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Product
Antiretroviral products (Stavir)
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Antiretroviral products (Stavir)
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Stavir
Stavudine Capsules
COMPOSITION
STAVIR-30
Each capsule contains Stavudine ………..30 mg
STAVIR-40
Each capsule contains Stavudine…………40 mg
PHARMACOLOGY
Pharmacodynamics:
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 beta and gamma and markedly reduces the synthesis of mitochondrial DNA. |
Pharmacokinetics
The pharmacokinetics of stavudine has been evaluated in HIV-infected adult and pediatric patients. Peak plasma concentrations (C max ) 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-infected adults are shown in Table 1.
Table 1: Steady-State Pharmacokinetics: Parameters of Stavudine in HIV-infected Adults
| Parameter
|
Stavudine 40 mg BID
Mean + SD (n = 8) |
| AUC (ng.h/mL) a |
2568 ± 454
|
| C max (ng/mL) |
536 ± 146 |
| C min (ng/mL) |
8 ± 9 |
a from 0 to 24 hours
AUC = area under the curve over 24 hours
C max = maximum plasma concentration
C min = trough or minimum plasma concentration |
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 2.
Metabolism : The metabolism of stavudine has not been elucidated in humans.
Elimination : In humans, renal elimination accounts for about 40% of the overall clearance regardless of the route of administration (Table 2). The mean renal clearance was about twice the average endogenous creatinine clearance, indicating active tubular secretion in addition to glomerular filtration. The remaining 60% of the drug is presumably eliminated by endogenous pathways. Significant drug interactions will occur with drugs metabolized through these pathways.
Table 2: Pharmacokinetic Parameters of Stavudine in HIV-infected Adults: Bioavailability, Distribution and Clearance
INDICATIONS
STAVIR capsules, in combination with other antiretroviral agents, are indicated for the treatment of HIV-1 infection.
DOSAGE AND ADMINISTRATION
The interval between doses of STAVIR should be 12 hours. STAVIR may be taken with or without food.
Adults
The recommended dose based on body weight is as follows:
40 mg every 12 hours for patients ≥ 60 kg
30 mg every 12 hours for patients <60 kg
Pediatrics
The recommended dose for newborns from birth to 13 days old is 0.5 mg/kg/dose given every 12 hours. The recommended dose for pediatric patients at least 14 days old and weighing less than 30 kg is 1 mg/kg/dose, given every 12 hours. Pediatric patients weighing 30 kg or greater should receive the recommended adult dosage.
Dosage Adjustment
Peripheral Neuropathy
Patients should be monitored for the development of peripheral neuropathy, which is usually characterized by numbness, tingling, or pain in the feet or hands. These symptoms may be difficult to detect in young children (see Warnings and Precautions ). If these symptoms develop during treatment, stavudine therapy should be interrupted. Symptoms 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 recommended dose.
20 mg every 12 hours for patients ≥ 60 kg
15 mg every 12 hours for patients <60 kg
If peripheral neuropathy recurs after resumption of stavudine, permanent discontinuation of stavudine should be considered.
Renal Impairment
Stavir may be administered to adult patients with impaired renal function with adjustment in dose as shown in Table 3.
Table 3: Recommended Dosage Adjustment for Renal Impairment
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. Although there are insufficient data to recommend a specific dose adjustment of stavudine in this patient population, a reduction in the dose and/or an increase in the interval between doses should be considered.
Hemodialysis Patients
The recommended dose is 20 mg every 24 hours ( > 60 kg) of 15 mg every 24 hours (< 60 kg), administered after the completion of hemodialysis and at the same time of day on non-dialysis days.
CONTRAINDICATIONS
STAVIR is contraindicated in patients with clinically significant hypersensitivity to stavudine or to any of the components contained in the formulation.
WARNINGS AND PRECAUTIONS
Lactic Acidosis/Severe Hepatomegaly with Steatosis/Hepatic Failure
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have 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 women who received the combination of stavudine and didanosine with other antiretroviral agents. 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 (see WARNINGS AND PRECAUTIONS : Pregnancy ).
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 sudden unexplained weight loss); respiratory symptoms (tachypnoea and dyspnoea); or neurologic symptoms (including motor weakness) might be indicative of 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 hyper lactatemia lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
An increased risk of hepatoxicity may occur in patients treated with stavudine in combination with didanosine and hydroxyurea compared to when stavudine is used alone. Deaths attributed to hepatoxicity have occurred in patients receiving this combination. Patients treated with this combination should be closely monitored for signs of liver toxicity.
Hepatic Impairment and 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.
Use with Didanosine and Hydroxyurea-Based Regimens
An increased risk of hepatotoxicity may occur in patients treated with stavudine in combination with didanosine and hydroxyurea compared to when stavudine is used alone. Deaths attributed to hepatotoxicity have occurred in patients receiving this combination. This combination should be avoided.
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/HCV virologic suppression) interaction was seen when ribavirin was co-administered with stavudine in HIV/HCV co-infected patients, hepatic decompensation (some fatal) has occurred in HIV/HCV co-infected patients receiving combination antiretroviral therapy for HIV 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 complete prescribing information for interferon and ribavirin ).
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-Barré syndrome (including respiratory failure). 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 stavudine therapy. Peripheral neuropathy has occurred more frequently in patients with advanced HIV disease, a history of neuropathy, or concurrent neurotoxic drug therapy including didanosine (see UNDESIRABLE EFFECTS ).
Pancreatitis
Fatal and nonfatal pancreatitis have occurred during therapy when stavudine was part of a combination regimen that included didanosine, with or without hydroxyurea, in both treatment-naïve and treatment-experienced patients, regardless of degree of immunosuppression. The combination of stavudine and didanosine (with or without hydroxyurea) and any other agents that are toxic to the pancreas should be suspended in patients with suspected pancreatitis. Reinstitution of stavudine 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.
Fat Redistribution
Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo lump), 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.
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.
Drug Interactions
Zidovudine competitively inhibits the intracellular phosphorylation of stavudine. Therefore, use of zidovudine in combination with stavudine should be avoided.
In vitro data indicate that the phosphorylation of stavudine is also inhibited at relevant concentrations by doxorubicin and ribavirin. The clinical significance of these in vitro interactions is unknown; therefore, concomitant use of stavudine with either of these drugs should be undertaken with caution.
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. It is recommended that stavudine dosage be modified in patients with reduced creatinine clearance and in patients receiving maintenance hemodialysis.
Hepatic Impairment
Stavudine pharmacokinetics was not altered in 5 non-HIV-infected patients with hepatic impairment secondary to cirrhosis (Child-Pugh classification B or C) following the administration of a single 40mg dose.
Pregnancy
Category C. There are no adequate and well-controlled studies in pregnant women. STAVIR should be used during pregnancy only if the potential benefit justifies the 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 non-pregnant individuals receiving nucleoside analogues (see WARNINGS AND PRECAUTIONS: 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 .
Presentation
Stavir 30/40….1 strip = 10 capsules
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