saquinavir mesylate
Dosage Form: tablet, film coated; capsules
FULL PRESCRIBING INFORMATION
Product identification in this document includes: Invirase in reference to saquinavir mesylate; saquinavir 200 mg soft gel capsule formulation1 in reference to saquinavir active base.
- 1
- The term "saquinavir soft gel capsules" used in this label refers to the drug product formerly marketed as "Fortovase" (saquinavir 200 mg soft gel capsule formulation). This formulation has been withdrawn from the market.
Indications and Usage for Invirase
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:
- –
- The twice daily administration of Invirase in combination with ritonavir is supported by safety data from the MaxCmin 1 study [see Adverse Reactions (6.1)] and pharmacokinetic data [see Clinical Pharmacology (12.3)].
- –
- 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 Dosage and Administration
Invirase must be used in combination with ritonavir, because it significantly inhibits saquinavir's metabolism to provide increased plasma saquinavir levels.
Adults (Over the Age of 16 Years)
- Invirase 1000-mg twice daily (5 × 200-mg capsules or 2 × 500-mg tablets) in combination with ritonavir 100-mg twice daily.
- Ritonavir should be taken at the same time as Invirase.
- Invirase and ritonavir should be taken within 2 hours after a meal.
Concomitant Therapy: Invirase with Lopinavir/Ritonavir
When administered with lopinavir/ritonavir 400/100 mg twice daily, the appropriate dose of Invirase is 1000 mg twice daily (with no additional ritonavir).
Dosage Forms and Strengths
Capsules: 200 mg
Film-coated tablets: 500 mg
Contraindications
QT interval prolongation and torsades de pointes have been reported rarely with Invirase/ritonavir use. Do not use 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 [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.2)].
Invirase is contraindicated in patients with complete atrioventricular (AV) block without implanted pacemakers, or patients who are at high risk of complete AV block [see Warnings and Precautions (5.2)].
Invirase is contraindicated in patients with clinically significant hypersensitivity (e.g., anaphylactic reaction, Stevens-Johnson syndrome) to saquinavir, saquinavir mesylate, or any of its ingredients including ritonavir.
Invirase when administered with ritonavir is contraindicated in patients with severe hepatic impairment.
Coadministration of Invirase/ritonavir is contraindicated with drugs that are CYP3A substrates for which increased plasma levels may result in serious or life-threatening reactions. These drugs and potentially related adverse events are listed in Table 1.
| Drug Class | Drugs Within Class That Are Contraindicated With Invirase | Clinical Comment |
|---|---|---|
| Alpha 1-adrenoreceptor antagonist | Alfuzosin | Potentially increased alfuzosin concentrations can result in hypotension. |
| Antiarrhythmics | Amiodarone, bepridil, dofetilide, flecainide, lidocaine (systemic), propafenone, quinidine | Potential for serious and/or life-threatening cardiac arrhythmia. |
| Antidepressant | Trazodone | Increased trazodone concentrations can result in potentially life threatening cardiac arrhythmia. |
| Antimycobacterial Agents | Rifampin | Rifampin should not be administered in patients taking ritonavir-boosted Invirase part of an ART regimen due to the risk of severe hepatocellular toxicity. |
| Ergot Derivatives | Dihydroergotamine, ergonovine, ergotamine, methylergonovine | Potential for serious and life threatening reactions such as ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues. |
| GI Motility Agent | Cisapride | Potential for serious and/or life threatening reactions such as cardiac arrhythmias. |
| HMG-CoA Reductase Inhibitors | Lovastatin, Simvastatin | Potential for myopathy including rhabdomyolysis. |
| Neuroleptics | Pimozide | Potential for serious and/or life threatening reactions such as cardiac arrhythmias. |
| PDE5 Inhibitors | Sildenafil (Revatio®)[for treatment of pulmonary arterial hypertension] | Increased potential for sildenafil-associated adverse events (which include visual disturbances, hypotension, prolonged erection, and syncope). A safe and effective dose has not been established when used with Invirase/ritonavir. |
| Sedative/Hypnotics | Triazolam, orally administered midazolam | Potential for serious and/or life threatening reactions such as prolonged or increased sedation or respiratory depression. Triazolam and orally administered midazolam are extensively metabolized by CYP3A4. Coadministration of triazolam and orally administered midazolam with Invirase/ritonavir may cause large increases in the concentration of these benzodiazepines. |
Warnings and Precautions
Invirase must be used in combination with ritonavir. Please refer to the ritonavir full prescribing information for additional precautionary measures.
