"The U.S. Food and Drug Administration today announced that new safety information has been added to the label for the HIV antiviral drug Invirase (saquinavir), describing potentially life-threatening side effects on the heart when used with Norvi"...
The following adverse reactions are discussed in greater detail in other sections of the labeling.
- Drug Interactions [see WARNINGS AND PRECAUTIONS]
- Hepatotoxicity [see WARNINGS AND PRECAUTIONS]
- Pancreatitis [see WARNINGS AND PRECAUTIONS]
- Allergic Reactions/Hypersensitivity [see WARNINGS AND PRECAUTIONS]
Adult Clinical Trial Experience
Because clinical trials are conducted under widely varying conditions, adverse reactions 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 practice.
The safety of NORVIR alone and in combination with other antiretroviral agents was studied in 1,755 adult patients. Table 3 lists treatment-emergent Adverse Reactions (with possible or probable relationship to study drug) occurring in greater than or equal to 1% of adult patients receiving NORVIR in combined Phase II/IV studies.
The most frequently reported adverse drug reactions among patients receiving NORVIR alone or in combination with other antiretroviral drugs were gastrointestinal (including diarrhea, nausea, vomiting, abdominal pain (upper and lower)), neurological disturbances (including paresthesia and oral paresthesia), rash, and fatigue/asthenia.
Table 3: Treatment-Emergent Adverse Reactions (With
Possible or Probable Relationship to Study Drug) Occurring in greater than or
equal to 1% of Adult Patients Receiving NORVIR in Combined Phase II/IV Studies
(N = 1,755)
|Abdominal Pain (upper and lower)*||464||26.4|
|Diarrhea including severe with electrolyte imbalance*||1,192||67.9|
|Gastroesophageal reflux disease (GERD)||19||1.1|
|General disorders and administration site conditions|
|Fatigue including asthenia*||811||46.2|
|Blood bilirubin increased (including jaundice)*||25||1.4|
|Hepatitis (including increased AST, ALT, GGT)*||153||8.7|
|Immune system disorders|
|Hypersensivity including urticatria and face edema*||114||8.2|
|Metabolism and nutrition disorders|
|Edema and peripheral edema*||110||6.3|
|Musculoskeletal and connective tissue disorders|
|Arthralgia and back pain*||326||18.6|
|Myopathy/creatine phosphokinase increased*||66||3.8|
|Nervous system disorders|
|Paresthesia (including oral paresthesia)*||889||50.7|
|Disturbance in attention||44||2.5|
|Renal and urinary disorders|
|Respiratory, thoracic and mediastinal disorders|
|Skin and subcutaneous tissue disorders|
|Rash (includes erythematous and maculopapular)*||475||27.1|
|Flushing, feeling hot*||232||13.2|
|Hypotension including orthostatic hypotension*||30||1.7|
|* Represents a medical concept including several similar MedDRA PTs|
Table 4 shows the percentage of adult patients who developed marked laboratory abnormalities.
Table 4: Percentage of Adult
Patients, by Study and Treatment Group, with Chemistry and Hematology
Abnormalities Occurring in greater than 3% of Patients Receiving NORVIR
|Variable||Limit||Study 245 Naive Patients||Study 247 Advanced Patients||Study 462 PI-Naive Patients|
|NORVIR plus ZDV||NORVIR||ZDV||NORVIR||Placebo||NORVIR plus Saquinavir|
|Cholesterol||> 240 mg/dL||30.7||44.8||9.3||36.5||8||65.2|
|CPK||> 1000 IU/L||9.6||12.1||11||9.1||6.3||9.9|
|GGT||> 300 IU/L||1.8||5.2||1.7||19.6||11.3||9.2|
|SGOT (AST)||> 180 IU/L||5.3||9.5||2.5||6.4||7||7.8|
|SGPT (ALT)||> 215 IU/L||5.3||7.8||3.4||8.5||4.4||9.2|
|Triglycerides||> 800 mg/dL||9.6||17.2||3.4||33.6||9.4||23.4|
|Triglycerides||> 1500 mg/dL||1.8||2.6||-||12.6||0.4||11.3|
|Triglycerides Fasting||> 1500 mg/dL||1.5||1.3||-||9.9||0.3||-|
|Uric Acid||> 12 mg/dL||-||-||-||3.8||0.2||1.4|
|Hemoglobin||< 8.0 g/dL||0.9||-||-||3.8||3.9||-|
|Neutrophils||≤ 0.5 x 109/L||-||-||-||6||8.3||-|
|RBC||< 3.0 x 1012/L||1.8||-||5.9||18.6||24.4||-|
|WBC||< 2.5 x 109/L||-||0.9||6.8||36.9||59.4||3.5|
|-Indicates no events reported.|
Pediatric Clinical Trial Experience
NORVIR has been studied in 265 pediatric patients greater than 1 month to 21 years of age. The adverse event profile observed during pediatric clinical trials was similar to that for adult patients.
