Agenerase (amprenavir) Side Effects, Warnings, and Drug Interactions

Agenerase (amprenavir) is a protease inhibitor used to treat human immunodeficiency virus (HIV) infection. The HIV virus multiplies within the body’s cells. Viruses are released from the cells and spread throughout the body where they infect other cells.

During the production of the viruses, new proteins, some of which are enzymes, manufacture DNA and other components for the new viruses. Protease is the enzyme that forms the new structural proteins and enzymes. 

Agenerase blocks the activity of protease and results in the formation of defective viruses unable to infect the body's cells. As a result, the viral load decreases. Agenerase does not prevent transmission of HIV, and it does not cure HIV or AIDS. Agenerase was discontinued in October 2007. 

Common side effects of Agenerase include:

• headache,
• weakness,
• diarrhea,
• nausea,
• stomach pain,
• and redistribution or accumulation of body fat.

Serious side effects of Agenerase include:

• severe skin reactions,
• breakdown of red blood cells,
• increased cholesterol,
• and worsening of diabetes.

The propylene glycol in the oral solution can cause: 

• seizures,
• stupor,
• increased heart rate,
• metabolic disturbance,
• and kidney failure. 

Drug interactions of Agenerase include:

• rifampin because it reduces plasma concentrations of Agenerase.
• Systemic corticosteroid combined with Agenerase can produce effects including:
  • Cushing's syndrome
  • and adrenal suppression.
• Agenerase used with St. John's wort substantially decreases protease inhibitor concentrations.
• Agenerase combined with HMG-CoA reductase inhibitors increases the risk of:
  • muscle disease, including rhabdomyolysis.
• Agenerase and sildenafil used together substantially increases sildenafil concentrations and may result in:
  • low blood pressure,
  • visual changes,
  • and prolonged erections.

Other drug interactions of Agenerase include:

• ergot derivatives,
• gastrointestinal motility agents,
• neuroleptics,
• non-nucleoside reverse transcriptase inhibitors (NNRTIs),
• oral contraceptives,
• sedative/hypnotics,
• other HIV-antiviral agents,
• antacids,
• antiarrhythmics,
• anticoagulants,
• anticonvulsants,
• antidepressants,
• antifungals,
• benzodiazepines,
• calcium channel blockers,
• immunosuppressants,
• and narcotics.

It is unknown Agenerase is secreted in breast milk. HIV-infected mothers should not breastfeed because of the potential risk of transmitting HIV to a nursing infant.

The most frequent side effects are:

• headache,
• weakness,
• diarrhea,
• nausea
• and stomach pain.

Amprenavir may also cause severe skin reactions and breakdown of red blood cells.

The propylene glycol in the oral solution can cause:

• seizures,
• stupor,
• increased heart rate,
• metabolic disturbance,
• and kidney failure.

Like other protease inhibitors, use of amprenavir may be associated with:

• redistribution or accumulation of body fat,
• increased cholesterol
• and worsening of diabetes.

• In clinical studies, adverse events leading to amprenavir discontinuation occurred primarily during the first 12 weeks of therapy, and were mostly due to: gastrointestinal events (nausea, vomiting, diarrhea, and abdominal pain/discomfort), which were mild to moderate in severity.
• Skin rash occurred in 22% of patients treated with amprenavir in studies PROAB3001 and PROAB3006.
• Rashes were usually maculopapular and of mild or moderate intensity, some with pruritus.
• Rashes had a median onset of 11 days after amprenavir initiation and a median duration of 10 days.
• Skin rashes led to amprenavir discontinuation in approximately 3% of patients.
• In some patients with mild or moderate rash, amprenavir dosing was often continued without interruption; if interrupted, reintroduction of amprenavir generally did not result in rash recurrence.

Severe or life-threatening rash (Grade 3 or 4), including cases of Stevens -Johnson syndrome, occurred in approximately 1% of recipients of Agenerase. Amprenavir therapy should be discontinued for severe or life-threatening rashes and for moderate rashes accompanied by systemic symptoms.

Table 9. Selected Clinical Adverse Events of All Grades Reported in > 5% of Adult Patients

Among amprenavir-treated patients in Phase 3 studies, 2 patients developed de novo diabetes mellitus, 1 patient developed a dorsocervical fat enlargement (buffalo hump), and 9 patients developed fat redistribution.

In studies PROAB3001 and PROAB3006, no increased frequency of Grade 3 or 4 AST, ALT, amylase, or bilirubin elevations was seen compared to controls.

Pediatric Patients: An adverse event profile similar to that seen in adults was seen in pediatric patients.

Concomitant Therapy with Ritonavir: Tables 10 and 11 present adverse clinical events and laboratory abnormalities observed in subjects who received Agenerase plus ritonavir. Since the trials were small, open-label, of varying duration, and often included different patient populations, direct comparisons to the frequency of events with Agenerase alone (see Table 9) cannot be made.

Table 10. Selected Clinical Adverse Events of All Grades Reported in Adult Patients in Open-Label Clinical Trials of Agenerase in Combination With Ritonavir

Table 11. Grade 3/4 Laboratory Abnormalities Reported in ≥ 2% of Adult Patients in Open-Label Clinical Trials of Agenerase in Combination With Ritonavir

Agenerase is an inhibitor of cytochrome P450 3A4 metabolism and therefore should not be administered concurrently with medications with narrow therapeutic windows that are substrates of CYP3A4. There are other agents that may result in serious and/or life-threatening drug interactions.

Table 7. Drugs That Should Not Be Coadministered With Agenerase

Table 8. Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction