Norvir: Indications, Dosage, Precautions, Adverse Effects
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Norvir - Product Information

Manufacture: AbbVie
Country: Canada
Condition: HIV Infection
Class: Antiviral boosters, Protease inhibitors
Form: Tablets, Syrup
Ingredients: ritonavir, copovidone, colloidal silicon dioxide/colloidal anhydrous silica, dibasic calcium phosphate anhydrous/calcium hydrogen phosphate anhydrous, hydroxypropyl cellulose, hypromellose, polyethylene glycol 400/macrogol type 400, polyethylene glycol 3350/macrogol type 3350, polysorbate 80, sorbitan monolaurate/sorbitan laurate, sodium stearyl fumarate, talc and titanium dioxide E171

NORVIR

ritonavir

Summary Product Information

Route of AdministrationDosage Form/StrengthClinically Relevant Non-medicinal Ingredients
oralfilm-coated tablets / 100 mgsorbitan monolaurate/sorbitan laurate
oral solution / 80 mg/mLethanol, polyoxyl 35 castor oil, propylene glycol
For a complete listing of non-medicinal ingredients, see DOSAGE FORMS, COMPOSITION AND PACKAGING section.

Indications and Clinical Use

NORVIR (ritonavir) film-coated tablets and NORVIR (ritonavir) oral solution are indicated in combination with other antiretroviral agents for:

  • the treatment of HIV infection when therapy is warranted.

For patients with advanced Human Immunodeficiency Virus (HIV) disease, this indication is based on the results from a study that showed a reduction in both mortality and AIDS-defining clinical events for patients who received NORVIR. Median duration of follow-up in this study was 6 months. The clinical benefit from NORVIR therapy for longer periods of treatment is unknown.

For patients with less advanced disease, this indication is based on changes in surrogate markers in studies evaluating patients who received NORVIR alone or in combination with other antiretroviral agents. See (CLINICAL TRIALS).

Geriatrics (≥ 65 years of age)

Clinical studies of NORVIR did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger subjects. In general, appropriate caution should be exercised in the administration and monitoring of NORVIR in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Pediatrics (2 to 16 years of age)

The safety and effectiveness of NORVIR in pediatric patients below the age of 2 years have not been established. Although the database in HIV-infected patients age 2 to 16 years is much smaller, the adverse event profile seen during a clinical trial and post-marketing experience was similar to that observed for adult patients.

Contraindications

When co-administering NORVIR (ritonavir) film-coated tablets or NORVIR (ritonavir) oral solution with other protease inhibitors, see the Product Monograph for that protease inhibitor including contraindication information.

  • NORVIR is contraindicated in patients with known hypersensitivity to NORVIR or any of its ingredients. For a complete listing, see the (DOSAGE FORMS, COMPOSITION AND PACKAGING) sections of the Product Monograph.
  • Co-administration of NORVIR is contraindicated with the drugs listed in Table 1 [see also (DRUG INTERACTIONS, Serious Drug Interactions) box] because competition for primarily CYP3A by NORVIR could result in inhibition of the metabolism of these drugs and create the potential for serious and/or life-threatening reactions such as cardiac arrhythmias, prolonged or increased sedation, and respiratory depression.
  • Table 1. Drugs that are Contraindicated with NORVIR
Drug ClassDrugs Within Class that are Contraindicated with NORVIRClinical Comment
Alpha1-Adrenoreceptor AntagonistAlfuzosinCONTRAINDICATED due to potential for serious reactions such as hypotension. See (DRUG INTERACTIONS, Drug-Drug Interactions, Table 5).
Antiarrhythmicsamiodarone, bepridil1, flecainide, propafenone, quinidineCONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Antibioticfusidic acidCONTRAINDICATED due to potential of increased fusidic acid-associated adverse events such as hepatitis or bone marrow suppression.
AnticoagulantrivaroxabanCONTRAINDICATED due to potential of increased rivaroxaban plasma concentrations which may lead to risk of increased bleeding.
AntifungalVoriconazoleCONTRAINDICATED due to a significant reduction in voriconazole plasma concentrations and possible loss of effect. See (DETAILED PHARMACOLOGY, Human, Pharmacokinetics, Table 13).
Antihistaminesastemizole1, terfenadine1CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Ergot Derivativesdihydroergotamine, ergonovine, ergotamine, methylergonovine1CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as acute ergot toxicity characterized by vasospasm and tissue ischemia.
GI Motility Agentcisapride1CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Herbal ProductsSt. John`s wort
(Hypericum perforatum)
CONTRAINDICATED: May lead to loss of virologic response and possible resistance to NORVIR or to the class of protease inhibitors.
HMG-CoA Reductase Inhibitorslovastatin, simvastatinCONTRAINDICATED: Potential for serious reactions such as risk of myopathy including rhabdomyolysis.
Long Acting Beta-AdrenoceptorsalmeterolCONTRAINDICATED: May result in potential increased risk of cardiovascular adverse events associated with salmeterol.
NeurolepticpimozideCONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
PDE5 Inhibitorssildenafil2, only when used for the treatment of pulmonary arterial hypertension (PAH)CONTRAINDICATED due to potential increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection.
vardenafilCONTRAINDICATED due to potential increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection.
Sedative/Hypnoticsmidazolam, triazolamCONTRAINDICATED due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression.

1 Product no longer marketed in Canada.

2 See (WARNINGS AND PRECAUTIONS) and (DRUG INTERACTIONS) for co-administration of sildenafil in patients with erectile dysfunction.

Warnings and Precautions

Serious Warnings and Precautions

  • Pancreatitis should be considered if clinical symptoms (nausea, vomiting, abdominal pain) or abnormalities in laboratory values (such as increased serum lipase or amylase values) suggestive of pancreatitis should occur. Patients who exhibit these signs or symptoms should be evaluated and NORVIR therapy should be discontinued if a diagnosis of pancreatitis is made. See (WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic, Pancreatitis).

