Eflaten 300 mg/600 mg Tablets

EFLATEN is indicated for the treatment of HIV-1 infected adults over 18 years of age, who have been treated and stabilised on a combination of the 3 (three) antiretrovirals contained in EFLATEN administered as separate formulations in similar dosages as contained in EFLATEN.

Adults: The recommended dose is one EFLATEN tablet once daily taken orally on an empty stomach. It is recommended that Efavirenz be taken on an empty stomach. The increased efavirenz concentrations observed following administration of Efavirenz with food may lead to an increase in frequency of adverse events. In order to improve the tolerability of nervous system undesirable effects, bedtime dosing is recommended.

Children and adolescents: The safety and efficacy of Tenofovir disoproxil fumarate in patients under the age of 18 years have not been established. Tenofovir disoproxil fumarate must not be administered to children or adolescents until further data become available describing the safety and efficacy of tenofovir disoproxil fumarate in patients under the age of 18 years. So, EFLATEN tablets are not recommended in children and adolescents.

Elderly: No data are available on which to make a dose recommendation for patients over the age of 65 years.

• Severe hepatic impairment (Child-Pugh Class C)
• Severe renal impairment
• Pregnancy and lactation
• Concurrent administration with astemizole, cisapride, midazolam, triazolam, pimozide, bepridil, ergot alkaloids, St Johnu2019s wort (hypericum perforatum) or zalcitabine.
• EFLATEN Tablets are contra-indicated in patients with known hypersensitivity to tenofovir or lamivudine or efavirenz.

EFLATEN should not be taken with any other medicinal products containing tenofovir disoproxil fumarate or lamivudine. Tenofovir disoproxil fumarate has not been studied in patients under the age of 18. Tenofovir is principally eliminated via the kidney. Tenofovir exposure may be markedly increased in patients with moderate or severe renal impairment (creatinine clearance < 50 ml/min) receiving daily doses of tenofovir disoproxil 245 mg (as fumarate). Consequently, a dosing interval adjustment is required in all patients with creatinine clearance < 50 ml/min. Careful monitoring for signs of toxicity, such as deterioration of renal function, but also for changes in viral load is required in patients with pre-existing renal impairment once Tenofovir disoproxil fumarate has been started at prolonged dosing intervals. The safety and efficacy of Tenofovir disoproxil fumarate in patients with renal impairment have not been established. Renal impairment, which may include hypophosphataemia, has been reported with the use of tenofovir disoproxil fumarate.

Monitoring of renal function (creatinine clearance and serum phosphate) is recommended before taking tenofovir disoproxil fumarate, every four weeks during the first year, and then every three months. In patients at risk for, or with a history of, renal dysfunction, and patients with renal insufficiency, consideration should be given to more frequent monitoring of renal function.

Tenofovir disoproxil fumarate has not been evaluated in patients receiving nephrotoxic medicinal products (e.g. aminoglycosides, amphotericin B, foscarnet, ganciclovir, pentamidine, vancomycin, cidofovir or interleukin-2). Use of tenofovir disoproxil fumarate should be avoided with concurrent or recent use of a nephrotoxic medicinal product. If concomitant use of tenofovir disoproxil fumarate and nephrotoxic agents is unavoidable, renal function should be monitored weekly.

Tenofovir disoproxil fumarate has not been clinically evaluated in patients receiving medicinal products which are secreted by the same renal transporter, human organic anion transporter 1 (hOAT1) (e.g. adefovir dipivoxil; cidofovir, a known nephrotoxic medicinal product). Tenofovir disoproxil fumarate should be avoided in antiretroviral experienced patients with strains harbouring the K65R mutation. Tenofovir disoproxil fumarate has not been studied in patients over the age of 65. Elderly patients are more likely to have decreased renal function; therefore caution should be exercised when treating elderly patients with tenofovir disoproxil fumarate.

Liver disease: Tenofovir and tenofovir disoproxil fumarate are not metabolized by liver enzymes. A pharmacokinetic study has been performed in non-HIV infected patients with various degrees of hepatic impairment. No significant pharmacokinetic alteration has been observed in these patients. The safety and efficacy data of tenofovir disoproxil fumarate are limited in patients with significant underlying liver disorders. Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse events. In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant product information for these medicinal products. 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 according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered.

