ZERIT 30mg capsules medication leaflet

Zerit 15 mg hard capsules

Zerit 20 mg hard capsules

Zerit 30 mg hard capsules

Zerit 40 mg hard capsules

Zerit 15 mg hard capsules

Each hard capsule contains 15 mg of stavudine.

Each hard capsule contains 80.84 mg of lactose anhydrous.

Each hard capsule contains 40.42 mg of lactose monohydrate.

Zerit 20 mg hard capsules

Each hard capsule contains 20 mg of stavudine.

Each hard capsule contains 121.30 mg of lactose anhydrous.

Each hard capsule contains 60.66 mg of lactose monohydrate.

Zerit 30 mg hard capsules

Each hard capsule contains 30 mg of stavudine.

Each hard capsule contains 121.09 mg of lactose anhydrous.

Each hard capsule contains 60.54 mg of lactose monohydrate.

Zerit 40 mg hard capsules

Each hard capsule contains 40 mg of stavudine.

Each hard capsule contains 159.06 mg of lactose anhydrous.

Each hard capsule contains 79.53 mg of lactose monohydrate.

For the full list of excipients, see section 6.1.

Hard capsule.

Zerit 15 mg hard capsules

The hard capsule is red and yellow, opaque and imprinted with “BMS” over a BMS code “1964” onone side and “15” on the other side.

Zerit 20 mg hard capsules

The hard capsule is brown, opaque and imprinted with “BMS” over a BMS code “1965” on one sideand “20” on the other side.

Zerit 30 mg hard capsules

The hard capsule is light and dark orange, opaque and imprinted with “BMS” over a BMS code“1966” on one side and “30” on the other side.

Zerit 40 mg hard capsules

The hard capsule is dark orange, opaque and imprinted with “BMS” over a BMS code “1967” on oneside and “40” on the other side.

Zerit is indicated in combination with other antiretroviral medicinal products for the treatment of HIVinfected adult patients and paediatric patients (over the age of 3 months) only when otherantiretrovirals can not be used. The duration of therapy with Zerit should be limited to the shortesttime possible (see section 4.2).

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

For patients starting therapy with Zerit, the duration should be limited to the shortest time possiblefollowed by a switch to an alternative appropriate therapy whenever possible. Patients continuingtreatment with Zerit should be assessed frequently and switched to an alternative appropriate therapywhenever possible (see section 4.4).

Adults: the recommended oral dosage is

Patient weight Zerit dosage< 60 kg 30 mg twice daily (every 12 hours)≥ 60 kg 40 mg twice daily (every 12 hours)

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

Patient weight Zerit dosage< 30 kg 1 mg/kg twice daily (every 12 hours)≥ 30 kg adult dosing

The powder formulation of ZERIT should be used for infants under the age of 3 months. Adultpatients that have problems swallowing capsules should ask their doctor about the possibility ofchanging to the powder formulation of this medicine.

Please refer to the Summary of Product Characteristics of the powder formulation.

Peripheral neuropathy: if symptoms of peripheral neuropathy develop (usually characterised bypersistent numbness, tingling, or pain in the feet and/or hands) (see section 4.4) patients should beswitched to an alternative treatment regimen, if appropriate. In the rare cases when this isinappropriate, dose reduction of stavudine may be considered, while the symptoms of peripheralneuropathy 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 - whichmay result from this measure (lower intracellular concentrations).

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 ofhaemodialysis, and at the same time on non-dialysis days.

Since urinary excretion is also a major route of elimination of stavudine in paediatric patients, theclearance of stavudine may be altered in paediatric patients with renal impairment. Although there areinsufficient data to recommend a specific dosage adjustment of Zerit in this patient population, areduction in the dose and/or an increase in the interval between doses proportional to the reduction foradults should be considered. There are no dosage recommendations for paediatric patients under theage of 3 months with renal impairment.

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 bycarefully opening the hard capsule and mixing the contents with food.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Co-administration with didanosine due to the potential for serious and/or life-threatening eventsnotably lactic acidosis, liver function abnormalities, pancreatitis and peripheral neuropathy (seesections 4.4 and 4.5).

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

Stavudine therapy is associated with several severe side effects, such as lactic acidosis, lipoatrophyand polyneuropathy, for which a potential underlying mechanism is mitochondrial toxicity. Giventhese potential risks, a benefit-risk assessment for each patients should be made and an alternativeantiretroviral should be carefully considered (see Lactic acidosis, Lipoatrophy, and Peripheralneuropathy below and section 4.8).

