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Invirase (Saquinavir Mesylate) - Drug Interactions, Contraindications, Overdosage, etc

 
 



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.

 

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 (see Table 3).

 

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.

 

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.

Table 3 Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or on Predicted Interaction with INVIRASE/ritonavir
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 ].
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 [see 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 subjects 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 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:
  • For patients with CLCR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%.
  • For patients with CLCR <30 mL/min the dose of clarithromycin should be decreased by 75%.
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 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
↑ Atorvastatin
Titrate atorvastatin dose carefully and use the lowest dose necessary; do not exceed atorvastatin 20 mg/day.
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 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 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):
  • Use of sildenafil (Revatio) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) [see Contraindications (4) ].
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.

[INVIRASE/ritonavir interaction has not been evaluated.]

[See ]

 

OVERDOSAGE

There is limited experience of overdose with saquinavir.

No acute toxicities or sequelae were noted in 1 subject who ingested 8 grams of INVIRASE as a single dose. The subject was treated with induction of emesis within 2 to 4 hours after ingestion. A second subject ingested 2.4 grams of INVIRASE in combination with 600 mg of ritonavir and experienced pain in the throat that lasted for 6 hours and then resolved. In an exploratory Phase II study of oral dosing with INVIRASE at 7200 mg per day (1200 mg q4h), there were no serious toxicities reported through the first 25 weeks of treatment.

Treatment of overdose with saquinavir should consist of general supportive measures including monitoring of vital signs and ECG and observations of the patient's clinical status. Since saquinavir is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the active substance.

 

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 and Clinical Pharmacology].

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 ].

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.

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.

Table 1 Drugs That Are Contraindicated With INVIRASE/ritonavir
Drug Class Drugs Within Class That Are Contraindicated With INVIRASE/ritonavir 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 or orally administered midazolam with INVIRASE/ritonavir may cause large increases in the concentration of these benzodiazepines.

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