Lactic acidosis: Lactic acidosis, usually associated with hepatic steatosis, has been reported with the use of nucleoside analogues. The preclinical and clinical data suggest that the risk of occurrence of lactic acidosis, a class effect of nucleoside analogues, is low for tenofovir disoproxil fumarate. However, as tenofovir is structurally related to nucleoside analogues, this risk cannot be excluded. Early symptoms (symptomatic hyperlactatemia) include benign digestive symptoms (nausea, vomiting and abdominal pain), non-specific malaise, and loss of appetite, weight loss, respiratory symptoms (rapid and/or deep breathing) or neurological symptoms (including motor weakness). Lactic acidosis has a high mortality and may be associated with pancreatitis, liver failure or renal failure. Lactic acidosis generally occurred after a few or several months of treatment. Treatment with nucleoside analogues should be discontinued in the setting of symptomatic hyperlactatemia and metabolic/lactic acidosis, progressive hepatomegaly, or rapidly elevating aminotransferase levels. Caution should be exercised when administering nucleoside analogues to any patient (particularly obese women) with hepatomegaly, hepatitis or other known risk factors for liver disease and hepatic steatosis (including certain medicinal products and alcohol). Patients co-infected with hepatitis C and treated with alpha interferon and ribavirin may constitute a special risk. Patients at increased risk should be followed closely.

Immune Reactivation Syndrome: In HIV infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and Pneumocystis carinii pneumonia. Any inflammatory symptoms should be evaluated and treatment instituted when necessary.

Based on the results of in vitro experiments and the known elimination pathway of tenofovir, the potential for CYP450 mediated interactions involving tenofovir with other medicinal products is low. Tenofovir is excreted renally, both by filtration and active secretion via the anionic transporter (hOAT1). Co-administration of tenofovir disoproxil fumarate with other medicinal products that are also actively secreted via the anionic transporter (e.g. cidofovir) may result in increased concentrations of tenofovir or of the co-administered medicinal product.

Concomitant antiretroviral medicinal products: Emtricitabine, lamivudine, indinavir, efavirenz, nelfinavir, and saquinavir (ritonavir boosted): Co-administration with tenofovir disoproxil fumarate did not result in any clinically relevant interaction. When tenofovir disoproxil fumarate was administered with lopinavir/ritonavir, no changes were observed in the pharmacokinetics of lopinavir and ritonavir. Tenofovir AUC was increased by approximately 30 % when tenofovir disoproxil fumarate was administered with lopinavir/ritonavir.

Other interactions: Co-administration of tenofovir disoproxil fumarate, methadone, ribavirin, adefovir dipivoxil or the hormonal contraceptive norgestimate/ethinyl oestradiol did not result in any pharmacokinetic interaction. Tenofovir disoproxil fumarate must be taken with food, as food enhances the bioavailability of Tenofovir. Co-administration of zidovudine results in a 13 % increase in zidovudine exposure and a 28 % increase in peak plasma levels. This is not considered to be of significance to patient safety and therefore no dosage adjustments are necessary.

Pregnancy: Tenofovir disoproxil fumarate No clinical data on exposed pregnancies are available for tenofovir disoproxil fumarate. Animal studies do not indicate direct or indirect harmful effects of tenofovir disoproxil fumarate with respect to pregnancy, fetal development, parturition or postnatal development. Tenofovir disoproxil fumarate should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus. However, given that the potential risks to developing human foetuses are unknown, the use of tenofovir disoproxil fumarate in women of childbearing potential must be accompanied by the use of effective contraception.

Lamivudine The safety of lamivudine in human pregnancy has not been established. Reproductive studies in animals have not shown evidence of teratogenicity, and showed no effect on male or female fertility. Lamivudine induces early embryonic death when administered to pregnant rabbits at exposure levels comparable to those achieved in man. In humans, consistent with passive transmission of lamivudine across the placenta, lamivudine concentrations in infant serum at birth were similar to those in maternal and cord serum at delivery. Although animal reproductive studies are not always predictive of the human response, administration is not recommended during the first three months of pregnancy.

Efavirenz Pregnancy should be avoided in women treated with efavirenz. Barrier contraception should always be used in combination with other methods of contraception (for example, oral or other hormonal contraceptives). Women of childbearing potential should undergo pregnancy testing before initiation of efavirenz. Efavirenz should not be used during pregnancy unless there are no other appropriate treatment options. There are no adequate and well-controlled studies of efavirenz in pregnant women. In postmarketing experience through an antiretroviral pregnancy registry, more than 200 pregnancies with first-trimester exposure to efavirenz as part of a combination antiretroviral regimen have been reported with no specific malformation pattern. Retrospectively in this registry, a small number of cases of neural tube defects, including meningomyelocele, have been reported but causality has not been established. Studies in animals have shown reproductive toxicity including marked teratogenic effects.

Lactation: Tenofovir disoproxil fumarate In animal studies it has been shown that tenofovir is excreted into milk. It is not known whether tenofovir is excreted in human milk. Therefore, it is recommended that mothers being treated with tenofovir disoproxil fumarate do not breast-feed their infants. As a general rule, it is recommended that HIV infected women do not breast-feed their infants in order to avoid transmission of HIV to the infant.

