Zerit

Interactions with herbs have not been established.

ZERIT (stavudine) may be taken without regard to meals. Absorption of stavudine was assessed in a study of 16 asymptomatic HIV-infected patients. Each patient received a 70 mg oral dose of ZERIT in the fasting state, 1 hour before a standardized meal, and immediately after a standardized meal. The results indicate that systemic exposure to stavudine is not reduced when ZERIT is taken with food. Although the rate of absorption decreased, the extent of absorption was not significantly (p=0.27) affected by the presence of food when ZERIT was taken immediately after a meal. Mean (±SD) C_max of stavudine was reduced from 1.44 (±0.49) μg/mL in the fasting state to 0.75 (±0.16) μg/mL after a meal, and the median time to achieve C_max was prolonged from 0.6 to 1.5 hours. However, mean (±SD) AUC_0→-∞ values were 2.50 (±0.71) μg·hr/mL and 2.31 (±0.55) μg·hr/mL in the fasting state and after a meal, respectively, indicating that systemic exposure was similar with or without the presence of food.

Zidovudine may competitively inhibit the intracellular phosphorylation of stavudine (see Action and Clinical Pharmacology). Therefore, use of zidovudine in combination with ZERIT is not recommended. In vitro data indicate that the phosphorylation of stavudine is also inhibited at relevant concentrations by doxorubicin and ribavirin; therefore coadministration of stavudine with either doxorubicin or ribavirin should be undertaken with caution.

No pharmacokinetic interactions were observed between ZERIT and didanosine, lamivudine (3TC), or nelfinavir when co-administered in clinical trials.

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.

Adults: Dosing adjustment is not necessary in subjects with stable hepatic impairment. In the event of rapidly elevating aminotransferase levels, treatment with ZERIT should be suspended.

Clinical symptoms of peripheral neuropathy which is usually characterized by numbness, tingling or pain in the feet or hands should prompt interruption of ZERIT treatment and evaluation of the patient. These symptoms may be difficult to detect in children (see Warnings and Precautions). If symptoms develop, ZERIT should be interrupted. Symptoms may resolve if therapy is withdrawn promptly. Some patients may experience a temporary worsening of symptoms following discontinuation of therapy. If symptoms resolve completely, resumption of treatment may be considered. If a reduced dose is warranted, use one-half the recommended dose.

The following events have been identified during post-approval use of ZERIT. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to their seriousness, frequency of reporting, causal connection to ZERIT, or a combination of these factors.

Because clinical trials are conducted under very specific conditions the adverse drug reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Many of the serious clinical adverse events reported from patients receiving stavudine in clinical trials were consistent with the course of HIV infection. Concurrent therapy with other medications was permitted in these trials. Therefore, it is difficult to distinguish which events were related to stavudine, the disease itself, or other therapies.

When ZERIT is used in combination with other agents with similar toxicities, the incidence of adverse events may be higher than when ZERIT is used alone. Pancreatitis, peripheral neuropathy, and liver function abnormalities occur more frequently in patients treated with the combination of ZERIT and didanosine.

Fatal pancreatitis and hepatotoxicity may occur more frequently in patients treated with ZERIT in combination with didanosine and hydroxyurea (see Warnings and Precautions).

Fatal lactic acidosis has occurred in patients treated with ZERIT in combination with other antiretroviral agents. Patients with suspected lactic acidosis should immediately suspend therapy with ZERIT. Permanent discontinuation of ZERIT should be considered for patients with confirmed lactic acidosis.

lactic acidosis and hepatic steatosis [including fatal cases (see Warnings and Precautions)], hepatitis and liver failure [including fatal cases (see Warnings and Precautions)].

abdominal pain, allergic reactions, chills/fever, redistribution/accumulation of body fat (see Warnings and Precautions, Fat Redistribution).

anemia, leukopenia, macrocytosis, and thrombocytopenia.

pancreatitis [including fatal cases (see Warnings and Precautions)].

diabetes mellitus, hyperglycemia.

insomnia, severe motor weakness (most often reported in the setting of symptomatic hyperlactatemia or lactic acidosis, including fatal cases, see Warnings and Precautions).

myalgia.

