Zerit 200 mg powder for oral solution

Each bottle contains 200 mg of stavudine .

The reconstituted solution contains 1 mg of stavudine per ml.

Excipients:

Each bottle contains:

3.15 mg of propylhydroxybenzoate (E216)

315 mg of methylhydroxybenzoate (E218)

1.015 g of sucrose

For a full list of excipients, see section 6.1.

Powder for oral solution.

Off-white to pale-pink, gritty powder.

Zerit is indicated in combination with other antiretroviral medicinal products for the treatment of HIV infected adult patients and paediatric patients (from birth) 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).

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: the recommended oral dosage is:

*The reduced posology in neonates from 0 to 13 days is based on average study data and may not correspond to invidual variation in kidney maturation. Dosing recommendations are not available for neonates with a gestational age < 37 weeks.

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.

Instructions for preparation, see section 6.6.

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.

Hypersensitivity to the active substance or to any of the excipients.

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).

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.

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.

In the event of rapidly elevating transaminase levels (ALT/AST, > 5 times upper limit of normal, ULN), discontinuation of Zerit and any potentially hepatotoxic medicinal products should be considered.

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.

In randomized controlled trials of treatment-naive patients, clinical lipoatrophy developed in a higher proportion of patients treated with stavudine compared to other nucleosides (tenofovir or abacavir). Dual energy x-ray absorptiometry (DEXA) scans demonstrated overall limb fat loss in stavudine treated patients compared to limb fat gain or no change in patients treated with other NRTIs (abacavir, tenofovir or zidovudine). The incidence and severity of lipoatrophy are cumulative over time with stavudine-containing regimens. In clinical trials, switching from stavudine to other nucleosides (tenofovir or abacavir) resulted in increases in limb fat with modest to no improvements in clinical lipoatrophy. Given the potential risks of using Zerit including lipoatrophy or lipodystrophy, a benefit-risk assessment for each patient should be made and an alternative antiretroviral carefully considered. Patients receiving Zerit should be frequently examined and questioned for signs of lipoatrophy. When such development is found, discontinuation of Zerit should be considered.

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, medicines 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

Pancreatitis: patients with a history of pancreatitis had an incidence of approximately 5% onZerit, 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.

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.

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.

Diabetic patients: the reconstituted powder for oral solution contains 50 mg sucrose per ml of reconstituted solution.

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.

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

Paediatric population

Infants under the age of 3 months: safety data are available from clinical trials up to 6 weeks of treatment in 179 newborns and infants < 3 months of age (see section 4.8).

Special consideration should be given to the antiretroviral treatment history and the resistance profile of the HIV strain of the mother.

Mitochondrial dysfunction: nucleoside and nucleotide analogues 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-natally to nucleoside analogues (see also section 4.8). The main adverse reactions reported are haematological disorders (anaemia, neutropenia), metabolic disorders (hyperlactatemia, hyperlipasemia). These events are often transitory. Some late-onset neurological disorders have been reported (hypertonia, convulsion, abnormal behaviour). Whether the neurological disorders are transient or permanent is currently unknown. Any child exposed in utero to nucleoside and nucleotide analogues, even HIV-negative children, should have clinical and laboratory follow-up and should be fully investigated for possible mitochondrial dysfunction in case of relevant signs or symptoms. These findings do not affect current national recommendations to use antiretroviral therapy in pregnant women to prevent vertical transmission of HIV.

Since stavudine is actively secreted by the renal tubules, interactions with other actively secreted medicinal products are possible, e.g. with trimethoprim. No clinically relevant pharmacokinetic interaction has, however, been seen with lamivudine.

Zidovudine and stavudine are phosphorylated by the cellular enzyme (thymidine kinase), which preferentially phosphorylates zidovudine, thereby decreasing the phosphorylation of stavudine to its active triphosphate form. Zidovudine is therefore not recommended to be used in combination with stavudine.

In vitro studies indicate that the activation of stavudine is inhibited by doxorubicin and ribavirin but not by other medicinal products used in HIV infection which are similarly phosphorylated, (e.g. didanosine, zalcitabine, ganciclovir and foscarnet) therefore, coadministration of stavudine with either doxorubicin or ribavirin should be undertaken with caution. Stavudine's influence on the phosphorylation kinetics of nucleoside analogues other than zidovudine has not been investigated.

Clinically significant interactions of stavudine or stavudine plus didanosine with nelfinavir have not been observed.

