Stavudine Oral Solution

FULL PRESCRIBING INFORMATION

WARNING: LACTIC ACIDOSIS and HEPATOMEGALY with STEATOSIS; PANCREATITIS

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 (5.1)].


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 and Precautions (5.4)].

Indications and Usage for Stavudine Oral Solution

Stavudine for oral solution, USP in combination with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus (HIV)-1 infection [see Clinical Studies (14)].

Stavudine Oral Solution Dosage and Administration

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

Recommended Adult Dosage

The recommended adult dosage is based on body weight as follows: 

• For patients weighing less than 60 kg: 30 mg every 12 hours.


• For patients weighing at least 60 kg: 40 mg every 12 hours.

Recommended Pediatric Dosage

• For newborns from birth to 13 days old: 0.5 mg/kg given every 12 hours.


• For pediatric patients at least 14 days old and weighing less than 30 kg: 1 mg/kg given every 12 hours.


• For pediatric patients weighing at least 30 kg: use the recommended adult dosage.

Dosage Adjustment

Renal Impairment


Adult Patients: Stavudine for oral solution may be administered to adult patients with impaired renal function with an adjustment in dosage as shown in Table 1.

Table 1: Recommended Dosage Adjustment for Adult Patients with Renal Impairment

Creatinine Clearance (mL/min)	Recommended Stavudine for Oral Solution Dose by Patient Weight
	at least 60 kg	less than 60 kg
* Administered after the completion of hemodialysis on dialysis days and at the same time of day on non-dialysis days.
greater than 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
Hemodialysis	20 mg every 24 hours*	15 mg every 24 hours*

Pediatric Patients: 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. There are insufficient data to recommend a specific dose adjustment of stavudine for oral solution in this patient population.

Method of Preparation for Oral Solution

Prior to dispensing, the pharmacist must constitute the dry powder with purified water to a concentration of 1 mg stavudine per mL of solution, as follows:  

1. Add 202 mL of purified water to the container.


2. Shake container vigorously until the powder dissolves completely. Constitution in this way produces 200 mL (deliverable volume) of 1 mg/mL stavudine solution. The solution may appear slightly hazy.


3. Dispense solution in original container with measuring cup provided. Instruct patient to shake the container vigorously prior to measuring each dose and to store the tightly closed container in a refrigerator, 2° to 8°C (36° to 46°F). Discard any unused portion after 30 days.

Dosage Forms and Strengths

• Stavudine for oral solution is a white to off-white, cherry flavored granular powder that provides 1 mg of stavudine per mL of solution upon constitution with water.

Contraindications

Stavudine for oral solution 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

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 Use in Specific Populations (8.1)].

 

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 Warnings and Precautions (5.3)] might be indicative of the development of symptomatic hyperlactatemia or lactic acidosis syndrome.

 

Treatment with stavudine should be suspended in any patient who develops clinical or laboratory findings suggestive of symptomatic hyperlactatemia, lactic acidosis, or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations). Permanent discontinuation of stavudine should be considered for patients with confirmed lactic acidosis.

Hepatic 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.

 

Hepatotoxicity and hepatic failure resulting in death were reported during postmarketing surveillance in HIV-infected patients treated with hydroxyurea and other antiretroviral agents. Fatal hepatic events were reported most often in patients treated with the combination of hydroxyurea, didanosine, and stavudine. This combination should be avoided. [See Adverse Reactions (6).]

 

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-1/HCV virologic suppression) interaction was seen when ribavirin was coadministered with stavudine in HIV-1/HCV co-infected patients [see Drug Interactions (7)], hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 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 >6) (see the full 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). If motor weakness develops, stavudine should be discontinued. Symptoms may continue or worsen following discontinuation of therapy.

 

Peripheral sensory neuropathy, manifested by numbness, tingling, or pain in the hands or feet, has been reported in patients receiving stavudine therapy. Peripheral neuropathy, which can be severe, is dose related and occurs more frequently in patients with advanced HIV-1 disease, a history of peripheral neuropathy, or in patients receiving other drugs that have been associated with neuropathy, including didanosine [see Adverse Reactions (6)].

