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Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (NRTI)s
Cases of fatal and nonfatal pancreatitis have occurred in treatment-naive and treatment-experienced patients treated with antiretroviral regimens that included both stavudine and didanosine, regardless of the degree of immunosuppression. Due to the increased risk for toxicity, concurrent treatment with stavudine and didanosine is contraindicated. If pancreatitis is suspected, treatment with stavudine and any other mediation that may be toxic to the pancreas should be suspended. Reinstitution of stavudine after a confirmed diagnosis of pancreatitis should be undertaken with particular caution and close monitoring.
Stavudine should be used with caution in patients with known risk factors for hepatic disease. Hepatotoxicity or lactic acidosis, including fatal cases, have been reported with the use of stavudine. Although relative rates of lactic acidosis have not been assessed in prospective well-controlled trials, cohort and longitudinal studies suggest that this infrequent adverse event may be more often associated with antiretroviral regimens containing stavudine. A majority of these cases occurred in females. It is unknown if pregnant women are at increased risk; however, fatal cases of lactic acidosis, two with and one without pancreatitis, have occurred in women who were either pregnant or postpartum and whose antiretroviral therapy during gestation included stavudine and didanosine. Two of the infants of these women died. Clinicians need to be alert for early diagnosis of this syndrome. Pregnant women receiving nucleoside analogs should have LFTs and serum electrolytes assessed more frequently during the last trimester and any new symptoms should be evaluated thoroughly. Alcoholism, obesity, and prolonged exposure to nucleosides may also be risk factors for hepatotoxicity. However, hepatotoxicity has been reported in patients with no risk factors. In addition, deaths attributed to hepatotoxicity have occurred in patients receiving the combination of stavudine, didanosine, and hydroxyurea. Due to increased risk for toxicity, concurrent treatment of stavudine and didanosine is contraindicated, and use of stavudine and hydroxyurea should be avoided. Patients should be closely monitored for signs of liver toxicity during stavudine therapy. Treatment with stavudine should be discontinued in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity, which may include hepatomegaly and steatosis even in the absence of marked elevation of hepatic enzymes. Permanent discontinuation of stavudine should be consider for patients with confirmed lactic acidosis.
Nucleoside reverse transcriptase inhibitor (NRTI)Used for treatment of HIV infection in combination with other antiretroviral agentsAssociated with higher incidence of lactic acidosis with hepatic steatosis than other NRTIs
Stavudine/Zerit Oral Cap: 15mg, 20mg, 30mg, 40mgStavudine/Zerit Oral Pwd F/Recon: 1mg, 1mL
40 mg PO every 12 hours is the FDA-approved dosage and recommended by HIV guidelines. 30 mg PO every 12 hours is recommended by WHO guidelines.
30 mg PO every 12 hours.
40 mg PO every 12 hours is the FDA-approved dosage and recommended by HIV guidelines. 30 mg PO every 12 hours is recommended by WHO guidelines.
30 mg PO every 12 hours.
1 mg/kg/dose PO every 12 hours.
0.5 mg/kg/dose PO every 12 hours.
Greater than to equal to 60 kg: 80 mg/day PO.Less than 60 kg: 60 mg/day PO.
Greater than or equal to 60 kg: 80 mg/day PO.Less than 60 kg: 60 mg/day PO.
Greater than or equal to 60 kg: 80 mg/day PO.30 kg to less than 60 kg: 60 mg/day PO.Less than 30 kg: 2 mg/kg/day PO.
2 mg/kg/day PO oral solution.
Greater than or equal to 14 days: 2 mg/kg/day PO oral solution.Less than 14 days: 1 mg/kg/day PO oral solution.
No dosage adjustment is required.