Vomiting, diarrhea, and skin rash/allergy were the only drug-related clinical adverse events of moderate to severe intensity observed in greater than or equal to 2% of pediatric patients enrolled in NORVIR clinical trials.
The following Grade 3-4 laboratory abnormalities occurred in greater than 3% of pediatric patients who received treatment with NORVIR either alone or in combination with reverse transcriptase inhibitors: neutropenia (9%), hyperamylasemia (7%), thrombocytopenia (5%), anemia (4%), and elevated AST (3%).
The following adverse events (not previously mentioned in the labeling) have been reported during post-marketing use of NORVIR. Because these reactions are reported voluntarily from a population of unknown size, it is not possible to reliably estimate their frequency or establish a causal relationship to NORVIR exposure.
Body as a Whole
Dehydration, usually associated with gastrointestinal symptoms, and sometimes resulting in hypotension, syncope, or renal insufficiency has been reported. Syncope, orthostatic hypotension, and renal insufficiency have also been reported without known dehydration.
Co-administration of ritonavir with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system.
First-degree AV block, second-degree AV block, third-degree AV block, right bundle branch block have been reported [see WARNINGS AND PRECAUTIONS].
Cardiac and neurologic events have been reported when ritonavir has been co-administered with disopyramide, mexiletine, nefazodone, fluoxetine, and beta blockers. The possibility of drug interaction cannot be excluded.
Cushing's syndrome and adrenal suppression have been reported when ritonavir has been co-administered with fluticasone propionate or budesonide.
There have been postmarketing reports of seizure. Also, see Cardiovascular System.
Skin and subcutaneous tissue disorders
Toxic epidermal necrolysis (TEN) has been reported.
Read the Norvir (ritonavir capsules, oral solution) Side Effects Center for a complete guide to possible side effects
When co-administering NORVIR with other protease inhibitors (atazanavir, darunavir, fosamprenavir, saquinavir, and tipranavir), see the full prescribing information for that protease inhibitor including important information for drug interactions.
Potential for NORVIR to Affect Other Drugs
Ritonavir has been found to be an inhibitor of cytochrome P450 3A (CYP3A) and may increase plasma concentrations of agents that are primarily metabolized by CYP3A. Agents that are extensively metabolized by CYP3A and have high first pass metabolism appear to be the most susceptible to large increases in AUC (greater than 3-fold) when co-administered with ritonavir. Thus, co-administration of NORVIR with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated. Co-administration with other CYP3A substrates may require a dose adjustment or additional monitoring as shown in Table 5.
Ritonavir also inhibits CYP2D6 to a lesser extent. Co-administration of substrates of CYP2D6 with ritonavir could result in increases (up to 2-fold) in the AUC of the other agent, possibly requiring a proportional dosage reduction. Ritonavir also appears to induce CYP3A, CYP1A2, CYP2C9, CYP2C19, and CYP2B6 as well as other enzymes, including glucuronosyl transferase.
Established and Other Potentially Significant Drug Interactions
Table 5 provides a list of established or potentially clinically significant drug interactions. Alteration in dose or regimen may be recommended based on drug interaction studies or predicted interaction [see CLINICAL PHARMACOLOGY for magnitude of interaction].
