Stavudine Information
Stavudine () . Dosage And Administration
Renal Impairment
Adult Patients:
Pediatric Patients:
Stavudine () . Warnings And Precautions
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 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.
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 () . This combination should be avoided. [See
Use with Interferon and Ribavirin-Based Regimens
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, including didanosine [see
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.
Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy.
In randomized controlled trials of treatment-naive patients, clinical lipoatrophy or lipodystrophy 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 or lipodystrophy 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 or lipodystrophy and questioned about body changes related to lipoatrophy or lipodystrophy. Given the potential risks of using Stavudine () including lipoatrophy or lipodystrophy, a benefit-risk assessment for each patient should be made and an alternative antiretroviral should be considered
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 infection, cytomegalovirus, 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.
Stavudine () . Adverse Reactions
The following adverse reactions are discussed in greater detail in other sections of the labeling:
When Stavudine () is used in combination with other agents with similar toxicities, the incidence of adverse reactions may be higher than when Stavudine () is used alone.
Because clinical 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.
Selected adverse reactions that occurred in adult patients receiving Stavudine () in a controlled monotherapy study (Study AI455-019) are provided in Table 2.
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.
Selected laboratory abnormalities reported in a controlled monotherapy study (Study AI455-019) are provided in Table 4.
Selected laboratory abnormalities reported in two controlled combination studies are provided in Tables 5 and 6.
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.
Digestive Disorders:
Hematologic Disorders:
Musculoskeletal:
Use with Didanosine- and Hydroxyurea-Based Regimens
When Stavudine () is used in combination with other agents with similar toxicities, the incidence of these toxicities may be higher than when Stavudine () is used alone. Thus, patients treated with Stavudine () in combination with didanosine, with or without hydroxyurea, may be at increased risk for pancreatitis and hepatotoxicity, which may be fatal, and severe peripheral neuropathy [see The combination of Stavudine () and hydroxyurea, with or without didanosine, should be avoided.
Stavudine () . Use In Specific Populations
Pregnancy Category C
Reproduction studies have been performed in rats and rabbits with exposures (based on C) up to 399 and 183 times, respectively, of that seen at a clinical dosage of 1 mg/kg/day and have revealed no evidence of teratogenicity. The incidence in fetuses of a common skeletal variation, unossified or incomplete ossification of sternebra, was increased in rats at 399 times human exposure, while no effect was observed at 216 times human exposure. A slight post-implantation loss was noted at 216 times the human exposure with no effect noted at approximately 135 times the human exposure. An increase in early rat neonatal mortality (birth to 4 days of age) occurred at 399 times the human exposure, while survival of neonates was unaffected at approximately 135 times the human exposure. A study in rats showed that Stavudine () is transferred to the fetus through the placenta. The concentration in fetal tissue was approximately one-half the concentration in maternal plasma. Animal reproduction studies are not always predictive of human response.
There are no adequate and well-controlled studies of Stavudine () in pregnant women. Stavudine () should be used during pregnancy only if the potential benefit justifies the potential risk.
Fatal lactic acidosis has been reported in pregnant women who received the combination of Stavudine () and didanosine with other antiretroviral agents. It is unclear if pregnancy augments the risk of lactic acidosis/hepatic steatosis syndrome reported in nonpregnant individuals receiving nucleoside analogues [see and
Healthcare providers caring for HIV-infected pregnant women receiving Stavudine () should be alert for early diagnosis of lactic acidosis/hepatic steatosis syndrome.
Antiretroviral Pregnancy Registry:
ID958
The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV.
mothers should be instructed not to breastfeed if they are receiving Stavudine ()
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 and
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 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
Stavudine () . Overdosage
Experience with adults treated with 12 to 24 times the recommended daily dosage revealed no acute toxicity. Complications of chronic overdosage include peripheral neuropathy and hepatic toxicity. Stavudine () can be removed by hemodialysis; the mean ± SD hemodialysis clearance of Stavudine () is 120 ± 18 mL/min. Whether Stavudine () is eliminated by peritoneal dialysis has not been studied.
Stavudine () . Description
Stavudine () (d4T) is a synthetic thymidine nucleoside analogue, active against the human immunodeficiency virus type 1 (HIV-1). The chemical name for Stavudine () is 2′,3′-didehydro-3′-deoxythymidine. Stavudine () has the following structural formula:
Stavudine () is a white to off-white crystalline solid with the molecular formula CHNO and a molecular weight of 224.2. The solubility of Stavudine () at 23°C is approximately 83 mg/mL in water and 30 mg/mL in propylene glycol. The n-octanol/water partition coefficient of Stavudine () at 23°C is 0.144.