FDA-approved recommendations in adults: CrCl greater than 50 mL/min: No dosage adjustment needed.CrCl 26 to 50 mL/min: Reduce recommended dose by 50% and give every 12 hours.CrCl 10 to 25 mL/min: Reduce recommended dose by 50% and extend dosing interval to every 24 hours. Other recommendations in adults: GFR greater than 50 mL/min: No dosage adjustment needed.GFR 10 to 50 mL/min: Reduce recommended dose by 50% and give every 12 to 24 hours.GFR less than 10 mL/min: Reduce recommended dose by 50% and give every 24 hours. Dosing recommendations in pediatric patients:GFR greater than 50 mL/min/1.73m2: No dosage adjustment needed.GFR 30 to 50 mL/min/1.73m2: Reduce recommended dose by 50% and give every 12 hours.GFR less than or equal to 29 mL/min/1.73m2: Reduce recommended dose by 75% and give every 24 hours. Intermittent hemodialysisFor adult patients, reduce recommended dose by 50% and give every 24 hours, administering after the completion of hemodialysis on dialysis days. For pediatric patients, reduce the recommended dose by 75% and give every 24 hours and administer after dialysis on dialysis days. Peritoneal dialysisNo data are available in adult patients. For pediatric patients, reduce the recommended dose by 75% and give every 24 hours. Continuos renal replacement therapy (CRRT)No dosage adjustment needed in adult patients. For pediatric patients, reduce the recommended dose by 50% and give every 12 hours.
May be administered without regard to meals.
Shake well prior to each administration. Measure dosage with the manufacturer provided measuring cup. Reconstitution:Review the manufacturer’s reconstitution instructions for the particular product and package size; the amount of water to be used for reconstitution may vary between manufacturers.Add purified water and shake vigorously until powder dissolves completely; the solution may appear slightly hazy.Storage: Store reconstituted solution in the refrigerator; discard any unused portion after 30 days.
Zerit:- Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
Unplanned stavudine therapy interruption may be necessary in specific situations, such as serious drug toxicity, intercurrent illness or surgery precluding oral intake (e.g., gastroenteritis), severe hyperemesis gravidarum unresponsive to antiemetics, or drug non-availability. If short-term treatment interruption (i.e., < 1—2 days) is necessary, in general it is recommended that all antiretroviral agents be discontinued simultaneously, especially if the interruption is because of serious toxicity. However, if a short-term treatment interruption is anticipated in the case of elective surgery, the pharmacokinetic properties and food requirements of specific drugs should be considered. When the antiretroviral regimen contains drugs with differing half-lives, stopping all drugs simultaneously may result in functional monotherapy of the drug with the longest half-life. For example, after discontinuation, the duration of detectable drug concentrations of efavirenz and nevirapine range from < 1 week to > 3 weeks. Simultaneously stopping all drugs in a regimen containing these agents may result in functional monotherapy with the NNRTI and may increase the risk of NNRTI-resistant mutations. Planned long-term treatment interruptions are not recommended due to the potential for HIV disease progression (i.e., declining CD4 counts, viral rebound, acute viral syndrome), development of minor HIV-associated manifestations or serious non-AIDS complications, development of drug resistance, increased risk of HIV transmission, and increased risk for opportunistic infections. If therapy must be discontinued, counsel patient on the potential risks and closely monitor for any clinical or laboratory abnormalities.
Perform hepatitis B virus (HBV) screening in any patient who presents with HIV infection to assure appropriate treatment. Patients with hepatitis B and HIV coinfection should be started on a fully suppressive antiretroviral (ARV) regimen with activity against both viruses (regardless of CD4 counts and HBV DNA concentrations). HIV treatment guidelines recommend these patients receive an ARV regimen that contains a dual NRTI backbone of tenofovir alafenamide with emtricitabine or tenofovir disoproxil fumarate with either lamivudine or emtricitabine. If tenofovir cannot be used, entecavir should be used in combination with a fully suppressive ARV regimen (note: entecavir should not be considered part of the ARV regimen). Avoid using single-drug therapy to treat HBV (i.e., lamivudine, emtricitabine, tenofovir, or entecavir as the only active agent) as this may result in HIV resistant strains. Further, HBV treatment regimens that include adefovir or telbivudine should also be avoided, as these regimens are associated with a higher incidence of toxicities and increased rates of HBV treatment failure. Most coinfected patients should continue treatment indefinitely with the goal of maximal HIV suppression and prevention of HBV relapse. If treatment must be discontinued, monitor transaminase concentrations every 6 weeks for the first 3 months, and every 3 to 6 months thereafter. For patients who refuse a fully suppressive ARV regimen, but still requires treatment for HBV, consider 48 weeks of peginterferon alfa; do not administer HIV-active medications in the absence of a fully suppressive ARV regimen. Instruct coinfected patients to avoid consuming alcohol, and offer vaccinations against hepatitis A and hepatitis B as appropriate. 