Table 5: Established and Other Potentially Significant
|Concomitant Drug Class: Drug Name||Effect on Concentration of Ritonavir or Concomitant Drug||Clinical Comment|
|HIV-1 Protease Inhibitor: atazanavir||When co-administered with reduced doses of atazanavir and ritonavir ↑ atazanavir (↑ AUC, ↑Cmax, ↑ Cmin)||Atazanavir plasma concentrations achieved with atazanavir 300 mg once daily and ritonavir 100 mg once daily are higher than those achieved with atazanavir 400 mg once daily. See the complete prescribing information for Reyataz® (atazanavir) for details on co-administration of atazanavir 300 mg once daily with ritonavir 100 mg once daily.|
|HIV-1 Protease Inhibitor: darunavir||When co-administered with reduced doses of ritonavir ↑darunavir (↑AUC, ↑Cmax, ↑Cmin)||See the complete prescribing information for Prezista® (darunavir) for details on co-administration of darunavir 600 mg twice daily with ritonavir 100 mg twice daily or darunavir 800 mg once daily with ritonavir 100 mg once daily.|
|HIV-1 Protease Inhibitor: fosamprenavir||When co-administered with reduced doses of ritonavir ↑ amprenavir (↑AUC, ↑Cmax, ↑Cmin)||See the complete prescribing information for Lexiva® (fosamprenavir) for details on co-administration of fosamprenavir 700 mg twice daily with ritonavir 100 mg twice daily, fosamprenavir 1400 mg once daily with ritonavir 200 mg once daily or fosamprenavir 1400 mg once daily with ritonavir 100 mg once daily.|
|HIV-1 Protease Inhibitor: indinavir||When co-administered with reduced doses of indinavir and ritonavir ↑ indinavir (↔ AUC, ↑ Cmax, ↑ Cmin)||Alterations in concentrations are noted when reduced doses of indinavir are co-administered with NORVIR. Appropriate doses for this combination, with respect to efficacy and safety, have not been established.|
|HIV-1 Protease Inhibitor: saquinavir||When co-administered with reduced doses of ritonavir ↑saquinavir (↑AUC, ↑Cmax, ↑Cmin)||See the complete prescribing information for Invirase® (saquinavir) for details on co-administration of saquinavir 1000 mg twice daily with ritonavir 100 mg twice daily. Saquinavir/ritonavir should not be given together with rifampin, due to the risk of severe hepatotoxicity (presenting as increased hepatic transaminases) if the three drugs are given together.|
|HIV-1 Protease Inhibitor: tipranavir||When co-administered with reduced doses of ritonavir ↑ tipranavir (↑AUC, ↑Cmax, ↑Cmin)||See the complete prescribing information for Aptivus® (tipranavir) for details on co-administration of tipranavir 500 mg twice daily with ritonavir 200 mg twice daily. There have been reports of clinical hepatitis and hepatic decompensation including some fatalities. All patients should be followed closely with clinical and laboratory monitoring, especially those with chronic hepatitis B or C co-infection, as these patients have an increased risk of hepatotoxicity. Liver function tests should be performed prior to initiating therapy with tipranavir/ritonavir, and frequently throughout the duration of treatment.|
|Non-Nucleoside Reverse Transcriptase Inhibitor: delavirdine||↑ ritonavir (↑AUC, ↑Cmax, ↑Cmin)||Appropriate doses of this combination with respect to safety and efficacy have not been established.|
|HIV-1 CCR5 – antagonist: maraviroc||↑maraviroc||Concurrent administration of maraviroc with ritonavir will increase plasma levels of maraviroc. For specific dosage adjustment recommendations, please refer to the complete prescribing information for Selzentry® (maraviroc).|
|Integrase Inhibitor: Raltegravir||↓ raltegravir||The effects of ritonavir on raltegravir with ritonavir dosage regimens greater than 100 mg twice daily have not been evaluated, however raltegravir concentrations may be decreased with ritonavir coadministration.|
|Analgesics, Narcotic: tramadol, propoxyphene||A dose decrease may be needed for these drugs when co-administered with ritonavir.|
|Anesthetic: meperidine||↓ meperidine/ ↑ normeperidine (metabolite)||Dosage increase and long-term use of meperidine with ritonavir are not recommended due to the increased concentrations of the metabolite normeperidine which has both analgesic activity and CNS stimulant activity (e.g., seizures).|
|Antialcoholics: disulfiram/ metronidazole||Ritonavir formulations contain alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).|
|Antiarrhythmics: disopyramide, lidocaine, mexiletine||↑antiarrhythmics||Caution is warranted and therapeutic concentration monitoring is recommended for antiarrhythmics when co-administered with ritonavir, if available.|
|Anticancer Agents: dasatinib, nilotinib, vincristine, vinblastine||↑ anticancer agents||Concentrations of these drugs may be increased when co-administered with ritonavir resulting in the potential for increased adverse events usually associated with these anticancer agents.