If a serious or severe toxicity occurs during treatment with Invirase, Invirase should be interrupted until the etiology of the event is identified or the toxicity resolves. At that time, resumption of treatment with full-dose Invirase may be considered. For antiretroviral agents used in combination with Invirase, physicians should refer to the complete product information for these drugs for dose adjustment recommendations and for information regarding drug-associated adverse reactions.
Drug Interactions
The combination Invirase/ritonavir is a potent inhibitor of CYP3A and may significantly increase the exposure of drugs primarily metabolized by CYP3A. See Table 1 for a listing of drugs that are contraindicated for use with Invirase/ritonavir due to potentially life-threatening adverse events or significant drug interactions [see Contraindications (4)]. See Table 3 for established and other potentially significant drug interactions [see Drug Interactions (7.3)].
5.2 PR Interval Prolongation
Saquinavir/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 [see Warnings and Precautions (5.3)].
The impact on the PR interval of co-administration of saquinavir/ritonavir with other drugs that prolong the PR interval (including calcium channel blockers, beta-adrenergic blockers, digoxin and atazanavir) has not been evaluated. As a result, co-administration of saquinavir/ritonavir with these drugs should be undertaken with caution, particularly with those drugs metabolized by CYP3A, and clinical monitoring is recommended [see Clinical Pharmacology (12.2)].
5.3 QT Interval Prolongation
Saquinavir/ritonavir causes dose-dependent QT prolongation. Torsades de pointes has been reported rarely post-marketing. Avoid saquinavir/ritonavir in patients with long QT syndrome. ECG monitoring is recommended if therapy is initiated in patients with congestive heart failure, bradyarrhythmias, hepatic impairment and electrolyte abnormalities. Correct hypokalemia or hypomagnesemia prior to initiating saquinavir/ritonavir and monitor these electrolytes periodically during therapy. Do not use in combination with drugs that both increase saquinavir plasma concentrations and prolong the QT interval (see Tables 1 and 3) [see Clinical Pharmacology (12.2)].
Patients initiating therapy with ritonavir-boosted Invirase:
An ECG should be performed prior to initiation of treatment. Patients with a QT interval > 450 msec should not receive ritonavir-boosted Invirase. For patients with a QT interval < 450 msec, an on-treatment ECG is suggested after approximately 3 to 4 days of therapy; patients with a QT interval > 480 msec or prolongation over pre-treatment by > 20 msec should discontinue ritonavir-boosted Invirase.
Patients requiring treatment with medications with the potential to increase the QT interval and concomitant ritonavir-boosted Invirase:
Such combinations should only be used where no alternative therapy is available and the potential benefits outweigh the potential risks. An ECG should be performed prior to initiation of the concomitant therapy, and patients with a QT interval > 450 msec should not initiate the concomitant therapy. If baseline QT interval < 450 msec, an on-treatment ECG should be performed after 3-4 days of therapy. For patients demonstrating a subsequent increase in QT interval to > 480 msec or increase by > 20 msec after commencing concomitant therapy, the physician should use best clinical judgment to discontinue either ritonavir-boosted Invirase or the concomitant therapy or both.
A cardiology consult is recommended if drug discontinuation or interruption is being considered on the basis of ECG assessment.
Diabetes Mellitus and Hyperglycemia
New onset diabetes mellitus, exacerbation of preexisting diabetes mellitus and hyperglycemia have been reported during postmarketing surveillance in HIV-1-infected patients receiving protease-inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for the treatment of these events. In some cases diabetic ketoacidosis has occurred. In those patients who discontinued protease-inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease-inhibitor therapy and these events has not been established.
Hepatotoxicity
In patients with underlying hepatitis B or C, cirrhosis, chronic alcoholism and/or other underlying liver abnormalities, there have been reports of worsening liver disease.
Hemophilia
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. In the majority of reported cases treatment with protease inhibitors was continued or restarted. A causal relationship between protease inhibitor therapy and these episodes has not been established.
Hyperlipidemia
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 with ritonavir, and at periodic intervals while on such therapy. In these patients, lipid disorders should be managed as clinically appropriate.
Lactose Intolerance
Each capsule contains lactose (anhydrous) 63.3 mg. This quantity should not induce specific symptoms of intolerance.
Fat Redistribution
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. A causal relationship between protease-inhibitor therapy and these events has not been established and the long-term consequences are currently unknown.
Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including Invirase. 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.
Resistance/Cross-resistance
Varying degrees of cross-resistance among HIV-1 protease inhibitors have been observed. Continued administration of Invirase therapy following loss of viral suppression may increase the likelihood of cross resistance to other protease inhibitors [see Clinical Pharmacology (12.4)].
Adverse Reactions
The following adverse reactions are discussed in greater detail in other sections of the labeling:
- PR Interval Prolongation [see Warnings and Precautions (5.2)]
- QT Interval Prolongation [see Warnings and Precautions (5.3)]
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
The original Invirase safety database consisted of a total of 574 patients who received saquinavir 600 mg alone or in combination with ZDV or ddC. Combination dosing with ritonavir is based on 352 HIV-1 infected patients and 166 healthy subjects who received various combinations of either saquinavir (hard gel or soft-gel capsules) with ritonavir.
The recommended dose of Invirase is 1000 mg twice daily co-administered with ritonavir 100 mg twice daily, in combination with other antiretroviral agents. Table 2 lists grade 2, 3 and 4 adverse events that occurred in ≥2% of patients receiving saquinavir soft gel capsules with ritonavir (1000/100 mg bid).
| Adverse Events | Saquinavir soft gel capsules 1000 mg plus Ritonavir 100 mg bid (48 weeks) N=148 n (%=n/N) |
|---|---|
| |
| Endocrine Disorders | |
| Diabetes mellitus/hyperglycemia | 4 (2.7) |
| Lipodystrophy | 8 (5.4) |
| Gastrointestinal Disorders | |
| Nausea | 16 (10.8) |
| Vomiting | 11 (7.4) |
| Diarrhea | 12 (8.1) |
| Abdominal Pain | 9 (6.1) |
| Constipation | 3 (2.0) |
| General Disorders and Administration Site Conditions | |
| Fatigue | 9 (6.1) |
| Fever | 5 (3.4) |
| Musculoskeletal Disorders | |
| Back Pain | 3 (2.0) |
| Respiratory Disorders | |
| Pneumonia | 8 (5.4) |
| Bronchitis | 4 (2.7) |
| Influenza | 4 (2.7) |
| Sinusitis | 4 (2.7) |
| Dermatological Disorders | |
| Rash | 5 (3.4) |
| Pruritus | 5 (3.4) |
| Dry lips/skin | 3 (2.0) |
| Eczema | 3 (2.0) |
Limited experience is available from three studies investigating the pharmacokinetics of the Invirase 500 mg film-coated tablet compared to the Invirase 200 mg capsule in healthy volunteers (n=140). In two of these studies saquinavir was boosted with ritonavir; in the other study, saquinavir was administered as single drug. The Invirase tablet and the capsule formulations were similarly tolerated. The most common adverse events were gastrointestinal disorders (such as diarrhea). Similar bioavailability was demonstrated and no clinically significant differences in saquinavir exposures were seen. Thus, similar safety profiles are expected between the two Invirase formulations.
In a study investigating the drug-drug interaction of rifampin 600 mg/day daily and Invirase 1000 mg/ritonavir 100 mg twice daily (ritonavir-boosted Invirase) involving 28 healthy volunteers, 11 of 17 healthy volunteers (65%) exposed concomitantly to rifampin and ritonavir-boosted Invirase developed severe hepatocellular toxicity which presented as increased hepatic transaminases. In some subjects, transaminases increased up to >20-fold the upper limit of normal and were associated with gastrointestinal symptoms, including abdominal pain, gastritis, nausea, and vomiting. Following discontinuation of all three drugs, clinical symptoms abated and the increased hepatic transaminases normalized [see Contraindications (4)].