Powder for Oral Solution: Stavudine () is available as a dye-free, fruit-flavored powder in bottles with child-resistant closures providing 200 mL of a 1 mg/mL Stavudine () oral solution upon constitution with water per label instructions. The powder for oral solution contains the following inactive ingredients: methyparaben, propylparaben, mannitol, carboxymethyl cellulose sodium, sodium saccharin and strawberry cream flavour.
Stavudine () . Clinical Pharmacology
The pharmacokinetics of Stavudine () have been evaluated in HIV-1-infected adult and pediatric patients (Tables 7, 8, and 9). Peak plasma concentrations (C) and area under the plasma concentration-time curve (AUC) increased in proportion to dose after both single and multiple doses ranging from 0.03 to 4 mg/kg. There was no significant accumulation of Stavudine () with repeated administration every 6, 8, or 12 hours.
Absorption
Following oral administration, Stavudine () is rapidly absorbed, with peak plasma concentrations occurring within 1 hour after dosing. The systemic exposure to Stavudine () is the same following administration as capsules or solution. Steady-state pharmacokinetic parameters of Stavudine () in HIV-1-infected adults are shown in Table 7.
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 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 acetylcysteine conjugate of the ribose after glycosidic cleavage, suggesting that thymine is also a metabolite of Stavudine () .
Elimination
Following an 80-mg dose of 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.
Special Populations
Pediatric
Pharmacokinetic parameters of Stavudine () in pediatric patients are presented in Table 9.
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 and T 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
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
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, with a 95% confidence interval (CI) when available, following coadministration of Stavudine () with didanosine, lamivudine, and nelfinavir. No clinically significant pharmacokinetic interactions were observed.
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=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) ranged from 0.009 to 4 μM against laboratory and clinical isolates of HIV-1. In cell culture, Stavudine () exhibited additive to antagonistic activity in combination with zidovudine. Stavudine () in combination with either abacavir, didanosine, tenofovir, or zalcitabine exhibited additive to synergistic anti-HIV-1 activity. 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 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 mutations (TAMs; M41L, D67N, K70R, L210W, T215Y/F, K219Q/E) associated with zidovudine resistance. HIV-1 isolates with one or more TAMs exhibited reduced susceptibility to Stavudine () in cell culture. These TAMs 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 mutations.
Stavudine () . Clinical Studies
The combination use of Stavudine () is based on the results of clinical studies in HIV-1-infected patients in double- and triple-combination regimens with other antiretroviral agents.
One of these studies (START 1) was a multicenter, randomized, open-label study comparing Stavudine () (40 mg twice daily) plus lamivudine plus indinavir to zidovudine plus lamivudine plus indinavir in 202 treatment-naive patients. Both regimens resulted in a similar magnitude of inhibition of HIV-1 RNA levels and increases in CD4 cell counts through 48 weeks.
The efficacy of Stavudine () was demonstrated in a randomized, double-blind study (AI455-019, conducted 1992-1994) comparing Stavudine () with zidovudine in 822 patients with a spectrum of HIV-1-related symptoms. The outcome in terms of progression of HIV-1 disease and death was similar for both drugs.
Stavudine () . Patient Counseling Information
See MEDICATION GUIDE.
Patients should be advised that Stavudine () is not a cure for HIV-1 infection, and that they may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients should be advised to remain under the care of a physician when using Stavudine () and the importance of adherence to any antiretroviral regimen including those that contain Stavudine () .
Patients should be advised to avoid doing things that can spread HIV-1 infection to others
Patients should be informed that when Stavudine () is used in combination with other agents with similar toxicities, the incidence of adverse reactions may be higher than when Stavudine () is used alone.
Patients should be instructed that if they miss a dose, to take it as soon as possible. If it is almost time for the next dose, skip the missed dose and continue the regular dosing schedule.
Patients should be instructed if they take too much Stavudine () , they should contact a poison control center or emergency room right away.
Patients should be informed that the Centers for Disease Control and Prevention (CDC) recommend that HIV-infected mothers not nurse newborn infants to reduce the risk of postnatal transmission of HIV infection.
Patients should be informed that an important toxicity of Stavudine () is peripheral neuropathy. Patients should be 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. Patients should be counseled 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.
Caregivers of young children receiving Stavudine () therapy should be instructed regarding detection and reporting of peripheral neuropathy.
Patients should be informed that an increased risk of pancreatitis, which may be fatal, may occur in patients treated with the combination of Stavudine () and didanosine. This combination should be avoided. Patients should be closely monitored for symptoms of pancreatitis.
The patient should be instructed to avoid alcohol while taking Stavudine () . Alcohol may increase the patient’s risk of pancreatitis or liver damage.
Stavudine ()
Stavudine ()
