasted conditions (see section 4.5). Co-administration of PREPETAM 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 PREPETAM should be monitored for PREPETAM-associated adverse events. PREPETAM should be discontinued in patients who develop PREPETAM-associated adverse events (see section 4.8).

Tenofovir decreases the AUC and C min of atazanavir (see section 4.5). When co-administered with PREPETAM, it is recommended that atazanavir 300 mg is given with ritonavir 100 mg. Atazanavir without ritonavir should not be co-administered with PREPETAM.

Since emtricitabine and tenofovir are primarily eliminated by the kidneys, co-administration of PREPETAM 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 PREPETAM in pregnancy and lactation has not been established (see section 4.3). A reliable method of contraception should be used to avoid pregnancy while taking PREPETAM.

Pregnancy

There are no adequate and well-controlled studies in pregnant women. PREPETAM should not be used in pregnancy (see section 4.3). Animal studies on emtricitabine and tenofovir disoproxil do not indicate reproductive toxicity (see section 5.3).

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 or 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 PREPETAM.

Fertility

No human data on the effect of PREPETAM are available. Reported animal studies do not indicate harmful effects of emtricitabine or tenofovir disoproxil on fertility.

No studies on the effects of either tenofovir DF or emtricitabine on the ability to drive and use machines have been performed. However, dizziness has been reported during treatment with both tenofovir DF and emtricitabine. If dizziness occurs, patients should be advised not to drive or operate machinery.

HIV-1 infection: The most frequently reported adverse reactions considered possibly or probably related to emtricitabine and/or tenofovir disoproxil were nausea and diarrhoea in a clinical study in adults. The safety profile of emtricitabine and tenofovir disoproxil in this study was consistent with the previous experience with these medicines when each was administered with other antiretroviral agents.

Pre-exposure prophylaxis: No new adverse reactions to tenofovir DF/emtricitabine as contained in PREPETAM were identified from reported studies in which HIV-1 uninfected adults received tenofovir DF/emtricitabine as contained in PREPETAM once daily for pre-exposure prophylaxis. The most frequent adverse reaction reported in the study was headache.

Tabulated summary of adverse reactions: Emtricitabine and Tenofovir DF

Frequency Emtricitabine Tenofovir disoproxil

Blood and lymphatic system disorders Frequent: neutropenia Less frequent: anaemia

Immune system disorders Frequent: allergic reaction, angioedema angioedema

Metabolism and nutrition disorders Frequent: hyperglycaemia, hypertriglyceridaemia hypophosphataemia Less frequent: hypokalaemia, lactic acidosis

Psychiatric disorders Frequent: insomnia, abnormal dreams

Nervous system disorders Frequent: headache, dizziness

Respiratory, thoracic and mediastinal disorders Frequent: dyspnoea

Gastrointestinal disorders Frequent: diarrhoea, nausea, elevated amylase including elevated pancreatic amylase, elevated serum lipase, vomiting, abdominal pain, dyspepsia Less frequent: pancreatitis

Hepatobiliary disorders Frequent: elevated serum aspartate aminotransferase (AST) and/or elevated serum alanine aminotransferase (ALT), increased transaminases Less frequent: hepatic steatosis, hepatitis

Skin and subcutaneous tissue disorders Frequent: vesiculobullous rash, pustular rash, maculopapular rash, rash, pruritus, urticaria, skin discolouration (increased pigmentation)

Musculoskeletal and connective tissue disorders Frequent: elevated creatine kinase Less frequent: rhabdomyolysis, muscular weakness, osteomalacia (manifested as bone pain and infrequently contributing to fractures), myopathy

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

General disorders and administration site conditions Frequent: pain, asthenia

1 This adverse reaction may occur as a consequence of proximal renal tubulopathy. It is not considered to be causally associated with tenofovir disoproxil in the absence of this condition.

2 Anaemia was common and skin discolouration (increased pigmentation).

3 This adverse reaction was identified through reported post-marketing surveillance.

Renal impairment

As PREPETAM may cause renal damage monitoring of renal function is recommended (see section 4.4). Proximal renal tubulopathy generally resolved or improved after tenofovir disoproxil discontinuation. However, in some HIV-1 infected patients, declines in creatinine clearance did not completely resolve despite tenofovir disoproxil discontinuation. Patients at risk of renal impairment (such as patients with baseline renal risk factors, advanced HIV disease, or patients receiving concomitant nephrotoxic medications) are at increased risk of experiencing incomplete recovery of renal function despite tenofovir disoproxil discontinuation (see section 4.4).

Interaction with didanosine

Co-administration of tenofovir disoproxil and didanosine is not recommended as it results in a 40 - 60 % increase in systemic exposure to didanosine that may increase the risk of didanosine-related adverse reactions (see section 4.5). Rarely, pancreatitis and lactic acidosis, sometimes fatal, have been reported.

Metabolic parameters

Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section 4.4).

Immune Reactivation Syndrome

In HIV infected patients with severe immune deficiency at the time of initiation of CART, an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (see section 4.4).

Osteonecrosis

Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to CART. The frequency of this is unknown (see section 4.4).

Other special populations

Individuals with renal impairment Since tenofovir disoproxil can cause renal toxicity, close monitoring of renal function is recommended in any adults with renal impairment receiving PREPETAM (see sections 4.2, 4.4 and 5.2). The use of PREPETAM is not recommended in individuals under the age of 18 years with renal impairment (see sections 4.2 and 4.4).

HIV/HBV or HCV co-infected patients The adverse reaction profile of emtricitabine and tenofovir disoproxil in a reported HIV-infected patient study who were co-infected with HBV or HCV was similar to that observed in patients infected with HIV without co-infection. However, as would be expected in this patient population, elevations in AST and ALT occurred more frequently than in the general HIV infected population.

Exacerbations of hepatitis after discontinuation of treatment In HBV infected patients, clinical and laboratory evidence of hepatitis have occurred after discontinuation of treatment (see section 4.4).

Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reaction Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

Symptoms

If overdose occurs the patient must be monitored for evidence of toxicity (see section 4.8), 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 DF

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.