DrugLib.com — Drug Information Portal

Rx drug information, pharmaceutical research, clinical trials, news, and more

Norvir (Ritonavir) - Drug Interactions, Contraindications, Overdosage, etc

 
 



DRUG INTERACTIONS

See also Contraindications (4), Warnings and Precautions , and Clinical Pharmacology

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 4.

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 4 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 4. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class:
Drug Name
Effect on Concentration of Ritonavir or Concomitant Drug Clinical Comments
    HIV-Antiviral Agents
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.
Other Agents
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:
warfarin
↓ R-warfarin
↓↑ S-warfarin
Initial frequent monitoring of the INR during ritonavir and 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
↑ itraconazole
↓ voriconazole
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:
  • For patients with CLCR 30 to 60 mL per min the dose of clarithromycin should be reduced by 50%.
  • For patients with CLCR less than 30 mL per min the dose of clarithromycin should be decreased by 75%.
No dose adjustment for patients with normal renal function is necessary.
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
↑ rosuvastatin
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
↑ fentanyl
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
↑ sildenafil
↑ tadalafil
↑ vardenafil
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 (4) ].

The following dose adjustments are recommended for use of tadalafil (AdcircaTM) 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:

  • Sildenafil: 25 mg every 48 hours
  • Tadalafil: 10 mg every 72 hours
  • Vardenafil: 2.5 mg every 72 hours


Use with increased monitoring for adverse events.
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.

OVERDOSAGE

Acute Overdosage - Human Overdose Experience

Human experience of acute overdose with NORVIR is limited. One patient in clinical trials took NORVIR 1500 mg per day for two days. The patient reported paresthesias which resolved after the dose was decreased. A post-marketing case of renal failure with eosinophilia has been reported with ritonavir overdose.

The approximate lethal dose was found to be greater than 20 times the related human dose in rats and 10 times the related human dose in mice.

Management of Overdosage

Treatment of overdose with NORVIR consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. There is no specific antidote for overdose with NORVIR. If indicated, elimination of unabsorbed drug should be achieved by emesis or gastric lavage; usual precautions should be observed to maintain the airway. Administration of activated charcoal may also be used to aid in removal of unabsorbed drug. Since ritonavir is extensively metabolized by the liver and is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the drug. A Certified Poison Control Center should be consulted for up-to-date information on the management of overdose with NORVIR.

CONTRAINDICATIONS

  • When co-administering NORVIR with other protease inhibitors, see the full prescribing information for that protease inhibitor including contraindication information.
  • NORVIR is contraindicated in patients with known hypersensitivity (e.g., toxic epidermal necrolysis (TEN) or Stevens-Johnson syndrome) to ritonavir or any of its ingredients.
  • Co-administration of NORVIR with several classes of drugs (including sedative hypnotics, antiarrhythmics, or ergot alkaloid preparations) is contraindicated and may result in potentially serious and/or life-threatening adverse events due to possible effects of NORVIR on the hepatic metabolism of these drugs (see Table 1). Voriconazole and St. John’s Wort are exceptions in that co-administration of NORVIR and voriconazole results in a significant decrease in plasma concentrations of voriconazole, and co-administration of NORVIR with St. John’s Wort may result in decreased ritonavir plasma concentrations.
* see Drug Interactions (7) for co-administration of sildenafil in patients with erectile dysfunction.
** For additional information for these contraindicated drugs, see also Drug Interactions (7).
Table 1. Drugs that are Contraindicated with NORVIR
Drug Class Drugs Within Class That Are Contraindicated With NORVIR** Clinical Comments
Alpha1-adrenoreceptor antagonist Alfuzosin HCL Potential for hypotension.
Antiarrhythmics Amiodarone, flecainide, propafenone, quinidine Potential for cardiac arrhythmias.
Antifungal Voriconazole Co-administration of voriconazole with ritonavir 400 mg every 12 hours significantly decreases voriconazole plasma concentrations and may lead to loss of antifungal response. Voriconazole is contraindicated with ritonavir doses of 400 mg every 12 hours or greater [see Drug Interactions ].
Ergot Derivatives Dihydroergotamine, ergonovine, ergotamine, methylergonovine Potential for acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system.
GI Motility Agent Cisapride Potential for cardiac arrhythmias.
Herbal Products St. John’s Wort (hypericum perforatum) Co-administration of NORVIR with St. John’s Wort may result in decreased ritonavir plasma concentrations and may lead to loss of virologic response and possible resistance to NORVIR or to the class of protease inhibitors.
HMG-CoA Reductase Inhibitors Lovastatin, simvastatin Potential for myopathy including rhabdomyolysis.
Neuroleptic Pimozide Potential for cardiac arrhythmias.
PDE5 enzyme inhibitor Sildenafil* (Revatio®) only when used for the treatment of pulmonary arterial hypertension (PAH) A safe and effective dose has not been established when used with ritonavir. There is an increased potential for sildenafil-associated adverse events, including visual abnormalities, hypotension, prolonged erection, and syncope [see Drug Interactions (7) ].
Sedative/hypnotics Oral midazolam, triazolam Prolonged or increased sedation or respiratory depression [see Drug Interactions ].

REFERENCES

  1. Sewester CS. Calculations. In: Drug Facts and Comparisons. St. Louis, MO: J.B. Lippincott Co; January, 1997:xix.

-- advertisement -- The American Red Cross
 
Home | About Us | Contact Us | Site usage policy | Privacy policy

All Rights reserved - Copyright DrugLib.com, 2006-2017