Ritonavir

Norvir

Ritonavir is a prescription medicine used in combination with other medications to treat human immunodeficiency virus (HIV) infections in adults and children. Ritonavir does not cure HIV infection or AIDS.

This medication may be prescribed for other uses.  Ask your doctor or pharmacist for more information.

Ritonavir may interact with other medicines, including those you take without a prescription. You must tell your doctor about all the medicines you are taking or are planning to take.

Do not take the following medicines with ritonavir because they can cause serious or life-threatening problems such as irregular heartbeat, breathing difficulties, or excessive sleepiness:

• Cordarone (amiodarone)
• Ergotamine, ergonovine, methylergonovine, and dihydroergotamine such as Cafergot, Migranal, D.H.E 45, and others
• Halcion (triazolam)
• Hismanal (astemizole)
• Orap (pimozide)
• Propulsid (cisapride)
• Quinidine, also known as Quinaglute, Cardioquin, Quinidex, and others
• Rythmol (propafenone)
• Seldane (terfenadine)
• Revatio (sildenafil) only when used for the treatment of pulmonary arterial hypertension
• Tambocor (flecainide)
• Uroxatral (alfuzosin hydrochloride)
• Vascor (bepridil)
• Versed (midazolam)
• Vfend (voriconazole)
• Do not take ritonavir with St. John's wort (hypericum perforatum), an herbal product sold as a dietary supplement or products containing St. John's wort. Talk with your doctor if you are taking or are planning to take St. John's wort. Taking St. John's wort may decrease ritonavir levels and lead to increased viral load and possible resistance to ritonavir or cross-resistance to other antiretroviral medicines.
• Do not take ritonavir with the cholesterol-lowering medicines Mevacor (lovastatin) or Zocor (simvastatin) because of possible serious reactions. There is also an increased risk of drug interactions between ritonavir and Lipitor (atorvastatin); talk to your doctor before you take any of these cholesterol-lowering medicines with ritonavir.

It is possible that your doctor may need to increase or decrease the dose of other medicines when you are also taking ritonavir. Remember to tell your doctor all medicines you are taking or plan to take.

The following medicines require dose reduction if taken with ritonavir:

If you are taking PDE5 inhibitors for erectile dysfunction including Viagra (sildenafil), Cialis (tadalafil), or Levitra (vardenafil), your doctor may lower your dose of these medications. You should not use sildenafil (Revatio) with ritonavir if you are being treated for pulmonary arterial hypertension. If you are taking AdcircaTM (tadalafil) for pulmonary arterial hypertension, your doctor may change your dose of this medicine.

Before you take Viagra, Cialis or Levitra with ritonavir, talk to your doctor about possible drug interactions and side effects. If you take these medications with ritonavir you may be at risk of side effects such as low blood pressure, visual changes, and penile erection lasting more than 4 hours. If an erection lasts longer than 4 hours, you should get medical help immediately to avoid permanent damage to your penis. Your doctor can explain these symptoms to you.

• If you are taking Oral contraceptives ("the pill") or the contraceptive patch to prevent pregnancy, you should use a different type of contraception since ritonavir may reduce the effectiveness of oral or patch contraceptives.
• If you are taking Mycobutin (rifabutin), your doctor will lower the dose of Mycobutin.
• If you are taking Colcrys (colchicine), your doctor will tell you what dose to use.
• If you are taking Tracleer (bosentan), your doctor will tell you what dose to use.


Other Special Considerations: 


• Ritonavir oral solution contains alcohol. Talk with your doctor if you are taking or planning to take metronidazole or disulfiram. Severe nausea and vomiting can occur.
• If you are taking both didanosine (Videx) and ritonavir: 
Didanosine and ritonavir should be separated by at least 2.5 hours.
• Rifampin, also known as Rimactane, Rifadin, Rifater, or Rifamate, may reduce blood levels of ritonavir. Be sure to tell your doctor if you are taking rifampin.
• If you are taking or before you begin using inhaled Flonase (fluticasone propionate), talk to your doctor about problems these two medicines may cause when taken together. Your doctor may choose not to keep you on inhaled Flonase.
• Rifampin and saquinavir should not be taken with ritonavir. Be sure to tell your doctor if you are taking rifampin and saquinavir.
• If you are taking or before you begin using Serevent (salmeterol) and ritonavir, talk to your doctor about problems these medicines may cause when taken together. Your doctor may choose not to keep you on Serevent (salmeterol).
• If you are taking or before you begin using Advair (salmeterol in combination with fluticasone propionate) and ritonavir, talk to your doctor about problems these two medicines may cause when taken together. Your doctor may choose not to keep you on Advair (salmeterol in combination with fluticasone propionate).