 

Patients should be monitored for the development of peripheral neuropathy. Stavudine-related peripheral neuropathy may resolve if therapy is withdrawn promptly. If peripheral neuropathy develops permanent discontinuation of stavudine should be considered. In some cases, symptoms may worsen temporarily following discontinuation of therapy.

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; avoid use in combination with didanosine.

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.

 

In randomized controlled trials of treatment-naive patients, clinical lipoatrophy or lipodystrophy developed in a higher proportion of patients treated with stavudine compared to other nucleosides (tenofovir or abacavir). Dual energy x-ray absorptiometry (DEXA) scans demonstrated overall limb fat loss in stavudine-treated patients compared to  limb fat gain or no gain in patients treated with other nucleosides (abacavir, tenofovir, or zidovudine). The incidence and severity of lipoatrophy or lipodystrophy are cumulative over time with stavudine-containing regimens. In clinical trials, switching from stavudine to other nucleosides (tenofovir or abacavir) resulted in increases in limb fat with modest to no improvements in clinical lipoatrophy. Patients receiving stavudine should be monitored for symptoms or signs of lipoatrophy or lipodystrophy and questioned about body changes related to  lipoatrophy or lipodystrophy. Given the potential risks of using stavudine including lipoatrophy or lipodystrophy, a benefit-risk assessment for each patient should be made and an alternative antiretroviral should be considered.

Immune Reconstitution Syndrome

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.

 

Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have  also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.

Adverse Reactions

The following adverse reactions are discussed in greater detail in other sections of the labeling: 

• lactic acidosis and severe hepatomegaly with steatosis [see Boxed Warning and Warnings and Precautions (5.1)]


• hepatic toxicity [see Warnings and Precautions (5.2)]


• neurologic symptoms and motor weakness [see Warnings and Precautions (5.3)]


• pancreatitis [see Boxed Warning and Warnings and Precautions (5.4)]


• lipoatrophy/lipodystrophy [see Warnings and Precautions (5.5)]

When stavudine is used in combination with other agents with similar toxicities, the incidence of adverse reactions may be higher than when stavudine is used alone.

Clinical Trial Experience in Adults

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

 

Selected adverse reactions that occurred in adult patients receiving stavudine in a controlled monotherapy study (Study AI455-019) are provided in Table 2.

Table 2: Selected Adverse Reactions in Study AI455-019a (Monotherapy)

Adverse Reaction	Percent (%)
	Stavudineb (40 mg twice daily) (n=412)	Zidovudine (200 mg 3 times daily) (n=402)
a The incidences reported included all severity grades and all reactions regardless of causality. b 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 study AI455-019.

 

Selected adverse reactions that occurred in antiretroviral-naive adult patients receiving stavudine from two controlled combination studies are provided in Table 3.

Table 3: Selected Adverse Reactionsa in START 1 and START 2b Studies (Combination Therapy)

Adverse Reaction	Percent (%)
	START 1		START 2b
	Stavudine + Lamivudine + Indinavir (n=100c)	Zidovudine + Lamivudine + Indinavir (n=102)	Stavudine + Didanosine + Indinavir (n=102c)	Zidovudine + Lamivudine + Indinavir (n=103)
a The incidences reported included all severity grades and all reactions regardless of causality. 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

Selected laboratory abnormalities reported in a controlled monotherapy study (Study AI455-019) are provided in Table 4.

Table 4: Selected Laboratory Abnormalities in Study AI455-019a,b

Parameter	Percent (%)
	Stavudine (40 mg twice daily) (n=412)	Zidovudine (200 mg 3 times daily) (n=402)
a Data presented for patients for whom laboratory evaluations were performed. b Median duration of stavudine therapy = 79 weeks; median duration of zidovudine therapy = 53 weeks. ULN = upper limit of normal.
AST (SGOT) (>5 x ULN)	11	10
ALT (SGPT) (>5 x ULN)	13	11
Amylase (≥1.4 x ULN)	14	13

Selected laboratory abnormalities reported in two controlled combination studies are provided in Tables 5 and 6. 