Lactic acidosis: lactic acidosis, usually associated with hepatomegaly and hepatic steatosis has beenreported with the use of stavudine. Early symptoms (symptomatic hyperlactatemia) include benigndigestive symptoms (nausea, vomiting and abdominal pain), non-specific malaise, loss of appetite,weight loss, respiratory symptoms (rapid and/or deep breathing) or neurological symptoms (includingmotor weakness). Lactic acidosis has a high mortality and may be associated with pancreatitis, liverfailure, renal failure, or motor paralysis.

Lactic acidosis generally occurred after a few or several months of treatment.

Treatment with stavudine should be discontinued if there is symptomatic hyperlactatemia andmetabolic/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 treatedwith alpha interferon and ribavirin may constitute a special risk.

Patients at increased risk should be followed closely (see also section 4.6).

Liver disease: hepatitis or liver failure, which was fatal in some cases, has been reported. The safetyand efficacy of stavudine has not been established in patients with significant underlying liverdisorders. Patients with chronic hepatitis B or C and treated with combination antiretroviral therapyare at an increased risk of severe and potentially fatal hepatic adverse reactions. In case of concomitantantiviral therapy for hepatitis B or C, please refer also to the relevant product information for thesemedicinal products.

Patients with pre-existing liver dysfunction including chronic active hepatitis have an increasedfrequency of liver function abnormalities during combination antiretroviral therapy and should bemonitored according to standard practice. If there is evidence of worsening liver disease in suchpatients, 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 beconsidered.

Lipoatrophy: on the basis of mitochondrial toxicity stavudine has been shown to cause loss ofsubcutaneous fat, which is most evident in the face, limbs and buttocks.

In randomized controlled trials of treatment-naive patients, clinical lipoatrophy developed in a higherproportion 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 stavudinetreated 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 withstavudine-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 clinicallipoatrophy. Given the potential risks of using Zerit including lipoatrophy, a benefit-risk assessmentfor each patient should be made and an alternative antiretroviral carefully considered. Patientsreceiving Zerit should be frequently examined and questioned for signs of lipoatrophy. When suchdevelopment is found, discontinuation of Zerit should be considered.

Weight and metabolic parameters: an increase in weight and in levels of blood lipids and glucose mayoccurr during antiretroviral therapy. Such changes may in part be linked to disease control and lifestyle. For lipids, there is in some cases evidence for a treatment effect, while for weight gain there isno strong evidence relating this to any particular treatment. For monitoring of blood lipids and glucosereference is made to established HIV treatment guidelines. Lipid disorders should be managed asclinically appropriate.

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 riskfactors (for example alcohol, medicines such as isoniazid) are at particular risk. Patients should bemonitored for symptoms (persistent numbness, tingling or pain in feet/hands) and if present patientsshould be switched to an alternate treatment regimen (see section 4.2 and Not recommendedcombinations, below).

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

Immune reactivation syndrome: in HIV-infected patients with severe immune deficiency at the time ofinstitution of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomaticor residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation ofsymptoms. Typically, such reactions have been observed within the first few weeks or months ofinitiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focalmycobacterial infections, and Pneumocystis carinii pneumonia. Any inflammatory symptoms shouldbe evaluated and treatment instituted when necessary. Autoimmune disorders (such as Graves' diseaseand autoimmune hepatitis) have also been reported to occur in the setting of immune reactivation;however, the reported time to onset is more variable and these events can occur many months afterinitiation of treatment.

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

Lactose intolerance: the hard capsule contains lactose. Patients with rare hereditary problems ofgalactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption, should not takethis medicine.

Not recommended combinations: pancreatitis (fatal and nonfatal) and peripheral neuropathy (severe insome cases) have been reported in HIV infected patients receiving stavudine in association withhydroxyurea and didanosine (see section 4.3). Hepatotoxicity and hepatic failure resulting in deathwere reported during postmarketing surveillance in HIV infected patients treated with antiretroviralagents and hydroxyurea; fatal hepatic events were reported most often in patients treated withstavudine, 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.

Infants under the age of 3 months: safety data are available from clinical trials up to 6 weeks oftreatment 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 profileof the HIV strain of the mother.