Patients with preexisting peripheral neuropathy should receive stavudine cautiously as it may exacerbate symptoms. Patients with advanced HIV disease or who are receiving concurrent neurotoxic agents are at increased risk. In an expanded access program, geriatric patients had a higher incidence of peripheral neuropathy than younger patients. Caregivers of infants or young children should be counseled regarding detection of peripheral neuropathies. Motor weakness has been reported rarely in patients receiving combination antiretroviral therapy including stavudine. Most of these occurred in the setting of lactic acidosis. The evolution of motor weakness may mimic the clinical presentation of neuromuscular disease, such as Guillain-Barre syndrome (including respiratory failure). Symptoms may continue or worsen following discontinuation of therapy.
Stavudine's renal clearance is considerably prolonged in patients with renal impairment. Dosage adjustments are required in patients with a creatinine clearance <= 50 ml/min and in patients with renal failure or receiving dialysis.
Antiretroviral therapy should be provided to all women during pregnancy, regardless of HIV RNA concentrations or CD4 cell count; however due to toxicity risk, guidelines recommend against the use of stavudine-containing treatment regimens in pregnant women. Using highly active antiretroviral combination therapy (HAART) to maximally suppress viral replication is the most effective strategy to prevent the development of resistance and to minimize the risk of perinatal transmission. In treatment-naive women, begin HAART as soon as pregnancy is recognized or HIV is diagnosed, without waiting for the results of resistance testing; subsequent modifications to the treatment regimen should be made once the test results are available. Women who are currently receiving antiretroviral treatment when pregnancy is recognized should continue their treatment regimen if it is currently effective in suppressing viral replication; consider resistance testing if HIV RNA concentrations more than 500 copies/mL. For women not currently receiving HAART, but who have previously received treatment, obtain a complete and accurate history of all prior antiretroviral regimens used and results of prior resistance testing, and perform resistance testing if HIV RNA concentrations more than 500 copies/mL; treatment should be initiated prior to receiving resistance test results. Available data from the Antiretroviral Pregnancy Registry, which includes 1st trimester exposures to stavudine (more than 800 exposures), have shown no difference in the risk of overall major birth defects when compared to the 2.7% background rate among pregnant women in the US. When stavudine exposure occurred in the 1st trimester, prevalence of defects was 2.6% (21 of 811 births; 95% CI: 1.6, 3.9). Nucleoside reverse transcriptase inhibitors (NRTIs) are known to induce mitochondrial dysfunction. An association of mitochondrial dysfunction in infants and in utero antiretroviral exposure has been suggested, but not established. While the development of severe or fatal mitochondrial disease in exposed infants appears to be extremely rare, more intensive monitoring of hematologic and electrolyte parameters during the first few weeks of life is advised. Nucleoside analogs have been associated with the development of lactic acidosis, especially during pregnancy. It is unclear if pregnancy augments the incidence of lactic acidosis/hepatic steatosis in patients receiving nucleoside analogs. However, because pregnancy itself can mimic some of the early symptoms of the lactic acid/hepatic steatosis syndrome or be associated with other significant disorders of liver metabolism, clinicians need to be alert for early diagnosis of this syndrome. Pregnant women receiving nucleoside analogs should have LFTs and serum electrolytes assessed more frequently during the last trimester of pregnancy and any new symptoms should be evaluated thoroughly. Cases of lactic acidosis, some fatal, have been reported in pregnant women receiving didanosine and stavudine together; concurrent use of these antiretroviral agents is contraindicated. Regular laboratory monitoring is recommended to determine antiretroviral efficacy. Monitor CD4 counts at the initial visit and at least every 3 months during pregnancy; consideration may be given to monitoring every 6 months in patients on HAART with consistently suppressed viral loads and a CD4 count well above the opportunistic infection threshold. Monitor plasma HIV RNA at the