General

When co-administering NORVIR (ritonavir) film-coated tablets or NORVIR (ritonavir) oral solution with other protease inhibitors, see the Product Monograph for that protease inhibitor including (WARNINGS AND PRECAUTIONS).

Co-administration of NORVIR with certain non-sedating antihistamines, sedative hypnotics, or antiarrhythmics may result in potentially serious and/or life-threatening adverse events due to possible effects of NORVIR on the hepatic metabolism of certain drugs. See (CONTRAINDICATIONS) and (DRUG INTERACTIONS).

NORVIR is an inhibitor of cytochrome P450 3A (CYP3A) both in vitro and in vivo. NORVIR also inhibits CYP2D6 in vitro, but to a lesser extent than CYP3A. Co-administration of NORVIR and drugs primarily metabolized by CYP3A or CYP2D6 may result in increased plasma concentrations of other drugs that could increase or prolong its therapeutic and adverse effects. See (CONTRAINDICATIONS, Table 1) and (DRUG INTERACTIONS, Table 5).

Cardiac and neurologic events have been reported with NORVIR when co-administered with disopyramide, mexiletine, nefazodone, fluoxetine and beta blockers. The possibility of drug interactions cannot be excluded.

There have been post-marketing reports of drug interactions, including increased itraconazole levels, when NORVIR and itraconazole were co-administered.

Due to inhibition of CYP3A by NORVIR, co-administration of NORVIR with quetiapine results in increased quetiapine concentrations. Serious and life-threatening quetiapine-related adverse reactions have been reported. NORVIR should not be used in combination with quetiapine (see DRUG INTERACTIONS).

Antimycobacterial

Saquinavir/NORVIR 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.

HMG-CoA Reductase Inhibitors

Concomitant use of NORVIR with lovastatin and simvastatin is contraindicated. See (CONTRAINDICATIONS). Caution should be exercised if HIV protease inhibitors, including NORVIR, are used concurrently with other HMG-CoA reductase inhibitors that are also metabolized by the CYP3A4 pathway (e.g. atorvastatin). While rosuvastatin elimination is not dependent on CYP3A, an elevation of rosuvastatin exposure has been reported with NORVIR co-administration. The risk of myopathy including rhabdomyolysis may be increased when HIV protease inhibitors, including NORVIR, are used in combination with these drugs.

Allergic Reactions

Allergic reactions including urticaria, skin eruptions, bronchospasm, and angioedema have been reported. Rare cases of anaphylaxis and Stevens-Johnson syndrome have also been reported.

Organ Targets for Toxicity

Toxicological studies in laboratory animals identified various organs as targets for toxicity at drug exposures below or approaching those achieved in patients participating in clinical trials with NORVIR. Because no safety margin or a small safety margin has been demonstrated in long-term studies, these organs should be assessed periodically or if clinical signs and symptoms occur during therapy. See (TOXICOLOGY).

Co-Administration with Tipranavir

Co-administration of tipranavir with 200 mg NORVIR has been associated with reports of clinical hepatitis and hepatic decompensation including some fatalities. See (DRUG INTERACTIONS). Refer to the tipranavir Product Monograph for more information.

Extra vigilance is warranted in patients with chronic hepatitis B or hepatitis C co-infection, as these patients have an increased risk of hepatotoxicity.

Carcinogenesis and Mutagenesis

For a brief discussion of pre-clinical animal data. See (TOXICOLOGY, Mutagenicity and Carcinogenicity).

Cardiovascular

PR Interval Prolongation

NORVIR has been shown to cause asymptomatic prolongation of the PR interval in some patients. Reports of second or third degree atrioventricular block in patients with underlying structural heart disease and pre-existing conduction system abnormalities or in patients receiving drugs known to prolong the PR interval (such as verapamil or atazanavir) have been reported in patients receiving NORVIR. NORVIR should be used with caution in such patients. See (ACTION AND CLINICAL PHARMACOLOGY, Pharmacodynamics, Effects on the Electrocardiogram).

Endocrine and Metabolism

Corticosteroids

Concomitant use of NORVIR and fluticasone or other glucocorticoids that are metabolized by CYP3A4 is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects.

A drug interaction study in healthy subjects has shown that NORVIR significantly increases plasma fluticasone propionate exposures, resulting in significantly decreased serum cortisol concentrations. Systemic corticosteroid effects, including Cushing’s syndrome and adrenal suppression have been reported during post-marketing use in patients receiving NORVIR and budesonide or inhaled/intranasally administered fluticasone propionate. See (DRUG INTERACTIONS, Table 5).

Diabetes Mellitus/Hyperglycemia

New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus and hyperglycemia have been reported during post-marketing surveillance in HIV-infected patients receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease inhibitor therapy and these events has not been established.

Fat Redistribution/Accumulation

Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

Lipid Disorders

Treatment with NORVIR therapy alone or in combination with saquinavir has resulted in substantial increases in the concentration of total triglycerides and cholesterol. See (ADVERSE REACTIONS, Abnormal Hematologic and Clinical Chemistry Findings). Triglycerides and cholesterol testing should be performed prior to initiating NORVIR therapy and at periodic intervals during therapy. Lipid disorders should be managed as clinically appropriate.

Hematologic

There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis, in patients with hemophilia type A and type B treated with protease inhibitors. In some patients, additional Factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or re-introduced. There is no proven relationship between protease inhibitors and such bleeding; however, the frequency of bleeding episodes should be closely monitored in patients on NORVIR.