A total of 202 patients in two clinical studies were treated with combination therapy that included stavudine in the regimen. The most clinically relevant serious adverse events, regardless of relationship to study treatment in these two clinical studies, included lactic acidosis, pancreatitis, hepatic dysfunction and peripheral neuropathy.

The most common adverse events in the stavudine-containing regimens of the combination therapy clinical studies, regardless of grade or relationship to study treatment, included asthenia, diarrhea, dry skin, headache, increased cough, nausea, pharyngitis, rash and vomiting. In total, 31 out of the 202 patients in the stavudine-containing regimens from these two clinical studies, discontinued study medication due to adverse events.

anorexia.

ZERIT therapy has rarely been associated with motor weakness, occurring predominantly in the setting of lactic acidosis. If motor weakness develops, ZERIT should be discontinued.

ZERIT (stavudine) therapy has also been associated with peripheral sensory neuropathy, which can be severe, is dose related, and occurs more frequently in patients being treated with neurotoxic drug therapy, including didanosine, in patients with advanced HIV infection, or in patients who have previously experienced peripheral neuropathy.

Patients should be monitored for the development of neuropathy, which is usually manifested by numbness, tingling, or pain in the feet or hands. Stavudine-related peripheral neuropathy may resolve if therapy is withdrawn promptly. In some cases, symptoms may worsen temporarily following discontinuation of therapy. If symptoms resolve completely, patients may tolerate resumption of treatment at one-half the dose (see Dosage and Administration). If neuropathy recurs after resumption of ZERIT, permanent discontinuation of ZERIT should be considered.

Adverse reactions and serious laboratory abnormalities in pediatric patients were similar in type and frequency to those seen in adult patients.

Each light yellow and dark red capsule, imprinted with “BMS 1964” and “15”, contains: stavudine 15 mg. Nonmedicinal ingredients: lactose, magnesium stearate, microcrystalline cellulose and sodium starch glycolate; capsule shell: gelatin, printing ink, silicon dioxide, sodium lauryl sulfate, titanium dioxide and yellow and red iron oxides. Bottles of 60.

Each light orange and dark orange capsule, imprinted with “BMS 1966” and “30”, contains: stavudine 30 mg. Nonmedicinal ingredients: lactose, magnesium stearate, microcrystalline cellulose and sodium starch glycolate; capsule shell: gelatin, printing ink, silicon dioxide, sodium lauryl sulfate, titanium dioxide and yellow and red iron oxides. Bottles of 60.

Each light brown capsule, imprinted with “BMS 1965” and “20”, contains: stavudine 20 mg. Nonmedicinal ingredients: lactose, magnesium stearate, microcrystalline cellulose and sodium starch glycolate; capsule shell: gelatin, black iron oxide (20 mg only), printing ink, silicon dioxide, sodium lauryl sulfate, titanium dioxide and yellow and red iron oxides. Bottles of 60.

Each dark orange capsule, imprinted with “BMS 1967” and “40” contains: stavudine 40 mg. Nonmedicinal ingredients: lactose, magnesium stearate, microcrystalline cellulose and sodium starch glycolate; capsule shell: gelatin, printing ink, silicon dioxide, sodium lauryl sulfate, titanium dioxide and yellow and red iron oxides. Bottles of 60.

In HIV-infected patients with renal impairment, renal clearance and apparent oral clearance of stavudine was decreased. The terminal elimination half-life (t½) was prolonged up to 8 hours. C_max and T_max were not significantly affected by reduced renal function. Based on these preliminary observations, it is recommended that stavudine dosage be modified in patients with reduced creatinine clearance (≤50 mL/min) (see Dosage and Administration).