initial visit, 2 to 4 weeks after initiating or changing therapy, monthly until undetectable, then at least every 3 months during pregnancy, and at 34 to 36 weeks gestation. Perform antiretroviral resistance assay (genotypic testing) at baseline in all women with HIV RNA concentrations greater than 500 copies/mL, unless they have already been tested for resistance. First trimester ultrasound is recommended to confirm gestational age and provide accurate estimation of gestational age at deliver. A second trimester ultrasound can be used for both anatomical survey and determination of gestational age in those patients not seen until later in gestation. Perform standard glucose screening in women receiving antiretroviral therapy at 24 to 28 weeks gestation, although it should be noted that some experts would perform earlier screening with ongoing chronic protease inhibitor-based therapy initiated prior to pregnancy, similar to recommendations for women with high-risk factors for glucose intolerance. All pregnant women should be counseled about the importance of adherence to their antiretroviral regimen to reduce the potential for development of resistance and perinatal transmission. It is strongly recommended that antiretroviral therapy, once initiated, not be discontinued. If a woman decides to discontinue therapy, a consultation with a HIV specialist is recommended. It is strongly recommended that health care providers report cases of antenatal antiretroviral drug exposure to the Antiretroviral Pregnancy Registry; telephone 800-258-4263; fax 800-800-1052; the Antiretroviral Pregnancy Registry is also accessible via the Internet.
To reduce the risk of postnatal transmission, HIV-infected mothers within the United States are advised by the Centers for Disease Control and Prevention to avoid breast-feeding. This recommendation applies to both untreated women and women who are receiving antiretroviral therapy, including stavudine. Stavudine is excreted in human breast milk; the ratio of drug concentrations in breast milk to those found in maternal plasma is 1 to 1.76. Other antiretroviral medications whose passage into human breast milk have been evaluated include nevirapine, zidovudine, lamivudine, and nelfinavir.
Testing for human immunodeficiency virus (HIV) infection resistance is recommended in all antiretroviral treatment-naive patients at the time of HIV diagnosis, regardless of whether treatment will be initiated. Additionally, perform resistance testing prior to initiating or changing any HIV treatment regimen. Transmission of drug-resistant HIV strains has been both well documented and associated with suboptimal virologic response to initial antiretroviral therapy. In high-income countries (e.g., US, some European countries, Australia, Japan), approximately 10% to 17% of treatment-naive individuals have resistance mutations to at least 1 antiretroviral drug; up to 8% (but generally less than 5%) of transmitted viruses will exhibit resistance to drugs from more than 1 class. Therefore, resistance testing at baseline can help optimize treatment and, thus, virologic response. In the absence of therapy, resistant viruses may decline over time to less than the detection limit of standard resistance tests, but may still increase the risk of treatment failure when therapy is eventually initiated. Thus, if therapy is deferred, resistance testing should still be performed during acute HIV infection with the genotypic resistance test result kept in the patient's medical record until it becomes clinically useful. Additionally, because of the possibility of acquisition of another drug-resistant virus before treatment initiation, repeat resistance testing at the time therapy is initiated would be prudent. As with all other antiretroviral agents, resistance can develop when stavudine is used either alone or in combination with other agents. Monotherapy with stavudine is not recommended.
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including stavudine. During the initial phase of HIV treatment, patients whose immune system responds to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as progressive multifocal leukoencephalopathy (PML), mycobacterium avium complex (MAC), cytomegalovirus (CMV), Pneumocystis carinii pneumonia (PCP), or tuberculosis (TB)), which may necessitate further evaluation and treatment. In addition, autoimmune disease (including Graves' disease, Guillain-Barre syndrome, and polymyositis) may also develop; the time to onset is variable and may occur months after treatment initiation.
