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Name:Stavudine
Manufacturer:Remedyrepack Inc.
Category:Prescription Marketed Drugs


STAVUDINE  - stavudine capsule 
REMEDYREPACK INC.

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BOXED WARNING




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. 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 ).
 
FATAL AND NONFATAL PANCREATITIS HAVE OCCURRED DURING THERAPY WHEN STAVUDINE WAS PART OF A COMBINATION REGIMEN THAT INCLUDED DIDANOSINE IN BOTH TREATMENT-­NAIVE AND TREATMENT-EXPERIENCED PATIENTS, REGARDLESS OF DEGREE OF IMMUNOSUPPRESSION (SEE WARNINGS).

DESCRIPTION

Stavudine capsules, USP contain stavudine (d4T), which is a synthetic thymidine nucleoside analogue, active against the human immunodeficiency virus (HIV).

Stavudine capsules, USP are supplied for oral administration in strengths of 15, 20, 30, and 40 mg of stavudine. Each capsule also contains inactive ingredients microcrystalline cellulose, sodium starch glycolate, anhydrous lactose, and magnesium stearate. The hard gelatin shell consists of gelatin, sodium lauryl sulfate, titanium dioxide, yellow iron oxide, and red iron oxide. In addition the 15 mg and 20 mg also contains black iron oxide. Black iron oxide is used for printing on the capsules.

The chemical name for stavudine is 2',3'-didehydro-3'-deoxythymidine. Stavudine has the following structural formula:

MM1



Stavudine is a white to off-white crystalline solid with the molecular formula C10H12N2O4 and a molecular weight of 224.2. The solubility of stavudine at 23is approximately 83 mg/mL in water and 30 mg/mL in propylene glycol. The n-octanol/water partition coefficient of stavudine at 23is 0.144.

MICROBIOLOGY



Mechanism of Action
Stavudine, a nucleoside analogue of thymidine, is phosphorylated by cellular kinases to the active metabolite stavudine triphosphate. Stavudine triphosphate inhibits the activity of HIV-1 reverse transcriptase (RT) by competing with the natural substrate thymidine triphosphate (Ki=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

 
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%  (EC50) 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 to 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.

Drug 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 to 29 months) stavudine monotherapy showed that post-therapy isolates from four patients exhibited EC50 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 mutations T215Y and K219E, and isolates from another patient contained the multiple-nucleoside-resistance-associated mutation 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 mutations associated with zidovudine resistance. HIV-1 isolates with one or more zidovudine­-resistance-associated mutations (M41L, D67N, K70R, L210W, T215Y/F, K219Q/E) exhibited reduced susceptibility to stavudine in cell culture.

CLINICAL PHARMACOLOGY



Pharmacokinetics
The pharmacokinetics of stavudine have been evaluated in HIV-infected adult and pediatric patients (Tables 1 to 3). Peak plasma concentrations (Cmax) 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 sameas capsules or solution. Steady-state pharmacokinetic parameters of stavudine in HIV-infected adults are shown in Table 1. 
Table 1: Steady-State Pharmacokinetic Parameters of Stavudine in HIV-Infected Adults
Parameter Stavudine 40 mg BID
Mean ± SD
(n=8)
from 0 to 24 hours.
AUC = area under the curve over 24 hours.
Cmax = maximum plasma concentration.
Cmin = trough or minimum plasma concentration.
AUC (ng•h/mL)a
2568 ± 454
Cmax (ng/mL)
536 ± 146
Cmin (ng/mL)
8 ± 9

Distribution
 
Binding of stavudine to serum proteins was negligible over the concentration range of 0.01 to 11.4 mcg/mL. Stavudine distributes equally between red blood cells and plasma. Volume of distribution is shown in Table 2.
 
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 14C-stavudine, while metabolites constituted minor components of the circulating radioactivity. Minor metabolites include oxidized stavudine, glucuronide conjugates of stavudine and its oxidized metabolite, and an N-acetylcysteine conjugate of the ribose after glycosidic cleavage, suggesting that thymine is also a metabolite of stavudine.
 