Hepatic/Biliary/Pancreatic

Impaired Hepatic Function

NORVIR is principally metabolized by the liver. Pre-clinical studies have identified the liver as a toxicity target. See (TOXICOLOGY). Therefore, appropriate tests should be performed at treatment initiation and at periodic intervals to assess hepatic function.

Caution should be exercised when administering NORVIR to patients with impaired hepatic function.

Hepatic Reactions

Hepatic transaminase elevations exceeding 5 times the upper limit of normal, clinical hepatitis, and jaundice have occurred in patients receiving NORVIR alone or in combination with other antiretroviral drugs. See (ADVERSE REACTIONS, Table 4). There may be an increased risk for transaminase elevations in patients with underlying hepatitis B or C. Therefore, caution should be exercised when administering NORVIR to patients with pre-existing liver disease, liver enzyme abnormalities, or hepatitis.

There have been post-marketing reports of hepatic dysfunction, including some fatalities. These have generally occurred in patients taking multiple concomitant medications and/or with advanced AIDS.

Pancreatitis

Pancreatitis has been observed in patients receiving NORVIR therapy, including those who developed hypertriglyceridemia. In some cases fatalities have been observed. Patients with advanced HIV disease may be at increased risk of elevated triglycerides and pancreatitis.

Pancreatitis should be considered if clinical symptoms (nausea, vomiting, abdominal pain) or abnormalities in laboratory values (such as increased serum lipase or amylase values) suggestive of pancreatitis should occur. Patients who exhibit these signs or symptoms should be evaluated and NORVIR therapy should be discontinued if a diagnosis of pancreatitis is made.

Immune

Immune Reconstitution Inflammatory Syndrome

Immune reconstitution inflammatory syndrome has been reported in HIV-infected patients treated with combination antiretroviral therapy, including NORVIR. During the initial phase of treatment, patients responding to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia, or tuberculosis), which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment.

Neurologic

Central nervous system (CNS) penetration of NORVIR has not been established.

Sexual Function/Reproduction

PDE5 Inhibitors

Particular caution should be used when prescribing sildenafil or tadalafil for the treatment of erectile dysfunction in patients receiving NORVIR. Co-administration of NORVIR with these drugs is expected to substantially increase their concentrations and may result in increased associated adverse events, such as hypotension, syncope, visual changes, and prolonged erection.

Concomitant use of sildenafil with NORVIR is contraindicated in pulmonary arterial hypertension patients. Concomitant use of vardenafil with NORVIR is contraindicated. See (CONTRAINDICATIONS) and (DRUG INTERACTIONS, Table 5).

Resistance/Cross-resistance

Resistance

HIV-1 isolates with reduced susceptibility to ritonavir have been selected in vitro. Genotypic analysis of these isolates showed mutations in the HIV protease gene at amino acid positions 84 (Ile to Val), 82 (Val to Phe), 71 (Ala to Val), and 46 (Met to Ile). Phenotypic (n = 18) and genotypic (n = 44) changes in HIV isolates from selected patients treated with NORVIR were monitored in Phase 1/2 trials over a period of 3 to 32 weeks. Mutations associated with the HIV viral protease in isolates obtained from 41 patients appeared to occur in a stepwise and ordered fashion; in sequence, these mutations were position 82 (Val to Ala/Phe), 54 (Ile to Val), 71 (Ala to Val/Thr), and 36 (Ile to Leu), followed by combinations of mutations at an additional 5 specific amino acid positions.

Of 18 patients for which both phenotypic and genotypic analysis were performed on free virus isolated from plasma, 12 showed reduced susceptibility to ritonavir in vitro. All 18 patients possessed one or more mutations in the viral protease gene. The 82 mutation appeared to be necessary but not sufficient to confer phenotypic resistance. Phenotypic resistance was defined as a ≥ 5-fold decrease in viral sensitivity in vitro from baseline. The clinical relevance of phenotypic and genotypic changes associated with NORVIR therapy has not been established.

Cross-Resistance

Among protease inhibitors variable cross-resistance has been recognized. Serial HIV isolates obtained from six patients during NORVIR therapy showed a decrease in ritonavir susceptibility in vitro but did not demonstrate a concordant decrease in susceptibility to saquinavir in vitro when compared to matched baseline isolates. However, isolates from two of these patients demonstrated decreased susceptibility to indinavir in vitro (8-fold). Isolates from five patients were also tested for cross-resistance to amprenavir and nelfinavir; isolates from two patients had a decrease in susceptibility to nelfinavir (12- to 14-fold), and none to amprenavir. Cross-resistance between NORVIR and reverse transcriptase inhibitors is unlikely because of the different enzyme targets involved. One zidovudine (ZDV)-resistant HIV isolate tested in vitro retained full susceptibility to ritonavir.

Special Populations

Pregnant Women

There are no adequate and well-controlled studies in pregnant women. As of January 2012, the Antiretroviral Pregnancy Registry (APR) has received prospective reports of 3860 exposures to ritonavir containing regimens (1567 exposed in the first trimester and 2293 exposed in the second and third trimester). Birth defects occurred in 35 of the 1567 (2.2%) live births (first trimester exposure) and 59 of the 2293 (2.6%) live births (second/third trimester exposure). The prevalence of birth defects after any trimester exposure to ritonavir is comparable to the prevalence observed in the general population.

Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

In rat fertility studies, hepatic toxicity precluded drug exposures equal to those achieved with the proposed human therapeutic dose. No effects on fertility in rats were produced at drug exposures approximately 40% (male) and 60% (female) of that achieved with the proposed human therapeutic dose.

No treatment-related malformations were observed when ritonavir was administered to pregnant rats or rabbits. Developmental toxicity observed in rats (early resorptions, decreased fetal body weight and ossification delays and developmental variations) occurred at a maternally toxic dosage at an exposure equivalent to approximately 30% of that achieved with the proposed therapeutic dose. A slight increase in the incidence of cryptorchidism was also noted in rats at an exposure approximately 22% of that achieved with the proposed therapeutic dose.