Additional Adverse Reactions Reported During Clinical Trials with Saquinavir
Blood and lymphatic system disorders: anemia, hemolytic anemia, leukopenia, lymphadenopathy, neutropenia, pancytopenia, thrombocytopenia
Cardiac disorders: heart murmur, syncope
Ear and labyrinth disorders: tinnitus
Eye disorders: visual impairment
Gastrointestinal disorders: abdominal discomfort, ascites, dyspepsia, dysphagia, eructation, flatulence, gastritis, gastrointestinal hemorrhage, intestinal obstruction, mouth dry, mucosal ulceration, pancreatitis
General disorders and administration site conditions: anorexia, asthenia, chest pain, edema, lethargy, wasting syndrome, weight increased
Hepatobiliary disorders: chronic active hepatitis, hepatitis, hepatomegaly, hyperbilirubinemia, jaundice, portal hypertension
Immune system disorders: allergic reaction
Investigations: ALT increase, AST increase, blood creatine phosphokinase increased, increased alkaline phosphatase, GGT increase, raised amylase, raised LDH
Metabolism and nutrition disorders: increased or decreased appetite, dehydration, hypertriglyceridemia
Musculoskeletal and connective tissue disorders: arthralgia, muscle spasms, myalgia, polyarthritis
Neoplasms benign, malignant and unspecified (incl cysts and polyps): acute myeloid leukemia, papillomatosis
Nervous system disorders: confusion, convulsions, coordination abnormal, dizziness, dysgeusia, headache, hypoaesthesia, intracranial hemorrhage leading to death, loss of consciousness, paresthesia, peripheral neuropathy, somnolence, tremor
Psychiatric disorders: anxiety, depression, insomnia, libido disorder, psychotic disorder, sleep disorder, suicide attempt
Renal and urinary disorders: nephrolithiasis
Respiratory, thoracic and mediastinal disorders: cough, dyspnea
Skin and subcutaneous tissue disorders: acne, alopecia, dermatitis bullous, drug eruption, erythema, severe cutaneous reaction associated with increased liver function tests, Stevens-Johnson syndrome, sweating increased, urticaria
Vascular disorders: hypertension, hypotension, thrombophlebitis, peripheral vasoconstriction
Postmarketing Experience
Additional adverse events that have been observed during the postmarketing period are similar to those seen in clinical trials with Invirase and saquinavir soft gel capsules alone or in combination with ritonavir. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to Invirase exposure.
Drug Interactions
Drug interaction studies have been completed with both Invirase and saquinavir soft gel capsules. Observations from drug interaction studies with saquinavir soft gel capsules may not be predictive for Invirase/ritonavir. Because ritonavir is coadministered with Invirase, prescribers should also refer to the prescribing information for ritonavir regarding drug interactions associated with this agent.
Potential for Invirase to Affect Other Drugs
The combination Invirase/ritonavir is a potent inhibitor of CYP3A and may significantly increase the exposure of drugs primarily metabolized by CYP3A. Drugs that are contraindicated specifically due to the observed or expected magnitude of interaction and potential for serious or life-threatening adverse events are listed in Table 1 [see Contraindications (4)]. Coadministration with other CYP3A substrates may require a dose adjustment or additional monitoring (Table 3).
Potential for Other Drugs to Affect Invirase
The metabolism of saquinavir is mediated primarily by CYP3A. Additionally, saquinavir is a substrate for P-glycoprotein (P-gp). Therefore, drugs that affect CYP3A and/or P-gp may modify the pharmacokinetics of saquinavir. Coadministration with drugs that are potent inducers of CYP3A (e.g., phenobarbital, phenytoin, carbamazepine) may result in decreased plasma concentrations of saquinavir and reduced therapeutic effect.
Established and Other Potentially Significant Drug Interactions
Based on the finding of dose-dependent prolongations of QT and PR intervals in healthy volunteers receiving Invirase/ritonavir, additive effects on QT and/or PR interval prolongation may occur with certain members of the following drug classes: antiarrhythmics class IA or class III, neuroleptics, antidepressive agents, PDE5 inhibitors (when used for pulmonary arterial hypertension), antimicrobials, antihistaminics and others. This effect might lead to an increased risk of ventricular arrhythmias, notably torsades de pointes. Therefore, concurrent administration of these agents with Invirase/ritonavir is contraindicated [see Contraindications (4)].
Table 3 provides a listing of established or potentially clinically significant drug interactions. Alteration in dose or avoidance of the combination may be recommended depending on the interaction.