Elimination
 
Following an 80 mg dose of 14C-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%, 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-infected patients, renal elimination of unchanged drug 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.
Table 2: Pharmacokinetic Parameters of Stavudine in HIV-Infected Adults: Bioavailability, Distribution, and Clearance
Parameter  Mean ± SD       n   
a following 1-hour IV infusion.
b following single oral dose.
c assuming a body weight of 70 kg.
d over 12 to 24 hours.
Oral bioavailability (%)
 
 Volume of distribution (L)a
 
 Total body clearance (mL/min)a
 
 Apparent oral clearance (mL/min)b
 
 Renal clearance (mL/min)a
 
 Elimination half-life, IV dose (h)a
 
 Elimination half-life, oral dose (h)b
 
 Urinary recovery of stavudine (% of dose)a,d 
86.4 ± 18.2
 
46 ± 21
 
594 ± 164
 
560 ± 182c
 
237 ± 98
 
1.15 ± 0.35
 
1.6 ± 0.23
 
42 ± 14
25   
 
   44   
 
   44   
 
    113     
 
   39   
 
   44   
 
   8   
 
   39   
Special Populations


Pediatric
 
For pharmacokinetic properties of stavudine in pediatric patients see Table 3.
Table 3: Pharmacokinetic Parameters (Mean ± SD) of Stavudine in HIV-Exposed or –Infected Pediatric Patients
Parameter Ages 5
 weeks to
15 years
   n    Ages 14 to
 28 days
   n    Day of
 Birth
   n   
a following 1-hour IV infusion.
b   at median time of 2.5 hours (range 2 to 3 hours) following multiple oral doses.
c  following single oral dose.
d  over 8 hours.
ND = not determined.
Oral bioavailability (%)
76.9 ± 31.7
20   
ND

ND

Volume of distribution (L/kg)a
0.73 ± 0.32
21   
ND

ND

Ratio of CSF: plasma concentrations (as %)
59 ± 35
8   
ND

ND

Total body clearance (mL/min/kg)a
9.75 ± 3.76
21   
ND

ND

Apparent oral clearance (mL/min/kg)c
13.75 ± 4.29 
20   
11.52 ± 5.93 
30     
5.08 ± 2.8
17     
Elimination half-life, IV dose (h)a
1.11 ± 0.28
21   
ND

ND

Elimination half-life, oral dose (h)c
0.96 ± 0.26
20     
1.59 ± 0.29
30   
5.27 ± 2.01 
17   
Urinary recovery of stavudine (% of dose)c,d 
34 ± 16
19   
ND

ND

Renal Impairment

Data from two studies in adults indicated that the apparent oral clearance of stavudine decreased and the terminal elimination half-life increased as creatinine clearance decreased (see Table 4). Cmax and Tmax 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 to 6 hours post-dose, was 31 ± 5%. Based on these observations, it is recommended that stavudine dosage be modified in patients with reduced creatinine clearance and in patients receiving maintenance hemodialysis (see DOSAGE AND ADMINISTRATION ).
Table 4: Mean ± SD Pharmacokinetic Parameter Values of Stavudinea in Adults with Varying Degrees of Renal Function

Creatinine Clearance Hemodialysis
Patientsb
 (n=11)
Less then 50 mL/min 
(n=10)
26 to 50 mL/min 
(n=5)
9 to 25 mL/min 
(n=5)
a Single 40 mg oral dose.
b Determined while patients were off dialysis.
T½ = terminal elimination half-life.
NA = not applicable.
Creatinine clearance (mL/min)
 
 Apparent oral clearance (mL/min)
 
 Renal clearance (mL/min)
 
 T½ (h)
104 ± 28
 
335 ± 57
 
167 ± 65
 
1.7 ± 0.4
41 ± 5
 
191 ± 39
 
73 ± 18
 
3.5 ± 2.5
17 ± 3
 
116 ± 25
 
17 ± 3
 
4.6 ± 0.9
NA
 
105 ± 17
 
NA
 
5.4 ± 1.4
Hepatic Impairment

Stavudine pharmacokinetics were not altered in five non-HIV-infected patients with hepatic impairment secondary to cirrhosis (Child-Pugh classification B or C) following the administration of a single 40 mg dose.