HIV treatment guidelines recommend all patients presenting with HIV infection undergo testing for hepatitis C, with continued annual screening advised for those persons considered high risk for acquiring hepatitis C. If hepatitis C and HIV coinfection is identified, consider treating both viral infections concurrently. For most patients, the benefits of concurrent therapy outweighs the potential risks (i.e., drug-induced hepatic injury, complex drug interactions, overlapping toxicities); therefore, it is recommended to initiate a fully suppressive antiretroviral (ARV) therapy and a hepatitis C regimen in all coinfected patients regardless of CD4 count. However, for antiretroviral naive patients with CD4 counts greater than 500 cells/mm3, consideration may be given to deferring ARV until the hepatitis C treatment regimen has been completed. Conversely, for patients with CD4 counts less than 200 cells/mm3, consider delaying initiation of the hepatitis C treatment regimen until the patient is stable on fully suppressive ARV regimen. Instruct coinfected patients to avoid consuming alcohol, and offer vaccinations against hepatitis A and hepatitis B as appropriate.
pancreatitis / Delayed / 0-1.0hepatic failure / Delayed / 0-1.0lactic acidosis / Delayed / 0-1.0Guillain-Barre syndrome / Delayed / 0-1.0hepatotoxicity / Delayed / Incidence not known
hyperbilirubinemia / Delayed / 0-68.0peripheral neuropathy / Delayed / 52.0-52.0hyperamylasemia / Delayed / 14.0-14.0elevated hepatic enzymes / Delayed / 11.0-13.0neutropenia / Delayed / 0-1.0thrombocytopenia / Delayed / 0-1.0leukopenia / Delayed / 0-1.0anemia / Delayed / 0-1.0hepatomegaly / Delayed / 0-1.0hepatitis / Delayed / 0-1.0hyperglycemia / Delayed / 0-1.0diabetes mellitus / Delayed / 0-1.0dyspnea / Early / Incidence not knownsteatosis / Delayed / Incidence not knowntachypnea / Early / Incidence not knownlipodystrophy / Delayed / Incidence not known
headache / Early / 54.0-54.0diarrhea / Early / 50.0-50.0rash / Early / 40.0-40.0vomiting / Early / 39.0-39.0nausea / Early / 39.0-39.0fever / Early / 0-1.0myalgia / Early / 0-1.0chills / Rapid / 0-1.0macrocytosis / Delayed / 0-1.0abdominal pain / Early / 0-1.0anorexia / Delayed / 0-1.0weakness / Early / 0-1.0insomnia / Early / 0-1.0weight loss / Delayed / Incidence not knownfatigue / Early / Incidence not known
Abacavir; Lamivudine, 3TC; Zidovudine, ZDV: (Severe) Zidovudine, ZDV, may competitively inhibit the intracellular phosphorylation of stavudine, d4T. Therefore, use of these drugs together is not recommended. At a molar ratio of 20:1 (stavudine:zidovudine), an antagonistic antiviral effect was detected, while at molar ratios of 100:1 and 500:1, antiviral effects were additive. Administration of zidovudine is recommended during labor and delivery in HIV-infected women; for women who are receiving a stavudine-containing regimen, discontinue stavudine during labor while intravenous zidovudine is being administered. Following delivery, the previous anti-retroviral regimen can be resumed. Adefovir: (Major) Patients who are concurrently taking adefovir with antiretrovirals (i.e., anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs)) are at risk of developing lactic acidosis and severe hepatomegaly with steatosis. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination with antiretrovirals. A majority of these cases have been in women; obesity and prolonged nucleoside exposure may also be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for hepatic disease; however, cases have also been reported in patients with no known risk factors. Suspend adefovir in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations). Bortezomib: (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like stavudine; the risk of peripheral neuropathy may be additive. Didanosine, ddI: (Severe) Concurrent administration of stavudine and didanosine is contraindicated. Use of these drugs together increases the risk for serious and life-threatening adverse events, including pancreatitis, lactic acidosis, hepatotoxicity, and peripheral neuropathy. Doxorubicin: (Moderate) It appears that doxorubicin inhibits the phosphorylation of stavudine in vitro. The clinical significance of this in vitro data is unknown and, therefore, concomitant use of stavudine and doxorubicin should be undertaken with caution. Echinacea: (Moderate) Use Echinacea sp. with caution in patients taking medications for human immunodeficiency virus (HIV) infection. Some experts have suggested that Echinacea's effects on the immune system might cause problems for patients with HIV infection, particularly with long-term use. There may be less risk with short-term use (less than 2 weeks). A few pharmacokinetic studies have shown reductions in blood levels of some antiretroviral medications when Echinacea was given, presumably due