Stavudine does not inhibit the major cytochrome P450 isoforms CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4; therefore, it is unlikely that clinically significant drug interactions will occur with medicines metabolised through these pathways.

Because stavudine is not protein-bound, it is not expected to affect the pharmacokinetics of protein-bound medicines.

There have been no formal interaction studies with other medicinal products.

Paediatric population

Interaction studies have only been performed in adults

Pregnancy

Zerit should not be used during pregnancy unless clearly necessary.

Clinical experience in pregnant women is limited, but congenital anomalies and abortions have been reported.

In study AI455-094, performed in South-Africa, 362 mother-infant pairs were included in a prevention of mother-to-child-transmission study. Treatment naive pregnant women were enrolled into the study at gestation week 34-36 and given antiretroviral treatment until delivery. Antiretroviral prophylaxis, the same medications as given to the mother, was given to the new-born infant within 36 hours of delivery and continued for 6 weeks. In the stavudine containing arms, the neonates were treated for 6 weeks with stavudine 1 mg/kg BID. The follow-up time was up to 24 weeks of age.

The mother-infant pairs were randomised to receive either stavudine (N= 91), didanosine (N= 94), stavudine + didanosine (N= 88) or zidovudine (N= 89).

95% Confidence intervals for the mother-to-child-transmission rates were 5.4-19.3% (stavudine), 5.2-18.7% (didanosine); 1.3-11.2% (stavudine + didanosine); and 1.9-12.6% for zidovudine.

Preliminary safety data from this study (see also section 4.8), showed 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. Data on lactic acid in serum were not collected in this study.

However, lactic acidosis (see section 4.4), sometimes fatal, has been reported in pregnant women who received the combination of didanosine and stavudine with or without other anti-retroviral treatment. Embryo-foetal toxicities were seen only at high exposure levels in animals. Preclinical studies showed placental transfer of stavudine (see section 5.3). Until additional data become available, Zerit should be given during pregnancy only after special consideration; there is insufficient information to recommend Zerit for prevention of mother-to-child transmission of HIV. Furthermore, the combination of stavudine and didanosine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk.

Breastfeeding

It is recommended that HIV infected women should not breast-feed under any circumstances in order to avoid transmission of HIV.

The data available on stavudine excretion into human breast milk are insufficient to assess the risk to the infant. Studies in lactating rats showed that stavudine is excreted in breast milk. Therefore, mothers should be instructed to discontinue breast-feeding prior to receiving Zerit.

Fertility

No evidence of impaired fertility was seen in rats at high exposure levels (up to 216 times that observed at the recommended clinical dose).

No studies on the effects on the ability to drive and use machines have been performed. Stavudine may cause dizziness 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.

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 (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.

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.

Experience in adults treated with up to 12 times the recommended daily dosage revealed no acute toxicity. Complications of chronic overdosage could include peripheral neuropathy and hepatic dysfunction. The mean haemodialysis clearance of stavudine is 120 ml/min. The contribution of this to the total elimination in an overdose situation is unknown. It is not known whether stavudine is removed by peritoneal dialysis.

Pharmacotherapeutic group: antivirals for systemic use, nucleoside and nucleotide reverse transcriptase inhibitors, ATC code: J05AF04

Mechanism of action: stavudine, a thymidine analogue, is phosphorylated by cellular kinases to stavudine triphosphate which inhibits HIV reverse transcriptase by competing with the natural substrate, thymidine triphosphate. It also inhibits viral DNA synthesis by causing DNA chain termination due to a lack of the 3'-hydroxyl group necessary for DNA elongation. Cellular DNA polymerase γ is also sensitive to inhibition by stavudine triphosphate, while cellular polymerases α and β are inhibited at concentrations 4,000-fold and 40-fold higher, respectively, than that needed to inhibit HIV reverse transcriptase.

Resistance: stavudine treatment can select for and/or maintain thymidine analogue mutations (TAMs) associated with zidovudine resistance. The decrease of susceptibility in vitro is subtle requiring two or more TAMs (generally M41L and T215Y) before stavudine susceptibility is decreased (>1.5 fold).

These TAMs are seen at a similar frequency with stavudine and zidovudine in virological treatment. The clinical relevance of these findings suggest that stavudine should be generally avoided in the presence of TAMs, especially M41L and T215Y.

The activity of stavudine is also affected by multi-drug resistance associated mutations such as Q151M. In addition, K65R has been reported in patients receiving stavudine/didanosine or stavudine/lamivudine, but not in patients receiving stavudine monotherapy. V75T is selected in vitro by stavudine and reduces susceptibility to stavudine by 2-fold. It occurs in ~1% of patients receiving stavudine.