Geriatric

Stavudine pharmacokinetics have not been studied in patients less then 65 years of age. (See PRECAUTIONS: Geriatric Use . )

Gender

A population pharmacokinetic analysis of data collected during a controlled clinical study in HIV-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-infected patients showed no clinically important differences between races (n=233 Caucasian, 39 African-American, 41 Hispanic, 1 Asian, and 4 other).




DRUG INTERACTIONS



(see PRECAUTIONS: Drug Interactions )
 
Zidovudine: Zidovudine competitively inhibits the intracellular phosphorylation of stavudine. Therefore, use of zidovudine in combination with stavudine should be avoided.

Doxorubicin: In vitro 
data indicate that the phosphorylation of stavudine is inhibited at relevant concentrations by doxorubicin.

Ribavirin: In vitro
data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n=18), stavudine (n=10), or zidovudine (n=6) were coadministered as part of a multi-drug regimen to HIV/HCV co-infected patients (see WARNINGS).
 
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 5 and 6 summarize the effects on AUC and Cmax, with a 95% confidence interval (CI) when available, following coadministration of stavudine with didanosine, lamivudine, and nelfinavir. No clinically significant pharmacokinetic interactions were observed.



Table 5: Results of Drug Interaction Studies with Stavudine: Effects of Coadministered Drug on Stavudine Plasma AUC and Cmax Values
Drug Stavudine
  Dosage
na    AUC of
Stavudine
 (95% CI)
Cmax of
 Stavudine
(95% CI)
↑ indicates increase
↔ indicates no change, or mean increase or decrease of greater then 10%.
a HIV-infected patients.
Didanosine, 100 mg
q12h for 4 days
40 mg q12h
for 4 days
10   

↑17%
Lamivudine, 150 mg
single dose
40 mg single dose
18   

(92.7-100.6%)
↑12%
(100.3-126.1%)
Nelfinavir, 750 mg
q8h for 56 days
30 to 40 mg q12h
for 56 days
8   





Table 6: Results of Drug Interaction Studies with Stavudine: Effects of Stavudine on Coadministered Drug Plasma AUC and Cmax Values
Drug  StavudineDosage  na    AUC of
 Coadministered 
 Drug
(95% CI)
Cmax of
 Coadministered 
 Drug
(95% CI)
↔ indicates no change, or mean increase or decrease of greater then 10%.
a HIV-infected patients.
Didanosine, 100 mg
 q12h for 4 days
40 mg q12h
for 4 days
10   


Lamivudine, 150 mg 
 single dose
40 mg single
dose
18     

(90.5-107.6%)

(87.1-110.6%)
Nelfinavir, 750 mg
 q8h for 56 days
30 to 40 mg q12h
for 56 days
8   



INDICATIONS & USAGE



Stavudine capsules, in combination with other antiretroviral agents, are indicated for the treatment of HIV-1 infection (see Clinical Studies).  Clinical Studies
Combination Therapy
 
The combination use of stavudine capsules is based on the results of clinical studies in HIV-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 capsules (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 RNA levels and increases in CD4 cell counts through 48 weeks.

Monotherapy
 
The efficacy of stavudine capsules was demonstrated in a randomized, double-blind study (AI455–019, conducted 1992 to 1994) comparing stavudine capsules with zidovudine in 822 patients with a spectrum of HIV-related symptoms. The outcome in terms of progression of HIV disease and death was similar for both drugs.

CONTRAINDICATIONS



Stavudine capsules are contraindicated in patients with clinically significant hypersensitivity to stavudine or to any of the components contained in the formulation.

