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Agenerase

Side Effects & Drug Interactions
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SIDE EFFECTS

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 (see WARNINGS). 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
Adverse Event
PROAB3001Therapy-Naive Patients
PROAB3006NRTI-Experienced Patients
AGENERASE/ Lamivudine/ Zidovudine (n = 113)
Lamivudine/ Zidovudine (n = 109)
AGENERASE/ NRTI (n = 245)
Indinavir/NRTI (n = 241)
Digestive
Nausea
74%
50%
43%
35%
Vomiting
34%
17%
24%
20%
Diarrhea or loose stools
39%
35%
60%
41%
Taste disorders
10%
6%
2%
8%
Skin
Rash
27%
6%
20%
15%
Nervous
Paresthesia, oral/perioral
26%
6%
31%
2%
Paresthesia, peripheral
10%
4%
14%
10%
Psychiatric
Depressive or mood disorders
16%
4%
9%
13%

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 inOpen-Label Clinical Trials of AGENERASE in Combination With Ritonavir
AGENERASE 1,200 mg plus Ritonavir 200 mg q.d.*
AGENERASE 600 mg plus Ritonavir 100 mg b.i.d.†
Adverse Event
(n = 101)
(n = 239)
Nausea
31%
23%
Diarrhea/loose stools
30%
28%
Headache
16%
12%
Abdominal symptoms
14%
14%
Vomiting
11%
9%
Rash
10%
9%
Paresthesias
9%
11%
Fatigue
7%
14%
Depressive & mood disorders
4%
9%
* Data from 2 open-label studies in treatment-naive patients also receiving abacavir/lamivudine.
† Data from 3 open-label studies in treatment-naive and treatment-experienced patients receiving combination antiretroviral therapy.

 

Table 11. Grade 3/4 Laboratory Abnormalities Reported in ≥2% of Adult Patients in Open-Label Clinical Trials of AGENERASE in Combination With Ritonavir
Laboratory Abnormality (non-fasting specimens) AGENERASE 1,200 mg plus Ritonavir 200 mg q.d.* (n = 101) AGENERASE 600 mg plus Ritonavir 100 mg b.i.d.† (n = 239)
Hypertriglyceridemia (>750 mg/dL)
8%
13%
Hyperglycemia (>251 mg/dL)
2%
3%
AST (>5 x ULN)
3%
5%
ALT (>5 x ULN)
4%
4%
Amylase (>2 x ULN)
4%
3%
* Data from 2 open-label studies in treatment-naive patients also receiving abacavir/lamivudine.
† Data from 3 open-label studies in treatment-naive and treatment-experienced patients receiving combination antiretroviral therapy.

DRUG INTERACTIONS

See also CONTRAINDICATIONS, WARNINGS, and CLINICAL PHARMACOLOGY: Drug Interactions.

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 (see CONTRAINDICATIONS and WARNINGS).

Table 7. Drugs That Should Not Be Coadministered With AGENERASE
Drug Class/Drug Name Antimycobacterials: Rifampin* Clinical Comment May lead to loss of virologic response and possible resistance to AGENERASE or to the class of protease inhibitors.
Ergot derivatives: Dihydroergotamine, ergonovine, ergotamine, methylergonovine CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
GI motility agents: Cisapride CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Herbal products: St. Johns wort (hypericum perforatum) May lead to loss of virologic response and possible resistance to AGENERASE or to the class of protease inhibitors.
HMG Co-reductase inhibitors: Lovastatin, simvastatin Potential for serious reactions such as risk of myopathy including rhabdomyolysis.
Neuroleptic: Pimozide CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Non-nucleoside reverse transcriptase inhibitor : Delavirdine* May lead to loss of virologic response and possible resistance to delavirdine.
Oral contraceptives: Ethinyl estradiol/norethindrone May lead to loss of virologic response and possible resistance to AGENERASE. Alternative methods of non-hormonal contraception are recommended.
Sedative/hypnotics: Midazolam, triazolam CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression.
*See CLINICAL PHARMACOLOGY for magnitude of interaction, Tables 3 and 4.

