Stavudine Oral Solution

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

Recommended Adults 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 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

* Administered after the completion of hemodialysis on dialysis days and at the same time of day on non-dialysis days.
Creatinine Clearance  (mL/min)	Recommended Stavudine Dose by Patient Weight
	At least 60 kg	Less than 60 kg
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 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 200 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°C to 8°C (36°F to 46°F). Discard any unused portion after 30 days.

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

AUC0-24 = Area under the curve over 24 hours.
Cmax = Maximum plasma concentration.
Cmin = Trough or minimum plasma concentration.
Parameter	Stavudine 40 mg BID Mean ± SD (n=8)
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 μg/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 62.0%, 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

* Following 1-hour IV infusion. † Following single oral dose. ‡ Assuming a body weight of 70 kg. § Over 12–24 hours
Parameter	Mean ± SD	n
Oral bioavailability (%)	86.4 ± 18.2	25
Volume of distribution (L)*	46 ± 21	44
Total body clearance (mL/min)*	594 ± 164	44
Apparent oral clearance (mL/min)†	560 ± 182‡	113
Renal clearance (mL/min)*	237 ± 98	39
Elimination half-life, IV dose (h)*	1.15 ± 0.35	44
Elimination half-life, oral dose (h)†	1.6 ± 0.23	8
Urinary recovery of stavudine (% of dose)*,§	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

ND = Not determined
* Following 1-hour IV infusion. † At median time of 2.5 hours (range 2–3 hours) following multiple oral doses. ‡ Following single oral dose. § Over 8 hours.
Parameter	Ages 5 weeks to  15 years	n	Ages 14 to 28  days	n	Day of Birth	n
Oral bioavailability (%)	76.9 ± 31.7	20	ND		ND
Volume of distribution  (L/kg)*	0.73 ± 0.32	21	ND		ND
Ratio of CSF: plasma  concentrations (as %)†	59 ± 35	8	ND		ND
Total body clearance  (mL/min/kg)*	9.75 ± 3.76	21	ND		ND
Apparent oral clearance  (mL/min/kg)‡	13.75 ± 4.29	20	11.52 ± 5.93	30	5.08 ± 2.80	17
Elimination half-life,  IV dose (h)*	1.11 ± 0.28	21	ND		ND
Elimination half-life , oral dose (h)‡	0.96 ± 0.26	20	1.59 ± 0.29	30	5.27 ± 2.01	17
Urinary recovery of  stavudine (% of dose)‡,§	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 10). 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 2–6 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 (2.3)].

Table 10: Mean ± SD Pharmacokinetic Parameter Values of Stavudine* in Adults with Varying Degrees of Renal Function

T½ = Terminal elimination half-life.
NA = Not applicable.
* Single 40-mg oral dose. † Determined while patients were off dialysis
	Creatinine Clearance
	>50 mL/min (n=10)	26–50 mL/min (n=5)	9–25 mL/min (n=5)	Hemodialysis Patients† (n=11)
Creatinine clearance (mL/min)	104 ± 28	41 ± 5	17 ± 3	NA
Apparent oral clearance (mL/min)	335 ± 57	191 ± 39	116 ± 25	105 ± 17
Renal clearance (mL/min)	167 ± 65	73 ± 18	17 ± 3	NA
T½ (h)	1.7 ± 0.4	3.5 ± 2.5	4.6 ± 0.9	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 >65 years of age. [See Use in Specific Populations (8.5).]

Gender

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

Drug Interaction Studies

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 11 and 12 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 11: Results of Drug Interaction Studies with Stavudine: Effects of Coadministered Drug on Stavudine Plasma AUC and Cmax Values

↑ Indicates increase.
↔ Indicates no change, or mean increase or decrease of <10%.
* HIV-1-infected patients
Drug	Stavudine Dosage	n*	AUC of Stavudine (95% CI)	Cmax of Stavudine (95% CI)
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	30–40 mg  q12h for 56 days	8	↔	↔

Table 12: Results of Drug Interaction Studies with Stavudine: Effects of Stavudine on Coadministered Drug Plasma AUC and Cmax Values

↔ Indicates no change, or mean increase or decrease of <10%.
* HIV-1-infected patients.
Drug	Stavudine Dosage	n*	AUC of  Coadministered Drug (95% CI)	Cmax of  Coadministered Drug (95% CI)
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	30–40 mg  q12h for 56 days	8	↔	↔

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 in Cell Culture

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 9–45 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.

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 (6–29 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 substitutions T215Y and K219E, and isolates from another patient contained the multiple-nucleoside-resistance-associated substitution 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 thymidine analogue mutations (TAMs; M41L, D67N, K70R, L210W, T215Y/F, K219Q/E) associated with zidovudine resistance. HIV-1 isolates with one or more TAMs exhibited reduced susceptibility to stavudine in cell culture. These TAMs are seen at a similar frequency with stavudine and zidovudine in virological treatment. The clinical relevance of these findings suggests that stavudine should be avoided in the presence of thymidine analogue mutations.

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 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 Cmax) up to 216 times that observed following a clinical dosage of 1 mg/kg/day.

Side effects that you should report to your doctor or health care professional as soon as possible:

• breathing difficulties
• increased hunger or thirst
• increased urination
• muscle weakness in arms and legs
• nausea, vomiting, unusual stomach upset or pain
• tingling, pain, burning, or numbness in the hands or feet
• unusual bleeding or bruising
• unusually weak or tired
• weight gain around waist, back, or thinning of face, arms, legs

Side effects that usually do not require medical attention (report to your doctor or health care professional if they continue or are bothersome):

• diarrhea
• difficulty sleeping
• fever, chills
• headache
• loss of appetite
• muscle pain
• weight loss