vitro data indicate that the phosphorylation of stavudine is inhibited at relevant concentrations by doxorubicin. the clinical significance of this interaction is unknown; therefore, concomitant use of stavudine with doxorubicin should be undertaken with caution. ribavirin: in vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine. the clinical significance of the interaction with stavudine is unknown; therefore, concomitant use of stavudine with ribavirin should be undertaken with caution. no pharmacokinetic (eg, plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (eg, loss of hiv-1/hcv virologic suppression) interaction was observed when ribavirin and lamivudine (n=18), stavudine (n=10), or zidovudine (n=6) were coadministered as part of a multi-drug regimen to hiv-1/hcv co-infected patients [see warnings and precautions ( 5.2 ) ].

been reported with the use of nucleoside analogues alone or in combination, including stavudine and other antiretrovirals. although relative rates of lactic acidosis have not been assessed in prospective well-controlled trials, longitudinal cohort and retrospective studies suggest that this infrequent event may be more often associated with antiretroviral combinations containing stavudine. female gender, obesity, and prolonged nucleoside exposure may be risk factors. fatal lactic acidosis has been reported in pregnant individuals who received the combination of stavudine and didanosine with other antiretroviral agents. coadministration of stavudine and didanosine is contraindicated [ see contraindications ( 4 ) and use in specific populations ( 8.1 ) ] particular caution should be exercised when administering stavudine to any patient with known risk factors for liver disease; however, cases of lactic acidosis have also been reported in patients with no known risk factors. generalized fatigue, digestive symptoms (nausea, vomiting, abdominal pain, and unexplained weight loss); respiratory symptoms (tachypnea and dyspnea); or neurologic symptoms, including motor weakness [see warnings and precautions ( 5.3 ) ] might be indicative of the development of symptomatic hyperlactatemia or lactic acidosis syndrome. treatment with stavudine should be suspended in any patient who develops clinical or laboratory findings suggestive of symptomatic hyperlactatemia, lactic acidosis, or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations). permanent discontinuation of stavudine should be considered for patients with confirmed lactic acidosis. 5.2 hepatic toxicity the safety and efficacy of stavudine have not been established in hiv-infected patients with significant underlying liver disease. during combination antiretroviral therapy, patients with preexisting liver dysfunction, including chronic active hepatitis, have an increased frequency of liver function abnormalities, including severe and potentially fatal hepatic adverse events, 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. hepatotoxicity and hepatic failure resulting in death were reported during postmarketing surveillance in hiv-infected patients treated with hydroxyurea and other antiretroviral agents. fatal hepatic events were reported most often in patients treated with the combination of hydroxyurea, didanosine, and stavudine. coadministration of stavudine and didanosine is contraindicated; and the combination of stavudine and hydroxyurea should be avoided. [ see contraindications ( 4 ) and drug interactions ( 7 ) ] use with interferon and ribavirin-based regimens in vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogues such as stavudine. although no evidence of a pharmacokinetic or pharmacodynamic (eg, loss of hiv-1/hcv virologic suppression) interaction was seen when ribavirin was coadministered with stavudine in hiv-1/hcv co-infected patients [see drug interactions ( 7 ) ], hepatic decompensation (some fatal) has occurred in hiv-1/hcv co-infected patients receiving combination antiretroviral therapy for hiv-1 and interferon and ribavirin. patients receiving interferon with or without ribavirin and stavudine should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. discontinuation of stavudine should be considered as medically appropriate. dose reduction or discontinuation of interferon, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (eg, child-pugh >6) (see the full prescribing information for interferon and ribavirin). 5.3 neurologic symptoms motor weakness has been reported rarely in patients receiving combination antiretroviral therapy including stavudine. most of these cases occurred in the setting of lactic acidosis. the evolution of motor weakness may mimic the clinical presentation of guillain-barre syndrome (including respiratory failure). if motor weakness develops, stavudine should be discontinued. symptoms may continue or worsen following discontinuation of therapy. peripheral sensory neuropathy, manifested by numbness, tingling, or pain in the hands or feet, has been reported in patients receiving stavudine therapy. peripheral neuropathy, which can be severe, is dose-related and occurs more frequently in patients with advanced hiv-1 disease, a history of peripheral neuropathy, or in patients receiving other drugs that have been associated with neuropathy [ see drug interactions ( 7 ) ]. patients should be monitored for the development of peripheral neuropathy. stavudine-related peripheral neuropathy may resolve if therapy is withdrawn promptly. if peripheral neuropathy develops permanent discontinuation of stavudine should be considered. in some cases, symptoms may worsen temporarily following discontinuation of therapy. 5.4 pancreatitis fatal and nonfatal pancreatitis have occurred during therapy when stavudine was part of a combination regimen that included didanosine in both treatment-naive and treatment-experienced patients, regardless of degree of immunosuppression. the combination of stavudine and any other agents that are toxic to the pancreas should be suspended in patients with suspected pancreatitis. coadministration of stavudine and didanosine is contraindicated [ see contraindications ( 4 ) ] . reinstitution of stavudine after a confirmed diagnosis of pancreatitis should be undertaken with particular caution and close patient monitoring 5.5 lipoatrophy 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 gain in patients treated with other nucleosides (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. patients receiving stavudine should be monitored for symptoms or signs of lipoatrophy and questioned about body changes related to lipoatrophy. given the potential risks of using stavudine including lipoatrophy, a benefit-risk assessment for each patient should be made and an alternative antiretroviral should be considered. 5.6 immune reconstitution syndrome immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including stavudine. during the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as mycobacterium avium infection, cytomegalovirus, pneumocystis jiroveci pneumonia (pcp), or tuberculosis), which may necessitate further evaluation and treatment. autoimmune disorders (such as graves disease, polymyositis, and guillain-barre syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.