For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when ritonavir is administered concurrently with vincristine or vinblastine. Clinicians should be aware that if the ritonavir containing regimen is withheld for a prolonged period, consideration should be given to altering the regimen to not include a CYP3A or P-gp inhibitor in order to control HIV-1 viral load. A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as NORVIR. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions.
|Anticoagulant:||↓ R-warfarin||Initial frequent monitoring of the INR during ritonavir and|
|warfarin||↓↑ S-warfarin||warfarin co-administration is indicated.|
|Anticoagulant: rivaroxaban||↑rivaroxaban||Avoid concomitant use of rivaroxaban and ritonavir. Co-administration of ritonavir and rivaroxaban is expected to result in increased exposure of rivaroxaban which may lead to risk of increased bleeding.|
|Anticonvulsants: carbamazepine, clonazepam, ethosuximide||↑ anticonvulsants||Use with caution. A dose decrease may be needed for these drugs when co-administered with ritonavir and therapeutic concentration monitoring is recommended for these anticonvulsants, if available.|
|Anticonvulsants: divalproex, lamotrigine, phenytoin||↓ anticonvulsants||Use with caution. A dose increase may be needed for these drugs when co-administered with ritonavir and therapeutic concentration monitoring is recommended for these anticonvulsants, if available.|
|Antidepressants: nefazodone, selective serotonin reuptake inhibitors (SSRIs): e.g. fluoxetine, paroxetine, tricyclics: e.g. amitriptyline, nortriptyline||↑antidepressants||A dose decrease may be needed for these drugs when co-administered with ritonavir.|
|Antidepressant: bupropion||↓ bupropion ↓ active metabolite, hydroxybupropion||Concurrent administration of bupropion with ritonavir may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving ritonavir and bupropion concurrently should be monitored for an adequate clinical response to bupropion.|
|Antidepressant: desipramine||↑desipramine||Dosage reduction and concentration monitoring of desipramine is recommended.|
|Antidepressant: trazodone||↑ trazodone||Concomitant use of trazodone and NORVIR increases plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and NORVIR. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered.|
|Antiemetic: dronabinol||↑dronabinol||A dose decrease of dronabinol may be needed when co-administered with ritonavir.|
|Antifungal: ketoconazole itraconazole voriconazole||↑ ketoconazole
|High doses of ketoconazole or itraconazole (greater than 200 mg per day) are not recommended. Co-administration of voriconazole and ritonavir doses of 400 mg every 12 hours or greater is contraindicated. Co-administration of voriconazole and ritonavir 100 mg should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole.|
|Anti-gout: colchicine||↑ colchicine||Patients with renal or hepatic impairment should not be given colchicine with ritonavir.
Treatment of gout flares-co-administration of colchicine in patients on ritonavir:
0.6 mg (one tablet) for one dose, followed by 0.3 mg (half tablet) one hour later.
Dose to be repeated no earlier than three days. Prophylaxis of gout flares-co-administration of colchicine in patients on 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.
Treatment of familial Mediterranean fever (FMF)-co-administration of colchicine in patients on ritonavir:
Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
|Anti-infective: clarithromycin||↑ clarithromycin||For patients with renal impairment the following dosage adjustments should be considered:
|Antimycobacterial: rifabutin||↑ rifabutin and rifabutin metabolite||Dosage reduction of rifabutin by at least three-quarters of the usual dose of 300 mg per day is recommended (e.g., 150 mg every other day or three times a week). Further dosage reduction may be necessary.|
|Antimycobacterial: rifampin||↓ ritonavir||May lead to loss of virologic response. Alternate antimycobacterial agents such as rifabutin should be considered (see Antimycobacterial: rifabutin, for dose reduction recommendations).|
|Antiparasitic: atovaquone||↓ atovaquone||Clinical significance is unknown; however, increase in atovaquone dose may be needed.|
|Antiparasitic: quinine||↑ quinine||A dose decrease of quinine may be needed when co-administered with ritonavir.|
|β-Blockers: metoprolol, timolol||↑Beta-Blockers||Caution is warranted and clinical monitoring of patients is recommended. A dose decrease may be needed for these drugs when co-administered with ritonavir.|
|Bronchodilator: theophylline||↓ theophylline||Increased dosage of theophylline may be required; therapeutic monitoring should be considered.|
|Calcium channel blockers: diltiazem, nifedipine, verapamil||↑calcium channel blockers||Caution is warranted and clinical monitoring of patients is recommended.A dose decrease may be needed for these drugs when co-administered with ritonavir.|
|Digoxin||↑ digoxin||Concomitant administration of ritonavir with digoxin may increase digoxin levels. Caution should be exercised when co-administering ritonavir with digoxin, with appropriate monitoring of serum digoxin levels.|
|Endothelin receptor antagonists: bosentan||↑ bosentan||Co-administration of bosentan in patients on ritonavir:
In patients who have been receiving 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 ritonavir in patients on bosentan:
Discontinue use of bosentan at least 36 hours prior to initiation of ritonavir.
