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.
|