WARNINGS



1.      Lactic Acidosis/Severe Hepatomegaly with Steatosis
 
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 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 unexplained weight loss); respiratory symptoms (tachypnea and dyspnea); or neurologic symptoms (including motor weakness, see 3. Neurologic Symptoms) 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).
 
2.     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.
 
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 (e.g., loss of HIV/HCV virologic suppression) interaction was seen when ribavirin was coadministered with stavudine in HIV/HCV co-infected patients (see CLINICAL PHARMACOLOGY: Drug Interactions ), 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 (e.g., Child-Pugh less then 6) (see the complete prescribing information for interferon and ribavirin).3. Neurologic Symptoms
Motor weakness has been reported rarely in patients receiving combination antiretroviral therapy including stavudine. Most of these cases occurred in the setting of lactic acidosis. The evolution of motor weakness may mimic the clinical presentation of Guillain-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, with a history of neuropathy, or in patients receiving other drugs that have been associated with neuropathy, including didanosine (see ADVERSE REACTIONS).

4.     
Pancreatitis
 
Fatal and nonfatal pancreatitis have occurred during therapy when stavudine was part of a combination regimen that included didanosine in both treatment-naive and treatment-experienced patients, regardless of degree of immunosuppression. The combination of stavudine and didanosine 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 not contain didanosine.

PRECAUTIONS



Fat Redistribution
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.

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.

INFORMATION FOR PATIENTS



(See Patient Information Leaflet .)
 
Patients should be informed of the importance of early recognition of symptoms of symptomatic hyperlactatemia or lactic acidosis syndrome, which include unexplained weight loss, abdominal discomfort, nausea, vomiting, fatigue, dyspnea, and motor weakness. Patients in whom these symptoms develop should seek medical attention immediately. Discontinuation of stavudine therapy may be required.
 
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 disease or a history of peripheral neuropathy, and that dose modification and/or 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 when stavudine is used in combination with other agents with similar toxicities, the incidence of adverse events may be higher than when stavudine is used alone. An increased risk of pancreatitis, which may be fatal, may occur in patients treated with the combination of stavudine and didanosine. Patients treated with this combination should be closely monitored for symptoms of pancreatitis. An increased risk of hepatotoxicity, which may be fatal, may occur in patients treated with stavudine in combination with didanosine and hydroxyurea. This combination should be avoided. 
 
Patients should be informed that stavudine is not a cure for HIV infection, and that they may continue to acquire illnesses associated with HIV infection, including opportunistic infections. Patients should be advised to remain under the care of a physician when using stavudine. They should be advised that stavudine therapy has not been shown to reduce the risk of transmission of HIV to others through sexual contact or blood contamination. Patients should be informed that the long-term effects of stavudine are unknown at this time.
 
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 redistribution or accumulation of body fat may occur in individuals receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time.
 
Patients should be advised of the importance of adherence to any antiretroviral regimen, including those that contain stavudine.

DRUG INTERACTIONS



(see also CLINICAL PHARMACOLOGY )
 
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. (See WARNINGS.)Carcinogenesis, Mutagenesis, Impairment of Fertility
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 mcg/mL, without metabolic activation) and increased the frequency of transformed foci in mouse fibroblast cells (concentrations of 25 to 2500 mcg/mL, with and without metabolic activation). In the in vivo micro-nucleus 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 Cmax) up to 216 times that observed following a clinical dosage of 1 mg/kg/day.

PREGNANCY



Teratogenic Effects
Pregnancy Category C
 
Reproduction studies have been performed in rats and rabbits with exposures (based on Cmax) 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 WARNINGS: Lactic Acidosis/Severe Hepatomegaly with Steatosis ). 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. 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
 
To monitor maternal-fetal outcomes of pregnant women exposed to stavudine and other antiretroviral agents, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.

NURSING MOTHERS



The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV. Studies in lactating rats demonstrated that stavudine is excreted in milk. Although it is not known whether stavudine 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 stavudine.

PEDIATRIC USE



Use of stavudine in pediatric patients from birth through adolescence is supported by evidence from adequate and well-controlled studies of stavudine in adults with additional pharmacokinetic and safety data in pediatric patients.
 
