Chemical formula: C₁₀H₁₂N₂O₄ Molecular mass: 224.213 g/mol PubChem compound: 18283
Stavudine interacts in the following cases:
The following dosages are recommended (according to creatinine clearance):
Patient weight <60 kg:
Patient weight ≥60 kg:
* Patients on haemodialysis should take stavudine 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 stavudine 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.
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.
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.
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 stavudine 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 stavudine including lipoatrophy, a benefit-risk assessment for each patient should be made and an alternative antiretroviral carefully considered. Patients receiving stavudine should be frequently examined and questioned for signs of lipoatrophy. When such development is found, discontinuation of stavudine should be considered.
If symptoms of peripheral neuropathy develop (usually characterised by persistent numbness, tingling, or pain in the feet and/or hands) 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).
Up to 20% of patients treated with stavudine 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.
Patients with a history of pancreatitis had an incidence of approximately 5% on stavudine, 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.
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.
Stavudine 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, 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. Embryo-foetal toxicities were seen only at high exposure levels in animals. Preclinical studies showed placental transfer of stavudine. Until additional data become available, stavudine should be given during pregnancy only after special consideration; there is insufficient information to recommend stavudine 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 stavudine.
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 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.
Motor weakness has been reported rarely in patients receiving combination antiretroviral therapy including stavudine. Most of these cases occurred in the setting of symptomatic hyperlactatemia or lactic acidosis syndrome. 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.
Lipoatrophy was commonly reported in patients treated with stavudine in combination with other antiretrovirals.
Peripheral neuropathy was seen in combination studies of stavudine 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. Pancreatitis was reported in < 1% of patients in combination therapy studies with stavudine.
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 stavudine 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.
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 stavudine should be frequently examined and questioned for signs of lipoatrophy. When such development is found, treatment with stavudine should not be continued.
Weight and levels of blood lipids and glucose may increase during antiretroviral therapy.
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.
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 stavudine 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 stavudine. Macrocytosis was not evaluated in these trials, but was found to be associated with stavudine in an earlier trial (MCV >112 fl occurred in 30% of patients treated with stavudine).
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 stavudine 2 mg/kg/day for a median of 6.4 months; a controlled clinical trial where 185 newborns received stavudine 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 stavudine 2 mg/kg/day in combination with didanosine and nelfinavir from birth through 4 weeks of age.
In study AI455-094, the safety follow-up period was restricted to only six months, which may be insufficient to capture long-term data on neurological adverse events and mitochondrial toxicity. Relevant grade 3-4 laboratory abnormalities in the 91 stavudine treated infants were low neutrophils in 7%, low hemoglobin in 1%, ALT increase in 1% and no lipase abnormality. Data on lactic acid in serum were not collected. No notable differences in the frequency of adverse drug reactions were seen between treatment groups. There was, however, an increased infant mortality in the stavudine + didanosine (10%) treatment group compared to the stavudine (2%), didanosine (3%) or zidovudine (6%) groups, with a higher incidence of stillbirths in the stavudine + didanosine group.
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. The HIV status for the newborns and infants ≤3 months of age was negative, for older infants it tended to be positive. The profile of the adverse events for newborns and infants ≤3 months of age showed increases in lactic acid levels, neutropenia, anaemia, thrombocytopenia, hepatic transaminase increases and increased lipids, including hypertriglyceridaemia. The number of reports in older infants was too small to identify a pattern.
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