Table 8. Established and Other Potentially Significant Drug Interactions: Alteration in Dose orRegimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction
Concomitant Drug Class: Drug Name
Effect on Concentration of Amprenavir or Concomitant Drug
Clinical Comment
HIV-Antiviral Agents
Non-nucleoside reversetranscriptase inhibitors: Efavirenz, nevirapine ¯Amprenavir Appropriate doses of the combinations with respect to safety and efficacy have not been established.
Nucleoside reverse transcriptase inhibitor: Didanosine (buffered formulation only) ¯Amprenavir Take AGENERASE at least 1 hour before or after the buffered formulation of didanosine.
HIV proteaseinhibitors: Indinavir*, lopinavir/ritonavir, nelfinavir* ­Amprenavir Appropriate doses of the combinations with respect to safety and efficacy have not been established.
Amprenavirseffect on other protease inhibitorsis not welle stablished.
HIV proteaseinhibitor: Ritonavir* ­Amprenavir The dose of amprenavir should be reduced when used in combination with ritonavir (see DOSAGE AND ADMINISTRATION). Also, see the full prescribing information for NORVIR for additional drug interaction information.
HIV proteaseinhibitor : Saquinavir* ¯Amprenavir Appropriate doses of the combination with respect to safety and efficacy have not been established.
Amprenavirseffect on saquinavir is notwell established.
Other Agents
Antacids ¯Amprenavir Take AGENERASE at least 1 hour before or after antacids.
Antiarrhythmics: Amiodarone, lidocaine (systemic), and quinidine ­Antiarrhythmics Caution is warranted and therapeutic concentration monitoring is recommended for antiarrhythmics when coadministered with AGENERASE, if available.
Antiarrhythmic: Bepridil ­Bepridil Use with caution. Increased bepridil exposure may be associated with life-threatening reactions such as cardiac arrhythmias.
Anticoagulant: Warfarin   Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
Anticonvulsants: Carbamazepine, phenobarbital, phenytoin ¯Amprenavir Use with caution. AGENERASE may be lesse ffective due to decreased amprenavir plasma concentrations in patients taking these agents concomitantly.
Antidepressant: Trazodone ­Trazodone Concomitant use of trazodone and AGENERASE with or without ritonavir may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as AGENERASE, the combination should be used with caution and a lower dose of trazodone should be considered.
Antifungals: Ketoconazole, itraconazole ­Ketoconazole Increase monitoring for adverse events due to ketoconazole or itraconazole. Dose reduction of ketoconazole or itraconazole may be needed for patients receiving more than 400 mg ketoconazole or itraconazole per day.
­Itraconazole
Antimycobacterial: Rifabutin* ­Rifabutin and rifabutin metabolite A dosage reduction of rifabutin to at least half the recommended dose is required when AGENERASE and rifabutin are coadministered.* A complete blood count should be performed weekly and as clinically indicated in order to monitor for neutropenia in patients receiving amprenavir and rifabutin.
Benzodiazepines: Alprazolam, clorazepate, diazepam, flurazepam ­Benzodiazepines Clinical significance is unknown; however, a decrease in benzodiazepine dose may be needed.
Calcium channel blockers: Diltiazem, felodipine, nifedipine, nicardipine, nimodipine, verapamil, amlodipine, nisoldipine, isradipine ­Calcium channel blockers Caution is warranted and clinical monitoring of patients is recommended.
Corticosteroid: Dexamethasone ¯Amprenavir Use with caution. AGENERASE may be less effective due to decreased amprenavir plasma concentrations in patients taking these agents concomitantly.
Erectile dysfunction agent : Sildenafil ­Sildenafil Use with caution at reduced doses of 25 mg every 48 hours with increased monitoring for adverse events.
HMG-CoA reductase inhibitors: Atorvastatin ­Atorvastatin Use lowest possible dose of atorvastatin with careful monitoring or consider other HMG-CoA reductase inhibitors such as pravastatin or fluvastatin in combination with AGENERASE.
Immunosuppressants: Cyclosporine, tacrolimus, rapamycin ­Immunosup-pressants Therapeutic concentration monitoring is recommended for immunosuppressant agents when coadministered with AGENERASE.
Inhaled/nasal steroid : Fluticasone AGENERASE ­ Fluticasone Concomitant use of fluticasone propionate and AGENERASE (without ritonavir) may increase plasma concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate, particularly for long-term use.
AGENERASE/ritonavir ­ Fluticasone Concomitant use of fluticasone propionate and AGENERASE/ritonavir may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Coadministration of fluticasone propionate and AGENERASE/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects (seeWARNINGS).
Narcotic analgesics : Methadone* ¯Amprenavir AGENERASE may be less effective due to decreased amprenavir plasma concentrations in patients taking these agents concomitantly. Alternative antiretroviral therapy should be considered.
¯Methadone Dosage of methadone may need to be increased when coadministered with AGENERASE.
Tricyclic antidepressants: Amitriptyline, imipramine ­Tricyclics Therapeutic concentration monitoring is recommended for tricyclic antidepressants when coadministered with AGENERASE.
*See CLINICAL PHARMACOLOGY for magnitude of interaction, Tables 3 and 4.

Brand Name: Agenerase
Generic Name: Amprenavir
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