Developmental toxicity observed in rabbits (resorptions, decreased litter size and decreased fetal weights) also occurred at a maternally toxic dosage equivalent to 1.8 times the proposed therapeutic dose based on a body surface area conversion factor.

Antiretroviral Pregnancy Registry

To monitor maternal-fetal outcomes of pregnant women exposed to NORVIR, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.

Nursing Women

HIV-infected mothers should not breast-feed their infants to avoid risking postnatal transmission of HIV. It is not known whether ritonavir is secreted in human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving NORVIR.

Pediatrics (2 to 16 years of age)

The safety and effectiveness of NORVIR in pediatric patients below the age of 2 years have not been established. Although the database in HIV-infected patients age 2 to 16 years is much smaller, the adverse event profile seen during a clinical trial and post-marketing experience was similar to that observed for adult patients.

Toxicity in Preterm Neonates

NORVIR oral solution should not be used in preterm neonates in the immediate postnatal period because of possible toxicities. NORVIR oral solution contains the excipients alcohol (43.2% v/v) and propylene glycol (26.57% w/v). When administered concomitantly with propylene glycol, ethanol competitively inhibits the metabolism of propylene glycol, which may lead to elevated concentrations. Preterm neonates may be at an increased risk of propylene glycol-associated adverse events due to diminished ability to metabolize propylene glycol, thereby leading to accumulation and potential adverse events. Infants should be monitored closely for toxicity related to ritonavir oral solution including: hyperosmolality, with or without lactic acidosis, renal toxicity, CNS depression (including stupor, coma, and apnea), seizures, hypotonia, cardiac arrhythmias and ECG changes, and hemolysis.

Total amounts of alcohol and propylene glycol from all medicines that are to be given to infants should be taken into account in order to avoid toxicity from these excipients.

Geriatrics (≥ 65 years of age)

Clinical studies of NORVIR did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger subjects. In general, appropriate caution should be exercised in the administration and monitoring of NORVIR in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Monitoring and Laboratory Tests

NORVIR has been associated with elevations in cholesterol, triglycerides, SGOT (AST), SGPT (ALT), GGT, CK, and uric acid. Appropriate laboratory testing should be performed prior to initiating NORVIR therapy and at periodic intervals or if any clinical signs or symptoms occur during therapy. For comprehensive information concerning laboratory test alterations associated with other antiretroviral agents, physicians should refer to the complete product information for each of these drugs.

Adverse Reactions

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

When co-administering NORVIR (ritonavir) film-coated tablets or NORVIR (ritonavir) oral solution with other protease inhibitors, see the Product Monograph for that protease inhibitor including (ADVERSE REACTIONS).

The safety of NORVIR alone and in combination with nucleoside reverse transcriptase inhibitors was studied in 1270 adult patients.

Table 2 lists treatment-emergent adverse events (at least possibly related and of at least moderate intensity) that occurred in 2% or greater of adult patients receiving NORVIR alone or in combination with nucleoside reverse transcriptase inhibitors in Study M94-247 or Study M94-245 and in combination with saquinavir in Study M94-462. In that study, 141 protease inhibitor-naïve, HIV-infected patients with mean baseline CD4 of 300 cells/microliter were randomized to one of four regimens of NORVIR plus saquinavir, including NORVIR 400 mg twice daily plus saquinavir 400 mg twice daily. Overall, the most frequently reported adverse drug reactions among patients receiving NORVIR alone or in combination with other antiretroviral drugs were gastrointestinal and neurological disturbances including diarrhea, nausea, vomiting, anorexia, abdominal pain (upper and lower), and neurological disturbances (including paresthesia and oral paresthesia), and fatigue/asthenia. Similar adverse event profiles were reported in adult patients receiving NORVIR in other trials.

Table 2. Percentage of Patients with Treatment-Emergent Adverse Events1 of Moderate or Severe Intensity Occurring in ≥ 2% of Adult Patients Receiving NORVIR
Adverse EventsStudy M94-247
Advanced Patients2
Study M94-245
Naïve Patients3
Study M94-462
PI-Naïve Patients4
NORVIR
(n = 541)
Placebo
(n = 545)
NORVIR + Zidovudine
(n = 116)
NORVIR
(n = 117)
Zidovudine
(n = 119)
NORVIR + Saquinavir
(n = 141)
Body as a Whole
Abdominal Pain8.35.15.26.05.92.1
Asthenia15.36.428.410.311.816.3
Fever5.02.41.70.91.70.7
Headache6.55.77.86.06.74.3
Malaise0.70.25.21.73.42.8
Pain (unspecified)2.21.80.91.70.84.3
Cardiovascular
Syncope0.60.00.91.70.82.1
Vasodilation1.70.03.41.70.83.5
Digestive
Anorexia7.84.28.61.74.24.3
Constipation0.20.43.40.00.81.4
Diarrhea23.37.925.015.42.522.7
Dyspepsia5.91.52.60.01.70.7
Fecal Incontinence0.00.00.00.00.02.8
Flatulence1.70.72.60.91.73.5
Liver Function Tests Abnormal3.30.92.61.71.75.0
Local Throat Irritation2.80.40.91.70.81.4
Nausea29.88.446.625.626.118.4
Vomiting17.44.423.313.712.67.1
Metabolic and Nutritional
Creatinine Phosphokinase (CK) Increase0.90.24.33.43.4N/A
Hyperlipidemia5.70.22.61.70.03.5
Weight Loss2.41.70.00.00.00.0
Musculoskeletal
Arthralgia1.70.70.00.00.02.1
Myalgia2.41.11.71.70.82.1
Nervous
Anxiety1.70.90.90.00.82.1
Circumoral Paresthesia6.70.45.23.40.06.4
Confusion0.60.60.00.90.02.1
Depression1.70.71.71.72.57.1
Dizziness3.91.15.22.63.48.5
Insomnia2.01.83.42.60.82.8
Paresthesia3.00.45.22.60.02.1
Peripheral Paresthesia5.01.10.06.00.85.7
Somnolence2.40.22.62.60.00.0
Thinking Abnormal0.90.42.60.00.80.7
Respiratory
Pharyngitis0.40.40.92.60.01.4
Skin and Appendages
Rash3.51.50.90.00.80.7
Sweating1.71.13.42.61.72.8
Special Senses
Taste Perversion7.02.217.211.18.45.0
Urogenital
Nocturia0.20.00.00.00.02.8

1 Includes those adverse events at least possibly related to study drug or of unknown relationship and excludes concurrent HIV conditions.

2 The median duration of treatment for patients randomized to regimens containing NORVIR in Study M94-247 was 9.4 months.

3 The median duration of treatment for patients randomized to regimens containing NORVIR in Study M94-245 was 9.1 months.

4 The median duration of treatment for patients in Study M94-462 was 48 weeks.

Definitions: N/A = Not available

Other Common Clinical Trial Adverse Drug Reactions

Table 3 includes other treatment-emergent adverse reactions (with possible or probable relationship to study drug) occurring in ≥ 1% of adult patients receiving NORVIR derived from cumulative data from combined Phase 2 to 4 studies.

Table 3. Treatment-Emergent Adverse Reactions (With Possible or Probable Relationship to Study Drug) Occurring in ≥ 1% of Adult Patients Receiving NORVIR in Combined Phase 2 to 4 Studies (N = 1,755)
Adverse Reactionsn%
Eye disorders
Blurred vision1136.4
Gastrointestinal disorders
Abdominal Pain (upper and lower)46426.4
Diarrhea including severe with electrolyte imbalance1.19267.9
Dyspepsia20111.5
Flatulence1428.1
Gastrointestinal hemorrhage412.3
Gastroesophageal reflux disease (GERD)191.1
Nausea1.00757.4
Vomiting55931.9
General disorders and administration site conditions
Fatigue including asthenia81146.2
Hepatobiliary disorders
Blood bilirubin increased (including jaundice)251.4
Hepatitis (including increased AST, ALT, GGT)1538.7
Immune system disorders
Hypersensivity including urticatria and face edema1148.2
Metabolism and nutrition disorders
Edema and peripheral edema1106.3
Gout241.4
Hypercholesterolemia523.0
Hypertriglyceridemia1589.0
Lipodystrophy acquired512.9
Musculoskeletal and connective tissue disorders
Arthralgia and back pain32618.6
Myopathy/creatine phosphokinase increased663.8
Myalgia1568.9
Nervous system disorders
Dizziness27415.6
Dysgeusia28516.2
Paresthesia (including oral paresthesia)88950.7
Peripheral neuropathy17810.1
Syncope583.3
Psychiatric disorders
Confusion523.0
Disturbance in attention442.5
Renal and urinary disorders
Increased urination744.2
Respiratory, thoracic and mediastinal disorders
Coughing38021.7
Oropharyngeal Pain27915.9
Skin and subcutaneous tissue disorders
Acne673.8
Pruritus21412.2
Rash (includes erythematous and maculopapular)47527.1
Vascular disorders
Flushing, feeling hot23213.2
Hypertension583.3
Hypotension including orthostatic hypotension301.7
Peripheral coldness211.2

Less Common Clinical Trial Adverse Drug Reactions (< 2%)

Adverse events occurring in less than 2% of adult patients receiving NORVIR in all Phase 2/Phase 3 studies and considered at least possibly related or of unknown relationship to treatment and of at least moderate intensity are listed below by body system.

Body as a Whole:Abdomen enlarged, accidental injury, cachexia, chest pain, chills, facial pain, flu syndrome, hormone level altered, hypothermia, kidney pain, neck pain, neck rigidity, pelvic pain, photosensitivity reaction, and substernal chest pain.
Cardiovascular System:Cardiovascular disorder, cerebral ischemia, cerebral venous thrombosis, hemorrhage, migraine, myocardial infarct, palpitation, peripheral vascular disorder, phlebitis, postural hypotension, tachycardia, and vasospasm.
Digestive System:Abnormal stools, bloody diarrhea, cheilitis, cholangitis, cholestatic jaundice, colitis, dry mouth, dysphagia, eructation, esophageal ulcer, esophagitis, gastritis, gastroenteritis, gastrointestinal disorder, gingivitis, hepatic coma, hepatomegaly, hepatosplenomegaly, ileitis, ileus, liver damage, melena, mouth ulcer, oral moniliasis, pancreatitis, periodontal abscess, pseudomembranous colitis, rectal disorder, rectal hemorrhage, sialadenitis, stomatitis, tenesmus, thirst, tongue edema, and ulcerative colitis.
Endocrine System:Adrenal cortex insufficiency and diabetes mellitus.
Hemic and Lymphatic System:Acute myeloblastic leukemia, anemia, ecchymosis, leukopenia, lymphadenopathy, lymphocytosis, myeloproliferative disorder, and thrombocytopenia.
Metabolism and Nutritional Disorders:Albuminuria, alcohol intolerance, avitaminosis, BUN increased, dehydration, enzymatic abnormality, glycosuria, and xanthomatosis.
Musculoskeletal System:Arthritis, arthrosis, bone disorder, bone pain, extraocular palsy, joint disorder, leg cramps, muscle cramps, muscle weakness, myositis, and twitching.
Nervous System:Abnormal dreams, abnormal gait, agitation, amnesia, aphasia, ataxia, coma, convulsion, dementia, depersonalization, diplopia, emotional lability, euphoria, grand mal convulsion, hallucinations, hyperesthesia, hyperkinesia, hypesthesia, incoordination, libido decreased, manic reaction, nervousness, neuralgia, neuropathy, paralysis, peripheral neuropathic pain, peripheral sensory neuropathy, personality disorder, sleep disorder, speech disorder, stupor, subdural hematoma, tremor, urinary retention, vertigo, and vestibular disorder.
Respiratory System:Asthma, bronchitis, dyspnea, epistaxis, hiccup, hypoventilation, interstitial pneumonia, larynx edema, lung disorder, rhinitis, and sinusitis.
Skin and Appendages:Contact dermatitis, dry skin, eczema, erythema multiforme, exfoliative dermatitis, folliculitis, fungal dermatitis, furunculosis, molluscum contagiosum, onychomycosis, psoriasis, pustular rash, seborrhea, skin discoloration, skin disorder, skin hypertrophy, skin melanoma, and vesiculobullous rash.
Special Senses:Abnormal electro-oculogram, abnormal electroretinogram, abnormal vision, amblyopia/blurred vision, blepharitis, conjunctivitis, ear pain, eye disorder, eye pain, hearing impairment, increased cerumen, iritis, parosmia, photophobia, taste loss, tinnitus, uveitis, visual field defect, and vitreous disorder.
Urogenital System:Acute kidney failure, breast pain, cystitis, dysuria, hematuria, impotence, kidney calculus, kidney failure, kidney function abnormal, kidney pain, menorrhagia, penis disorder, polyuria, pyelonephritis, urethritis, urinary frequency, urinary tract infection, and vaginitis.