12 hours. for pediatric patients at least 14 days old and weighing less than 30 kg: 1 mg/kg given every 12 hours. for pediatric patients weighing at least 30 kg: use the recommended adult dosage. 2.3 dosage adjustment renal impairment adult patients: stavudine may be administered to adult patients with impaired renal function with an adjustment in dosage as shown in table 1. table 1: recommended dosage adjustment for adult patients with renal impairment * administered after the completion of hemodialysis on dialysis days and at the same time of day on non-dialysis days creatinine clearance (ml/min) recommended stavudine dose by patient weight at least 60 kg less than 60 kg greater than 50 40 mg every 12 hours 30 mg every 12 hours 26 – 50 20 mg every 12 hours 15 mg every 12 hours 10 – 25 20 mg every 24 hours 15 mg every 24 hours hemodialysis 20 mg every 24 hours * 15 mg every 24 hours * pediatric patients: since urinary excretion is also a major route of elimination of stavudine in pediatric patients, the clearance of stavudine may be altered in children with renal impairment. there are insufficient data to recommend a specific dose adjustment of stavudine in this patient population. 2.4 method of preparation for oral solution prior to dispensing, the pharmacist must constitute the dry powder with purified water to a concentration of 1 mg stavudine per ml of solution, as follows: add 200 ml of purified water to the container. shake container vigorously until the powder dissolves completely. constitution in this way produces 200 ml (deliverable volume) of 1 mg/ml stavudine solution. the solution may appear slightly hazy. dispense solution in original container with measuring cup provided. instruct patient to shake the container vigorously prior to measuring each dose and to store the tightly closed container in a refrigerator, 2°c to 8°c (36°f to 46°f). discard any unused portion after 30 days.

al trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. clinical trials experience in adults selected adverse reactions that occurred in adult patients receiving stavudine in a controlled monotherapy study (study ai455-019) are provided in table 2. table 2: selected adverse reactions in study ai455-019 a (monotherapy) a the incidences reported included all severity grades and all reactions regardless of causality. b median duration of stavudine therapy = 79 weeks, median duration of zidovudine therapy = 53 weeks percent(%) adverse reaction stavudine b (40 mg twice daily) (n = 412) zidovudine (200 mg 3 times daily) (n=402) headache 54 49 diarrhea 50 44 peripheral neurologic symptoms/neuropathy 52 39 rash 40 35 nausea and vomiting 39 44 pancreatitis was observed in 3 of the 412 adult patients who received stavudine in study ai455-019. selected adverse reactions that occurred in antiretroviral-naive adult patients receiving stavudine from two controlled combination studies are provided in table 3. table 3: selected adverse reactions a in start 1 and start 2 b studies (combination therapy) a the incidences reported included all severity grades and all reactions regardless of causality. b start 2 compared two triple-combination regimens in 205 treatment-naïve patients. patients received either stavudine (40 mg twice daily) plus didanosine plus indinavir or zidovudine plus lamivudine plus indinavir. c duration of stavudine therapy=48 weeks percent (%) start 1 start 2 b adverse reaction stavudine + lamivudine + indinavir (n = 100 c ) zidovudine + lamivudine + indinavir (n = 102) stavudine + didanosine + indinavir (n=102 c ) zidovudine + lamivudine + indinavir (n = 103) nausea 43 63 53 67 diarrhea 34 16 45 39 headache 25 26 46 37 rash 18 13 30 18 vomiting 18 33 30 35 peripheral neurologic symptoms/neuropathy 8 7 21 10 selected laboratory abnormalities reported in a controlled monotherapy study (study ai455-019) are provided in table 4. table 4: selected laboratory abnormalities in study ai455-019 a, b uln = upper limit of normal a data presented for patients for whom laboratory evaluations were performed. b median duration of stavudine therapy = 79 weeks; median duration of zidovudine therapy = 53 weeks. percent(%) parameter stavudine b (40 mg twice daily) (n = 412) zidovudine (200 mg 3 times daily) (n=402) ast (sgot) (> 5.0 x uln) 11 10 alt (sgpt) (> 5.0 x uln) 13 11 amylase (≥ 1.4 x uln) 14 13 selected laboratory abnormalities reported in two controlled combination studies are provided in tables 5 and 6. table 5: selected laboratory abnormalities in start 1 and start 2 studies (grades 3–4) uln = upper limit of normal percent (%) start 1 start 2 parameter stavudine + lamivudine + indinavir (n=100) zidovudine + lamivudine + indinavir (n=102) stavudine + didanosine + indinavir (n=102) zidovudine + lamivudine + indinavir (n=103) bilirubin (>2.6 x uln) 7 6 16 8 ast (sgot) (>5 x uln) 5 2 7 7 alt (sgpt) (>5 x uln) 6 2 8 5 ggt (>5 x uln) 2 2 5 2 lipase (>2 x uln) 6 3 5 5 amylase (>2 x uln) 4 <1 8 2 table 6: selected laboratory abnormalities in start 1 and start 2 studies (all grades) percent (%) start 1 start 2 parameter stavudine + lamivudine + indinavir (n=100) zidovudine + lamivudine + indinavir (n=102) stavudine + didanosine + indinavir (n=102) zidovudine + lamivudine + indinavir (n=103) total bilirubin 65 60 68 55 ast (sgot) 42 20 53 20 alt (sgpt) 40 20 50 18 ggt 15 8 28 12 lipase 27 12 26 19 amylase 21 19 31 17 clinical trials experience in pediatric patients adverse reactions and serious laboratory abnormalities reported in pediatric patients from birth through adolescence during clinical trials were similar in type and frequency to those seen in adult patients [ see use in specific populations ( 8.4 ) ]. 