Lamivudine Following oral administration lamivudine was excreted in breast milk at similar concentrations to those found in serum. Since lamivudine and the virus pass into breast milk, it is recommended that mothers taking Lamivudine Tablets do not breast-feed their infants. It is recommended that HIV infected women do not breast-feed their infants under any circumstances in order to avoid transmission of HIV.

Efavirenz Studies in rats have demonstrated that efavirenz is excreted in milk reaching concentrations much higher than those in maternal plasma. It is not known whether efavirenz is excreted in human milk. Since animal data suggest that the substance may be passed into breast milk, it is recommended that mothers taking efavirenz do not breast feed their infants. It is recommended that HIV infected women do not breast feed their infants under any circumstances in order to avoid transmission of HIV.

No studies on the effects on the ability to drive or use machines have been performed. However, patients should be informed that dizziness has been reported during treatment with tenofovir disoproxil fumarate. Efavirenz may cause dizziness, impaired concentration, and/or somnolence. Patients should be instructed that if they experience these symptoms they should avoid potentially hazardous tasks such as driving or operating machinery.

Assessment of adverse reactions is based on post-marketing experience and experience in two studies in 653 treatment-experienced patients receiving treatment with tenofovir disoproxil fumarate (n = 443) or placebo (n = 210) in combination with other antiretroviral medicinal products for 24 weeks and also in a double-blind comparative controlled study in which 600 treatment-nau00efve patients received treatment with tenofovir disoproxil 245 mg (as fumarate) (n = 299) or stavudine (n = 301) in combination with lamivudine and efavirenz for 144 weeks. Approximately one third of patients can be expected to experience adverse reactions following treatment with tenofovir disoproxil fumarate in combination with other antiretroviral agents. These reactions are usually mild to moderate gastrointestinal events.

The adverse reactions with suspected (at least possible) relationship to treatment are listed below by body system organ class and absolute frequency. Frequencies are defined as very common (u2265 1/10), common (u2265 1/100, < 1/10), uncommon (u2265 1/1000, < 1/100), rare (u2265 1/10,000, < 1/1000) or very rare (< 1/10,000) including isolated reports, or not known (identified through post-marketing safety surveillance and the frequency cannot be estimated from the available data).

Metabolism and nutrition disorders: Very common: hypophosphataemia Rare: lactic acidosis

Nervous system disorders: Very common: dizziness

Respiratory, thoracic and mediastinal disorders: Very rare: dyspnoea

Gastrointestinal disorders: Very common: diarrhoea, nausea, vomiting Common: flatulence Rare: pancreatitis

Hepatobiliary disorders: Rare: increased transaminases Very rare: hepatitis

Skin and subcutaneous tissue disorders: Rare: rash

Musculoskeletal and connective tissue disorders: Not known: myopathy, osteomalacia (both associated with proximal renal tubulopathy)

Renal and urinary disorders: Rare: renal failure, acute renal failure, proximal tubulopathy (including Fanconi syndrome), increased creatinine Very rare: acute tubular necrosis Not known: nephritis (including acute interstitial nephritis), nephrogenic diabetes insipidus.

General disorders and administration site conditions: Very rare: asthenia Approximately 1 % of tenofovir disoproxil fumarate treated patients discontinued treatment due to the gastrointestinal events.

Combination antiretroviral therapy has been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia. Combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy) in HIV patients.

Tenofovir disoproxil fumarate: If overdose occurs the patient must be monitored for evidence of toxicity and standard supportive treatment applied as necessary. Tenofovir can be removed by haemodialysis; the median haemodialysis clearance of tenofovir is 134 ml/min. The elimination of tenofovir by peritoneal dialysis has not been studied.

Lamivudine: Administration of lamivudine at very high dose levels in acute animal studies did not result in any organ toxicity. Limited data are available on the consequences of ingestion of acute overdoses in humans. No fatalities occurred, and the patients recovered. No specific signs or symptoms have been identified following such overdose. If overdosage occurs the patient should be monitored, and standard supportive treatment applied as required. Since lamivudine is dialysable, continuous haemodialysis could be used in the treatment of overdosage, although this has not been studied.

Efavirenz: Some patients accidentally taking 600 mg twice daily have reported increased nervous system symptoms. One patient experienced involuntary muscle contractions. Treatment of overdose with efavirenz should consist of general supportive measures, including monitoring of vital signs and observation of the patient's clinical status. Administration of activated charcoal may be used to aid removal of unabsorbed efavirenz. There is no specific antidote for overdose with efavirenz. Since efavirenz is highly protein bound, dialysis is unlikely to remove significant quantities of it from blood.