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U.S. Department of Health and Human Services

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Changes to Crixivan (indinavir sulfate) capsules product label and patient package insert

The following revisions were made to the Crixivan product label

1. The following changes were made to the CLINICAL PHARMACOLOGY section

• Text was revised in Delavirdine section and now reads:
"Delavirdine inhibits the metabolism of indinavir such that coadministration of 400-mg or 600-mg
indinavir three times daily with 400-mg delavirdine three times daily alters indinavir Area Under the Curve (AUC), Maximum Concentration (Cmax ) and Minimum Concentration (Cmin). Indinavir had no effect on delavirdine pharmacokinetics

(see DOSAGE AND ADMINISTRATION, Concomitant Therapy, Delavirdine), based on a
comparison to historical delavirdine pharmacokinetic data."

• Text was revised in the Methadone section and now reads:
"Administration of indinavir (800 mg every 8 hours) with methadone (20 mg to 60 mg daily) for
one week in subjects on methadone maintenance resulted in no change in methadone AUC.
Based on a comparison to historical data, there was little or no change in indinavir AUC."

• Text was revised in Ritonavir section and now reads:
"Compared to historical data in patients who received indinavir 800 mg every 8 hours alone,
twice-daily coadministration to volunteers of indinavir 800 mg and ritonavir with food for two
weeks resulted in an 2.7-fold increase of indinavir AUC24h, a 1.6-fold increase in indinavir Cmax,
and an 11-fold increase in indinavir Cmin for a 100-mg ritonavir dose and a 3.6-fold increase of
indinavir AUC24h, a 1.8-fold increase in indinavir Cmax, and a 24-fold increase in indinavir Cmin
for a 200-mg ritonavir dose. In the same study, twice-daily coadministration of indinavir (800 mg)
and ritonavir (100 or 200 mg) resulted in ritonavir AUC24h increases versus the same doses of
ritonavir alone (see Table 3)."

• Vardenafil text was added, and reads:
Vardenafil: Indinavir (800 mg every 8 hours) coadministered with a single 10-mg dose of vardenafil resulted in a 16-fold increase in vardenafil AUC, a 7-fold increase in vardenafil Cmax, and a 2-fold
increase in vardenafil half-life (see WARNINGS, Drug Interactions and PRECAUTIONS,

Drug Interactions).

2. In the WARNINGS: Drug Interactions section text was added to include references to tadalafil,
sildenafil, and vardenafil.

3. In the PRECAUTIONS: Information for Patients section the following sentence was revised to include
reference PDE5 inhibitors.

"Patients receiving a phosphodiesterase type 5 (PDE5) inhibitor (sildenafil, tadalafil, or vardenafil)
should be advised that they may be at an increased risk of PDE5 inhibitor-associated adverse
events including hypotension, visual changes, and priapism, and should promptly report any
symptoms to their doctors."

4. In the PRECAUTIONS section, atazanavir was added to Table 8: "Drugs that should not be
Coadministered with CRIXIVAN"

5. In the DOSAGE AND ADMINISTRATION section, text regarding efavirenz was deleted.

The following revisions were made to the Crixivan Patient Package Insert

• Seldane (terfenadine) was deleted and Cordarone (amiodarone) and D.H.E. 45,
Migranal, Ergotrate, and Methergine were added under "Medicines you should not take
with CRIXIVAN" in the "Can CRIXIVAN be taken with other medications?" section.

• The following sentence was added to "Medicines you should not take with CRIXIVAN" in the
"Can CRIXIVAN be taken with other medications?" section:

"Taking CRIXIVAN with REYATAZ (atazanavir) is not recommended because they can both
sometimes cause increased levels of bilirubin in the blood."

• A paragraph under the "Can CRIXIVAN be taken with other medications?" section was revised and now reads:

"Before you take VIAGRA (sildenafil), CIALIS (tadalafil), or LEVITRA (vardenafil) with
CRIXIVAN, talk to your doctor about possible drug interactions and side effects. If you take any
of these medicines together with CRIXIVAN, you may be at increased risk of side effects such
as low blood pressure, visual changes, and penile erection lasting more than 4 hours, which have
been associated with sildenafil, tadalafil, and vardenafil. If an erection lasts longer than 4 hours,
you should seek immediate medical assistance to avoid permanent damage to your penis.
Your doctor can explain these symptoms to you."

• "CRESTOR (rosuvastatin)" was added to "Medicines you can take with CRIXIVAN" in the "Can
CRIXIVAN be taken with other medications?" section.

• The following sentences were added to the "Can CRIXIVAN be taken with other medications?" section:

"Calcium Channel Blockers: Tell your doctor if you are taking calcium channel blockers (e.g., amlodipine, felodipine).

Antiarrhythmics: Tell your doctor if you are taking antiarrhythmics (e.g., quinidine).

Anticonvulsants: Tell your doctor if you are taking anticonvulsants (e.g., phenobarbital, phenytoin, or carbamazepine).

Steroids: Tell your doctor if you are taking steroids (e.g., dexamethasone)."

 

The complete revised label is available on the web at http://www.fda.govhttp://www.accessdata.fda.gov/drugsatfda_docs/label/ 2004/20685slr046,047_crixivan_lbl.pdf

Richard Klein
Office of Special Health Issues
Food and Drug Administration

Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration