Usual Adult Dose for HIV Infection

Initial Dose (lead-in dosing period):

• Immediate-release formulations: 200 mg orally once a day for 14 days

Maintenance Dose (after lead-in dosing period):

• Immediate-release formulations: 200 mg orally twice a day
• Extended-release tablets: 400 mg orally once a day

Use: In combination with other antiretroviral agents, for the treatment of HIV-1 infection

Usual Pediatric Dose for HIV Infection

Initial Dose (lead-in dosing period):
Immediate-release formulations:

• Age 15 days or older: 150 mg/m2 orally once a day for 14 days

Maximum initial dose: 200 mg/day

Maintenance Dose (after lead-in dosing period):
Immediate-release formulations:

• Age 15 days or older: 150 mg/m2 orally twice a day

Extended-release tablets:

• Age 6 years or older:
• BSA 0.58 to 0.83 m2: 200 mg orally once a day
• BSA 0.84 to 1.16 m2: 300 mg orally once a day
• BSA at least 1.17 m2: 400 mg orally once a day

Maximum maintenance dose: 400 mg/day

Use: In combination with other antiretroviral agents, for the treatment of HIV-1 infection

Panel on Antiretroviral Therapy and Medical Management of Children Infected with HIV Recommendations:
Immediate-release formulations:

• Gestational age 34 to less than 37 weeks, less than 1 month of age: 4 mg/kg orally twice a day for the first week followed by 6 mg/kg orally twice a day
• Gestational age at least 37 weeks, less than 1 month of age: 6 mg/kg orally twice a day
• Age 1 month to less than 8 years:
• Initial dose (lead-in dosing): 200 mg/m2 orally once a day for 14 days
• Maintenance dose: 200 mg/m2 orally twice a day
• Age 8 years or older:
• Initial dose (lead-in dosing): 120 to 150 mg/m2 orally once a day for 14 days
• Maintenance dose: 120 to 150 mg/m2 orally twice a day

Maximum dose: 200 mg/dose

Extended-release tablets:

• Age 6 years or older (maintenance dose):
• BSA 0.58 to 0.83 m2: 200 mg orally once a day
• BSA 0.84 to 1.16 m2: 300 mg orally once a day
• BSA at least 1.17 m2: 400 mg orally once a day

Comments:

• In children up to 2 years of age, some experts start this drug without lead-in dosing.
• As long as there are no side effects, the mg dose does not need to be decreased when the child reaches 8 years; the mg dose is left the same to achieve the appropriate mg/m2 dosage as the child grows larger.
• The total daily dose should not exceed 400 mg.
• Current guidelines should be consulted for additional information.

Usual Pediatric Dose for Reduction of Perinatal Transmission of HIV

Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission Recommendations:
Prophylaxis dosage (3 doses total):

• Birth weight 1.5 to 2 kg: 8 mg orally within 48 hours of birth, 48 hours after first dose, and 96 hours after second dose
• Birth weight greater than 2 kg: 12 mg orally within 48 hours of birth, 48 hours after first dose, and 96 hours after second dose

Treatment dosage:

• Gestational age 34 to less than 37 weeks at birth, up to 1 week of age: 4 mg/kg orally twice a day
• Gestational age 34 to less than 37 weeks at birth, 1 to 6 weeks of age: 6 mg/kg orally twice a day
• Gestational age at least 37 weeks at birth, up to 6 weeks of age: 6 mg/kg orally twice a day

Comments:

• Immediate-release formulation recommended.
• Combination antiretroviral prophylaxis with 3 doses of this drug (using prophylaxis dosage) plus 6 weeks of zidovudine OR empiric HIV therapy using this drug (using treatment dosage) plus zidovudine and lamivudine recommended for higher risk of perinatal HIV transmission and presumed neonate HIV exposure
• This drug (using treatment dosage) plus zidovudine and lamivudine recommended for neonates with confirmed HIV
• Optimum duration of empiric HIV therapy in neonates at higher risk of perinatal HIV transmission is unknown; many experts use 6 weeks of combination therapy while others stop this drug and/or lamivudine after newborn testing returns negative.
• Therapy should be started as close to time of birth as possible, preferably within 6 to 12 hours of delivery.
• Current guidelines should be consulted for additional information.

Renal Dose Adjustments

CrCl at least 20 mL/min (and not requiring dialysis): No adjustment recommended.
CrCl less than 20 mL/min: Data not available

Comments:

• The extended-release tablets have not been studied in patients with renal dysfunction.

Liver Dose Adjustments

Moderate or severe liver dysfunction (Child-Pugh B or C): Contraindicated

Comments:

• The extended-release tablets have not been assessed in patients with liver dysfunction.

Dose Adjustments

Patients with Dose Interruption:

• If this drug is interrupted for more than 7 days, it should be restarted at the lower lead-in dose (using the immediate-release formulation) for the first 14 days.

