Important Label Update for Norvir (Ritonavir)

November 23, 2009

On November 23, 2009, FDA approved changes to the Norvir package insert (product label) to include drug-drug interaction information for concurrent ritonavir administration with:

• inhaled medicines such as salmeterol or salmeterol in combination with fluticasone propionate (Serevent, Advair)
• sildenafil (Revatio)

Also other revisions to the Contraindications, Warnings, Precautions: Drug Interactions and Dosage and Administration as follows.

The CONTRAINDICATIONS was updated as follows:
When co-administering NORVIR with other protease inhibitors, see the full prescribing information for that protease inhibitor including contraindication information.
NORVIR is contraindicated in patients with known hypersensitivity to ritonavir or any of its ingredients.
Co-administration of NORVIR is contraindicated with the drugs listed in Table 4 (also see PRECAUTIONS -- Table 5. Drugs that Should Not be Co-administered with NORVIR) because ritonavir mediated CYP3A inhibition can result in serious and/or life-threatening reactions. Voriconazole and St. John's Wort are exceptions in that co-administration of NORVIR and voriconazole results in a significant decrease in plasma concentrations of voriconazole, and co-administration of NORVIR with St. John's Wort may result in decreased ritonavir plasma concentrations.

Table 4. Drugs that are Contraindicated with NORVIR
Drug Class	Drugs Within Class That Are CONTRAINDICATED With NORVIR**
Alpha1-adrenoreceptor antagonist	Alfuzosin HCL
Antiarrhythmics	Amiodarone, bepridil, flecainide, propafenone, quinidine
Antifungal	Voriconazole
Ergot Derivatives	Dihydroergotamine, ergonovine, ergotamine, methylergonovine
GI Motility Agent	Cisapride
Herbal Products	St. John's Wort (hypericum perforatum)
HMG-CoA Reductase Inhibitors:	Lovastatin, simvastatin
Neuroleptic	Pimozide
PDE5 enzyme inhibitor	Sildenafil* (Revatio®) only when used for the treatment of pulmonary arterial hypertension (PAH)
Sedative/hypnotics	Oral midazolam, triazolam
* see WARNINGS - Drug Interactions and PRECAUTIONS -- Table 6. Established and Other Potentially Significant Drug Interactions for coadministration of sildenafil in patients with erectile dysfunction. ** For additional information for these contraindicated drugs, see also PRECAUTIONS -- Table 5. Drugs that Should Not be Co-administered with NORVIR.

The WARNINGS section for Drug Interactions was updated as follows
Drug Interactions
See CONTRAINDICATIONS- Table 4 for a listing of drugs that are contraindicated with NORVIR due to potentially life-threatening adverse events, significant drug interactions, or loss of virologic activity. Also, see PRECAUTIONS -- Table 5 and Table 6 for drugs that should not be co-administered with NORVIR and for a listing of drugs with established and other significant drug interactions.

The PRECAUTIONS section with regard to drug interactions was updated as follows:

Table 5. Drugs that Should Not be Co-administered with NORVIR
Drug Class: Drug Name	Clinical Comment
Alpha Adrenergic Antagonist: alfuzosin	CONTRAINDICATED due to potential for serious reactions such as hypotension.
Antiarrhythmics: amiodarone, bepridil, flecainide, propafenone, quinidine	CONTRAINDICATED due to potential for serious and/or life threatening reactions such as cardiac arrhythmias.
Antifungal: voriconazole	CONTRAINDICATED due to significant decreases in voriconazole plasma concentrations and may lead to loss of antifungal response.
Ergot Derivatives: dihydroergotamine, ergonovine, ergotamine, methylergonovine	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system.
GI Motility Agent: cisapride	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Herbal Products: St. John's wort (hypericum perforatum)	CONTRAINDICATED as the combination may lead to loss of virologic response and possible resistance to NORVIR or to the class of protease inhibitors.
HMG-CoA Reductase Inhibitors: lovastatin, simvastatin	CONTRAINDICATED due to potential for serious reactions such as risk of myopathy including rhabdomyolysis.
Neuroleptic: pimozide	CONTRAINDICATED due to the potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
PDE5 enzyme inhibitor: Sildenafil* (Revatio®)	CONTRAINDICATED in the treatment of pulmonary arterial hypertension (PAH). A safe and effective dose has not been established when used with ritonavir. There is an increased potential for sildenafil-associated adverse events, including visual abnormalities, hypotension, prolonged erection, and syncope.
Sedative/hypnotics: oral midazolam, triazolam	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression.