Abnormal Hematologic and Clinical Chemistry Findings

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 ≥ 2% of Patients Receiving NORVIR
VariableLimitStudy M94-247
Advanced Patients
Study M94-245
Naïve Patients
Study M94-462
PI-Naïve Patients
NORVIR
(n = 541)
Placebo
(n=545)
NORVIR + ZDV
(n = 116)
NORVIR
(n = 117)
ZDV
(n=119)
NORVIR + Saquinavir
(n = 141)
ChemistryHigh
Alkaline Phosphatase> 550 IU/L2.32.2-0.9--
Cholesterol> 6.22 mmol/L36.58.030.744.89.365.2
CK> 1000 IU/L9.16.39.612.111.09.9
GGT> 300 IU/L19.611.31.85.21.79.2
Glucose> 13.88 mmol/L0.91.32.60.90.80.7
SGOT/AST> 180 IU/L6.47.05.39.52.57.8
SGPT/ALT> 215 IU/L8.54.45.37.83.49.2
Total Bilirubin> 61.56 micromol/L1.30.2-0.90.82.1
Triglycerides> 9.04 mmol/L33.69.49.617.23.423.4
Triglycerides> 16.95 mmol/L12.60.41.82.6-11.3
Triglycerides Fasting> 16.95 mmol/L9.90.31.51.3--
Uric Acid> 713.76 micromol/L3.80.2---1.4
ChemistryLow
Potassium< 3.0 mEq/L3.02.0-1.7-2.1
HematologyHigh
Eosinophils> 1.0 x 109/L2.63.3-2.61.70.7
Neutrophils> 20 x 109/L2.31.3----
HematologyLow
Hematocrit< 30%17.322.02.6-0.80.7
Hemoglobin< 80 g/L3.83.90.9---
Neutrophils≤ 0.5 x 109/L6.08.3----
Red Blood Cells (RBC)< 3.0 x 1012/L18.624.41.8-5.9-
White Blood Cells (WBC)< 2.5 x 109/L36.959.4-0.96.83.5

– Indicates no events reported.

Definitions: CK = creatinine; ULN = upper limit of the normal range; N/A = Not Applicable; SGPT/ALT = serum glutamic-pyruvic transaminase/alanine aminotransferase; SGOT/AST = serum glutamic-oxaloacetic transaminase/aspartate aminotransferase; GGT = gamma-glutamyl transpeptidase; ZDV = zidovudine.

Post-Market Adverse Drug Reactions

The following adverse events 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.

Cardiovascular System:Myocardial infarction has been reported. Cardiac and neurologic events have been reported when NORVIR has been co-administered with disopyramide, mexiletine, nefazodone, fluoxetine, and beta blockers. The possibility of drug interaction cannot be excluded.
Endocrine System:Hyperglycemia has been reported in individuals with and without a known history of diabetes.
Cushing's syndrome and adrenal suppression have been reported when NORVIR has been co-administered with fluticasone propionate or budesonide.
Hemic and Lymphatic System:There have been reports of increased bleeding in patients with hemophilia A or B. See (WARNINGS AND PRECAUTIONS, Hematologic).
Immune System:Immune Reconstitution Inflammatory Syndrome. See (WARNINGS AND PRECAUTIONS, Immune)
Metabolism and Nutrition Disorders:Redistribution/accumulation of body fat has been reported. See (WARNINGS AND PRECAUTIONS). 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 NORVIR 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.
Nervous System Disorders:There have been post-marketing reports of seizure. Cause and effect relationship has not been established.
Reproductive System and Breast Disorders:Menorrhagia has been reported.
Skin and Subcutaneous Tissue Disorders:Stevens-Johnson syndrome, and Toxic epidermal necrolysis (TEN).

