"The U.S. Food and Drug Administration today approved Tivicay (dolutegravir), a new drug to treat HIV-1 infection.
Tivicay is an integrase strand transfer inhibitor that interferes with one of the enzymes necessary for HIV to multiply. "...
The following adverse reactions are discussed in greater detail in other sections of the labeling:
- PR Interval Prolongation [see WARNINGS AND PRECAUTIONS]
- QT Interval Prolongation [see WARNINGS AND PRECAUTIONS ]
Clinical Trial Experience in Adult Subjects
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 adult subjects who received saquinavir 600 mg alone or in combination with ZDV or ddC. Combination dosing with ritonavir is based on 352 HIV-1 infected subjects 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 subjects receiving saquinavir soft gel capsules with ritonavir (1000/100 mg bid).
Table 2 : Grade 2, 3 and 4 Adverse Events (All
Causalitya) Reported in ≥ 2% of Adult Subjects in the
MaxCmin 1 Study of Saquinavir Soft Gel Capsules in Combination with Ritonavir
1000/100 mg twice a day
|Adverse Events||Saquinavir soft gel capsules 1000 mg plus Ritonavir 100 mg bid (48 weeks)
|Diabetes mellitus/hyperglycemia||4 (3)|
|Abdominal Pain||9 (6)|
|General Disorders and Administration Site Conditions|
|Back Pain||3 (2)|
|Dry lips/skin||3 (2)|
|aIncludes events with unknown relationship to study drug|
Limited experience is available from three trials 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 trials saquinavir was boosted with ritonavir; in the other trial, 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 nausea, vomiting, and 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.
A study investigating the drug-drug interaction of rifampin 600 mg/day daily and INVIRASE 1000 mg/ritonavir 100 mg twice daily enrolled 28 healthy volunteers. Eleven 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].
Additional Adverse Reactions Reported During Clinical Trials with Saquinavir
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
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
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
Clinical Trial Experience in Pediatric Subjects
Limited safety data are available from two pediatric clinical trials of saquinavir hard gel capsules (approximately 50 mg per kg twice daily) used in combination with either low dose ritonavir or lopinavir/ritonavir. These trials enrolled pediatric subjects aged 4 months to 16 years old. In the HIVNAT 017 study (INVIRASE + lopinavir/ritonavir), adverse events were reported in 90% of the 50 subjects enrolled. The most commonly reported adverse events considered related to study treatment were diarrhea (18%) and vomiting (10%). In the NV20911 study (INVIRASE + ritonavir), 4 subjects (22% of 18 enrolled) experienced adverse events that were considered related to INVIRASE + ritonavir. These events (n) were vomiting (3), abdominal pain (1) and diarrhea (1). All reported adverse events were mild or moderate in intensity. The adverse reaction profile of INVIRASE in the pediatric trials is similar to that observed in adult trials.
Additional adverse events identified during postmarketing use are similar to those observed 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. In addition, torsades de pointes has been reported rarely [see WARNINGS AND PRECAUTIONS].
Read the Invirase (saquinavir mesylate) Side Effects Center for a complete guide to possible side effects
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]. Coadministration with other CYP3A substrates may require a dose adjustment or additional monitoring (see 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].
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
|Concomitant Drug Class: Drug Name||Effect on Concentration of Saquinavir or Concomitant Drug||Clinical 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.|
|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.|
|HIV-1 protease inhibitor: Atazanavira||INVIRASE/ritonavir
|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: Indinavirb||↑ 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/ritonavira (coformulated tablet)||↔ Saquinavir
|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].
|HIV-1 protease inhibitor: Tipranavir/ritonavira||↓ Saquinavir||Combining saquinavir with tipranavir/ritonavir is not recommended.|
|HIV-1 fusion inhibitor: Enfuvirtidea||Saquinavir soft gel capsules/ritonavir
|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).|
|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].|
|Anticoagulant: Warfarinb||↑ Warfarin||Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.|
|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.|
|Anti-gout: Colchicine||↑Colchicine||Treatment of gout flares-coadministration of colchicine in patients on INVIRASE/ritonavir:
0.6 mg (1 tablet) x 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.
|Due to the known effect of ritonavir on clarithromycin concentrations, the following dose adjustments are recommended for patients with renal impairment:
|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].|
|Antifungal: Ketoconazolea , itraconazoleb||↔ Saquinavir
|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.|
|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.
|Benzodiazepinesb: Alprazolam, clorazepate, diazepam, flurazepam||↑ Benzodiazepines||Clinical significance is unknown; however, a decrease in benzodiazepine dose may be needed.|
|Benzodiazepineb: 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 ]. 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 blockersb: Diltiazem, felodipine, nifedipine, nicardipine, nimodipine, verapamil, amlodipine, nisoldipine, isradipine||↑Calcium channel blockers||Caution is warranted and clinical monitoring of patients is recommended.|
|Corticosteroid: Dexamethasoneb||↓Saquinavir||Use with caution. Saquinavir may be less effective due to decreased saquinavir plasma concentrations.|
|Digitalis Glycosides: Digoxina||↑ 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: Fluticasoneb||INVIRASE/ritonavir
|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 inhibitorsb: Atorvastatin||↑ Atorvastatin||Titrate atorvastatin dose carefully and use the lowest dose necessary; do not exceed atorvastatin 20 mg/day.|
|Immunosuppressantsb: Cyclosporine, tacrolimus, rapamycin||↑Immunosuppressants||Therapeutic concentration monitoring is recommended for immunosuppressant agents when coadministered with INVIRASE/ritonavir.|
|Narcotic analgesic: Methadonea||↓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].
|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].|
|Oral contraceptives: Ethinyl estradiolb||↓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): Sildenafila, vardenafilb , tadalafilb||↑ Sildenafil
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:
|Tricyclic antidepressantsb: Amitriptyline, imipramine||↑ Tricyclics||Therapeutic concentration monitoring is recommended for tricyclic antidepressants when coadministered with INVIRASE/ritonavir.|
|Proton pump inhibitors: Omeprazolea||↑ 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 wortb (hypericum perforatum)||↑ Saquinavir||Coadministration may lead to loss of virologic response and possible resistance to INVIRASE or to the class of protease inhibitors.|
|Garlic Capsulesb||↓ 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.|
|aSee Table 5 and Table 6 for
magnitude of interactions.
bINVIRASE/ritonavir interaction has not been evaluated.
Read the Invirase Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 12/18/2012
This monograph has been modified to include the generic and brand name in many instances.
Additional Invirase Information
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