Table 5: Selected Laboratory Abnormalities in START 1 and START 2 Studies (Grades 3 to 4)

Parameter	Percent (%)
	START 1		START 2
	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 (>2.6 x ULN)	7	6	16	8
AST (SGOT) (>5 x ULN)	5	2	7	7
ALT (SGPT) (>5 x ULN)	6	2	8	5
GGT (>5 x ULN)	2	2	5	2
Lipase (>2 x ULN)	6	3	5	5
Amylase (>2 x ULN)	4	<1	8	2

Table 6: Selected Laboratory Abnormalities in START 1 and START 2 Studies (All Grades)

Parameter	Percent (%)
	START 1		START 2
	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

Clinical Trial Experience in Pediatric Patients

Adverse reactions and serious laboratory abnormalities reported in pediatric patients from birth through adolescence during clinical trials were similar in type and frequency to those seen in adult patients. [See Use in Specific Populations (8.4).]

Postmarketing Experience

The following adverse reactions have been identified during postmarketing use of stavudine. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These reactions have been chosen for inclusion due to their seriousness, frequency of reporting, causal connection to stavudine, or a combination of these factors.


Body as a Whole: abdominal pain, allergic reaction, chills/fever, and redistribution/accumulation of body fat [see Warnings and Precautions (5.5)].


Digestive Disorders: anorexia.

 

Exocrine Gland Disorders: pancreatitis, including fatal cases [see Warnings and Precautions (5.4)].


Hematologic Disorders: anemia, leukopenia, thrombocytopenia, neutropenia, and macrocytosis.


Liver: symptomatic hyperlactatemia/lactic acidosis and hepatic steatosis [see Warnings and Precautions (5.1)], hepatitis and liver failure.


Metabolic Disorders: lipoatrophy, lipodystrophy [see Warnings and Precautions (5.5)], diabetes mellitus and hyperglycemia.


Musculoskeletal: myalgia.


Nervous System: insomnia, severe motor weakness (most often reported in the setting of lactic acidosis) [see Warnings and Precautions (5.1, 5.3)].


Use with Didanosine- and Hydroxyurea-Based Regimens

 

When stavudine is used in combination with other agents with similar toxicities, the incidence of these toxicities may be higher than when stavudine is used alone. Thus, patients treated with stavudine in combination with didanosine, with or without hydroxyurea, may be at increased risk for pancreatitis and hepatotoxicity, which may be fatal, and severe peripheral neuropathy [see Warnings and Precautions (5)]. The combination of stavudine and hydroxyurea, with or without didanosine, should be avoided.

Drug Interactions

Stavudine is unlikely to interact with drugs metabolized by cytochrome P450 isoenzymes.


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. The clinical significance of this interaction is unknown; therefore, concomitant use of stavudine with doxorubicin should be undertaken with caution.


Ribavirin: In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine. The clinical significance of the interaction with stavudine is unknown; therefore, concomitant use of stavudine with ribavirin should be undertaken with caution. No pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV-1/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-1/HCV co-infected patients [see Warnings and Precautions (5.2)].

USE IN SPECIFIC POPULATIONS

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 Boxed Warning and Warnings and Precautions (5.1)]. 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 breastfeed 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 breastfeed 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 [see Dosage and Administration (2.2) and Adverse Reactions (6.2)].

 

Adverse reactions and laboratory abnormalities reported to occur in pediatric patients in clinical studies were generally consistent with the safety profile of stavudine in adults. These studies include ACTG 240, where 105 pediatric patients ages 3 months to 6 years received stavudine 2 mg/kg/day for a median of 6.4 months; a controlled clinical trial where 185 newborns received stavudine 2 mg/kg/day either alone or in combination with didanosine from birth through 6 weeks of age; and a clinical trial where 8 newborns received stavudine 2 mg/kg/day in combination with didanosine and nelfinavir from birth through 4 weeks of age.

 

Stavudine pharmacokinetics have been evaluated in 25 HIV-1-infected pediatric patients ranging in age from 5 weeks to 15 years and in weight from 2 to 43 kg after IV or oral administration of single doses and twice-daily regimens and in 30 HIV-1-exposed or -infected newborns ranging in age from birth to 4 weeks after oral administration of twice-daily regimens [see Clinical Pharmacology (12.3, Table 9)].