| Concomitant Drug Class: Drug Name | Effect on Concentration of Saquinavir or Concomitant Drug | Clinical Comment |
|---|---|---|
| ||
| HIV-1 Antiviral Agents | ||
| Non-nucleoside reverse transcriptase inhibitor: Delavirdine* | ↑ Saquinavir Effect on delavirdine is not well established | Appropriate doses of the combination with respect to safety and efficacy have not been established. |
| Non-nucleoside reverse transcriptase inhibitor: Efavirenz†, nevirapine* | ↓ Saquinavir ↔ Efavirenz | Appropriate doses of the combination of efavirenz or nevirapine and Invirase/ritonavir with respect to safety and efficacy have not been established. |
| HIV-1 protease inhibitor: Atazanavir† | Invirase/ritonavir ↑ Saquinavir ↑ Ritonavir ↔ Atazanavir | Atazanavir in combination with Invirase/ritonavir should be used with caution. Additive effects on PR interval prolongation may occur with Invirase/ritonavir [see Warnings and Precautions (5.2)]. |
| HIV-1 protease inhibitor: Indinavir* | ↑ Saquinavir Effect on indinavir is not well established | Appropriate doses of the combination of indinavir and Invirase/ritonavir with respect to safety and efficacy have not been established. |
| HIV-1 protease inhibitor: Lopinavir/ritonavir† (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 saquinavir/ritonavir 1000/100 mg. The recommended dose for this combination is saquinavir 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 [Warnings and Precautions (5.2, 5.3)]. |
| HIV-1 protease inhibitor: Tipranavir/ritonavir† | ↓ Saquinavir | Combining saquinavir with tipranavir/ritonavir is not recommended. |
| HIV-1 fusion inhibitor: Enfuvirtide† | Saquinavir soft gel capsules/ritonavir ↔ enfuvirtide | No clinically significant interaction was noted from a study in 12 HIV-1 patients who received enfuvirtide concomitantly with saquinavir soft gel capsules/ritonavir 1000/100 mg bid. No dose adjustments are required. |
| HIV-1 CCR5 antagonist: Maraviroc | ↑ maraviroc | Maraviroc dose should be 150 mg twice daily when coadministered with Invirase/ritonavir. For further details see complete prescribing information for Selzentry® (maraviroc). |
| 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 (5.2, 5.3)]. | |
| Anticoagulant: Warfarin* | ↑ Warfarin | Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored. |
| Anticonvulsants: Carbamazepine*, phenobarbital*, phenytoin* | ↓ 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. |
| Anti-gout: Colchicine | ↑ Colchicine | Treatment of gout flares-coadministration of colchicine in patients on Invirase/ritonavir: 0.6 mg (1 tablet) × 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days. Treatment of familial Mediterranean fever (FMF) coadministration of colchicine in patients on Invirase/ritonavir: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). Prophylaxis of gout-flares-co-administration of colchicine in patients on Invirase/ritonavir: If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Patients with renal or hepatic impairment should not be given colchicine with Invirase/ritonavir. |
| Anti-infective: Clarithromycin† | ↑ Saquinavir ↑ Clarithromycin | Due to the known effect of ritonavir on clarithromycin concentrations, the following dose adjustments are recommended for patients with renal impairment:
No dose adjustment for patients with normal renal function is necessary. |
| Erythromycin Halofantrine Pentamidine | Use with caution. Additive effects on QT and/or PR interval prolongation may occur with Invirase/ritonavir [see Contraindications (4) and Warnings and Precautions (5.2, 5.3)]. | |
| Antifungal: Ketoconazole†, itraconazole* | ↔ Saquinavir ↔ Ritonavir ↑ Ketoconazole | When Invirase/ritonavir and ketoconazole are coadministered, plasma concentrations of ketoconazole are increased (see Table 3). Hence, doses of ketoconazole or itraconazole >200 mg/day are not recommended. |
| Antimycobacterial: Rifabutin† | ↔ Saquinavir ↑ Rifabutin ↔ Ritonavir | No dose adjustment of Invirase/ritonavir (1000/100 mg bid) is required if ritonavir-boosted Invirase 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 is warranted in patients receiving the combination. Consider monitoring rifabutin concentrations to ensure adequate exposure. |
| Benzodiazepines*: Alprazolam, clorazepate, diazepam, flurazepam | ↑ Benzodiazepines | Clinical significance is unknown; however, a decrease in benzodiazepine dose may be needed. |
| Benzodiazepine*: Intravenously administered Midazolam | ↑ Midazolam | Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, Invirase should not be given with orally administered midazolam [see Contraindications (4)]. If Invirase is coadministered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered. |
| 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* | ↓ Saquinavir | Use with caution. Saquinavir may be less effective due to decreased saquinavir plasma concentrations. |
| Digitalis Glycosides: Digoxin† | ↑ Digoxin Increases in serum digoxin concentration were greater in female subjects as compared to male subjects when digoxin was coadministered with Invirase/ritonavir. | Concomitant use of Invirase/ritonavir with digoxin results in a significant increase in serum concentrations of digoxin. Caution should be exercised when Invirase/ritonavir and digoxin are coadministered; serum digoxin concentrations should be monitored and the dose of digoxin may need to be reduced when coadministered with Invirase/ritonavir. |