Table 6 below was revised to include updated information on coadministration with darunavir, tipranavir, maravoric, voriconazole, PDE5 inhibitor for pulmonary arterial hypertension (sildenafil (Revatio)) and parenteral midazolam

Table 6. Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen Recommended Based on Drug Interaction Studies or Predicted Interaction (see CLINICAL PHARMACOLOGY -- Table 2 and Table 3 for Magnitude of Interaction)
Concomitant Drug Class: Drug Name	Effect on Concentration of Ritonavir or Concomitant Drug	Clinical Comment
HIV-Antiviral Agents
HIV Protease Inhibitor: darunavir	When co-administered with reduced doses of ritonavir ↑ darunavir (↑ AUC, ↑ Cmax, ↑ Cmin)	See the complete prescribing information for Prezista® (darunavir) for details on co-administration of darunavir 600 mg b.i.d with ritonavir 100 mg b.i.d. or darunavir 800 mg q.d. with ritonavir 100 mg q.d.
HIV Protease Inhibitor: tipranavir	When co-administered with reduced doses of ritonavir ↑ tipranavir (↑ AUC, ↑ Cmax, ↑ Cmin)	See the complete prescribing information for Aptivus® (tipranavir) for details on co-administration of tipranavir 500 mg b.i.d with ritonavir 200 mg b.i.d. There have been reports of clinical hepatitis and hepatic decompensation including some fatalities. All patients should be followed closely with clinical and laboratory monitoring, especially those with chronic hepatitis B or C co-infection, as these patients have an increased risk of hepatotoxicity. Liver function tests should be performed prior to initiating therapy with tipranavir/ritonavir, and frequently throughout the duration of treatment.
HIV Protease Inhibitor: fosamprenavir	When co-administered with reduced doses of ritonavir ↑ amprenavir (↑ AUC, ↑ Cmax, ↑ Cmin)	See the complete prescribing information for Lexiva® (fosamprenavir) for details on co administration fosamprenavir 700 mg b.i.d with ritonavir 100 mg b.i.d., fosamprenavir 1400 mg q.d. with ritonavir 200 mg q.d. or fosamprenavir 1400 mg q.d. with 100 mg q.d.
HIV CCR5 -- antagonist: maraviroc	↑ maraviroc	Concurrent administration of maraviroc with ritonavir will increase plasma levels of maraviroc. For specific dosage adjustment recommendations, please refer to the complete prescribing information for Selzentry® (maraviroc).
Other Agents
Antifungal: voriconazole	↓ voriconazole	Coadministration of voriconazole and ritonavir doses of 400 mg every 12 hours or greater is contraindicated. Coadministration of voriconazole and ritonavir 100 mg should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole.
Long-acting beta-adrenoceptor agonist: salmeterol	↑ salmeterol	Concurrent administration of salmeterol and ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
PDE5 Inhibitors: sildenafil, tadalafil, vardenafil	↑ sildenafil ↑ tadalafil ↑ vardenafil	Particular caution should be used when prescribing sildenafil, tadalafil or vardenafil in patients receiving ritonavir. Coadministration of ritonavir with sildenafil is expected to substantially increase sildenafil concentrations (11-fold increase in AUC). Use of sildenafil, tadalafil or vardenafil may result in an increase in associated adverse events, including hypotension, syncope, visual changes, and prolonged erection. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Sildenafil (Revatio®) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) because a safe and effective dose has not been established when used with ritonavir (see CONTRAINDICATIONS and PRECAUTIONS -- Drug Interactions, Table 5). Use of PDE5 inhibitors for erectile dysfunction: Sildenafil: The starting does should not, in any case, exceed 25 mg in a 48-hour period in patients receiving concomitant ritonavir therapy (see WARNINGS). Tadalafil: Use tadalafil with caution at reduced doses of no more than 10 mg every 72 hours with increased monitoring for adverse events(see WARNINGS). Vardenafil: Use vardenafil with caution at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring for adverse events(see WARNINGS).
Sedative/hypnotics: Parenteral midazolam	↑ midazolam	Co-administration of oral midazolam with NORVIR is CONTRAINDICATED. Concomitant use of parenteral midazolam with NORVIR may increase plasma concentrations of midazolam. Co-administration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered.

The DOSAGE AND ADMINISTRATION section was revised to include the following statement.

Adults
Dose modification for NORVIR
Dose reduction of NORVIR is necessary when used with other protease inhibitors: amprenavir, atazanavir, darunavir, fosamprenavir, saquinavir, and tipranavir. Prescribers should consult the full prescribing information and clinical study information of these protease inhibitors if they are co-administered with a reduced dose of ritonavir.

The complete revised labeling will be available at Drugs@FDA.

Norvir is a protease inhibitor, marketed by Abbott Laboratories.