After at least 10 days following the initiation of ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
|HMG-CoA Reductase Inhibitor: atorvastatin rosuvastatin||↑atorvastatin
|Titrate atorvastatin and rosuvastatin dose carefully and use the lowest necessary dose.
If NORVIR is used with another protease inhibitor, see the complete prescribing information for the concomitant protease inhibitor for details on co-administration with atorvastatin and rosuvastatin.
|Immunosuppressants: cyclosporine, tacrolimus, sirolimus (rapamycin)||↑ immunosuppressants||Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with ritonavir.|
|Inhaled or Intranasal Steroid: e.g. fluticasone budesonide||↑glucocorticoids||Concomitant use of ritonavir and fluticasone or other glucocorticoids that are metabolized by CYP3A is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects. Concomitant use may result in increased steroid concentrations and reduced serum cortisol concentrations.
Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during postmarketing use in patients when ritonavir has been coadministered with fluticasone propionate or budesonide.
|Long-acting beta-adrenoceptor agonist: salmeterol||↑ salmeterol||Concurrent administration of salmeterol and 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.|
|Narcotic Analgesic: methadone fentanyl||↓ methadone
|Dosage increase of methadone may be considered. Concentrations of fentanyl are expected to increase. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with NORVIR.|
|Neuroleptics: perphenazine, risperidone, thioridazine||↑neuroleptics||A dose decrease may be needed for these drugs when co-administered with ritonavir.|
|Oral Contraceptives or Patch Contraceptives: ethinyl estradiol||↓ethinyl estradiol||Alternate methods of contraception should be considered.|
|PDE5 Inhibitors: avanafil sildenafil, tadalafil, vardenafil||↑avanafil
|Do not use ritonavir with avanafil because a safe and effective avanafil dosage regimen has not been established.
Particular caution should be used when prescribing sildenafil, tadalafil or vardenafil in patients receiving ritonavir. Coadministration of ritonavir with these drugs is expected to substantially increase their concentrations and may result in an increase in PDE5 inhibitor associated adverse events, including hypotension, syncope, visual changes, and prolonged erection.
Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH):
Sildenafil (Revatio®) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) because a safe and effective dose has not been established when used with ritonavir [see CONTRAINDICATIONS]. The following dose adjustments are recommended for use of tadalafil (Adcirca™) with ritonavir:
Co-administration of ADCIRCA in patients on ritonavir:
In patients receiving ritonavir for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.
Co-administration of ritonavir in patients on ADCIRCA:
Avoid use of ADCIRCA during the initiation of ritonavir. Stop ADCIRCA at least 24 hours prior to starting ritonavir. After at least one week following the initiation of ritonavir, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.
Use of PDE5 inhibitors for the treatment of erectile dysfunction:
It is recommended not to exceed the following doses:
|Sedative/hypnotics: buspirone, clorazepate, diazepam, estazolam, flurazepam, zolpidem||↑sedative/hypnotics||A dose decrease may be needed for these drugs when co-administered with ritonavir.|
|Sedative/hypnotics: Parenteral midazolam||↑ midazolam||Co-administration of oral midazolam with NORVIR is CONTRAINDICATED. Concomitant use of parenteral midazolam with NORVIR may increase plasma concentrations of midazolam. Co-administration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered.|
|Steroids (systemic): e.g. budesonide, dexamethasone, prednisone||↑ glucocorticoids||Concomitant use of glucocorticoids that are metabolized by CYP3A is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects. Concomitant use may result in increased steroid concentrations and reduced serum cortisol concentrations. This may increase the risk for development of systemic corticosteroid effects including Cushing's syndrome and adrenal suppression.|
|Stimulant: methamphetamine||↑ methamphetamine||Use with caution. A dose decrease of methamphetamine may be needed when co-administered with ritonavir.|
Read the Norvir Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 11/22/2013
This monograph has been modified to include the generic and brand name in many instances.
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