Mitochondrial dysfunction following exposure in utero: nucleos(t)ide analogues may impactmitochondrial function to a variable degree, which is most pronounced with stavudine, didanosine andzidovudine. There have been reports of mitochondrial dysfunction in HIV-negative infants exposed inutero and/or post-natally to nucleoside analogues (see also section 4.8); these have predominantlyconcerned treatment with regimens containing zidovudine. The main adverse reactions reported arehaematological disorders (anaemia, neutropenia) and metabolic disorders (hyperlactatemia,hyperlipasemia). These events have often been transitory. Late-onset neurological disorders have beenreported rarely (hypertonia, convulsion, abnormal behaviour). Whether such neurological disorders aretransient or permanent is currently unknown. These findings should be considered for any childexposed in utero to nucleos(t)ide analogues, that present with severe clinical findings of unknownetiology, particularly neurologic findings. These findings do not affect current nationalrecommendations to use antiretroviral therapy in pregnant women to prevent vertical transmission of

HIV.

The combination of stavudine with didanosine is contraindicated given that both drugs exhibits highrisk of mitochondrial toxicity (see sections 4.3 and 4.4).

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

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

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

Clinically significant interactions of stavudine or stavudine plus didanosine with nelfinavir have notbeen 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 occurwith medicines metabolised through these pathways.

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

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

Interaction studies have only been performed in adults.

Zerit should not be used during pregnancy unless clearly necessary.

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

In study AI455-094, performed in South-Africa, 362 mother-infant pairs were included in a preventionof mother-to-child-transmission study. Treatment naive pregnant women were enrolled into the studyat 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 ofdelivery and continued for 6 weeks. In the stavudine containing arms, the neonates were treatedfor 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), pct. 5.2-18.7% (didanosine); 1.3-11.2% (stavudine + didanosine); and 1.9-12.6% forzidovudine.

Preliminary safety data from this study (see also section 4.8), showed an increased infant mortality inthe 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, sometimes fatal, has been reported in pregnant women who received thecombination of didanosine and stavudine with or without other anti-retroviral treatment (see sections4.3 and 4.4). Embryo-foetal toxicities were seen only at high exposure levels in animals. Preclinicalstudies showed placental transfer of stavudine (see section 5.3). Until additional data becomeavailable, Zerit should be given during pregnancy only after special consideration; there is insufficientinformation to recommend Zerit for prevention of mother-to-child transmission of HIV.

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

The data available on stavudine excretion into human breast milk are insufficient to assess the risk tothe 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.

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

No studies on the effects on the ability to drive and use machines have been performed. Stavudine maycause dizziness and/or somnolence. Patients should be instructed that if they experience thesesymptoms they should avoid potentially hazardous tasks such as driving or operating machinery.

Stavudine therapy is associated with several severe adverse reactions, such as lactic acidosis,lipoatrophy and polyneuropathy, for which a potential underlying mechanism is mitochondrialtoxicity. Given these potential risks, a benefit-risk assessment for each patient should be made and analternative antiretroviral should be carefully considered (see section 4.4 and below).

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

Motor weakness has been reported rarely in patients receiving combination antiretroviral therapyincluding Zerit. Most of these cases occurred in the setting of symptomatic hyperlactatemia or lacticacidosis syndrome (see section 4.4). The evolution of motor weakness may mimic the clinicalpresentation of Guillain-Barré syndrome (including respiratory failure). Symptoms may continue orworsen following discontinuation of therapy.

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

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

Peripheral neuropathy was seen in combination studies of Zerit with lamivudine plus efavirenz; thefrequency of peripheral neurologic symptoms was 19% (6% for moderate to severe) with a rate ofdiscontinuation due to neuropathy of 2%. The patients usually experienced resolution of symptomsafter dose reduction or interruption of stavudine.

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

Adverse reactions of moderate or greater severity with at least a possible relationship to treatmentregimen (based on investigator attribution) reported from 467 patients treated with Zerit incombination with lamivudine and efavirenz in two randomised clinical trials and along-term follow-upstudy (follow-up: median 56 weeks ranging up to 119 weeks) are listed below. Also listed are adversereactions observed post-marketing in association with stavudine-containing antiretroviral treatment.

The frequency of adverse reactions listed below is defined using the following convention: verycommon (≥ 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). Within each frequency grouping, undesirable effects are presentedin order of decreasing seriousness.