6.2 postmarketing experience the following adverse reactions have been identified during postmarketing use of stavudine. because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. these reactions have been chosen for inclusion due to their seriousness, frequency of reporting, causal connection to stavudine, or a combination of these factors. body as a whole: abdominal pain, allergic reaction, chills/fever. digestive disorders: anorexia. exocrine gland disorders: pancreatitis, including fatal cases [see warnings and precautions ( 5.4 ) ]. hematologic disorders: anemia, leukopenia, thrombocytopenia, neutropenia, and macrocytosis. liver: symptomatic hyperlactatemia/lactic acidosis and hepatic steatosis [see warnings and precautions ( 5.1 ) ], hepatitis and liver failure. metabolic disorders: lipoatrophy [see warnings and precautions ( 5.5 ) ], diabetes mellitus and hyperglycemia. musculoskeletal: myalgia. nervous system: insomnia, severe motor weakness (most often reported in the setting of lactic acidosis) [see warnings and precautions ( 5.1 , 5.3 ) ].

vitro data indicate that the phosphorylation of stavudine is inhibited at relevant concentrations by doxorubicin. the clinical significance of this interaction is unknown; therefore, concomitant use of stavudine with doxorubicin should be undertaken with caution. ribavirin: in vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine. the clinical significance of the interaction with stavudine is unknown; therefore, concomitant use of stavudine with ribavirin should be undertaken with caution. no pharmacokinetic (eg, plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (eg, loss of hiv-1/hcv virologic suppression) interaction was observed when ribavirin and lamivudine (n=18), stavudine (n=10), or zidovudine (n=6) were coadministered as part of a multi-drug regimen to hiv-1/hcv co-infected patients [see warnings and precautions ( 5.2 ) ].

didanosine is contraindicated [ see contraindications ( 4 ) ]. prospective pregnancy data from apr are not sufficient to adequately assess the risk of major birth defects, miscarriage or adverse developmental outcomes. available data from the apr show no increase in overall risk of major birth defects compared with 2.7% in the u.s. reference population of the metropolitan atlanta congenital defects program (macdp). the rate of miscarriage is not reported in the apr. in the u.s. general population, the estimated background risks of miscarriage in clinically recognized pregnancies is 15 to 20%. in animal reproduction studies, no adverse developmental effects were observed with oral administration of stavudine at clinically relevant exposures. no developmental toxicities were observed in rats and rabbits at systemic exposures 112 (auc) and 183 (c max ) times, respectively, the exposures in humans at the recommended human dose (rhd) of stavudine (see data) . clinical considerations maternal adverse reactions cases of lactic acidosis syndrome, sometimes fatal have occurred in pregnant individuals using stavudine in combination with didanosine. stavudine is associated with an increased risk of lactic acidosis syndrome/hepatic steatosis syndrome [ see warnings and precautions ( 5.1 ) ]. data human data based on prospective reports to the apr of live births following exposure to stavudine-containing regimens during pregnancy (including 811 exposed in the first trimester and 196 exposed in the second/third trimester), the prevalence of birth defects in live births for stavudine was 2.6% (95% ci: 1.6 % to 3.9%) with first trimester exposure and 3.1% (95% ci: 1.1% to 6.5%) with second/third trimester exposure compared to the background birth defect rate of 2.7% in the u.s. reference population of the macdp. prospective reports from the apr of overall major birth defects in pregnancies exposed to stavudine is compared with a u.s. background major birth defect rate. methodological limitations of the apr include the use of macdp as the external comparator group. limitations of using an external comparator include differences in methodology and populations, as well as confounding due to the underlying disease. animal data stavudine was administered orally to pregnant rats (0, 50, 250, and 1000 mg/kg/day from gestation day 6 to 17) and rabbits (0, 60, 150, 300 and 600 mg/kg/day from gestation day 6 to 18). in rats, fetal skeletal variations, including increased unossified or incomplete ossification of sternebra, were observed at the highest dose (1000 mg/kg/day) (approximately 488 times human auc exposure at the rhd). in rabbits, there were no developmental effects up to the highest dose of 600 mg/kg (approximately 183 times human cmax exposure at the rhd). in the pre/post-natal development study, stavudine was administered orally to rats at 0, 50, 250, and 1000 mg/kg/day from gestation day 17 to postnatal day 21. post-implantation loss and an increase in early neonatal mortality was observed at 1000 mg/kg/day (approximately 488 times human auc exposure at the rhd). no developmental effects were observed at 250 mg/kg/day (approximately 112 times human auc exposure at the rhd). stavudine was transferred to the fetus through the placenta in rats with concentrations in fetal tissues approximately half the concentration detected in maternal plasma. 8.2 lactation risk summary the centers for disease control and prevention recommend that hiv-infected mothers not breastfeed their infants to avoid risking postnatal transmission of hiv. based on limited data, stavudine has been detected in human milk. no data are available regarding the effects of stavudine on the breastfed infant, or the effects on milk production. because of the potential for (1) hiv transmission (in hiv-negative infants), (2) developing viral resistance (in hiv-positive infants) and (3) adverse reactions in breastfed infants similar to those seen in adults, instruct mothers not to breastfeed if they are receiving stavudine. 