INVIRASE in combination with ritonavir and other antiretroviral agents is indicated for the treatment of HIV-1 infection in adults (over the age of 16 years).

The following points should be considered when initiating therapy with INVIRASE/ritonavir:

• The twice daily administration of INVIRASE in combination with ritonavir is supported by safety data from the MaxCmin 1 trial and pharmacokinetic data
• The efficacy of INVIRASE with ritonavir has not been compared against the efficacy of antiretroviral regimens currently considered standard of care
• The number of baseline primary protease inhibitor mutations affects the virologic response to INVIRASE/ritonavir

INVIRASE must be used in combination with ritonavir because ritonavir significantly inhibits saquinavir metabolism to provide increased plasma saquinavir levels.

Cobicistat is not interchangeable with ritonavir to increase systemic exposure of saquinavir. 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. 

Ritonavir should be taken at the same time as INVIRASE. INVIRASE and ritonavir should be taken within 2 hours after a meal.

INVIRASE/ritonavir is contraindicated in patients with congenital long QT syndrome, those with refractory hypokalemia or hypomagnesemia, and in combination with drugs that both increase saquinavir plasma concentrations and prolong the QT interval.

INVIRASE/ritonavir is contraindicated in patients with complete atrioventricular (AV) block without implanted pacemakers, or patients who are at high risk of complete AV block.

INVIRASE/ritonavir is contraindicated in patients with clinically significant hypersensitivity (e.g., anaphylactic reaction, Stevens-Johnson syndrome) to saquinavir, saquinavir mesylate, or any of its ingredients.

INVIRASE/ ritonavir is contraindicated in patients with severe hepatic impairment.

INVIRASE/ritonavir is contraindicated in patients receiving the following co-administered drugs; however, it should be noted that this list is not intended to be exhaustive:

• Alpha 1-adrenoreceptor antagonist: alfuzosin
• Antiarrhythmics: amiodarone, bepridil, dofetilide, flecainide, lidocaine (systemic), propafenone, quinidine
• Antidepressant: trazodone
• Anti-infectives: clarithromycin, erythromycin, halofantrine, pentamidine
• Antimycobacterial Agents: rifampin
• Antipsychotics: lurasidone, clozapine, haloperidol, pimozide, sertindole, ziprasidone, phenothiazines (e.g. chlorpromazine, mesoridazine, thioridazine)
• Ergot Derivatives: dihydroergotamine, ergonovine, ergotamine, methylergonovine
• HIV-1 Protease Inhibitor: atazanavir
• HMG-CoA Reductase Inhibitors: lovastatin, simvastatin
• Immunosuppressant: tacrolimus
• Non-nucleoside reverse transcriptase inhibitor (NNRTI): rilpivirine (concomitant use and switching from rilpivirine to NVIRASE/ritonavir without a washout period of at least 2 weeks is contraindicated)
• PDE5 Inhibitors: sildenafil (Revatio) [for treatment of pulmonary arterial hypertension]
• Sedative/Hypnotics: triazolam, and orally administered midazolam
• Tyrosine kinase inhibitors: dasatinib, sunatinib
• Other drugs that are CYP3A substrates: disopyramide, quinine

INVIRASE/ritonavir is contraindicated with drugs that are CYP3A substrates for which increased plasma levels may result in serious or life-threatening reactions.

INVIRASE/ritonavir prolongs the PR interval in a dose-dependent fashion. Cases of second or third degree atrioventricular block have been reported rarely. Patients with underlying structural heart disease, pre existing conduction system abnormalities, cardiomyopathies and ischemic heart disease may be at increased risk for developing cardiac conduction abnormalities. ECG monitoring is recommended in these patients. Discontinue INVIRASE/ritonavir if significant arrhythmias, QT or PR prolongation occur.

An ECG should be performed prior to initiation of treatment. Patients with a QT interval ≥ 450 msec should not initiate treatment with INVIRASE/ritonavir.

For patients with a baseline QT interval < 450 msec, an on-treatment ECG is recommended after approximately 10 days of therapy.

Discontinue INVIRASE/ritonavir in patients with a QT interval prolongation > 20 msec over pre-treatment.

Patients requiring treatment with medications with the potential to increase the QT interval and concomitant INVIRASE/ritonavir: Such combinations should only be used where no alternative therapy is available, and the potential benefits outweigh the potential risks.

A cardiology consult is recommended if drug discontinuation or interruption is being considered on the basis of ECG assessment.

New onset of diabetes mellitus, exacerbation of preexisting diabetes mellitus and hyperglycemia have been reported during postmarketing surveillance in HIV-1-infected patients receiving protease-inhibitor therapy.

In patients with underlying hepatitis B or C, cirrhosis, chronic alcoholism or other underlying liver abnormalities, there have been reports of worsening of the underlying liver disease and development of portal hypertension after starting INVIRASE/ritonavir. Jaundice and exacerbation of chronic liver disease with grade 4 elevated liver function tests were also observed.

There have been reports of spontaneous bleeding in patients with hemophilia A and B treated with protease inhibitors. In some patients, additional factor VIII was required.

Elevated cholesterol and/or triglyceride levels have been observed in some patients taking saquinavir in combination with ritonavir. Marked elevation in triglyceride levels is a risk factor for development of pancreatitis. Cholesterol and triglyceride levels should be monitored prior to initiating combination dosing regimen of INVIRASE/ritonavir, and at periodic intervals while on such therapy.

INVIRASE is not recommended in patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption (autosomal recessive disorder).

Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), facial wasting, peripheral wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy.

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including INVIRASE/ritonavir. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of treatment.

Varying degrees of cross-resistance among HIV-1 protease inhibitors have been observed.