In 2-year carcinogenicity studies in mice and rats, stavudine was noncarcinogenic at doses which produced exposures (AUC) 39 and 168 times, respectively, human exposure at the recommended clinical dose. Benign and malignant liver tumors in mice and rats and malignant urinary bladder tumors in male rats occurred at levels of exposure 250 (mice) and 732 (rats) times human exposure at the recommended clinical dose.

Stavudine was not mutagenic in the Ames, E. coli reverse mutation, or the CHO/HGPRT mammalian cell forward gene mutation assays, with and without metabolic activation. Stavudine produced positive results in the in vitro human lymphocyte clastogenesis and mouse fibroblast assays, and in the in vivo mouse micronucleus test. In the in vitro assays, stavudine elevated the frequency of chromosome aberrations in human lymphocytes (concentrations of 25 to 250 μg/mL, without metabolic activation) and 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 C_max) up to 216 times that observed following a clinical dosage of 1 mg/kg/day.

The safety and effectiveness of ZERIT have been established in pediatric patients supported by evidence from adequate and well-controlled studies of stavudine in adults with additional data concerning safety and pharmacokinetics in pediatric patients.

Patients should be monitored for clinically significant elevations of hepatic transaminases. If these elevations develop on treatment, ZERIT therapy should be interrupted. If the hepatic transaminase values return to pretherapy levels, resumption of treatment may be considered using a dosage schedule of 1 mg/kg/day, not to exceed the recommended adult dose of 20 mg twice daily.

One open-label, phase I trial enrolled 38 subjects aged 5 weeks to 15 years; 9 had received no prior antiretroviral therapy and 29 had received zidovudine for a median duration of 104 weeks. Patients in this trial received ZERIT in initial doses ranging from 0.125 to 4.0 mg/kg/day with an average dose of 1.7 mg/kg/day for a median duration of 84 weeks (range 8-140 weeks). A second open-label trial, initiated to provide stavudine for children who had failed or were intolerant of alternative antiretroviral therapy, enrolled 51 subjects aged 8 months to 18 years who had received prolonged zidovudine and didanosine. These patients were treated with ZERIT at a dose of 2 mg/kg/day, for a median duration of 33 weeks (range 2 days - 82 weeks).

A multi-centre, randomized, double-blind trial (Study ACTG 240) evaluated ZERIT [d4t] (2 mg/kg/day) versus zidovudine [ZDV] (200 mg QID) in the treatment of HIV-infected pediatric patients who had received ≤6 weeks of prior antiretroviral therapy. Two hundred and sixteen subjects, with a median baseline CD4 cell count of 1000 cells/mm³, were enrolled. CD4 cell counts were better maintained on ZERIT treatment as compared with ZDV (p<0.05). Patients on ZDV experienced more neutropenia (19%) versus patients on ZERIT (7%) (p<0.01). No differences were observed in any other laboratory parameters, signs or symptoms.

Fatal and nonfatal pancreatitis have occurred during therapy when ZERIT was part of a combination regimen that included didanosine or didanosine and hydroxyurea, in both treatment-naive and treatment-experienced patients, regardless of degree of immunosuppression. This combination of ZERIT and didanosine and any other agents that are toxic to the pancreas should be suspended in patients with suspected pancreatitis. Reinstitution of ZERIT after a confirmed diagnosis of pancreatitis should be undertaken with particular caution and close patient monitoring. The new regimen should contain neither didanosine nor hydroxyurea.

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 not known if pregnancy augments the risk of lactic acidosis/hepatic steatosis syndrome reported in nonpregnant individuals receiving nucleoside analogues (see Warnings and Precautions, Serious Warnings and Precautions Box, Lactic Acidosis/Severe Hepatomegaly with Steatosis/Hepatic Failure). The combination of stavudine and didanosine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk. Health care providers caring for HIV-infected pregnant women receiving stavudine should be alert for early diagnosis of lactic acidosis/hepatic steatosis syndrome.

Reproduction studies have been performed in rats and rabbits with exposures (based on C_max) 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 or impaired fertility. A slight post-implantation loss was noted at 216 times the human exposure with no effect noted at approximately 135 times the human exposure. 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. 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. Stavudine has been shown to cross the human placenta in an ex vivo term model. Animal reproduction studies are not always predictive of human response.