8.4 pediatric use use of stavudine in pediatric patients from birth through adolescence is supported by evidence from adequate and well-controlled studies of stavudine in adults with additional pharmacokinetic and safety data in pediatric patients [see dosage and administration ( 2.2 ) and adverse reactions ( 6.1 ) ]. adverse reactions and laboratory abnormalities reported to occur in pediatric patients in clinical studies were generally consistent with the safety profile of stavudine in adults. these studies include actg 240, where 105 pediatric 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. stavudine pharmacokinetics have been evaluated in 25 hiv-1-infected pediatric patients ranging in age from 5 weeks to 15 years and in weight from 2 to 43 kg after iv or oral administration of single doses and twice-daily regimens and in 30 hiv-1-exposed or -infected newborns ranging in age from birth to 4 weeks after oral administration of twice-daily regimens [see clinical pharmacology ( 12.3 , table 9) ]. 8.5 geriatric use clinical studies of stavudine did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently than younger patients. greater sensitivity of some older individuals to the effects of stavudine cannot be ruled out. in a monotherapy expanded access program for patients with advanced hiv-1 infection, peripheral neuropathy or peripheral neuropathic symptoms were observed in 15 of 40 (38%) elderly patients receiving 40 mg twice daily and 8 of 51 (16%) elderly patients receiving 20 mg twice daily. of the approximately 12,000 patients enrolled in the expanded access program, peripheral neuropathy or peripheral neuropathic symptoms developed in 30% of patients receiving 40 mg twice daily and 25% of patients receiving 20 mg twice daily. elderly patients should be closely monitored for signs and symptoms of peripheral neuropathy. stavudine is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function. dose adjustment is recommended for patients with renal impairment [see dosage and administration ( 2.3 ) ]. 8.6 renal impairment data from two studies in adults indicated that the apparent oral clearance of stavudine decreased and the terminal elimination half-life increased as creatinine clearance decreased. based on these observations, it is recommended that the stavudine dosage be modified in patients with reduced creatinine clearance and in patients receiving maintenance hemodialysis [see dosage and administration ( 2.3 ) and clinical pharmacology ( 12.3 ) ].

f major birth defects compared with 2.7% in the u.s. reference population of the metropolitan atlanta congenital defects program (macdp). the rate of miscarriage is not reported in the apr. in the u.s. general population, the estimated background risks of miscarriage in clinically recognized pregnancies is 15 to 20%. in animal reproduction studies, no adverse developmental effects were observed with oral administration of stavudine at clinically relevant exposures. no developmental toxicities were observed in rats and rabbits at systemic exposures 112 (auc) and 183 (c max ) times, respectively, the exposures in humans at the recommended human dose (rhd) of stavudine (see data) . clinical considerations maternal adverse reactions cases of lactic acidosis syndrome, sometimes fatal have occurred in pregnant individuals using stavudine in combination with didanosine. stavudine is associated with an increased risk of lactic acidosis syndrome/hepatic steatosis syndrome [ see warnings and precautions ( 5.1 ) ]. data human data based on prospective reports to the apr of live births following exposure to stavudine-containing regimens during pregnancy (including 811 exposed in the first trimester and 196 exposed in the second/third trimester), the prevalence of birth defects in live births for stavudine was 2.6% (95% ci: 1.6 % to 3.9%) with first trimester exposure and 3.1% (95% ci: 1.1% to 6.5%) with second/third trimester exposure compared to the background birth defect rate of 2.7% in the u.s. reference population of the macdp. prospective reports from the apr of overall major birth defects in pregnancies exposed to stavudine is compared with a u.s. background major birth defect rate. methodological limitations of the apr include the use of macdp as the external comparator group. limitations of using an external comparator include differences in methodology and populations, as well as confounding due to the underlying disease. animal data stavudine was administered orally to pregnant rats (0, 50, 250, and 1000 mg/kg/day from gestation day 6 to 17) and rabbits (0, 60, 150, 300 and 600 mg/kg/day from gestation day 6 to 18). in rats, fetal skeletal variations, including increased unossified or incomplete ossification of sternebra, were observed at the highest dose (1000 mg/kg/day) (approximately 488 times human auc exposure at the rhd). in rabbits, there were no developmental effects up to the highest dose of 600 mg/kg (approximately 183 times human cmax exposure at the rhd). in the pre/post-natal development study, stavudine was administered orally to rats at 0, 50, 250, and 1000 mg/kg/day from gestation day 17 to postnatal day 21. post-implantation loss and an increase in early neonatal mortality was observed at 1000 mg/kg/day (approximately 488 times human auc exposure at the rhd). no developmental effects were observed at 250 mg/kg/day (approximately 112 times human auc exposure at the rhd). stavudine was transferred to the fetus through the placenta in rats with concentrations in fetal tissues approximately half the concentration detected in maternal plasma.