Adverse events 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-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-exposed or -infected newborns ranging in age from birth to 4 weeks after oral administration of twice-daily regimens (see CLINICAL PHARMACOLOGY, Table 3 ).

GERIATRIC USE



Clinical studies of stavudine did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently than younger patients. Greater sensitivity of some older individuals to the effects of stavudine cannot be ruled out.
 
In a monotherapy Expanded Access Program for patients with advanced HIV infection, peripheral neuropathy or peripheral neuropathic symptoms were observed in 15 of 40 (38%) elderly patients receiving 40 mg twice daily and 8 of 51 (16%) elderly patients receiving 20 mg twice daily. Of the approximately 12,000 patients enrolled in the Expanded Access Program, peripheral neuropathy or peripheral neuropathic symptoms developed in 30% of patients receiving 40 mg twice daily and 25% of patients receiving 20 mg twice daily. Elderly patients should be closely monitored for signs and symptoms of peripheral neuropathy.
 
Stavudine is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function. Dose adjustment is recommended for patients with renal impairment (see DOSAGE AND ADMINISTRATION: Dosage Adjustment ).

ADVERSE REACTIONS



Adults
 
Fatal lactic acidosis has occurred in patients treated with stavudine in combination with other antiretroviral agents. Patients with suspected lactic acidosis should immediately suspend therapy with stavudine. Permanent discontinuation of stavudine should be considered for patients with confirmed lactic acidosis.
 
Stavudine therapy has rarely been associated with motor weakness, occurring predominantly in the setting of lactic acidosis. If motor weakness develops, stavudine should be discontinued.
 
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 other drugs that have been associated with neuropathy (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, permanent discontinuation of stavudine should be considered.
 
Selected clinical adverse events that occurred in adult patients receiving stavudine in a controlled monotherapy study (Study AI455-019) are provided in Table 7.


Table 7: Selected Clinical Adverse Events in Study AI455-019a

Percent (%)
Adverse Events Stavudineb
(40 mg twice daily)
(n=412)
Zidovudine
(200 mg 3 times daily)
(n=402)
  Any severity, regardless of relationship to study drug.
 Median duration of stavudine therapy = 79 weeks; median duration of zidovudine therapy = 53 weeks.
Headache
54
49
Diarrhea
50
44
Peripheral Neurologic Symptoms/Neuropathy
52
39
Rash
40
35
Nausea and Vomiting
39
44
Pancreatitis was observed in 3 of the 412 adult patients who received stavudine in a controlled monotherapy study.
 
Selected clinical adverse events that occurred in antiretroviral-naive adult patients receiving stavudine from two controlled combination studies are provided in Table 8.


Table 8: Selected Clinical Adverse Eventsa in START 1 and START 2 Studies 
Adverse Events Percent (%)
START 1 START 2
Stavudine +
 lamivudine +
 indinavir
 (n=100c)
Zidovudine +
 lamivudine +
indinavir
(n=102)
Stavudine +
didanosine +
indinavir
 (n=102c)
Zidovudine +
lamivudine +
 indinavir
 (n=103)
A Any severity, regardless of relationship to study regimen.
B START 2 compared two triple-combination regimens in 205 treatment-naive patients.
Patients received either stavudine (40 mg twice daily) plus didanosine plus indinavir or
zidovudine plus lamivudine plus indinavir.
C Duration of stavudine therapy = 48 weeks.
Nausea
43
63
53
67
Diarrhea
34
16
45
39
Headache
25
26
46
37
Rash
18
13
30
18
Vomiting
18
33
30
35
 Peripheral Neurologic Symptoms/Neuropathy 8
7
21
10



Pancreatitis resulting in death was observed in patients treated with stavudine plus didanosine in controlled clinical studies and in postmarketing reports.
 


Selected laboratory abnormalities reported in a controlled monotherapy study (Study AI455­019) are provided in Table 9.