Clinical efficacy

Zerit has been studied in combination with other antiretroviral agents, e.g. didanosine, lamivudine, ritonavir, indinavir, saquinavir, efavirenz, and nelfinavir.

In antiretroviral naive patients

Study AI455-099 was a 48-week, randomised, double-blind study withZerit (40 mg twice daily), in combination with lamivudine (150 mg twice daily) plus efavirenz (600 mg once daily), in 391 treatment-naive patients, with a median CD4 cell count of 272 cells/mm³ (range 61 to 1,215 cells/mm³) and a median plasma HIV-1 RNA of 4.80 log₁₀ copies/ml (range 2.6 to 5.9 log ₁₀ copies/ml) at baseline. Patients were primarily males (70%) and non-white (58%) with a median age of 33 years (range 18 to 68 years).

Study AI455-096 was a 48-week, randomised, double-blind study with Zerit (40 mg twice daily), in combination with lamivudine (150 mg twice daily) plus efavirenz (600 mg once daily), in 76 treatment-naive patients, with a median CD4 cell count of 261 cells/mm³ (range 63 to 962 cells/mm³) and a median plasma HIV-1 RNA of 4.63 log₁₀ copies/ml (range 3.0 to 5.9 log₁₀ copies/ml) at baseline. Patients were primarily males (76%) and white (66%) with a median age of 34 years (range 22 to 67 years).

The results of AI455-099 and AI455-096 are presented in Table 1. Both studies were designed to compare two formulations of Zerit, one of which was the marketed formulation dosed as currently approved in product labelling. Only the data from the marketed formulation are presented.

Table 1: Efficacy Outcomes at Week 48 (Studies AI455-099 and AI455-096)

^a Number of patients evaluable.

Paediatric population

The use of stavudine in adolescents, children and infants is supported by pharmacokinetic and safety data in paediatric patients (see also sections 4.8 and 5.2).

Adults

Absorption: the absolute bioavailability is 86±18%. After multiple oral administration of 0.5-0.67 mg/kg doses, a C_max value of 810±175 ng/ml was obtained. C_max and AUC increased proportionally with dose in the dose ranges, intravenous 0.0625-0.75 mg/kg, and oral 0.033-4.0 mg/kg.

In eight patients receiving 40 mg twice daily in the fasted state, steady-state AUC_0-12h was 1284±227 ngh/ml (18%) (mean ± SD [% CV]), C_max was 536±146 ng/ml (27%), and C_min was 9±8 ng/ml (89%). A study in asymptomatic patients demonstrated that systemic exposure is similar while C_max is lower and T_max is prolonged when stavudine is administered with a standardised, high-fat meal compared with fasting conditions. The clinical significance of this is unknown.

Distribution: the apparent volume of distribution at steady state is 46±21 l. It was not possible to detect stavudine in cerebrospinal fluid until at least 2 hours after oral administration. Four hours after administration, the CSF/plasma ratio was 0.39±0.06. No significant accumulation of stavudine is observed with repeated administration every 6, 8, or 12 hours.

Binding of stavudine to serum proteins was negligible over the concentration range of 0.01 to 11.4 µg/ml. Stavudine distributes equally between red blood cells and plasma.

Metabolism: Unchanged stavudine was the major drug-related component in total plasma radioactivity circulating after an oral 80 mg dose of ¹⁴C-stavudine in healthy subjects. The AUC(inf) for stavudine was 61% of the AUC(inf) of the total circulating radioactivity. Metabolites include oxidised stavudine, glucuronide conjugates of stavudine and its oxidised metabolite, and an N-acetylcysteine conjugate of the ribose after glycosidic cleavage, suggesting that thymine is also a metabolite of stavudine.

Elimination: following an oral 80-mg dose of ¹⁴C-stavudine to healthy subjects, approximately 95% and 3% of the total radioactivity was recovered in urine and faeces, respectively. Approximately 70% of the orally administered stavudine dose was excreted as an unchanged drug in urine. Mean renal clearance of the parent compound is approximately 272 ml/min, accounting for approximately 67% of the apparent oral clearance, indicating active tubular secretion in addition to glomerular filtration.

