Zerit

4). For patients starting therapy with Zerit, the duration should be limited to the shortest time possible followed by a switch to an alternative appropriate therapy whenever possible. 4). Posology Adults: the recommended oral dosage is Patient weight Zerit dosage < 60 kg ≥ 60 kg 30 mg twice daily (every 12 hours) 40 mg twice daily (every 12 hours) Paediatric population Adolescents, children and infants over the age of 3 months: the recommended oral dosage is Patient weight Zerit dosage < 30 kg ≥ 30 kg 1 mg/kg twice daily (every 12 hours) adult dosing The powder formulation of ZERIT should be used for infants under the age of 3 months.

Adult patients that have problems swallowing capsules should ask their doctor about the possibility of changing to the powder formulation of this medicine. Please refer to the Summary of Product Characteristics of the powder formulation.

4) patients should be switched to an alternative treatment regimen, if appropriate. In the rare cases when this is inappropriate, dose reduction of stavudine may be considered, while the symptoms of peripheral neuropathy are under close monitoring and satisfactory virological suppression is maintained.

0vMedicinal product no longer authorised 4 Special populations Elderly: Zerit has not been specifically investigated in patients over the age of 65. Hepatic impairment: no initial dosage adjustment is necessary. Renal impairment: the following dosages are recommended Zerit dosage (according to creatinine clearance) Patient weight 26-50 ml/min ≤ 25 ml/min (including dialysis dependence*) < 60 kg 15 mg twice daily 15 mg every 24 hours ≥ 60 kg 20 mg twice daily 20 mg every 24 hours * Patients on haemodialysis should take Zerit after the completion of haemodialysis, and at the same time on non-dialysis days.

Since urinary excretion is also a major route of elimination of stavudine in paediatric patients, the clearance of stavudine may be altered in paediatric patients with renal impairment. Although there are insufficient data to recommend a specific dosage adjustment of Zerit in this patient population, a reduction in the dose and/or an increase in the interval between doses proportional to the reduction for adults should be considered.

There are no dosage recommendations for paediatric patients under the age of 3 months with renal impairment. e. at least 1 hour prior to meals) but, if this is not possible, it may be taken with a light meal. Zerit may also be administered by carefully opening the hard capsule and mixing the contents with food.

Summary of the safety profile Stavudine therapy is associated with several severe adverse reactions, such as lactic acidosis, lipoatrophy and polyneuropathy, for which a potential underlying mechanism is mitochondrial toxicity. 4 and below).

4). Motor weakness has been reported rarely in patients receiving combination antiretroviral therapy including Zerit. 4). The evolution of motor weakness may mimic the clinical presentation of Guillain-Barré syndrome (including respiratory failure).

Symptoms may continue or worsen following discontinuation of therapy. 4). 0vMedicinal product no longer authorised 9 Peripheral neuropathy was seen in combination studies of Zerit with lamivudine plus efavirenz; the frequency of peripheral neurologic symptoms was 19% (6% for moderate to severe) with a rate of discontinuation due to neuropathy of 2%.

The patients usually experienced resolution of symptoms after dose reduction or interruption of stavudine. 4). Pancreatitis was reported in < 1% of patients in combination therapy studies with Zerit. Tabulated summary of adverse reactions Adverse reactions of moderate or greater severity with at least a possible relationship to treatment regimen (based on investigator attribution) reported from 467 patients treated with Zerit in combination with lamivudine and efavirenz in two randomised clinical trials and along-term follow-up study (follow-up: median 56 weeks ranging up to 119 weeks) are listed below.

Also listed are adverse reactions observed post-marketing in association with stavudine-containing antiretroviral treatment. The frequency of adverse reactions listed below is defined using the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000).

0vMedicinal product no longer authorised 10 Blood and lymphatic system disorders: rare: anaemia* very rare: neutropenia *, thrombocytopenia* Endocrine disorders: uncommon: gynaecomastia Metabolism and nutrition disorders: common: lipoatrophy**, asymptomatic hyperlactatemia uncommon: lactic acidosis (in some cases involving motor weakness), anorexia rare: hyperglycaemia* very rare: diabetes mellitis* Psychiatric disorders: common: depression uncommon: anxiety, emotional lability Nervous system disorders: common: peripheral neurologic symptoms including peripheral neuropathy, paresthesia, and peripheral neuritis; dizziness; abnormal dreams; headache, insomnia; abnormal thinking; somnolence very rare: motor weakness* (most often reported in the setting of symptomatic hyperlactatemia or lactic acidosis syndrome) Gastrointestinal disorders: common: diarrhoea, abdominal pain, nausea, dyspepsia uncommon: pancreatitis, vomiting Hepatobiliary disorders: uncommon: hepatitis or jaundice rare: hepatic steatosis* very rare: liver failure* Skin and subcutaneous tissue disorders: common: rash, pruritus uncommon: urticaria Musculoskeletal and connective tissue disorders: uncommon: arthralgia, myalgia General disorders and administration site conditions: common: fatigue uncommon: asthenia * Adverse reactions observed post-marketing in association with stavudine-containing antiretroviral treatment ** See Section Description of selected adverse reactions for more details.

While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines.

Stavudine therapy is associated with several severe side effects, such as lactic acidosis, lipoatrophy and polyneuropathy, for which a potential underlying mechanism is mitochondrial toxicity. 8). Lactic acidosis: lactic acidosis, usually associated with hepatomegaly and hepatic steatosis has been reported with the use of stavudine.

Early symptoms (symptomatic hyperlactatemia) include benign digestive symptoms (nausea, vomiting and abdominal pain), non-specific malaise, loss of appetite, weight loss, respiratory symptoms (rapid and/or deep breathing) or neurological symptoms (including motor weakness).

0vMedicinal product no longer authorised 5 Lactic acidosis generally occurred after a few or several months of treatment. Treatment with stavudine should be discontinued if there is symptomatic hyperlactatemia and metabolic/lactic acidosis, progressive hepatomegaly, or rapidly elevating aminotransferase levels.

Caution should be exercised when administering stavudine 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. 6). Liver disease: hepatitis or liver failure, which was fatal in some cases, has been reported. The safety and efficacy of stavudine has not been established 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 of severe and potentially fatal hepatic adverse reactions. In case of concomitant antiviral therapy for hepatitis B or C, please refer also to the relevant product information for these medicinal products.

1. 5).