Patients with Hepatic Events:

• This drug should be permanently discontinued if a clinical (symptomatic) hepatic event occurs.
• This drug must not be restarted after recovery.

Patients with Rash:

• This drug should be discontinued if a severe rash or any rash accompanied by constitutional findings develops.
• If patient has mild to moderate rash without constitutional symptoms during the 14-day lead-in period with an immediate-release formulation:
• The dose of the immediate-release formulation should not be increased OR therapy with the extended-release tablets should not be started until rash has resolved.
• The total duration of the lead-in dosing period should not exceed 28 days, at which point another regimen should be used.

Precautions

US BOXED WARNINGS:

• HEPATOTOXICITY: Severe, life-threatening, and in some cases fatal, hepatotoxicity (especially in the first 18 weeks) reported with this drug. Some patients presented with nonspecific prodromal signs/symptoms of hepatitis and progressed to hepatic failure; such events were often associated with rash. Increased risk with female gender and higher CD4+ cell counts at start of therapy; greatest risk in women with CD4+ cell counts greater than 250 cells/mm3 (including pregnant women using this drug with other antiretrovirals for treatment of HIV-1 infection). However, drug-related hepatotoxicity can occur in both genders, all CD4+ cell counts, and at any time during therapy. Hepatic failure also reported in patients without HIV using this drug for postexposure prophylaxis (PEP); use of this drug for occupational and nonoccupational PEP is contraindicated. Patients with signs/symptoms of hepatitis (or with increased transaminases together with rash/other systemic symptoms) must stop this drug and seek medical evaluation immediately.
• SKIN REACTIONS: Severe and life-threatening skin reactions (including fatalities) reported with this drug; such reactions included Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions (indicated by rash, constitutional findings, organ dysfunction). Patients with signs/symptoms of severe skin reactions or hypersensitivity reactions must stop this drug and seek medical evaluation immediately. All patients developing a rash within the first 18 weeks of therapy should have transaminase levels checked at once. The 14-day lead-in period with the immediate-release formulation has been shown to reduce the incidence of rash and must be followed.
• MONITORING FOR HEPATOTOXICITY AND SKIN REACTION: Intensive monitoring recommended during the first 18 weeks of therapy to detect potentially life-threatening hepatotoxicity or skin reactions. Extra vigilance necessary during the first 6 weeks of therapy (the time of greatest risk for such events). This drug should not be restarted after clinical hepatitis (or increased transaminases together with rash/other systemic symptoms) or after severe skin rash/hypersensitivity reactions; some cases of hepatic injury progressed even though treatment was stopped.

CONTRAINDICATIONS:
Moderate or severe liver dysfunction (Child-Pugh B or C); use as part of occupational and nonoccupational postexposure prophylaxis regimens

Safety and efficacy of the extended-release tablets have not been established in patients younger than 6 years.

Consult WARNINGS section for additional precautions.

Dialysis

Hemodialysis:

• Immediate-release formulations: A supplemental 200 mg dose should be administered after each dialysis session.
• Extended-release tablets: Data not available

Comments:

• Metabolites of this drug may accumulate in patients on dialysis; clinical significance not established.

Other Comments

Administration advice:

• Due to serious and life-threatening hepatotoxicity seen in trials, do not start this drug (unless benefits outweigh risks) in adult females with CD4+ cell counts greater than 250 cells/mm3 or adult males with CD4+ cell counts greater than 400 cells/mm3.
• Do not use as a single agent to treat HIV-1 or add to a failing regimen as a single agent.
• May administer without regard to food
• If the oral suspension is used, shake gently before each use and use an oral syringe to measure an accurate dose.
• Swallow the extended-release tablets whole and do not chew, crush, or divide; consider ability to swallow tablets before prescribing the extended-release formulation.
• Do not administer the immediate-release and extended-release formulations concurrently.

General:

• No recommendations provided regarding use of 4 extended-release 100 mg tablets to replace 1 extended-release 400 mg tablet.
• The tablet formulations contain lactose; the oral suspension contains sucrose, sorbitol, methylparaben, and propylparaben.

Monitoring:

• General: Clinical and laboratory (baseline and during first 18 weeks of therapy [the manufacturer product information should be consulted]); drug-induced toxicity in patients with hepatic fibrosis or cirrhosis
• Hepatic: Liver enzymes (baseline and during first 18 weeks of therapy [the manufacturer product information should be consulted])

Patient advice:

• Read the US FDA-approved patient labeling (Medication Guide).
• Stop this drug and seek medical attention (including laboratory monitoring) at once if signs/symptoms of liver disease or severe skin reactions develop.
• Stop this drug and seek medical attention at once if signs/symptoms of hepatitis occur.
• If any rash occurs during the 2-week lead-in period, do not escalate the immediate-release formulation dose or start the extended-release tablets; stop this drug and consult physician if severe rash or hypersensitivity reactions develop.
• Consult healthcare provider immediately regarding any signs/symptoms of infection.