In HIV-infected patients, total clearance of stavudine is 594±164 ml/min, and renal clearance is 237±98 ml/min. The total clearance of stavudine appears to be higher in HIV-infected patients, while the renal clearance is similar between healthy subjects and HIV-infected patients. The mechanism and clinical significance of this difference are unknown. After intravenous administration, 42% (range: 13% to 87%) of dose is excreted unchanged in the urine. The corresponding values after oral single and multiple dose administration are 35% (range: 8% to 72%) and 40% (range: 12% to 82%), respectively. The mean terminal elimination half-life of stavudine is 1.3 to 2.3 hours following single or multiple doses, and is independent of dose. In vitro, stavudine triphosphate has an intracellular half-life of 3.5 hours in CEM T-cells (a human T-lymphoblastoid cell line) and peripheral blood mononuclear cells, supporting twice daily dosing.

The pharmacokinetics of stavudine was independent of time, since the ratio between AUC_(ss) at steady state and the AUC_(0-t) after the first dose was approximately 1. Intra-and interindividual variation in pharmacokinetic characteristics of stavudine is low, approximately 15% and 25%, respectively, after oral administration.

Special Populations

Renal impairment: the clearance of stavudine decreases as creatinine clearance decreases; therefore, it is recommended that the dosage of Zerit be adjusted in patients with reduced renal function (see section 4.2).

Hepatic impairment: stavudine pharmacokinetics in patients with hepatic impairment were similar to those in patients with normal hepatic function.

Paediatric population

Adolescents, children and infants: total exposure to stavudine was comparable between adolescents, children and infants 14 days receiving the 2 mg/kg/day dose and adults receiving 1 mg/kg/day. Apparent oral clearance was approximately 14 ml/min/kg for infants ages 5 weeks to 15 years, 12 ml/min/kg for infants ages 14 to 28 days, and 5 ml/min/kg for infants on the day of birth. Two to three hours post-dose, CSF/plasma ratios of stavudine ranged from 16% to 125% (mean of 59%±35%).

Animal data showed embryo-foetal toxicity at very high exposure levels. An ex vivo study using a term human placenta model demonstrated that stavudine reaches the foetal circulation by simple diffusion. A rat study also showed placental transfer of stavudine, with the foetal tissue concentration approximately 50% of the maternal plasma concentration.

Stavudine was genotoxic in in vitro tests in human lymphocytes possessing triphosphorylating activity (in which no no-effect level was established), in mouse fibroblasts, and in an in vivo test for chromosomal aberrations. Similar effects have been observed with other nucleoside analogues.

Stavudine was carcinogenic in mice (liver tumours) and rats (liver tumours: cholangiocellular, hepatocellular, mixed hepatocholangiocellular, and/or vascular; and urinary bladder carcinomas) at very high exposure levels. No carcinogenicity was noted at doses of 400 mg/kg/day in mice and 600 mg/kg/day in rats, corresponding to exposures ~ 39 and 168 times the expected human exposure, respectively, suggesting an insignificant carcinogenic potential of stavudine in clinical therapy.

Cherry flavour

Methylhydroxybenzoate (E218)

Propylhydroxybenzoate (E216)

Silicon dioxide

Simethicone

Sodium carmellose

Sorbic acid

Stearate emulsifiers

Sucrose

Not applicable.

2 years.

After reconstitution, store the prepared oral solution in a refrigerator (2°C - 8°C) for 30 days.

Do not store the dry powder above 30°C.

Store in the original package.

Keep the bottle tightly closed in order to protect from excessive moisture.

For storage conditions of the reconstituted medicinal product, see section 6.3.

HDPE bottle with child resistant screw cap, fill mark (200 ml of solution after reconstitution) and measuring cup.

Instructions for preparation

Zerit should be reconstituted with water to a 200 ml deliverable volume solution (stavudine concentration of 1 mg/ml).

To reconsistute Zerit, add 202 ml of water to the original bottle (when the patient makes up the solution, they should be instructed to fill to the mark). Replace the cap.

The bottle should be shaken well, until the powder dissolves completely. The solution appears as a colourless to slightly pink, hazy solution.

The solution should be dispensed with the measuring cup provided, or for doses less than 10 ml, dispense with a syringe. The patient should be instructed to shake the bottle well prior to measuring each dose.

Disposal

Any unused product or waste material should be disposed of in accordance with local requirements.

BRISTOL-MYERS SQUIBB PHARMA EEIG

Uxbridge Business Park

Sanderson Road

Uxbridge UB8 1DH

United Kingdom

EU/1/96/009/009

Date of first authorisation: 08 May 1996

Date of last renewal: 08 June 2006

March 2011

Detailed information on this product is available on the website of the European Medicines Agency http://www.ema.europa.eu/.