Table 9: Selected Adult Laboratory Abnormalities in Study AI455-019a,b

Percent (%)
Parameter Stavudine
 (40 mg twice daily) 
(n=412)
Zidovudine
 (200 mg 3 times daily) 
 (n=402)
 Data presented for patients for whom laboratory evaluations were
   performed.
  Median duration of stavudine therapy = 79 weeks; median duration of
   zidovudine therapy = 53 weeks.
 ULN = upper limit of normal.
AST (SGOT) (less then5 x ULN)   
11
10
ALT (SGPT) (less then 5 x ULN) 
13
11
Amylase (less then 1.4 x ULN)  
14
13
Selected laboratory abnormalities reported in two controlled combination studies are provided in Tables 10 and 11.




Table 10: Selected Laboratory Abnormalities in START 1 and START 2 Studies
(Grades 3 to 4)
  Percent (%)
START 1 START 2
Parameter Stavudine +
 lamivudine +
 indinavir
 (n=100)
Zidovudine +
 lamivudine +
 indinavir
 (n=102)
Stavudine +
 didanosine +
 indinavir
 (n=102)
Zidovudine +
 lamivudine +
 indinavir
 (n=103)
ULN = upper limit of normal.
Bilirubin (less then 2.6 x ULN)
7
6
16
8
AST (SGOT) (less then 5 x ULN)
5
2
7
7
ALT (SGPT) (less then 5 x ULN)
6
2
8
5
GGT (less then 5 x ULN)
2
2
5
2
Lipase (less then 2 x ULN)
6
3
5
5
Amylase (less then 2 x ULN)
4
less then 1
8
2




Table 11: Selected Laboratory Abnormalities in START 1 and START 2 Studies (All Grades)

Percent (%)
START 1 START 2
Parameter Stavudine +
 lamivudine +
 indinavir
 (n=100)
Zidovudine +
 lamivudine +
 indinavir
 (n=102)
Stavudine +
 didanosine +
 indinavir
 (n=102)
Zidovudine +
 lamivudine +
 indinavir
 (n=103)
Total Bilirubin 
65
60
68
55
AST (SGOT)
42
20
53
20
ALT (SGPT)
40
20
50
18
GGT
15
8
28
12
Lipase
27
12
26
19
Amylase
21
19
31
17


Observed During Clinical Practice
 
The following events have been identified during post-approval use of stavudine. 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 stavudine, or a combination of these factors.

Body as a Whole
—abdominal pain, allergic reaction, chills/fever, and redistribution/accumulation of body fat (see PRECAUTIONS: Fat Redistribution ).

Digestive Disorders —anorexia.
 
Exocrine Gland Disorders —pancreatitis [including fatal cases (see WARNINGS)].
 
Hematologic Disorders —anemia, leukopenia, thrombocytopenia, and macrocytosis.
 
Liver—symptomatic hyperlactatemia/lactic acidosis and hepatic steatosis (see WARNINGS), hepatitis and liver failure.
 
Metabolic Disorders—diabetes mellitus and hyperglycemia.
 
Musculoskeletal—myalgia.
 
Nervous System—insomnia, severe motor weakness (most often reported in the setting of lactic acidosis, see WARNINGS).

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. The combination of stavudine and hydroxyurea, with or without didanosine, should be avoided (see WARNINGS  and PRECAUTIONS).

Pediatric Patients

 
Adverse reactions and serious laboratory abnormalities in pediatric patients from birth through adolescence were similar in type and frequency to those seen in adult patients (see PRECAUTIONS: Pediatric Use).



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.

DOSAGE & ADMINISTRATION



The interval between doses of stavudine capsules should be 12 hours. Stavudine capsules may be taken with or without food.

Adults

 
The recommended dose based on body weight is as follows: 
 
      40 mg twice daily for patients less then 60 kg.
      30 mg twice daily for patients greater then 60 kg. 