Do not breastfeed if you are taking ritonaviir. You should not breastfeed if you have HIV. If you are a woman who has or will have a baby, talk with your doctor about the best way to feed your baby. You should be aware that if your baby does not already have HIV, there is a chance that HIV can be transmitted through breastfeeding.

WARNING: DRUG-DRUG INTERACTIONS LEADING TO POTENTIALLY SERIOUS AND/OR LIFE THREATENING REACTIONS

Co-administration of ritonavir with several classes of drugs including sedative hypnotics, antiarrhythmics, or ergot alkaloid preparations may result in potentially serious and/or life-threatening adverse events due to possible effects of ritonavir on the hepatic metabolism of certain drugs. Review medications taken by patients prior to prescribing ritonavir or when prescribing other medications to patients already taking ritonavir.

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

• Critical nature of compliance with HIV therapy and importance of remaining under the care of a clinician.1 209 Importance of taking as prescribed; do not alter or discontinue antiretroviral regimen without consulting clinician.1 209

• Importance of using in conjunction with other antiretroviralsnot for monotherapy.1 209

• Antiretroviral therapy is not a cure for HIV infection; opportunistic infections and other complications associated with HIV disease may still occur.1 209

• Advise patients that sustained decreases in plasma HIV RNA have been associated with reduced risk of progression to acquired immunodeficiency syndrome (AIDS) and death.1 209

• Advise patients that effective antiretroviral regimens can decrease HIV concentrations in blood and genital secretions and strict adherence to such regimens in conjunction with risk-reduction measures may decrease, but cannot absolutely eliminate, the risk of secondary transmission of HIV to others.200 Importance of continuing to practice safer sex (e.g., using latex or polyurethane condoms to minimize sexual contact with body fluids), never sharing personal items that can have blood or body fluids on them (e.g., toothbrushes, razor blades), and never reusing or sharing needles.1 200

• When tablets are used, importance of taking with a meal.209 When capsules or oral solution are used, take with a meal if possible.1 209

• If a dose is missed, it should be taken as soon as it is remembered and the next dose taken at the regularly scheduled time; if a dose is skipped, the next dose should not be doubled.1 209

• Advise patients that ECG changes (PR prolongation) have occurred; importance of consulting clinician if dizziness, lightheadedness, abnormal heart beats, or loss of consciousness occurs.1 209

• Redistribution/accumulation of body fat may occur, with as yet unknown long-term health effects.1 209

• Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements (e.g., St. John’s wort), and any concomitant illnesses.1 209

• Advise patients receiving a selective PDE5 inhibitor (e.g., sildenafil, tadalafil, vardenafil) that they may be at increased risk of PDE5 inhibitor-associated adverse effects (e.g., hypotension, syncope, visual changes, prolonged penile erection) and that any symptoms should be promptly reported to clinician.1 209 Should not be used in patients receiving avanafil for treatment of erectile dysfunction188 or sildenafil for treatment of PAH.1 209

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 209 Advise HIV-infected women not to breast-feed.1 209

• Importance of advising patients of other important precautionary information.1 209 (See Cautions.)

In the U.S.

• Norvir

Available Dosage Forms:

• Capsule, Liquid Filled
• Tablet
• Powder
• Solution

Therapeutic Class: Antiretroviral Agent

Pharmacologic Class: Protease Inhibitor

HIV-1 infection as a pharmacokinetic “booster” for other protease inhibitors:

Based on the Department of Health and Human Services (HHS) Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents and the Centers for Disease Control and Prevention, US Department of Health and Human Services updated guidelines for antiretroviral postexposure prophylaxis after sexual, injection drug use, or other nonoccupational exposure to HIV, ritonavir is recommended as a pharmacokinetic “booster” for other protease inhibitors in certain antiretroviral treatment regimens for HIV-infected patients and in certain antiretroviral regimens for postexposure prophylaxis of HIV-1 infection following nonoccupational exposure (nPEP) in individuals exposed to blood, genital secretions, or other potentially infectious body fluids that may contain HIV.

Note: Must be given in combination with other antiretroviral agents. Norvir tablets are not bioequivalent to Norvir capsules. Patients who take ritonavir capsules may experience more GI adverse reactions such as nausea, vomiting, abdominal pain, or diarrhea when switching from the capsule to the tablet because of the greater maximum plasma concentration (Cmax) achieved with the tablet compared with the capsule.

Treatment of HIV-1 infection:

Infants >1 month and Children: Oral: Initiate dose at 250 mg/m2/dose twice daily; titrate dose upward every 2 to 3 days by 50 mg/m2 twice daily to recommended dosage of 350 to 400 mg/m2/dose twice daily (maximum dose: 600 mg twice daily). If 400 mg/m2/dose twice daily is not tolerated, the highest tolerated dose may be used for maintenance therapy. Note: Oral solution should not be administered to neonates before a postmenstrual age (first day of mother's last period to birth plus the time elapsed after birth) <44 weeks. Oral powder should only be used for dosing increments of 100 mg; oral solution is the preferred formulation for doses <100 mg or incremental doses between 100 mg intervals.