Clinical studies of ZERIT 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 ZERIT cannot be ruled out.

In a monotherapy Expanded Access Program for patients with advanced HIV infection, peripheral neuropathy or peripheral neuropathic symptoms were observed in 15 of 40 (38%) elderly patients receiving 40 mg b.i.d. and 8 of 51 (16%) elderly patients receiving 20 mg b.i.d. 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 b.i.d. and 25% of patients receiving 20 mg b.i.d. 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, Recommended Dose and Dosage Adjustment).

ZERIT capsules contain lactose (120 and 240 mg depending on capsule strength). This amount is probably insufficient to induce specific symptoms of intolerance.

Immune Reconstitution Syndrome: During the initial phase of treatment, patients responding to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as MAC, CMV, PCP, and TB), which may necessitate further evaluation and treatment.

Motor weakness (which was fatal in some cases) has been reported rarely in patients receiving combination antiretroviral therapy including ZERIT. Most of these cases occurred in the setting of symptomatic hyperlactatemia or lactic acidosis syndrome. The evolution of motor weakness may mimic the clinical presentation of Guillain-Barré syndrome (including respiratory failure). If motor weakness develops in a patient receiving ZERIT, the drug should be discontinued. Symptoms may continue or worsen following discontinuation of therapy.

Peripheral neuropathy, manifested by numbness, tingling, or pain in the hands or feet, has been reported in patients receiving ZERIT therapy. Peripheral neuropathy, which is dose related, has occurred more frequently in patients with advanced HIV disease, a history of neuropathy, or concurrent neurotoxic drug therapy, including didanosine (see Adverse Reactions).

Peripheral neuropathy, which was severe in some cases, has been reported in HIV-infected patients receiving hydroxyurea in combination with antiretroviral agents, including didanosine with or without stavudine.

Patients receiving ZERIT (stavudine) or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV infection and, therefore, should remain under close clinical observation by physicians experienced in the treatment of patients with HIV disease and associated complications.

Complete blood counts and clinical laboratory tests should be performed prior to initiating ZERIT therapy and at appropriate intervals thereafter.

Moderate elevations of mean corpuscular volume may be observed in patients taking ZERIT and may provide an indication of treatment compliance.

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. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

Studies in which lactating rats were administered a single dose (5 or 100 mg/kg) of stavudine demonstrated that stavudine is readily excreted into breast milk.

Although it is not known whether ZERIT is excreted in human milk, there exists the potential for adverse effects from stavudine in nursing infants. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving ZERIT.

Patients receiving ZERIT should be advised of the following:

• The importance of early recognition of symptoms of lactic acidosis, which include abdominal discomfort, nausea, vomiting, fatigue, dyspnea, and motor weakness. Patients in whom these symptoms develop should seek medical attention immediately. Discontinuation of ZERIT therapy may be required.

  
  

• Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long term health effects of these conditions are not known at this time.

  
  

• The long-term effects of ZERIT are unknown at this time.

  
  

• ZERIT therapy has not been shown to reduce the risk of HIV transmission.

  
  

• They may continue to develop opportunistic infections and other complications of HIV infection and, therefore, should remain under the care of a physician experienced in treating HIV-associated diseases.

  
  

• An important toxicity of ZERIT 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 counselled that peripheral neuropathy occurs with greatest frequency in patients who have advanced HIV disease, a history of peripheral neuropathy and in patients who are taking concurrent neurotoxic drug therapy, including didanosine; and that dose modification and/or discontinuation of ZERIT may be required if toxicity develops.

  
  

• Caregivers of young children receiving ZERIT therapy should be instructed regarding detection and reporting of peripheral neuropathy.