to CYP induction. However, more study is needed for various HIV treatment regimens. Of the agents studied, the interactions do not appear to be significant or to require dose adjustments at the time of use. Although no dose adjustments are required, monitoring drug concentrations may give reassurance during co-administration. Monitor viral load and other parameters carefully during therapy. Food: (Moderate) The pharmacokinetic parameters of anti-retroviral medications (anti-retroviral non-nucleoside reverse transcriptase inhibitors (NNRTIs), anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs), anti-retroviral nucleotide reverse transcriptase inhibitors, and anti-retroviral protease inhibitors) metabolized through the CYP isoenzyme system are slightly altered by smoked and oral marijuana. Despite this interaction, marijuana is not expected to adversely affect anti-retroviral efficacy. However, the incidence of marijuana associated adverse effects may change following coadministration with anti-retroviral drugs. Many anti-retrovirals are inhibitors of CYP3A4, an isoenzyme partially responsible for the metabolism of marijuana's most psychoactive compound, delta-9-tetrahydrocannabinol (Delta-9-THC). When given concurrently with anti-retrovirals, the amount of Delta-9-THC converted to the active metabolite 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-THC) may be reduced. These changes in Delta-9-THC and 11-OH-THC plasma concentrations may result in an altered marijuana adverse event profile. Hydroxyurea: (Major) It is recommended that hydroxyurea not be used in patients with HIV; reports of hydroxyurea's improvement of viral suppression are inconsistent and hydroxyurea is associated with decreased CD4 counts. While there have been reports that hydroxyurea may enhance the antiretroviral activity of stavudine, the overall results of these reports are inconsistent, and the combined use of these drugs is associated with an increased incidence of stavudine-associated adverse effects, including pancreatitis and peripheral neuropathy. Additionally, there are postmarketing reports of hepatotoxicity and hepatic failure resulting in death with a treatment regimen of hydroxyurea and stavudine. Interferon Alfa-2b; Ribavirin: (Major) While ribavirin inhibits the phosphorylation reactions required to activate stavudine, d4T, no evidence of a pharmacokinetic or pharmacodynamic interaction has been observed. However, the co-treatment of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) has the potential to result in complex drug interactions, and patients receiving ribavirin in combination with stavudine should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. Dose reduction or discontinuation of ribavirin should be considered if toxicities develop. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons, with or without ribavirin, appeared to be at increased risk for the development of hepatic decompensation (e.g., Childs-Pugh >= 6) compared to patients not receiving HAART. Additionally, stavudine has been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Interferons: (Major) Patients receiving stavudine with interferons (with or without ribavirin) should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation compared to patients not receiving HAART. Additionally, stavudine has been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. 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 (e.g., Child-Pugh score greater than 6). Lamivudine, 3TC; Zidovudine, ZDV: (Severe) Zidovudine, ZDV, may competitively inhibit the intracellular phosphorylation of stavudine, d4T. Therefore, use of these drugs together is not recommended. At a molar ratio of 20:1 (stavudine:zidovudine), an antagonistic antiviral effect was detected, while at molar ratios of 100:1 and 500:1, antiviral effects were additive. Administration of zidovudine is recommended during labor and delivery in HIV-infected women; for women who are receiving a stavudine-containing regimen, discontinue stavudine during labor while intravenous zidovudine is being administered. Following delivery, the previous anti-retroviral regimen can be resumed. Methadone: (Minor) Methadone decreases the bioavailability stavudine, d4T by slowing its absorption and increasing its first-pass metabolism. As a result, stavudine's AUC and Cmax are decreased by 18% and 39%, respectively; however, these effects are probably not clinically significant. Orlistat: (Major) According to the manufacturer of orlistat, HIV RNA levels should be frequently monitored in patients receiving orlistat while being treated for HIV infection with anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs). Loss of virological control has been reported in HIV-infected patients taking orlistat with atazanavir, ritonavir, tenofovir disoproxil