ed in 25 hiv-1-infected pediatric patients ranging in age from 5 weeks to 15 years and in weight from 2 to 43 kg after iv or oral administration of single doses and twice-daily regimens and in 30 hiv-1-exposed or -infected newborns ranging in age from birth to 4 weeks after oral administration of twice-daily regimens [see clinical pharmacology ( 12.3 , table 9) ].

a under the curve over 24 hours. c max = maximum plasma concentration. c min = trough or minimum plasma concentration. parameter stavudine 40 mg bid mean ± sd (n=8) auc 0-24 (ng•h/ml) 2568 ± 454 c max (ng/ml) 536 ± 146 c min (ng/ml) 8 ± 9 distribution 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. volume of distribution is shown in table 8. metabolism metabolism plays a limited role in the clearance of stavudine. unchanged stavudine was the major drug-related component circulating in plasma after an 80-mg dose of 14 c-stavudine, while metabolites constituted minor components of the circulating radioactivity. minor metabolites include oxidized stavudine, glucuronide conjugates of stavudine and its oxidized metabolite, and an n- acetylcysteine conjugate of the ribose after glycosidic cleavage, suggesting that thymine is also a metabolite of stavudine. elimination following an 80-mg dose of 14 c-stavudine to healthy subjects, approximately 95% and 3% of the total radioactivity was recovered in urine and feces, respectively. radioactivity due to parent drug in urine and feces was 73.7% and 62.0%, respectively. the mean terminal elimination half-life is approximately 2.3 hours following single oral doses. mean renal clearance of the parent compound is approximately 272 ml/min, accounting for approximately 67% of the apparent oral clearance. in hiv-1-infected patients, renal elimination of unchanged drug accounts for about 40% of the overall clearance regardless of the route of administration (table 8). the mean renal clearance was about twice the average endogenous creatinine clearance, indicating active tubular secretion in addition to glomerular filtration. table 8: pharmacokinetic parameters of stavudine in hiv-1-infected adults:bioavailability, distribution, and clearance a following 1-hour iv infusion. b following single oral dose. c assuming a body weight of 70 kg. d over 12–24 hours parameter mean ± sd n oral bioavailability (%) 86.4 ± 18.2 25 volume of distribution (l) a 46 ± 21 44 total body clearance (ml/min) a 594 ± 164 44 apparent oral clearance (ml/min) b 560 ± 182 c 113 renal clearance (ml/min) a 237 ± 98 39 elimination half-life, iv dose (h) a 1.15 ± 0.35 44 elimination half-life, oral dose (h) b 1.6 ± 0.23 8 urinary recovery of stavudine (% of dose) a , d 42 ± 14 39 special populations pediatric pharmacokinetic parameters of stavudine in pediatric patients are presented in table 9. table 9: pharmacokinetic parameters (mean ± sd) of stavudine in hiv-1-exposed or infected pediatric patients nd = not determined a following 1-hour iv infusion. b at median time of 2.5 hours (range 2–3 hours) following multiple oral doses. c following single oral dose. d over 8 hours parameter ages 5 weeks to 15 years n ages 14 to 28 days n day of birth n oral bioavailability (%) 76.9 ± 31.7 20 nd nd volume of distribution (l/kg) a 0.73 ± 0.32 21 nd nd ratio of csf: plasma concentrations (as %) b 59 ± 35 8 nd nd total body clearance (ml/min/kg) a 9.75 ± 3.76 21 nd nd apparent oral clearance (ml/min/kg) c 13.75 ± 4.29 20 11.52 ± 5.93 30 5.08 ± 2.80 17 elimination half-life, iv dose (h) a 1.11 ± 0.28 21 nd nd elimination half-life , oral dose (h) c 0.96 ± 0.26 20 1.59 ± 0.29 30 5.27 ± 2.01 17 urinary recovery of stavudine (% of dose) c , d 34 ± 16 19 nd nd renal impairment data from two studies in adults indicated that the apparent oral clearance of stavudine decreased and the terminal elimination half-life increased as creatinine clearance decreased (see table 10). c max and t max were not significantly altered by renal impairment. the mean ± sd hemodialysis clearance value of stavudine was 120 ± 18 ml/min (n=12); the mean ± sd percentage of the stavudine dose recovered in the dialysate, timed to occur between 2–6 hours post-dose, was 31 ± 5%. based on these observations, it is recommended that stavudine dosage be modified in patients with reduced creatinine clearance and in patients receiving maintenance hemodialysis [see dosage and administration ( 2.3 ) ]. table 10: mean ± sd pharmacokinetic parameter values of stavudine a in adults with varying degrees of renal function t ½ = terminal elimination half-life. na = not applicable. a single 40-mg oral dose. b determined while patients were off dialysis creatinine clearance >50 ml/min (n=10) 26–50 ml/min (n=5) 9–25 ml/min (n=5) hemodialysis patients b (n=11) creatinine clearance (ml/min) 104 ± 28 41 ± 5 17 ± 3 na apparent oral clearance (ml/min) 335 ± 57 191 ± 39 116 ± 25 105 ± 17 renal clearance (ml/min) 167 ± 65 73 ± 18 17 ± 3 na t ½ (h) 1.7 ± 0.4 3.5 ± 2.5 4.6 ± 0.9 5.4 ± 1.4 hepatic impairment stavudine pharmacokinetics were not altered in five non-hiv-infected patients with hepatic impairment secondary to cirrhosis (child-pugh classification b or c) following the administration