Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Bristol-Myers Squibb Pharma EEIG, Plaza 254, Blanchardstown Corporate Park 2, Dublin 15, D15 T867, Ireland
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 events notably lactic acidosis, liver function abnormalities, pancreatitis and peripheral neuropathy (see sections 4.4 and 4.5).
While effective viral suppression with antiretroviral therapy has been proven to substantially reduce the risk of sexual transmission, a residual risk cannot be excluded. Precautions to prevent transmission should be taken in accordance with national guidelines.
Stavudine therapy is associated with several severe side effects, such as lactic acidosis, lipoatrophy and polyneuropathy, for which a potential underlying mechanism is mitochondrial toxicity. 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, Lipoatrophy, and Peripheral neuropathy below and section 4.8).
Lactic acidosis, usually associated with hepatomegaly and hepatic steatosis has been reported with the use of stavudine. Early symptoms (symptomatic hyperlactatemia) include benign digestive symptoms (nausea, vomiting and abdominal pain), non-specific malaise, loss of appetite, weight loss, respiratory symptoms (rapid and/or deep breathing) or neurological symptoms (including motor weakness). Lactic acidosis has a high mortality and may be associated with pancreatitis, liver failure, 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 and metabolic/lactic acidosis, progressive hepatomegaly, or rapidly elevating aminotransferase levels.
Caution should be exercised when administering stavudine to any patient (particularly obese women) with hepatomegaly, hepatitis or other known risk factors for liver disease and hepatic steatosis (including certain medicinal products and alcohol). Patients co-infected with hepatitis C and treated with alpha interferon and ribavirin may constitute a special risk.
Patients at increased risk should be followed closely (see also section 4.6).
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.
On the basis of mitochondrial toxicity stavudine has been shown to cause loss of subcutaneous fat, which is most evident in the face, limbs and buttocks.
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, 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.
An increase in weight and in levels of blood lipids and glucose may occurr during antiretroviral therapy. Such changes may in part be linked to disease control and life style. For lipids, there is in some cases evidence for a treatment effect, while for weight gain there is no strong evidence relating this to any particular treatment. For monitoring of blood lipids and glucose reference is made to established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.
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 combinations, below).
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.
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. Autoimmune disorders (such as Graves' disease and 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 after initiation of treatment.
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.
The hard capsule contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption, should not take this medicine.
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 (see section 4.3). 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.
Zerit has not been specifically investigated in patients over the age of 65.
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.
Nucleos(t)ide analogues may impact mitochondrial function to a variable degree, which is most pronounced with stavudine, didanosine and zidovudine. 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); these have predominantly concerned treatment with regimens containing zidovudine. The main adverse reactions reported are haematological disorders (anaemia, neutropenia) and metabolic disorders (hyperlactatemia, hyperlipasemia). These events have often been transitory. Late-onset neurological disorders have been reported rarely (hypertonia, convulsion, abnormal behaviour). Whether such neurological disorders are transient or permanent is currently unknown. These findings should be considered for any child exposed in utero to nucleos(t)ide analogues, that present with severe clinical findings of unknown etiology, particularly neurologic findings. These findings do not affect current national recommendations 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 high risk of mitochondrial toxicity (see sections 4.3 and 4.4).
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.
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 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, sometimes fatal, has been reported in pregnant women who received the combination of didanosine and stavudine with or without other anti-retroviral treatment (see sections 4.3 and 4.4). 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.
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.
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.
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 (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.
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). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Rare: anaemia*
Very rare: neutropenia*, thrombocytopenia*
Uncommon: gynaecomastia
Common: lipoatrophy**, asymptomatic hyperlactatemia
Uncommon: lactic acidosis (in some cases involving motor weakness), anorexia
Rare: hyperglycaemia*
very rare: diabetes mellitis*
Common: depression
Uncommon: anxiety, emotional lability
Common: peripheral neurologic symptoms including peripheral neuropathy, paresthesia, and peripheral neuritis; dizziness; abnormal dreams; headache, insomnia; abnormal thinking; somnolence
Very rare: motor weakness* (most often reported in the setting of symptomatic hyperlactatemia or lactic acidosis syndrome)
Common: diarrhoea, abdominal pain, nausea, dyspepsia
Uncommon: pancreatitis, vomiting
Uncommon: hepatitis or jaundice
Rare: hepatic steatosis*
Very rare: liver failure*
Common: rash, pruritus
Uncommon: urticaria
Uncommon: arthralgia, myalgia
Common: fatigue
Uncommon: asthenia
* Adverse reactions observed post-marketing in association with stavudine-containing antiretroviral treatment.
** See Section Description of selected adverse reactions for more details.
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. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment (see section 4.4).
Stavudine has been shown to cause loss of subcutaneous fat, which is most evident in the face, limbs and buttocks. The incidence and severity of lipoatrophy are related to cumulative exposure, and is often not reversible when stavudine treatment is stopped. Patients receiving Zerit should be frequently examined and questioned for signs of lipoatrophy. When such development is found, treatment with Zerit should not be continued (see section 4.4).
Weight and levels of blood lipids and glucose may increase during antiretroviral therapy (see section 4.4).
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 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).
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.
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.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
Not applicable.
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