  
  

• When ZERIT is used in combination with other agents with similar toxicities, the incidence of adverse events may be higher than when ZERIT is used alone. Patients treated with ZERIT in combination with didanosine, may be at increased risk for pancreatitis, which may be fatal. These patients should be followed closely for symptoms of pancreatitis. Patients treated with ZERIT in combination with didanosine and hydroxyurea may be at increased risk for lactic acidosis and hepatotoxicity, which may be fatal. These patients should be closely monitored for signs of liver toxicity.

Hepatitis or liver failure, which was fatal in some cases, have been reported with ZERIT. Hepatotoxicity and hepatic failure resulting in death were reported during postmarketing surveillance in HIV-infected patients treated with antiretroviral agents in combination with hydroxyurea. Fatal hepatic events were reported most often in patients treated with the combination of hydroxyurea, didanosine, and stavudine. This combination should be avoided.

The safety and efficacy of ZERIT have not been established in patients with significant underlying liver disorders. 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.

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.

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.

ZERIT (stavudine), also known as d4T, is a synthetic thymidine nucleoside analogue active against the Human Immunodeficiency Virus (HIV).

In vitro studies demonstrate that stavudine is converted to the triphosphate by cellular kinases. The 5'-triphosphate is the active form of the drug. In cell culture studies with two different cell lines, stavudine triphosphate had an intracellular half-life of 3.5 hours. Stavudine triphosphate has been shown to be a potent competitive inhibitor of HIV reverse transcriptase (ki=0.0083 to 0.032 µM). In addition, both stavudine triphosphate and the natural substrate, thymidine triphosphate, are used by HIV reverse transcriptase in vitro for incorporation into the nascent DNA chain. Stavudine lacks the 3'-hydroxyl group necessary for DNA elongation and once incorporated into DNA, functions as a DNA chain terminator in vitro. Both the inhibition of binding of thymidine triphosphate to reverse transcriptase and DNA chain termination may be partially responsible for inhibition of HIV replication in vitro. In addition to the inhibitory effect on HIV reverse transcriptase, stavudine triphosphate exhibits some inhibitory effect on DNA polymerase beta and gamma, and markedly reduces the syntheses of mitochondrial DNA.

Clinically, ZERIT has been studied in various combinations with other classes of anti-retroviral drugs, including didanosine, lamivudine (3TC), ritonavir, nelfinavir, saquinavir, indinavir, and hydroxyurea. However, zidovudine in combination with ZERIT is not recommended (see Warnings and Precautions, Drug Interactions). Both drugs are phosphorylated by the same cellular enzyme (thymidine kinase), which may preferentially phosphorylate zidovudine, thereby decreasing the phosphorylation of stavudine to its active triphosphate form.

Based on in vitro testing, the activation of stavudine has also been shown to be inhibited by other drugs. Among the several drugs tested, the only ones that may interfere with stavudine phosphorylation at relevant concentrations are doxorubicin and ribavirin, but not other drugs used in the therapy of HIV infection which are similarly phosphorylated. The clinical significance of this is unknown.

Clinical trials supporting the use of ZERIT in appropriate antiretroviral regimens for the treatment of HIV-infected patients, demonstrated, overall, greatest inhibition of HIV RNA levels and greatest increase in CD4 cell counts with triple-combination regimens.

Renal elimination accounted for about 40% of the overall clearance regardless of the route of administration. The mean renal clearance was about twice the average endogenous creatinine clearance, indicating active tubular secretion in addition to glomerular filtration.

Five of 11 stavudine post-treatment isolates developed moderate resistance to zidovudine (9- to 176-fold) and 3 of those 11 isolates developed moderate resistance to didanosine (7- to 29-fold). The clinical relevance of these findings is unknown.

The metabolic fate of stavudine has not been elucidated in humans.

HIV isolates with reduced susceptibility to stavudine have been selected in vitro and were also obtained from patients treated with stavudine. Phenotypic analysis of HIV isolates from stavudine-treated patients revealed, in 3 of 20 paired isolates, a 4- to 12-fold decrease in susceptibility to stavudine in vitro. The genetic basis for these susceptibility changes has not been identified. The clinical relevance of changes in stavudine susceptibility has not been established.