of a single 40-mg dose. geriatric stavudine pharmacokinetics have not been studied in patients >65 years of age. [see use in specific populations ( 8.5 )] gender a population pharmacokinetic analysis of data collected during a controlled clinical study in hiv-1-infected patients showed no clinically important differences between males (n=291) and females (n=27). race a population pharmacokinetic analysis of data collected during a controlled clinical study in hiv-1-infected patients showed no clinically important differences between races (n=233 caucasian, 39 african-american, 41 hispanic, 1 asian, and 4 other). drug interaction studies 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 drugs metabolized through these pathways. because stavudine is not protein-bound, it is not expected to affect the pharmacokinetics of protein-bound drugs. tables 11 and 12 summarize the effects on auc and c max , with a 95% confidence interval (ci) when available, following coadministration of stavudine with didanosine, lamivudine, and nelfinavir. no clinically significant pharmacokinetic interactions were observed. table 11: results of drug interaction studies with stavudine: effects of coadministered drug on stavudine plasma auc and c max values ↑ indicates increase. ↔ indicates no change, or mean increase or decrease of <10%. a hiv-1-infected patients drug stavudine dosage n a auc of stavudine (95% ci) c max of stavudine (95% ci) didanosine, 100 mg q12h for 4 days 40 mg q12h for 4 days 10 ↔ ↑ 17% lamivudine, 150 mg single dose 40 mg single dose 18 ↔ (92.7–100.6%) ↑ 12% (100.3–126.1%) nelfinavir, 750 mg q8h for 56 days 30–40 mg q12h for 56 days 8 ↔ ↔ table 12: results of drug interaction studies with stavudine: effects of stavudine on coadministered drug plasma auc and c max values ↔ indicates no change, or mean increase or decrease of <10%. a hiv-1-infected patients. drug stavudine dosage n a auc of coadministered drug (95% ci) c max of coadministered drug (95% ci) didanosine, 100 mg q12h for 4 days 40 mg q12h for 4 days 10 ↔ ↔ lamivudine, 150 mg single dose 40 mg single dose 18 ↔ (90.5–107.6%) ↔ (87.1–110.6%) nelfinavir, 750 mg q8h for 56 days 30–40 mg q12h for 56 days 8 ↔ ↔ 12.4 microbiology mechanism of action stavudine, a nucleoside analogue of thymidine, is phosphorylated by cellular kinases to the active metabolite stavudine triphosphate. stavudine triphosphate inhibits the activity of hiv-1 reverse transcriptase (rt) by competing with the natural substrate thymidine triphosphate (k i =0.0083 to 0.032 μm) and by causing dna chain termination following its incorporation into viral dna. stavudine triphosphate inhibits cellular dna polymerases β and γ and markedly reduces the synthesis of mitochondrial dna. antiviral activity in cell culture the cell culture antiviral activity of stavudine was measured in peripheral blood mononuclear cells, monocytic cells, and lymphoblastoid cell lines. the concentration of drug necessary to inhibit hiv-1 replication by 50% (ec 50 ) ranged from 0.009 to 4 μm against laboratory and clinical isolates of hiv-1. in cell culture, stavudine exhibited antagonistic activity in combination with zidovudine. the anti-hiv-1 activity of stavudine in combination with either abacavir, didanosine, tenofovir, or zalcitabine was not antagonistic. ribavirin, at the 9–45 μm concentrations tested, reduced the anti-hiv-1 activity of stavudine by 2.5- to 5-fold. the relationship between cell culture susceptibility of hiv-1 to stavudine and the inhibition of hiv-1 replication in humans has not been established. resistance hiv-1 isolates with reduced susceptibility to stavudine have been selected in cell culture (strain-specific) and were also obtained from patients treated with stavudine. phenotypic analysis of hiv-1 isolates from 61 patients receiving prolonged (6–29 months) stavudine monotherapy showed that post-therapy isolates from four patients exhibited ec 50 values more than 4-fold (range 7- to 16-fold) higher than the average pretreatment susceptibility of baseline isolates. of these, hiv-1 isolates from one patient contained the zidovudine-resistance-associated substitutions t215y and k219e, and isolates from another patient contained the multiple-nucleoside-resistance-associated substitution q151m. mutations in the rt gene of hiv-1 isolates from the other two patients were not detected. the genetic basis for stavudine susceptibility changes has not been identified. cross-resistance cross-resistance among hiv-1 reverse transcriptase inhibitors has been observed. several studies have demonstrated that prolonged stavudine treatment can select and/or maintain thymidine analogue mutation (tams) substitutions in the hiv-1 rt (m41l, d67n, k70r, l210w, t215y/f, k219q/e) associated with zidovudine resistance. hiv-1 isolates with one or more tams substitutions exhibited reduced susceptibility to stavudine in cell culture. these tams substitutions are seen at a similar frequency with stavudine and zidovudine in virological treatment. the clinical relevance of these findings suggests that stavudine should be avoided in the presence of thymidine analogue mutation substitutions.