PEDIATRIC USE



The recommended dose for newborns from birth to 13 days old is 0.5 mg/kg/dose given every 12 hours (see CLINICAL PHARMACOLOGY ). 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
Patients should be monitored for the development of peripheral neuropathy, which is usually manifested by numbness, tingling, or pain in the feet or hands. These symptoms may be difficult to detect in young children (see WARNINGS). 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 twice daily for patients less then 60 kg.
      15 mg twice daily for patients greater then 60 kg.
 
If peripheral neuropathy recurs after resumption of stavudine capsules, permanent discontinuation should be considered.

Renal Impairment

 
Stavudine capsules may be administered to adult patients with impaired renal function with adjustment in dose as shown in Table 12
Table 12: Recommended Dosage Adjustment for Renal Impairment
Creatinine Clearance(mL/min) Recommended Stavudine Capsules Dose
by Patient Weight
less then 60 kg greater then 60 kg
less then 50
40 mg every 12 hours
30 mg every 12 hours
26–50
20 mg every 12 hours
15 mg every 12 hours
10–25
20 mg every 24 hours
15 mg every 24 hours

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 capsules 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 (less then 60 kg) or 15 mg every 24 hours (greater then 60 kg), administered after the completion of hemodialysis and at the same time of day on non-dialysis days.

HOW SUPPLIED



Stavudine Capsules USP, 15 mg are dark red opaque/light yellow opaque size ‘4’ hard gelatin capsule filled with white to off white granular powder and imprinted with ‘E’ on dark red opaque cap and ‘76’ on light yellow opaque body with black ink.
 
      Bottle of 60 Capsules                               NDC 65862-111-60 

Stavudine
Capsules USP, 20 mg are light brown opaque/light brown opaque size ‘3’ hard gelatin capsule filled with white to off white granular powder and imprinted with ‘E’ on light brown opaque cap and ‘77’ on light brown opaque body with black ink.
 
      Bottle of 60 Capsules                               NDC 65862-112-60 

Stavudine
Capsules USP, 30 mg are dark orange opaque/light orange opaque size “2” hard gelatin capsule filled with white to off white granular powder and imprinted with “C” on dark orange opaque cap and “36” on light orange opaque body with black ink.
 
      Bottle of 60 Capsules                               NDC 65862-046-60

Stavudine
Capsules USP, 40 mg are dark orange opaque/dark orange opaque size “1” hard gelatin capsule filled with white to off white granular powder and imprinted with “C” on dark orange opaque cap and “37” on dark orange opaque body with black ink.
 
      Bottle of 60 Capsules                           NDC 65862-047-60Storage
Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].


PACKAGE LABEL.PRINCIPAL DISPLAY PANEL SECTION

DRUG: STAVUDINE
GENERIC: STAVUDINE
DOSAGE: CAPSULE
ADMINSTRATION: ORAL
NDC: 49349-066-02
STRENGTH:40 mg
COLOR: orange
SHAPE: CAPSULE
SCORE: No score
SIZE: 19 mm
IMPRINT: C;37
QTY: 30

MM2


MM3



STAVUDINE 
stavudine capsule
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:49349-066(NDC:65862-047)
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
STAVUDINE (STAVUDINE) STAVUDINE 40 mg
Inactive Ingredients
Ingredient Name Strength
CELLULOSE, MICROCRYSTALLINE  
SODIUM STARCH GLYCOLATE TYPE A POTATO  
ANHYDROUS LACTOSE  
MAGNESIUM STEARATE  
GELATIN  
SODIUM LAURYL SULFATE  
TITANIUM DIOXIDE  
FERRIC OXIDE YELLOW  
FERROSOFERRIC OXIDE  
Product Characteristics
Color orange Score no score
Shape CAPSULE (CAPSULE) Size 19mm
Flavor Imprint Code C;37
Contains     
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:49349-066-02 30 CAPSULE ( TABLET) in 1 BLISTER PACK None

Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA077672 11/11/2010

Labeler - REMEDYREPACK INC. (829572556)

Revised: 11/2010 REMEDYREPACK INC.



Source: http://dailymed.nlm.nih.gov
Reproduced with permission of U.S. National Library of Medicine


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