Adolescents: Refer to adult dosing.

Concerns related to adverse effects:

• Hypersensitivity reactions: Protease inhibitors have been associated with a variety of hypersensitivity events (some severe), including rash, anaphylaxis (rare), angioedema, bronchospasm, erythema multiforme, toxic epidermal necrolysis, and/or Stevens-Johnson syndrome (rare). It is generally recommended to discontinue treatment if severe rash or moderate symptoms accompanied by other systemic symptoms occur.

• Fat redistribution: May cause redistribution/accumulation of fat (eg, central obesity, buffalo hump, peripheral wasting, facial wasting, breast enlargement, cushingoid appearance).

• Hepatotoxicity: May cause hepatitis, jaundice, and/or exacerbation of preexisting hepatic dysfunction (including fatalities); use with caution in patients with underlying hepatic disease, such as hepatitis B or C, cirrhosis, or those with high baseline transaminases; consider increased monitoring of transaminases in these patients.

• Immune reconstitution syndrome: Patients may develop immune reconstitution syndrome resulting in the occurrence of an inflammatory response to an indolent or residual opportunistic infection during initial HIV treatment or activation of autoimmune disorders (eg, Graves’ disease, polymyositis, Guillain-Barré syndrome) later in therapy; further evaluation and treatment may be required.

• Increased cholesterol: Increases in total cholesterol and triglycerides have been reported; screening should be done prior to therapy and periodically throughout treatment.

• PR interval prolongation: Ritonavir has been associated with AV block (including second- and third-degree block) due to prolongation of PR interval; use caution with drugs that prolong the PR interval.

Disease-related concerns:

• Cardiovascular disease: Use with caution in patients with cardiomyopathy, ischemic heart disease, preexisting conduction abnormalities, or structural heart disease; may be at increased risk of conduction abnormalities (eg, second- or third-degree AV block).

• Diabetes: Hyperglycemia, exacerbation of diabetes, diabetic ketoacidosis, and new-onset diabetes mellitus have been reported in patients receiving protease inhibitors. Consider monitoring for these conditions. In some patients who discontinued protease inhibitors, hyperglycemia persisted.

• Hemophilia A or B: Use with caution in patients with hemophilia A or B; increased bleeding events, including spontaneous skin hematoma and hemarthrosis, during protease inhibitor therapy have been reported. Additional factor VIII may be needed.

• Hepatic impairment: Use is not recommended in patients with severe hepatic impairment (Child-Pugh class C).

• Pancreatitis: Use with caution in patients with increased triglycerides; pancreatitis has been observed (including fatalities). Monitor serum lipase and amylase, and for symptoms of nausea, vomiting, and/or abdominal pain. Temporary or permanent discontinuation may be clinically indicated.

Concurrent drug therapy issues:

• Drug-drug interactions: [US Boxed Warning]: Coadministration of ritonavir with several classes of drugs, including antiarrhythmics, ergot alkaloids, and sedatives/hypnotics, may result in potentially serious and/or life-threatening adverse reactions due to possible effects of ritonavir on the hepatic metabolism of certain drugs. Review medications taken by patients prior to prescribing ritonavir or when prescribing other medications to patients already taking ritonavir. Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Preterm neonates: Oral solution contains ethanol and propylene glycol; ethanol competitively inhibits propylene glycol metabolism; preterm infants may be at increased risk of toxicity due to decreased ability to metabolize propylene glycol. Postmarketing adverse reactions (cardiac toxicity, lactic acidosis, renal failure, CNS depression, respiratory complications, acute renal failure including fatalities) have been reported in preterm neonates receiving ritonavir-containing solutions. Do not use in neonates with a postmenstrual age (first day of mother's last menstrual period to birth plus elapsed time after birth) <44 weeks, unless benefit outweighs risk and neonate is closely monitored (serum creatinine and osmolality, CNS depression, renal toxicity, lactic acidosis, cardiac conduction abnormalities, hemolysis).

Dosage form specific issues:

• Bioequivalence: Norvir tablets are not bioequivalent to Norvir capsules. Gastrointestinal side effects (eg, nausea, vomiting, abdominal pain, diarrhea) or paresthesias may be more common when patients are switching from the capsule to the tablet formulation due to a higher Cmax (26% increase) observed with the tablet formulation compared to the capsule. These side effects may decrease as therapy is continued.

• Oral solution: The oral solution contains large amounts of ethanol (43.2%) and propylene glycol (26.57%). Healthcare providers should pay special attention to accurate calculation, measurement, and administration of dose. Overdose (or cumulative ethanol or propylene glycol content in medications) in a child may lead to lethal ethanol or propylene glycol toxicity.