. parameter stavudine 40 mg bid mean ± sd (n=8) auc 0-24 (ng•h/ml) 2568 ± 454 c max (ng/ml) 536 ± 146 c min (ng/ml) 8 ± 9 distribution 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. volume of distribution is shown in table 8. metabolism metabolism plays a limited role in the clearance of stavudine. unchanged stavudine was the major drug-related component circulating in plasma after an 80-mg dose of 14 c-stavudine, while metabolites constituted minor components of the circulating radioactivity. minor metabolites include oxidized stavudine, glucuronide conjugates of stavudine and its oxidized metabolite, and an n- acetylcysteine conjugate of the ribose after glycosidic cleavage, suggesting that thymine is also a metabolite of stavudine. elimination following an 80-mg dose of 14 c-stavudine to healthy subjects, approximately 95% and 3% of the total radioactivity was recovered in urine and feces, respectively. radioactivity due to parent drug in urine and feces was 73.7% and 62.0%, respectively. the mean terminal elimination half-life is approximately 2.3 hours following single oral doses. mean renal clearance of the parent compound is approximately 272 ml/min, accounting for approximately 67% of the apparent oral clearance. in hiv-1-infected patients, renal elimination of unchanged drug accounts for about 40% of the overall clearance regardless of the route of administration (table 8). the mean renal clearance was about twice the average endogenous creatinine clearance, indicating active tubular secretion in addition to glomerular filtration. table 8: pharmacokinetic parameters of stavudine in hiv-1-infected adults:bioavailability, distribution, and clearance a following 1-hour iv infusion. b following single oral dose. c assuming a body weight of 70 kg. d over 12–24 hours parameter mean ± sd n oral bioavailability (%) 86.4 ± 18.2 25 volume of distribution (l) a 46 ± 21 44 total body clearance (ml/min) a 594 ± 164 44 apparent oral clearance (ml/min) b 560 ± 182 c 113 renal clearance (ml/min) a 237 ± 98 39 elimination half-life, iv dose (h) a 1.15 ± 0.35 44 elimination half-life, oral dose (h) b 1.6 ± 0.23 8 urinary recovery of stavudine (% of dose) a , d 42 ± 14 39 special populations pediatric pharmacokinetic parameters of stavudine in pediatric patients are presented in table 9. table 9: pharmacokinetic parameters (mean ± sd) of stavudine in hiv-1-exposed or infected pediatric patients nd = not determined a following 1-hour iv infusion. b at median time of 2.5 hours (range 2–3 hours) following multiple oral doses. c following single oral dose. d over 8 hours parameter ages 5 weeks to 15 years n ages 14 to 28 days n day of birth n oral bioavailability (%) 76.9 ± 31.7 20 nd nd volume of distribution (l/kg) a 0.73 ± 0.32 21 nd nd ratio of csf: plasma concentrations (as %) b 59 ± 35 8 nd nd total body clearance (ml/min/kg) a 9.75 ± 3.76 21 nd nd apparent oral clearance (ml/min/kg) c 13.75 ± 4.29 20 11.52 ± 5.93 30 5.08 ± 2.80 17 elimination half-life, iv dose (h) a 1.11 ± 0.28 21 nd nd elimination half-life , oral dose (h) c 0.96 ± 0.26 20 1.59 ± 0.29 30 5.27 ± 2.01 17 urinary recovery of stavudine (% of dose) c , d 34 ± 16 19 nd nd renal impairment data from two studies in adults indicated that the apparent oral clearance of stavudine decreased and the terminal elimination half-life increased as creatinine clearance decreased (see table 10). c max and t max were not significantly altered by renal impairment. the mean ± sd hemodialysis clearance value of stavudine was 120 ± 18 ml/min (n=12); the mean ± sd percentage of the stavudine dose recovered in the dialysate, timed to occur between 2–6 hours post-dose, was 31 ± 5%. based on these observations, it is recommended that stavudine dosage be modified in patients with reduced creatinine clearance and in patients receiving maintenance hemodialysis [see dosage and administration ( 2.3 ) ]. table 10: mean ± sd pharmacokinetic parameter values of stavudine a in adults with varying degrees of renal function t ½ = terminal elimination half-life. na = not applicable. a single 40-mg oral dose. b determined while patients were off dialysis creatinine clearance >50 ml/min (n=10) 26–50 ml/min (n=5) 9–25 ml/min (n=5) hemodialysis patients b (n=11) creatinine clearance (ml/min) 104 ± 28 41 ± 5 17 ± 3 na apparent oral clearance (ml/min) 335 ± 57 191 ± 39 116 ± 25 105 ± 17 renal clearance (ml/min) 167 ± 65 73 ± 18 17 ± 3 na t ½ (h) 1.7 ± 0.4 3.5 ± 2.5 4.6 ± 0.9 5.4 ± 1.4 hepatic impairment stavudine pharmacokinetics were not altered in five non-hiv-infected patients with hepatic impairment secondary to cirrhosis (child-pugh classification b or c) following the administration of a single 40-mg dose. geriatric stavudine pharmacokinetics have not been studied in patients >65 years of age. [see use in specific populations ( 8.5 )] gender a population pharmacokinetic analysis of data collected during a controlled clinical study in hiv-1-infected