Side Effects of Norvir (ritonavir)

Norvir (ritonavir) is a type of antiviral drug called a protease inhibitor used to treat human immunodeficiency virus (HIV) infection.

During infection with HIV, the HIV virus multiplies within the body's cells. Viruses are released from the cells and spread throughout the body where they infect other cells. During the production of the viruses, new proteins are made. Some of the proteins are structural proteins, which are proteins that form the body of the virus. Other proteins are enzymes which manufacture DNA and other components for the new viruses. Protease is the enzyme that forms the new structural proteins and enzymes. 

Norvir blocks the activity of protease and results in the formation of defective viruses that are unable to infect the body's cells. As a result, the number of viruses in the body (the viral load) decreases. Norvir does not prevent the transmission of HIV, and it does not cure HIV or AIDS. 

Common side effects of Norvir include

• diarrhea,
• nausea and vomiting,
• changes in taste,
• abnormal skin sensations (burning, prickling and tingling),
• headache,
• weakness,
• insomnia (difficulty sleeping),
• fat redistribution,
• high cholesterol, and
• high triglycerides.

Serious side effects of Norvir include

• liver failure,
• inflammation of the pancreas (pancreatitis),
• heart block,
• severe allergic reactions,
• elevated blood glucose resulting in new onset diabetes,
• spontaneous bleeding in patients with hemophilia, and
• immune reconstitution syndrome (inflammatory response to combination antiretroviral therapy).

Norvir increases the blood levels of these drugs and may lead to serious side effects:

• amiodarone,
• quinidine,
• triazolam,
• midazolam,
• pimozide,
• ergot derivatives,
• alfuzosin,
• propafenone, and
• flecainide.

 Norvir should not be combined with voriconazole because it reduces blood levels of voriconazole.

Norvir also increases the concentrations in blood of rifabutin and sildenafil. The blood concentrations of oral contraceptives, methadone, and theophylline are reduced by Norvir, and this could reduce the effectiveness of these drugs.

Norvir decreases the concentration of meperidine and reduces the effect of meperidine while increasing its side effects. Norvir may increase the blood concentration of lovastatin, simvastatin, and atorvastatin and may result in increased occurrence of muscle pain or rhabdomyolysis (muscle breakdown). 

St. John's wort and rifampin decrease the concentration of Norvir in the body and may reduce the effectiveness of Norvir. Clarithromycin, ketoconazole, fluconazole, and fluoxetine may increase blood concentrations of Norvir and result in increased side effects from Norvir. 

Norvir increases blood levels of sildenafil and the risk of side effects such as low blood pressure, prolonged erection, and fainting. 

Use of Norvir during pregnancy has not been adequately evaluated. To monitor outcomes of pregnant women that received Norvir, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263. It is unknown if Norvir passes into breast milk. HIV-infected mothers should not breastfeed because of the potential risk of transmitting HIV to an infant.

The most serious side effects are:

• liver failure,
• inflammation of the pancreas (pancreatitis),
• heart block, and
• severe allergic reactions.

Ritonavir also may elevate blood glucose resulting in new onset diabetes. Fat redistribution, elevated triglycerides, and elevated cholesterol levels also occur. Patients with hemophilia may experience spontaneous bleeding. Immune reconstitution syndrome which is an inflammatory response to infection may occur in patients treated with combination antiretroviral therapy.

Other important side effects include:

• diarrhea,
• nausea and vomiting,
• taste disturbance,
• abnormal
• skin sensations (burning, prickling and tingling),
• headache,
• weakness, and
• insomnia (difficulty sleeping).

The following adverse reactions are discussed in greater detail in other sections of the labeling.

• Drug Interactions
• Hepatotoxicity
• Pancreatitis
• Allergic Reactions/Hypersensitivity

When co-administering Norvir with other protease inhibitors, see the full prescribing information for that protease inhibitor including adverse reactions.

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.

Adverse Reactions In Adults

The safety of Norvir alone and in combination with other antiretroviral agents was studied in 1,755 adult patients. Table 2 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 2. 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)

Laboratory Abnormalities in Adults

Table 3 shows the percentage of adult patients who developed marked laboratory abnormalities.

Table 3. Percentage of Adult Patients, by Study and Treatment Group, with Chemistry and Hematology Abnormalities Occurring in greater than 3% of Patients Receiving Norvir

Adverse Reactions In Pediatric Patients

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.

Laboratory Abnormalities in Pediatric Patients

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%).

Postmarketing Experience

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.

Cardiovascular System

First-degree AV block, second-degree AV block, third-degree AV block, right bundle branch block have been reported .

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.

Endocrine System

Cushing's syndrome and adrenal suppression have been reported when ritonavir has been co-administered with fluticasone propionate or budesonide.

Nervous System

There have been postmarketing reports of seizure.

Skin And Subcutaneous Tissue disorders

Toxic epidermal necrolysis (TEN) has been reported.

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 is 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 for magnitude of interaction.

Table 4. Established and Other Potentially Significant Drug Interactions