| Endothelin receptor antagonists: Bosentan | ↑ Bosentan | Coadministration 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. Coadministration 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. |
| Inhaled beta agonist: Salmeterol | ↑ Salmeterol | 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. |
| Inhaled/nasal steroid: Fluticasone* | Invirase/ritonavir ↑ Fluticasone | Concomitant use of fluticasone propionate and Invirase/ritonavir may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. 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. |
| HMG-CoA reductase inhibitors*: Atorvastatin, rosuvastatin | ↑ Atorvastatin ↑ Rosuvastatin | Use lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as fluvastatin in combination with Invirase/ritonavir. |
| Immunosuppressants*: Cyclosporine, tacrolimus, rapamycin | ↑ Immunosuppressants | Therapeutic concentration monitoring is recommended for immunosuppressant agents when coadministered with Invirase/ritonavir. |
| Narcotic analgesic: Methadone† | ↓ Methadone | 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 [see Contraindications (4) and Warnings and Precautions (5.2, 5.3)]. |
| Neuroleptics: Clozapine Haloperidol Mesoridazine Phenothiazines Thioridazine Ziprasidone | Use with caution. Additive effects on QT and/or PR interval prolongation may occur with Invirase/ritonavir [see Contraindications (4) and Warnings and Precautions (5.2, 5.3)]. | |
| Oral contraceptives: Ethinyl estradiol* | ↓ Ethinyl estradiol | Alternative or additional contraceptive measures should be used when estrogen-based oral contraceptives and Invirase/ritonavir are coadministered. |
| PDE5 inhibitors (phosphodiesterase type 5 inhibitors): Sildenafil†, vardenafil*, tadalafil* | ↑ Sildenafil ↔ Saquinavir ↑ Vardenafil ↑ Tadalafil Only the combination of sildenafil with saquinavir soft gelatin capsules has been studied at doses used for treatment of erectile dysfunction. | May result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism. Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH):
The following dose adjustments are recommended for use of tadalafil (ADCIRCA®) with Invirase/ritonavir: Coadministration of ADCIRCA in patients on Invirase/ritonavir: In patients receiving Invirase/ritonavir for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Coadministration of Invirase/ritonavir in patients on ADCIRCA: Avoid use of ADCIRCA during the initiation of Invirase/ritonavir. Stop ADCIRCA at least 24 hours prior to starting Invirase/ritonavir. After at least one week following the initiation of Invirase/ritonavir, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: Use sildenafil with caution at reduced doses of 25 mg every 48 hours with increased monitoring of adverse events when administered concomitantly with Invirase/ritonavir. Use vardenafil with caution at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring of adverse events when administered concomitantly with Invirase/ritonavir. Use tadalafil with caution at reduced doses of no more than 10 mg every 72 hours with increased monitoring of adverse events when administered concomitantly with Invirase/ritonavir. |
| Tricyclic antidepressants*: Amitriptyline, imipramine | ↑ Tricyclics | Therapeutic concentration monitoring is recommended for tricyclic antidepressants when coadministered with Invirase/ritonavir. |
| Proton pump inhibitors: Omeprazole† | ↑ Saquinavir | 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. |
| Herbal Products: St. John's wort* (hypericum perforatum) | ↓ Saquinavir | Coadministration may lead to loss of virologic response and possible resistance to Invirase or to the class of protease inhibitors. |
| Garlic Capsules* | ↓ Saquinavir | Coadministration 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. |
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category B
Reproduction studies conducted with saquinavir have shown no embryotoxicity or teratogenicity in both rats and rabbits. Because of limited bioavailability of saquinavir in animals and/or dosing limitations, the plasma exposures (AUC values) in the respective species were approximately 29% (using rat) and 21% (using rabbit) of those obtained in humans at the recommended clinical dose boosted with ritonavir. Clinical experience in pregnant women is limited. Saquinavir should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Antiretroviral Pregnancy Registry
To monitor maternal-fetal outcomes of pregnant women exposed to antiretroviral medications, including Invirase, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.
Nursing Mothers
The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV. It is not known whether saquinavir is excreted in human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving Invirase.
Pediatric Use
Safety and effectiveness of Invirase in HIV-1-infected pediatric patients younger than 16 years of age have not been established.
Geriatric Use
Clinical studies of Invirase did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from
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