fumarate, emtricitabine, lopinavir; ritonavir, and emtricitabine; efavirenz; tenofovir disoproxil fumarate. The exact mechanism for this interaction is not known, but may involve inhibition of systemic absorption of the anti-retroviral agent. If an increased HIV viral load is confirmed, orlistat should be discontinued. Probenecid: (Minor) Stavudine undergoes active tubular secretion, and renal elimination may be affected by probenecid, a drug known to interfere with tubular secretion. Resultant increases in serum levels can lead to toxicity. Ribavirin: (Major) While ribavirin inhibits the phosphorylation reactions required to activate stavudine, d4T, no evidence of a pharmacokinetic or pharmacodynamic interaction has been observed. However, the co-treatment of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) has the potential to result in complex drug interactions, and patients receiving ribavirin in combination with stavudine should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. Dose reduction or discontinuation of ribavirin should be considered if toxicities develop. In a study of 14 patients with chronic, cirrhotic HCV co-infected with HIV, patients receiving NRTIs and alpha interferons, with or without ribavirin, appeared to be at increased risk for the development of hepatic decompensation (e.g., Childs-Pugh >= 6) compared to patients not receiving HAART. Additionally, stavudine has been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Zalcitabine, ddC: (Severe) It is recommended that zalcitabine, ddC not be used in combination with stavudine, d4T due to additive neuropathy seen with concomitant use. Zidovudine, ZDV: (Severe) Zidovudine, ZDV, may competitively inhibit the intracellular phosphorylation of stavudine, d4T. Therefore, use of these drugs together is not recommended. At a molar ratio of 20:1 (stavudine:zidovudine), an antagonistic antiviral effect was detected, while at molar ratios of 100:1 and 500:1, antiviral effects were additive. Administration of zidovudine is recommended during labor and delivery in HIV-infected women; for women who are receiving a stavudine-containing regimen, discontinue stavudine during labor while intravenous zidovudine is being administered. Following delivery, the previous anti-retroviral regimen can be resumed.
Stavudine inhibits the replication of retroviruses. In vitro studies show it inhibits replication of HIV in human cells. Antiretroviral activity is dependent on phosphorylation by cellular kinases to stavudine triphosphate. Once in the active form, stavudine inhibits HIV reverse transcriptase by competing with the natural substrate deoxythymidine triphosphate and by its incorporation into viral DNA causing a termination of DNA elongation. Stavudine inhibits DNA elongation because it lacks an essential 3'-OH group. Stavudine triphosphate also inhibits cellular DNA polymerase beta and gamma and reduces the synthesis of mitochondrial DNA. Some resistance, including cross-resistance to zidovudine and didanosine, has been demonstrated in in vitro studies. Prolonged treatment can select and/or maintain thymidine analogue mutations that are associated with zidovudine resistance. Use should be avoided in the presence of thymidine analogue mutations.
Stavudine is administered orally. Stavudine distributes equally between red blood cells and plasma. Stavudine crosses the blood-brain barrier and distributes into cerebrospinal fluid. Protein binding is negligible. The volume of distribution is 46 +/- 21 L. Metabolism plays a limited role in stavudine clearance. 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. Approximately 95% a radiolabeled dose was recovered in the urine, with 73.7% recovered as parent drug. Approximately 3% of the radiolabeled dose was recovered in the feces, with 62% recovered as parent drug. Body clearance of the drug is independent of dose, regardless of route of administration. Terminal half-life following oral administration is roughly 2.3 hours in adults after a single oral dose. The mean elimination half-life after an IV dose is 1.15 +/- 0.35 h and the mean elimination half-life after an oral dose is 1.6 +/- 0.23 h. Excretion is about 40% renal via active tubular secretion and glomerular filtration.
Stavudine is rapidly absorbed following oral administration. The systemic exposure is the same regardless of capsule or solution administration. Mean absolute bioavailability is 86.4% +/- 18.2. Bioavailability increases proportionally to dosage, with peak concentrations occurring within 1 hour. In HIV-infected adults, the steady-state AUC is 2568 +/- 454 ng x h/ml, the steady-state Cmax is 536 +/- 146 ng/ml, and the steady-state Cmin is 8 +/- 9 ng/ml. Peak serum concentration is decreased approximately 45% if the drug is administered with food, but total bioavailability remains unchanged.