Drug Interactions

Serious Drug Interactions

  • See (CONTRAINDICATIONS).
  • Co-administration (saquinavir/rifampin/NORVIR): Saquinavir and NORVIR should not be given together with rifampin due to risk of severe hepatotoxicity (presenting as increased transaminases) if the three drugs are given together.
  • Co-administration (tipranavir/NORVIR): Tipranavir co-administered with 200 mg of NORVIR has been associated with reports of clinical hepatitis and hepatic decompensation including some fatalities. Extra vigilance is warranted in patients with chronic hepatitis B or hepatitis C co-infection, as these patients have an increased risk of hepatotoxicity.

Overview

When co-administering NORVIR (ritonavir) film-coated tablets or NORVIR (ritonavir) oral solution with other protease inhibitors, see the Product Monograph for that protease inhibitor including information on 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 (> 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. Therefore, decreased plasma concentrations of the co-administered drugs and potential loss of therapeutic effects may signify the need for dosage alteration of these agents.

When co-administering NORVIR with any agent having a narrow therapeutic margin, such as anticoagulants, anticonvulsants, and antiarrhythmics, special attention is warranted.

Potential for Other Drugs to Affect NORVIR

Agents which increase CYP3A activity (e.g. phenobarbital, carbamazepine, dexamethasone, phenytoin, rifampin, and rifabutin) would be expected to increase the clearance of NORVIR resulting in decreased ritonavir plasma concentrations. Tobacco use is associated with an 18% decrease in the area under the concentration-time curve (AUC) of ritonavir.

Drug-Drug Interactions

Table 5 lists the established and other potentially significant drug interactions. Alteration in dose or regimen may be recommended based on drug interaction studies or predicted interaction. See also (CONTRAINDICATIONS) and (DETAILED PHARMACOLOGY, Human, Pharmacokinetics) for magnitude of interaction.