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-1 infection, peripheral neuropathy or peripheral neuropathic symptoms were observed in 15 of 40 (38%) elderly patients receiving 40 mg twice daily and 8 of 51 (16%) elderly patients receiving 20 mg twice daily. Of the approximately 12,000 patients enrolled in the Expanded Access Program, peripheral neuropathy or peripheral neuropathic symptoms developed in 30% of patients receiving 40 mg twice daily and 25% of patients receiving 20 mg twice daily. Elderly patients should be closely monitored for signs and symptoms of peripheral neuropathy.

 

Stavudine is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function. Dose adjustment is recommended for patients with renal impairment [see Dosage and Administration (2.3)].

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. Based on these observations, it is recommended that the stavudine dosage be modified in patients with reduced creatinine clearance and in patients receiving maintenance hemodialysis [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

Overdosage

Experience with adults treated with 12 to 24 times the recommended daily dosage revealed no acute toxicity. Complications of chronic overdosage include peripheral neuropathy and hepatic toxicity. Stavudine can be removed by hemodialysis; the mean ± SD hemodialysis clearance of stavudine is 120 ± 18 mL/min. Whether stavudine is eliminated by peritoneal dialysis has not been studied.

Stavudine Oral Solution Description

Stavudine Oral Solution, USP contains stavudine (d4T), which is a synthetic thymidine nucleoside analogue, active against the human immunodeficiency virus type 1 (HIV-1). The chemical name for stavudine is 2′,3′-didehydro-3′-deoxythymidine. Stavudine has the following structural formula:

Stavudine USP 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 23°C is approximately 83 mg/mL in water and 30 mg/mL in propylene glycol. The n-octanol/water partition coefficient of stavudine at 23°C is 0.144.

 

Stavudine for oral solution, USP is supplied as a white to off-white, cherry flavored granular powder in bottles with child-resistant closures providing 200 mL of a 1 mg/mL stavudine solution upon constitution with water per label instructions. The powder for oral solution contains the following inactive ingredients: methylparaben, propylparaben, carboxymethylcellulose sodium, 30% simethicone emulsion, sucrose, and art.cherry flavor.

Stavudine Oral Solution - Clinical Pharmacology

Mechanism of Action

Stavudine is an antiviral drug [see Clinical Pharmacology (12.4)].

Pharmacokinetics

The pharmacokinetics of stavudine have been evaluated in HIV-1-infected adult and pediatric patients (Tables 7, 8, and 9). 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 same following administration as capsules or solution. Steady-state pharmacokinetic parameters of stavudine in HIV-1-infected adults are shown in Table 7.

Table 7: Steady-State Pharmacokinetic Parameters of Stavudine in HIV-1-Infected Adults

Parameter	Stavudine 40 mg BID Mean ± SD (n=8)
AUC0-24 = Area under the curve over 24 hours. Cmax = Maximum plasma concentration. Cmin = Trough or minimum plasma concentration.
AUC0-24 (ng•h/mL)	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 8.


Metabolism

 

Metabolism plays a limited role in the clearance of stavudine. Unchanged stavudine was the major drug-related component circulating in plasma after an 80 mg dose of 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-1-infected patients, renal elimination of unchanged drug accounts for about 40% of the overall clearance regardless of the route of administration (Table 8). The mean renal clearance was about twice the average endogenous creatinine clearance, indicating active tubular secretion in addition to glomerular filtration.

Table 8: Pharmacokinetic Parameters of Stavudine in HIV-1-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 (%)	86.4 ± 18.2	25
Volume of distribution (L)a	46 ± 21	44
Total body clearance (mL/min)a	594 ± 164	44
Apparent oral clearance (mL/min)b	560 ± 182c	113
Renal clearance (mL/min)a	237 ± 98	39
Elimination half-life, IV dose (h)a	1.15 ± 0.35	44
Elimination half-life, oral dose (h)b	1.6 ± 0.23	8
Urinary recovery of stavudine (% of dose)a,d	42 ± 14	39

Special Populations


Pediatric

 

Pharmacokinetic parameters of stavudine in pediatric patients are presented in Table 9.

Table 9: Pharmacokinetic Parameters (Mean ± SD) of Stavudine in HIV-1-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 %)b	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