Blood and lymphatic system rare: anaemia*disorders: very rare: neutropenia *, thrombocytopenia*

Endocrine disorders: uncommon: gynaecomastia

Metabolism and nutrition common: lipoatrophy**, asymptomatic hyperlactatemiadisorders: uncommon: lactic acidosis (in some cases involving motorweakness), anorexiarare: hyperglycaemia*very rare: diabetes mellitis*

Psychiatric disorders: common: depressionuncommon: anxiety, emotional lability

Nervous system disorders: common: peripheral neurologic symptoms including peripheralneuropathy, paresthesia, and peripheral neuritis;dizziness; abnormal dreams; headache, insomnia;abnormal thinking; somnolencevery rare: motor weakness* (most often reported in the setting ofsymptomatic hyperlactatemia or lactic acidosis syndrome)

Gastrointestinal disorders: common: diarrhoea, abdominal pain, nausea, dyspepsiauncommon: pancreatitis, vomiting

Hepatobiliary disorders: uncommon: hepatitis or jaundicerare: hepatic steatosis*very rare: liver failure*

Skin and subcutaneous tissue common: rash, pruritusdisorders: uncommon: urticaria

Musculoskeletal and connective uncommon: arthralgia, myalgiatissue disorders:

General disorders and common: fatigueadministration site conditions: uncommon: asthenia

* Adverse reactions observed post-marketing in association with stavudine-containing antiretroviraltreatment

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

Immune reactivation syndrome: in HIV-infected patients with severe immune deficiency at the time ofinitiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic orresidual opportunistic infections may arise. Autoimmune disorders (such as Graves' disease andautoimmune hepatitis) have also been reported; however, the reported time to onset is more variableand these events can occur many months after initiation of treatment (see section 4.4).

Lipoatrophy: stavudine has been shown to cause loss of subcutaneous fat, which is most evident in theface, limbs and buttocks. The incidence and severity of lipoatrophy are related to cumulativeexposure, and is often not reversible when stavudine treatment is stopped. Patients receiving Zeritshould be frequently examined and questioned for signs of lipoatrophy. When such development isfound, treatment with Zerit should not be continued (see section 4.4).

Metabolic parameters: weight and levels of blood lipids and glucose may increase duringantiretroviral therapy (see section 4.4).

Osteonecrosis: cases of osteonecrosis have been reported, particularly in patients with generallyacknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviraltherapy (CART). The frequency of this is unknown (see section 4.4).

Laboratory abnormalities: laboratory abnormalities reported in these two trials and an ongoingfollow-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 reportedin 5%, thrombocytopenia (platelets < 50,000/mm3) in 2%, and low haemoglobin (< 8 g/dl) in < 1% ofpatients receiving Zerit.

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

Adolescents, children and infants: adverse reactions and serious laboratory abnormalities reported tooccur in paediatric patients ranging in age from birth through adolescence who received stavudine inclinical 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 medianof 6.4 months; a controlled clinical trial where 185 newborns received Zerit 2 mg/kg/day either aloneor in combination with didanosine from birth through 6 weeks of age; and a clinical trialwhere 8 newborns received Zerit 2 mg/kg/day in combination with didanosine and nelfinavir frombirth through 4 weeks of age.

In study AI455-094 (see also section 4.6), the safety follow-up period was restricted to only sixmonths, which may be insufficient to capture long-term data on neurological adverse events andmitochondrial toxicity. Relevant grade 3-4 laboratory abnormalities in the 91 stavudine treated infantswere 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 adversedrug reactions were seen between treatment groups. There was, however, an increased infant mortalityin 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 reactionsindicative of mitochondrial dysfunction have been reported in the neonate and infant populationexposed to one or more nucleoside analogues (see also section 4.4). The HIV status for the newbornsand infants ≤ 3 months of age was negative, for older infants it tended to be positive. The profile of theadverse 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 apattern.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

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

Stavudine, a thymidine analogue, is phosphorylated by cellular kinases to stavudine triphosphatewhich inhibits HIV reverse transcriptase by competing with the natural substrate, thymidinetriphosphate. It also inhibits viral DNA synthesis by causing DNA chain termination due to a lack ofthe 3’-hydroxyl group necessary for DNA elongation. Cellular DNA polymerase γ is also sensitive toinhibition by stavudine triphosphate, while cellular polymerases α and β are inhibited atconcentrations 4,000-fold and 40-fold higher, respectively, than that needed to inhibit HIV reversetranscriptase.

Stavudine treatment can select for and/or maintain thymidine analogue mutations (TAMs) associatedwith 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 thepresence 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 orstavudine/lamivudine, but not in patients receiving stavudine monotherapy. V75T is selected in vitroby stavudine and reduces susceptibility to stavudine by 2-fold. It occurs in ~1% of patients receivingstavudine.

