Bristol-Myers Squibb Pharmaceutical Limited

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 (see section 4.2).

optimal absorption, Zeritpatients starting therapy with Zerit, the duration should be taken on an empty

stomach (i.e. at least 1 hour priorlimited

to meals) but, if this is notthe shortest time possible, it may be taken with

a light meal. Zerit may also be administered followed

by carefully opening the hard capsule and mixing the

contents with fooda switch to an alternative appropriate therapy whenever possible. Patients continuing treatment

.

60 kg

30 mg twice daily (every 12 hours)

40 mg twice daily

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.

Section 6.4 updated as below: 


6.4     Special precautions for storage

Store below 25°C (aclar/alu blisters)

Do not store above 30°C. (HDPE bottles)

Store in the original package.

Oral use.

Posology

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

Adults: the recommended dosage is:

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

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.

Infants under the age of 3 months: please refer to the Summary of Product Characteristics of the powder formulation.

Elderly: Zerit has not been specifically investigated in patients over the age of 65.

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. 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.

Section 4.4

Peripheral neuropathy: patients with a history of peripheral neuropathy are at increased risk for development of neuropathy. If Zerit must be administered in this setting, careful clinical monitoring is essential. Symptoms of peripheral neuropathy are characterised by persistent numbness, tingling, or pain in the feet and/or hands.

Pancreatitis: patients with a history of pancreatitis had an incidence of approximately 5% on Zerit, as compared to approximately 2% in patients without such a history. Patients with a high risk of pancreatitis or those receiving products known to be associated with pancreatitis should be closely followed for symptoms of this condition.

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. Given these potential risks, a benefit-risk assessment for each patients should be made and an alternative antiretroviral should be carefully considered (see Lactic acidosis, Lipodystrophy and metabolic abnormalities, and Peripheral neuropathy below and section 4.8).

Lipodystrophy and metabolic abnormalities: combination antiretroviral therapy has been associated with the redistribution of body fat (lipodystrophy) in HIV patients. Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis and Protease Inhibitors and lipoatrophy and NRTIs has been hypothesised. A higher risk of lipodystrophy has been associated with individual factors such as older age, and with drug related factors such as longer duration of antiretroviral treatment and associated metabolic disturbances.

Consideration should be given to the measurement of fasting serum lipids and blood glucose. Lipid disorders should be managed as clinically appropriate (see section 4.8).

Peripheral neuropathy: up to 20% of patients treated with Zerit will develop peripheral neuropathy, often starting after some months of treatment. Patients with a history of neuropathy, or with other risk factors (for example alcohol, medications such as isoniazid) are at particular risk. Patients should be monitored for symptoms (persistent numbness, tingling or pain in feet/hands) and if present patients should be switched to an alternate treatment regimen (see section 4.2 and Not recommended combinations, below).

Pancreatitis: patients with a history of pancreatitis had an incidence of approximately 5% on Zerit, as compared to approximately 2% in patients without such a history. Patients with a high risk of pancreatitis or those receiving products known to be associated with pancreatitis should be closely followed for symptoms of this condition.

Lipodystrophy and metabolic abnormalities: combination antiretroviral therapy has been associated with the redistribution of body fat (lipodystrophy) in HIV patients. The long‑term consequences of these events are currently unknown. Knowledge about the mechanism is incomplete. A connection between visceral lipomatosis and Protease Inhibitors and lipoatrophy and NRTIs has been hypothesised. A higher risk of lipodystrophy has been associated with individual factors such as older age, and with drug related factors such as longer duration of antiretroviral treatment and associated metabolic disturbances. Clinical examination should include evaluation for physical signs of fat redistribution. Consideration should be given to the measurement of fasting serum lipids and blood glucose. Lipid disorders should be managed as clinically appropriate (see section 4.8).

There is evidence that mitochondrial DNA toxicity may be associated with specific features of lipoatrophy in patients using stavudine. This should be taken into account when considering initiation of combination antiretroviral therapy with stavudine.

Osteonecrosis: although the etiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV-disease and/or long-term exposure to combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.

Not recommended combinations: pancreatitis (fatal and nonfatal) and peripheral neuropathy (severe in some cases) have been reported in HIV infected patients receiving stavudine in association with hydroxyurea and didanosine. Hepatotoxicity and hepatic failure resulting in death were reported during postmarketing surveillance in HIV infected patients treated with antiretroviral agents and hydroxyurea; fatal hepatic events were reported most often in patients treated with stavudine, hydroxyurea and didanosine. Hence, hydroxyurea should not be used in the treatment of HIV infection.

Lactose intolerance: the hard capsule contains lactose (180 mg). Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose‑galactose malabsorption, should not take this medicine.

Elderly: Zerit has not been specifically investigated in patients over the age of 65.

Paediatric population

Not recommended combinations: pancreatitis (fatal and nonfatal) and peripheral neuropathy (severe in some cases) have been reported in HIV infected patients receiving stavudine in association with hydroxyurea and didanosine. Hepatotoxicity and hepatic failure resulting in death were reported during postmarketing surveillance in HIV infected patients treated with antiretroviral agents and hydroxyurea; fatal hepatic events were reported most often in patients treated with stavudine, hydroxyurea and didanosine. Hence, hydroxyurea should not be used in the treatment of HIV infection.

Lactose intolerance: the hard capsule contains lactose (180 mg). Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose‑galactose malabsorption, should not take this medicine.

Section 4.5

Paediatric population

Interaction studies have only been performed in adults

4.8     Undesirable effects

Adults: extensive safety experience is available for Zerit used as monotherapy and in combination regimens. Many of the serious undesirable effects with stavudine were consistent with the course of HIV infection or with the side effects of concomitant therapies.

Peripheral neuropathy: 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%. Dose‑related peripheral neuropathy occurred in monotherapy trials with Zerit (see sections 4.2 and 4.4). The patients usually experienced resolution of symptoms after dose reduction or interruption.

Pancreatitis: 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 .

Lactic acidosis: cases of lactic acidosis, sometimes fatal, usually associated with severe hepatomegaly and hepatic steatosis, have been reported with the use of nucleoside analogues (see section 4.4).

a. Summary of the safety profile

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. 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, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 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.

* 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).

The frequency of adverse reactions listed below is defined using the following convention:

very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000); very rare (< 1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Undesirable effects (moderate to severe) were reported from 467 patients treated with Zerit in combination with lamivudine and efavirenz in two randomised clinical trials and an ongoing long‑term follow‑up study (total follow‑up: median 56 weeks ranging up to 119 weeks). The following undesirable effects considered possibly related to study regimen based on investigators’ attribution, have been identified:

*Lipoatrophy was observed in a long-term follow-up study of stavudine in combination with lamivudine and efavirenz (total follow-up: median 148 weeks ranging up to 207 weeks).

Discontinuation due to undesirable events was 7% for the patients treated with Zerit.

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: undesirable effects 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 (see also section 4.6), 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.

Postmarketing

The following events have been reported spontaneously during postmarketing experience: