Drug Class Description

Generic Name

Drug Description

Presentation

Indications

Zerit is indicated in combination with other antiretroviral medicinal products for the treatment of HIV infected adult patients and paediatric patients (over the age of 3 months) only when other antiretrovirals can not be used. The duration of therapy with Zerit should be limited to the shortest time possible.

Adult Dosage

The therapy should be initiated by a doctor experienced in the management of HIV infection (see also section 4.4).

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. Patients continuing treatment with Zerit should be assessed frequently and switched to an alternative appropriate therapy whenever possible (see section 4.4).

Posology

Adults: the recommended oral dosage is:

Paediatric population:

Adolescents, children and infants over the age of 3 months: the recommended oral dosage is:

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.

Dose adjustments

Peripheral neuropathy: if symptoms of peripheral neuropathy develop (usually characterised by persistent numbness, tingling, or pain in the feet and/or hands) (see section 4.4) 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.

The possible benefits of a dose reduction should be balanced in each case against the risks - which may result from this measure (lower intracellular concentrations).

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:

* 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.

Method of administration

For optimal absorption, Zerit should be taken on an empty stomach (i.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.

Child Dosage

Paediatric population:

Adolescents, children and infants over the age of 3 months: the recommended oral dosage is:

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.

Elderly Dosage

Contra Indications

Special Precautions

Interactions

Adverse Reactions

a. 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. Given these potential risks, a benefit-risk assessment for each patient should be made and an alternative antiretroviral should be carefully considered (see section 4.4 and below).

Cases of lactic acidosis, sometimes fatal, usually associated with severe hepatomegaly and hepatic steatosis, have been reported in < 1% of patients taking stavudine in combination with other antiretrovirals (see section 4.4).

Motor weakness has been reported rarely in patients receiving combination antiretroviral therapy including Zerit. Most of these cases occurred in the setting of symptomatic hyperlactatemia or lactic acidosis syndrome (see section 4.4). 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.

Hepatitis or liver failure, which was fatal in some cases, has been reported with the use of stavudine and with other nucleoside analogues (see section 4.4).

Lipoatrophy was commonly reported in patients treated with stavudine in combination with other antiretrovirals (see section 4.4).

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.

Pancreatitis, occasionally fatal, has been reported in up to 2-3% of patients enrolled in monotherapy clinical studies (see section 4.4). Pancreatitis was reported in < 1% of patients in combination therapy studies with Zerit.

b. 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); or not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

* adverse reactions observed post-marketing in association with stavudine-containing antiretroviral treatment

** See Section c. Description of selected adverse reactions for more details.

c. Description of selected adverse reactions

Immune reactivation syndrome: in HIV-infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise (see section 4.4).

Lipodystrophy and metabolic abnormalities: combination antiretroviral therapy has been associated with redistribution of body fat (lipodystrophy) in HIV patients including the loss of peripheral and facial subcutaneous fat, increased intra-abdominal and visceral fat, breast hypertrophy and dorsocervical fat accumulation (buffalo hump). In randomized controlled trials of treatment-naive patients, clinical lipoatrophy developed in a higher proportion of patients treated with stavudine compared to other NRTIs (tenofovir or abacavir). In one study, after 2 years of treatment, about 40% of stavudine-treated patients had lost greater than 20% of limb fat and after 3 years the amount of limb fat was only about half of the normal amount (4.5 kg vs about 8 kg).. The incidence and severity of lipoatrophy are cumulative over time; lipoatrophy may affect most patients with time and is often not reversible when stavudine treatment is stopped (see section 4.4).

Combination antiretroviral therapy has been associated with metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia and hyperlactataemia (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 combination antiretroviral therapy (CART). The frequency of this is unknown (see section 4.4).

Laboratory abnormalities

Laboratory abnormalities reported in these two trials and an ongoing follow-up study included elevations of ALT (> 5 x ULN) in 3%, of AST (> 5 x ULN) in 3%, of lipase ( 2.1 ULN) in 3% of the patients in the Zerit group. Neutropenia (< 750 cells/mm³) was reported in 5%, thrombocytopenia (platelets < 50,000/mm³) in 2%, and low haemoglobin (< 8 g/dl) in < 1% of patients receiving Zerit.

Macrocytosis was not evaluated in these trials, but was found to be associated with Zerit in an earlier trial (MCV > 112 fl occurred in 30% of patients treated with Zerit).

d. Paediatric population

Adolescents, children and infants: adverse reactions and serious laboratory abnormalities reported to occur in paediatric patients ranging in age from birth through adolescence who received stavudine in clinical studies were generally similar in type and frequency to those seen in adults. However, clinically significant peripheral neuropathy is less frequent. These studies include ACTG 240, where 105 paediatric patients ages 3 months to 6 years received Zerit 2 mg/kg/day for a median of 6.4 months; a controlled clinical trial where 185 newborns received Zerit 2 mg/kg/day either alone or in combination with didanosine from birth through 6 weeks of age; and a clinical trial where 8 newborns received Zerit 2 mg/kg/day in combination with didanosine and nelfinavir from birth through 4 weeks of age.

In study AI455-094, the safety follow-up period was restricted to only six months, which may be insufficient to capture long-term data on neurological adverse events and mitochondrial toxicity. Relevant grade 3-4 laboratory abnormalities in the 91 stavudine treated infants were low neutrophils in 7%, low hemoglobin in 1%, ALT increase in 1% and no lipase abnormality. Data on lactic acid in serum were not collected. No notable differences in the frequency of adverse drug reactions were seen between treatment groups. There was, however, an increased infant mortality in the stavudine + didanosine (10%) treatment group compared to the stavudine (2%), didanosine (3%) or zidovudine (6%) groups, with a higher incidence of stillbirths in the stavudine + didanosine group.

Mitochondrial dysfunction: review of the postmarketing safety database shows that adverse reactions indicative of mitochondrial dysfunction have been reported in the neonate and infant population exposed to one or more nucleoside analogues (see also section 4.4). The HIV status for the newborns and infants  3 months of age was negative, for older infants it tended to be positive. The profile of the adverse events for newborns and infants  3 months of age showed increases in lactic acid levels, neutropenia, anaemia, thrombocytopenia, hepatic transaminase increases and increased lipids, including hypertriglyceridaemia. The number of reports in older infants was too small to identify a pattern.

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