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 with Zerit (40 mg twice daily), incombination 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), incombination 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 tocompare two formulations of Zerit, one of which was the marketed formulation dosed as currentlyapproved 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)

AI455-099 AI455-096

Zerit + lamivudine + Zerit + lamivudine +efavirenz efavirenz

Parameter n=391 n=76

HIV RNA < 400 copies/ml, treatment response, %

All patients 73 66

HIV RNA < 50 copies/ml, treatment response, %

All patients 55 38

HIV RNA Mean Change from Baseline, log10 copies/ml

All patients -2.83 (n=321a) -2.64 (n=58)

CD4 Mean Change from Baseline, cells/mm3

All patients 182 (n=314) 195 (n=55)a Number of patients evaluable.

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

The absolute bioavailability is 86±18%. After multiple oral administration of 0.5-0.67 mg/kg doses, a

Cmax value of 810±175 ng/ml was obtained. Cmax and AUC increased proportionally with dose in thedose 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 AUC0-12hwas 1284±227 ng⋅h/ml (18%) (mean ± SD [% CV]), Cmax was 536±146 ng/ml (27%), and Cminwas 9±8 ng/ml (89%). A study in asymptomatic patients demonstrated that systemic exposure issimilar while Cmax is lower and Tmax is prolonged when stavudine is administered with a standardised,high-fat meal compared with fasting conditions. The clinical significance of this is unknown.

The apparent volume of distribution at steady state is 46±21 l. It was not possible to detect stavudinein 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 withrepeated administration every 6, 8, or 12 hours.

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

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

Following an oral 80-mg dose of 14C-stavudine to healthy subjects, approximately 95% and 3% of thetotal radioactivity was recovered in urine and faeces, respectively. Approximately 70% of the orallyadministered stavudine dose was excreted as an unchanged drug in urine. Mean renal clearance of theparent compound is approximately 272 ml/min, accounting for approximately 67% of the apparentoral 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 clearanceis 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. Themechanism and clinical significance of this difference are unknown. After intravenousadministration, 42% (range: 13% to 87%) of dose is excreted unchanged in the urine. Thecorresponding 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 stavudineis 1.3 to 2.3 hours following single or multiple doses, and is independent of dose. In vitro, stavudinetriphosphate has an intracellular half-life of 3.5 hours in CEM T-cells (a human T-lymphoblastoid cellline) and peripheral blood mononuclear cells, supporting twice daily dosing.

The pharmacokinetics of stavudine was independent of time, since the ratio between AUC(ss) at steadystate and the AUC(0-t) after the first dose was approximately 1. Intra- and interindividual variation inpharmacokinetic characteristics of stavudine is low, approximately 15% and 25%, respectively, afteroral administration.

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

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

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 weeksto 15 years, 12 ml/min/kg for infants ages 14 to 28 days, and 5 ml/min/kg for infants on the day ofbirth. Two to three hours post-dose, CSF/plasma ratios of stavudine ranged from 16% to 125% (meanof 59%±35%).

Animal data showed embryo-foetal toxicity at very high exposure levels. An ex vivo study using aterm human placenta model demonstrated that stavudine reaches the foetal circulation by simplediffusion. A rat study also showed placental transfer of stavudine, with the foetal tissue concentrationapproximately 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 forchromosomal 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) atvery high exposure levels. No carcinogenicity was noted at doses of 400 mg/kg/day in miceand 600 mg/kg/day in rats, corresponding to exposures ~ 39 and 168 times the expected humanexposure, respectively, suggesting an insignificant carcinogenic potential of stavudine in clinicaltherapy.

Magnesium stearate

Microcrystalline cellulose

Sodium starch glycolate

Gelatin

Iron oxide colorant (E172)

Silicon dioxide

Sodium laurilsulphate

Titanium dioxide (E171)

Black ink containing

Shellac

Propylene Glycol

Purified Water

Potassium Hydroxide

Iron Oxide (E172)

Not applicable.

2 years.

Store below 25°C (aclar/alu blisters).

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

Store in the original package.

HDPE bottles with child resistant screw cap (60 hard capsules per bottle).

Aclar/aluminum blisters with 14 hard capsules per card and 4 cards (56 hard capsules) per carton.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Bristol-Myers Squibb Pharma EEIG

Plaza 254

Blanchardstown Corporate Park 2

Dublin 15, D15 T867

Ireland

EU/1/96/009/001 - 008

Date of first authorisation: 08 May 1996

Date of last renewal: 20 April 2011

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu/.