patients showed no clinically important differences between males (n=291) and females (n=27). race a population pharmacokinetic analysis of data collected during a controlled clinical study in hiv-1-infected patients showed no clinically important differences between races (n=233 caucasian, 39 african-american, 41 hispanic, 1 asian, and 4 other). drug interaction studies 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 drugs metabolized through these pathways. because stavudine is not protein-bound, it is not expected to affect the pharmacokinetics of protein-bound drugs. tables 11 and 12 summarize the effects on auc and c max , with a 95% confidence interval (ci) when available, following coadministration of stavudine with didanosine, lamivudine, and nelfinavir. no clinically significant pharmacokinetic interactions were observed. table 11: results of drug interaction studies with stavudine: effects of coadministered drug on stavudine plasma auc and c max values ↑ indicates increase. ↔ indicates no change, or mean increase or decrease of <10%. a hiv-1-infected patients drug stavudine dosage n a auc of stavudine (95% ci) c max of stavudine (95% ci) didanosine, 100 mg q12h for 4 days 40 mg q12h for 4 days 10 ↔ ↑ 17% lamivudine, 150 mg single dose 40 mg single dose 18 ↔ (92.7–100.6%) ↑ 12% (100.3–126.1%) nelfinavir, 750 mg q8h for 56 days 30–40 mg q12h for 56 days 8 ↔ ↔ table 12: results of drug interaction studies with stavudine: effects of stavudine on coadministered drug plasma auc and c max values ↔ indicates no change, or mean increase or decrease of <10%. a hiv-1-infected patients. drug stavudine dosage n a auc of coadministered drug (95% ci) c max of coadministered drug (95% ci) didanosine, 100 mg q12h for 4 days 40 mg q12h for 4 days 10 ↔ ↔ lamivudine, 150 mg single dose 40 mg single dose 18 ↔ (90.5–107.6%) ↔ (87.1–110.6%) nelfinavir, 750 mg q8h for 56 days 30–40 mg q12h for 56 days 8 ↔ ↔

increased the frequency of transformed foci in mouse fibroblast cells (concentrations of 25 to 2500 μg/ml, with and without metabolic activation). in the in vivo micronucleus assay, stavudine was clastogenic in bone marrow cells following oral stavudine administration to mice at dosages of 600 to 2000 mg/kg/day for 3 days. no evidence of impaired fertility was seen in rats with exposures (based on auc) up to 137 times human exposure at the rhd.

stration of stavudine with hydroxyurea [ see warnings and precautions ( 5.2 ) and drug interactions ( 7 ) ]. peripheral neuropathy inform patients that an important toxicity of stavudine is peripheral neuropathy. make patients aware that peripheral neuropathy is manifested by numbness, tingling, or pain in hands or feet, and that these symptoms should be reported to their physicians. counsel patients that peripheral neuropathy occurs with greatest frequency in patients who have advanced hiv-1 disease or a history of peripheral neuropathy, and discontinuation of stavudine may be required if toxicity develops. instruct caregivers of young children receiving stavudine therapy regarding detection and reporting of peripheral neuropathy [ see warnings and precautions ( 5.3 ) ]. pancreatitis inform patients that an increased risk of pancreatitis, which may be fatal, may occur in patients treated with the combination of stavudine and didanosine. stavudine is contraindicated in combination with didanosine [ see contraindications ( 4 ) ]. closely monitor patients for symptoms of pancreatitis such as severe abdominal pain, nausea and vomiting, and fever. instruct patients to avoid alcohol while taking stavudine. alcohol may increase the patient's risk of pancreatitis or liver damage [ see warnings and precautions ( 5.4 ) ]. lipoatrophy inform patients that loss of body fat (e.g., loss of fat from arms, legs, or face) may occur in individuals receiving stavudine. monitor patients receiving stavudine for clinical signs and symptoms of lipoatrophy. patients should be questioned routinely about body changes related to lipoatrophy [ see warnings and precautions ( 5.5 ) ]. pregnancy registry inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes of pregnant individuals exposed to stavudine [ see use in specific populations ( 8.1 ) ]. lactation advise mothers with hiv-1 not to breastfeed because hiv-1 can be passed to the baby in breast milk [ see use in specific populations ( 8.2 ) ]. dosing information instruct patients not to miss a dose but if they do, patients should take stavudine as soon as possible. inform patients that it is important to take stavudine on a regular dosing schedule and to avoid missing doses as it can result in development of resistance. patients should be instructed if they take too much stavudine, they should contact a poison control center or emergency room right away. pharmacists: detach and dispense the enclosed medication guide to each patient. manufactured by cipla ltd. verna, goa 403 722 india revised: january 2019