sábado, 19 de diciembre de 2015

Invirase Labeling Updated

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FDA approved changes to the Invirase (saquinavir mesylate) label to provide updated for drugs that are contraindicated or interact with Invirase/ritonavir.
Also a warning was added to state cobicistat is not recommended for concomitant use with Invirase. The specific changes are summarized below.
Section 2: DOSAGE AND ADMINISTRATION was updated as follows:
Cobicistat is not interchangeable with ritonavir to increase systemic exposure of saquinavir.
For patients already taking ritonavir 100 mg twice daily as part of their antiretroviral regimen, no additional ritonavir is needed.
Section 4: CONTRAINDICATIONS was updated to contraindicate the following agents.
Drugs That Are Contraindicated With INVIRASE/ritonavir
Drug ClassDrugs Within Class That Are Contraindicated With INVIRASE/ritonavirClinical Comment
Anti-infectivesClarithromycin, erythromycin, halofantrine, pentamidinePotential for serious and/or life-threatening cardiac arrhythmia.
HIV-1 Protease InhibitorAtazanavirPotential for serious and/or life-threatening cardiac arrhythmia.
ImmunosuppressantTacrolimusPotential for serious and/or life-threatening cardiac arrhythmia.
NeurolepticsPimozide
Chlorpromazine
Sertindole
Clozapine
Haloperidol
Mesoridazine
Phenothiazines
Thioridazine
Ziprasidone
Potential for serious and/or life threatening reactions such as cardiac arrhythmias.
Other drugs that are CYP3A substratesDapsone
Disopyramide
Quinine
Potential for serious and/or life-threatening cardiac arrhythmia.

The following statement was added to section 5: WARNINGS and PRECAUTIONS. INVIRASE is not recommended for use in combination with cobicistat.
Dosing recommendations for this combination have not been established. Cobicistat is also not recommended in combination with regimens containing
ritonavir due to similar effects of cobicistat and ritonavir on CYP3A. Please refer to the cobicistat full prescribing information for additional precautionary
measures.
The following changes were made to section 7: Drug Interactions to provide clinical comments regarding when coadministration is not recommended or
when additional monitoring is needed.
Concomitant Drug Class:
Drug Name
Effect on Concentration of Saquinavir or Concomitant DrugClinical Comment
HIV-1 Antiviral Agents
Non-nucleoside reverse transcriptase inhibitor:
Delavirdineb
Saquinavir

Effect on delavirdine is not well established
Appropriate doses of the combination with respect to safety and efficacy have not been established. Coadministration is not recommended.
Liver function should be monitored frequently if this combination is prescribed.
Non-nucleoside reverse transcriptase inhibitor:
Efavirenza,
nevirapineb
↓ Saquinavir
↔ Efavirenz


Appropriate doses of the combination of efavirenz or nevirapine and INVIRASE/ritonavir with respect to safety and efficacy have not been established. Coadministration is not recommended.
HIV-1 protease inhibitor:
AtazanavirIndinavirb
Saquinavir
Indinavir
↔ Atazanavir

Atazanavir in Appropriate doses of the combination of indinavir and INVIRASE/ritonavir with respect to safety and efficacy have not been established. Coadministration is not recommended.
may result in nephrolithiasis. For further details see complete prescribing information for Crixivan® (indinavir).
HIV-1 protease inhibitor:
IndinavirLopinavir/ritonavira(coformulated tablet)
« Saquinavir
« Lopinavir
↓ Ritonavir
Evidence from several clinical trials indicates that saquinavir concentrations achieved with the saquinavir and lopinavir/ritonavir combination are similar to those achieved following INVIRASE/ritonavir 1000/100 mg. The recommended dose for this combination is INVIRASE 1000 mg plus lopinavir/ritonavir 400/100 mg bid.

Lopinavir/ritonavir in combination with INVIRASE should be used with caution. Additive effects on QT and/or PR interval prolongation may occur with INVIRASE [see Warnings and Precautions (5.25.3)].
Appropriate doses of the combination of indinavir and INVIRASE/ritonavir with respect to safety and e
HIV-1 protease inhibitor:
Lopinavir/ritonavirNelfinavir
Saquinavir
Other Agents
Ibutilide
Sotalol
Use with caution. Additive effects on QT and/or PR interval prolongation may occur with INVIRASE/ritonavir [see Contraindications (4) and Warnings and Precautions (5.25.3)]. Coadministration of INVIRASE/ritonavir and ibutilide or sotalol is not recommended.
Anticonvulsants:Carbamazepineb, phenobarbitalb, phenytoinb¯ Saquinavir

Effect on carbamazepine, phenobarbital, and phenytoin is not well established
Use with caution. Saquinavir may be less effective due to decreased saquinavir plasma concentrations in patients taking these agents concomitantly. Coadministration is not recommended.
Anti-infective:Streptogramin antibiotics
(quinupristin/dalfopristinb)                    
Streptogramin antibiotics such as quinupristin/dalfopristin inhibit CYP3A4; saquinavir concentrations may be increasedMonitoring for saquinavir toxicity is recommended. Use with caution due to possible cardiac arrhythmias.
Antimycobacterial: Rifabutina↔ Saquinavir
Rifabutin
↔ Ritonavir

No dose adjustment of INVIRASE/ritonavir (1000/100 mg bid) is required if INVIRASE/ritonavir is administered in combination with rifabutin.

Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse events including neutropenia and liver enzyme levels is warranted in patients receiving the combination.

Consider monitoring rifabutin concentrations to ensure adequate exposure.
Benzodiazepinesb:
Alprazolam, clorazepate, diazepam, flurazepam
BenzodiazepinesClinical significance is unknown. Careful monitoring of patients for benzodiazepine effects is warranted; a decrease in benzodiazepine dose may be needed.
Corticosteroid:Dexamethasoneb¯ Saquinavir
Use with caution. SaquinavirINVIRASE/ritonavir may be less effective due to decreased saquinavir plasma concentrations. Coadministration is not recommended.
Inhaled/nasal steroids:
Fluticasoneb
Budesonide
FluticasoneConcomitant use of fluticasone propionate and INVIRASE/ritonavir may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Several cases of Cushing’s disease associated with this interaction have been reported in the literature. Coadministration of fluticasone propionate and INVIRASE/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects. If the combination is nevertheless considered necessary, a dose reduction of fluticasone propionate with close monitoring of local and systemic effects is recommended.

A switch to a corticosteroid which is not a substrate for CYP3A (e.g., beclomethasone) should be considered. In case of withdrawal of corticosteroids, progressive dose reduction may have to be performed over a longer period.
HMG-CoA reductase inhibitorsb:
Atorvastatin
Atorvastatin
Titrate atorvastatin dose carefully and use the lowest dose necessary; do not exceed atorvastatin 20 mg/day. Patients should be carefully monitored for signs and symptoms of myopathy (e.g., muscle weakness, muscle pain, rising creatininecreatine kinase).
Immunosuppressantsb:
Cyclosporine, rapamycin
ImmunosuppressantsTherapeutic concentration monitoring is recommended for immunosuppressant agents when coadministered with INVIRASE/ritonavir.
Narcotic analgesic:
Methadonea
¯ MethadoneDosage of methadone may need to be increased when coadministered with INVIRASE/ritonavir.

Use with caution. Additive effects on QT and/or PR interval prolongation may occur with INVIRASE/ritonavir [see Contraindications (4) and Warnings and Precautions (5.25.3)].
Tricyclic antidepressantsb:Amitriptyline, clomipramine, imipramine, maprotiline
TricyclicsTherapeutic concentration monitoring is recommended for tricyclic antidepressants when coadministered with INVIRASE/ritonavir.
Other antidepressants:
Nefazodone
SaquinavirMonitoring for saquinavir toxicity is recommended.
Herbal Products:
St. John’s wort(hypericum perforatum)
↓ SaquinavirHerbal products containing St. John’s wort should not be used concomitantly with INVIRASE/ritonavir because coadministration may lead to loss of virologic response and possible resistance to INVIRASE or to the class of protease inhibitors.
Other drugs that are substrates of CYP3A:Fentanylb
Alfentanilb
Fentanyl
Alfentanil
Coadministration with these drugs may accentuate the side effects reported with use of fentanyl or alfentanil including respiratory depression, apnea and bradycardia.
Vasodilators (peripheral):
Intravenously administered Vincamine
VincamineMonitoring for vincamine toxicity is recommended. Use with caution due to potential cardiac arrhythmias.

7.4  Drugs without Clinically Significant Interactions with INVIRASE/ritonavir
Based on drug interaction studies conducted with INVIRASE/ritonavir, no clinically significant effect was observed for saquinavir when coadministered
with fosamprenavir. No clinically significant effect was observed for enfuvirtide when coadministered with INVIRASE/ritonavir.
Section 12: Clinical Pharmacology was updated to include the following statement
The HIV-1 antiviral drugs didanosine, tenofovir, and zidovudine are not predicted to have any clinically significant effect on the pharmacokinetics of
saquinavir with and without ritonavir.  No clinically significant effect on the pharmacokinetic parameters of enfuvirtide was observed with
coadministration of INVIRASE/ritonavir. No clinically significant effect on the pharmacokinetic parameters of saquinavir was observed with coadministration
of fosamprenavir.
You will be able to view the complete label at drugs@fda or dailymed.
Richard Klein
Office of Health and Constituent Affairs
Food and Drug Administration
Kimberly Struble
Division of Antiviral Products
Food and Drug Administration
Steve Morin
Office of Health and Constituent Affairs
Food and Drug Administration
For more information about the HIV Liaison Program visit the FDA Patient Network

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