Co-administration with delavirdineb, efavirenza, or  nevirapineb is not recommended.

Co-administration with indinavir is not recommended.

Lopinavir/ritonavir in combination with INVIRASE should be used with caution. Additive effects on QT and/or PR interval prolongation may occur with INVIRASE.

Combining saquinavir/ritonavir with nelfinavir is not recommended.

Combining saquinavir with tipranavir/ritonavir is not recommended.

Maraviroc dose should be 150 mg twice daily when co-administered with INVIRASE/ritonavir.

INVIRASE/ritonavir and ibutilide or sotalol is not recommended.

Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.

Co-administration with anticonvulsants may make Saquinavir less effective due to decreased saquinavir plasma.

Co-administration with carbamazepine, phenobarbital, and phenytoin is not recommended.

Therapeutic concentration monitoring is recommended for tricyclic antidepressants when co-administered with INVIRASE/ritonavir.

When INVIRASE/ritonavir and ketoconazole are co-administered, plasma concentrations of ketoconazole are increased. Hence, doses of ketoconazole or itraconazole > 200 mg/day are not recommended.

Clinical monitoring for saquinavir toxicity is recommended when co-administered with itraconazole. Use with caution due to possible cardiac arrhythmias.

Patients with renal or hepatic impairment should not be given colchicine with INVIRASE/ritonavir.

Use caution with co-administration of quinupristin/dalfopristin due to possible cardiac arrhythmias. Monitoring for saquinavir toxicity is recommended.

Concomitant use of fusidic acid and INVIRASE/ritonavir is not recommended due to potential for increased mutual toxicities.

Co-administration of saquinavir/ritonavir with drugs that are metabolized by CYP3A4 pathway may result in elevated plasma concentrations of these drugs. Co-administration with oral dapsone is not recommended.

If INVIRASE/ritonavir is co-administered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered.

Close clinical monitoring of patients is recommended when used with calcium channel blockers.

Co-administration of INVIRASE/ritonavir with systemic dexamethasone or other systemic corticosteroids that induce CYP3A may result in loss of therapeutic effect and development of resistance to saquinavir. Consider alternative corticosteroids.

Co-administration of INVIRASE/ritonavir with corticosteroids of which exposures are significantly increased by strong CYP3A inhibitors can increase the risk for Cushing’s syndrome and adrenal suppression. Alternative corticosteroids including beclomethasone and prednisolone (for which PK and/or PD are less affected by strong CYP3A inhibitors relative to other steroids) should be considered, particularly for long term use.

Caution should be exercised when INVIRASE/ritonavir and digoxin are co-administered; serum digoxin concentrations should be monitored and the dose of digoxin may need to be reduced when co-administered with INVIRASE/ritonavir.

Co-administration of bosentan in patients on INVIRASE/ritonavir: In patients who have been receiving INVIRASE/ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

Co-administration of INVIRASE/ritonavir in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of INVIRASE/ritonavir. After at least 10 days following the initiation of  INVIRASE/ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

Herbal products containing St. John’s wort should not be used concomitantly with INVIRASE/ritonavir because co-administration may lead to loss of virologic response and possible resistance to INVIRASE or to the class of protease inhibitors.

Co-administration of garlic capsules and saquinavir is not recommended due to the potential for garlic capsules to induce the metabolism of saquinavir which may result in sub-therapeutic saquinavir concentrations.

Therapeutic concentration monitoring is recommended for immunosuppressant agents when co administered with INVIRASE/ritonavir.

Concurrent administration of salmeterol with INVIRASE/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.

Dosage 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.

Alternative or additional contraceptive measures should be used when estrogen-based oral contraceptives and INVIRASE/ritonavir are co-administered.

Use with PDE5 inhibitors (phosphodiesterase type 5 inhibitors) (e.g., sildenafil, vardenafil, tadalafil) may result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism. Co-administration is contraindicated when sildenafil (Revatio) is used for the
treatment of pulmonary arterial hypertension (PAH).

When INVIRASE/ritonavir is co-administered with omeprazole, saquinavir concentrations are increased significantly. If omeprazole or another proton pump inhibitor is taken concomitantly with INVIRASE/ritonavir, caution is advised and monitoring for potential saquinavir toxicities is recommended, particularly gastrointestinal symptoms, increased triglycerides, deep vein thrombosis, and QT prolongation.

With intravenously administered Vincamine, monitor for vincamine toxicity is recommended. Use with caution due to potential cardiac arrhythmias.

Co-administration with fentanyl or alfentanil, may accentuate the side effects reported with use of fentanyl or alfentanil including respiratory depression, apnea and bradycardia.

Clinical experience in pregnant women is limited.

The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1.

GoToSource

• Use in patients under the age of 16. GoToSource

Hyperglycemia (high blood sugar) and new onset diabetes. GoToSource

Fat redistribution or accumulation of body fat. GoToSource

Prolonged PR and QT interval and complete heart block. GoToSource

Liver injury and exacerbation of chronic hepatitis B or C. GoToSource

Hyperlipidemia (high levels of fats or lipids in blood). GoToSource

Eruptive cheilitis (inflammation of the lips). GoToSource

Sexual dysfunction. GoToSource

Gynecomastia (male breast enlargement). GoToSource

Fixed drug reactions. GoToSource

Hypersensitivity reactions. GoToSource

Increased risk of bleeding. GoToSource

Erythema multiforme (skin reaction). GoToSource

Immune reconstitution inflammatory syndrome (worsening of a known condition or the appearance of a new condition after initiating antiretroviral therapy). GoToSource

Lawsuits filed for abnormal heart rhythm and heart block.