Table 5. Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen Recommended Based on Drug Interaction Studies or Predicted Interaction.
Concomitant Drug Class:
Drug Name
Effect on
Concentration of
NORVIR or
Concomitant Drug
Clinical Comment
HCV-Antiviral Agents
HCV Protease Inhibitors:
simeprevir↑ simeprevirA pharmacokinetic study demonstrated that concomitant administration of simeprevir 200 mg once daily with NORVIR 100 mg twice daily resulted in an increase in simeprevir concentrations. It is not recommended to co-administer NORVIR with simeprevir.
HIV-Antiviral Agents
HIV Protease Inhibitors:
amprenavir, fosamprenavir↑ amprenavirLiterature reports have shown that concentrations of the HIV-protease inhibitor, amprenavir, are increased when co-administered with NORVIR.
Refer to the fosamprenavir Product Monograph for details on co-administration of fosamprenavir 700 mg twice daily with NORVIR 100 mg twice daily or fosamprenavir 1400 mg once daily with NORVIR 200 mg once daily.
atazanavirWhen co-administered with reduced doses of atazanavir and NORVIR
↑ atazanavir
Atazanavir plasma concentrations achieved with atazanavir 300 mg once daily and NORVIR 100 mg once daily are higher than those achieved with atazanavir 400 mg once daily. Refer to the atazanavir Product Monograph for details on co-administration of atazanavir 300 mg once daily, with NORVIR 100 mg once daily.
darunavirWhen co-administered with reduced doses of NORVIR
↑ darunavir
Refer to the darunavir Product Monograph for details on co-administration of darunavir 600 mg twice daily with NORVIR 100 mg twice daily.
indinavirWhen co-administered with reduced doses of indinavir and NORVIR
↑ indinavir
Alterations in concentrations are noted when reduced doses of indinavir are co-administered with NORVIR.
The safety and efficacy of this combination have not yet been established.
The risk of nephrolithiasis may be increased when doses of indinavir equal to or greater than 800 mg twice daily are given with NORVIR. Adequate hydration and monitoring of the patients is warranted.
nelfinavir↑ M8 (major active metabolite of nelfinavir)NORVIR increases the concentrations of nelfinavir major active metabolite, M8. This interaction is likely to involve cytochrome P450 inhibition and induction.
saquinavirWhen co-administered with reduced doses of saquinavir and NORVIR
↑ saquinavir
The recommended dosage regimen is saquinavir 1000 mg with NORVIR 100 mg twice daily taken within 2 hours after a meal. Dose adjustment may be needed if other HIV-protease inhibitors are used in combination with saquinavir and NORVIR.
Saquinavir and NORVIR should not be given together with rifampin due to risk of severe hepatotoxicity (presenting as increased hepatic transaminases) if the three drugs are given together.
In some cases, co-administration of saquinavir and NORVIR has led to severe adverse events, mainly diabetic ketoacidosis and liver disorders, especially in patients with pre-existing liver disease. Refer to the saquinavir Product Monograph for prescribing information.
tipranavirWhen co-administered with NORVIR
↑ tipranavir
Refer to the tipranavir Product Monograph for details on co-administration of tipranavir 500 mg twice daily with NORVIR 200 mg twice daily.
Nucleoside Reverse Transcriptase Inhibitors:
didanosine↓ didanosineDosing of didanosine and NORVIR should be separated by 2.5 hours to avoid formulation incompatibility.
tenofovir↑ tenofovirLopinavir/ritonavir has been shown to increase tenofovir concentrations. Higher tenofovir concentrations could potentiate tenofovir-associated adverse events, including renal disorders. Patients receiving NORVIR and tenofovir disoproxil fumarate should be monitored for tenofovir-associated adverse events. Refer to the tenofovir Product Monograph for more information.
Non-Nucleoside Reverse Transcriptase Inhibitors:
delavirdine↑ ritonavir
↔ delavirdine
When used in combination with delavirdine, a dose reduction of NORVIR should be considered. Based on comparison to historical data, the pharmacokinetics of delavirdine did not appear to be affected by NORVIR. The safety and efficacy of this combination (delavirdine/ NORVIR) have not been established.
efavirenz↑ efavirenzIn healthy volunteers receiving 500 mg NORVIR twice daily with efavirenz 600 mg once daily, the steady state AUC was increased by 21%. An associated increase in the AUC of NORVIR of 17% was observed.
Integrase Inhibitor:
raltegravir↓ raltegravirA pharmacokinetic study showed that co-administration of NORVIR 100 mg twice daily and raltegravir 400 mg single dose resulted in a reduction in raltegravir plasma concentration.
CCR5 Antagonist:
maravirocWhen co-administered with reduced dose of NORVIR
↑ maraviroc
Concurrent administration of maraviroc with NORVIR increases plasma levels of maraviroc. The dose of maraviroc should be decreased during co-administration with NORVIR. Refer to the maraviroc Product Monograph for details on co-administration of maraviroc 150 mg twice daily with NORVIR.
Other agents
Alpha1-adrenoreceptor Antagonist:
alfuzosin↑ alfuzosinBased on results of a drug interaction study with ketoconazole, another potent inhibitor of CYP3A4, a significant increase in alfuzosin exposure is expected in the presence of NORVIR (600 mg twice daily). Therefore, alfuzosin is contraindicated with NORVIR. See (CONTRAINDICATIONS).
Analgesics, Narcotic:
fentanyl↑ fentanylNORVIR inhibits CYP3A4 and as a result is expected to increase the plasma concentrations of fentanyl, tramadol, propoxyphene. Careful monitoring of therapeutic and adverse effects (including respiratory depression) is recommended when NORVIR is co-administered with fentanyl, including extended-release, transdermal or transmucosal preparations. Use tramadol and propoxyphene with caution, dose reduction of these drugs may be needed.
tramadol↑ tramadol
propoxyphene↑ propoxyphene
methadone↓ methadoneDosage increase of methadone may be considered.
Anesthetic:
meperidine↓ meperidine
↑ normeperidine (metabolite)
Dosage increase and long-term use of meperidine with NORVIR 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/metronidazoleNORVIR 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↑ disopyramide
↑ lidocaine
↑ mexiletine
Plasma concentrations of these drugs are expected to increase by co-administration with NORVIR. Use with caution, dose reduction of these drugs may be needed.
Antibacterial:
fusidic acid↑ fusidic acid
↑ ritonavir
Coadministration of protease inhibitors, including NORVIR with fusidic acid is expected to increase fusidic acid, as well as the protease inhibitor concentration in plasma. See (CONTRAINDICATIONS).
Anticancer agents:
dasatinib, nilotinib, vincristine, vinblastine↑ anticancer agentsSerum concentrations increase when co-administered with NORVIR resulting in the potential for increased incidence of adverse events.
Anticoagulants:
rivaroxaban↑ rivaroxabanA study has shown that co-administration of NORVIR and rivaroxaban resulted in increased exposure of rivaroxaban which may lead to risk of increased bleeding. NORVIR and rivaroxaban should not be used concomitantly. See (CONTRAINDICATIONS).
warfarin↓ R-warfarin
↓ ↑ S-warfarin
Initial frequent monitoring of the INR (International Normalized Ratio) during NORVIR and warfarin co-administration is indicated.
Anticonvulsants:
clonazepam↑ clonazepamPlasma concentrations of clonazepam and ethosuximide are expected to increase by co-administration with NORVIR. Use with caution, dose reduction of these drugs may be needed.
Plasma concentrations of divalproex and lamotrigine are expected to decrease by co-administration with NORVIR. Use with caution, dose increase of these drugs may be needed.
ethosuximide↑ ethosuximide
divalproex↓ divalproex
lamotrigine↓ lamotrigine
carbamazepine, phenobarbital, phenytoin↑ carbamazepine
↓ phenytoin
↓ ritonavir
Plasma concentrations of carbamazepine is expected to increase by co-administration with NORVIR. Use with caution, dose reduction of carbamazepine may be needed.
Plasma concentrations of phenytoin is expected to decrease by co-administration with NORVIR. Use with caution, dose increase of phenytoin may be needed.
Carbamazepine, phenobarbital, phenytoin, which increase CYP3A activity, would be expected to increase the clearance of NORVIR resulting in decreased ritonavir plasma concentrations. Use with caution, dose adjustment of NORVIR may be needed.
Antidepressants:
amitriptyline, clomipramine, fluoxetine, imipramine, maprotiline, nefazodone, nortriptyline, paroxetine, sertraline, trimipramine, venlafaxine↑ antidepressantsPlasma concentrations of these drugs are expected to increase by co-administration with NORVIR. Use with caution, dose reduction of these drugs may be needed.
bupropion↓ bupropionBupropion is primarily metabolized by CYP2B6. Concurrent administration of bupropion with repeated doses of NORVIR decreases bupropion levels.
desipramine↑ desipramineA study has shown that co-administration of NORVIR and desipramine resulted in increased exposure of desipramine. Dosage reduction and concentration monitoring of desipramine is recommended.
trazodone↑ trazodoneConcomitant use of NORVIR and trazodone increases concentrations of trazodone. Adverse events of nausea, dizziness, hypertension and syncope have been observed. If trazodone is used with a CYP3A4 inhibitor such as NORVIR, the combination should be used with caution and a lower dose of trazodone should be considered.
Antiemetics:
dronabinol↑ dronabinolPlasma concentrations of dronabinol are expected to increase by co-administration with NORVIR. Use with caution, dose reduction of dronabinol may be needed.
Antifungal:
ketoconazole↑ ketoconazoleHigh doses of ketoconazole or itraconazole (> 200 mg/day) are not recommended.
itraconazole↑ itraconazole
Antigout:
colchicine↑ colchicinePatients with renal or hepatic impairment should not be given colchicine with NORVIR.
NORVIR and co-administration of colchicine:
Treatment of gout flares: 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.
Prophylaxis of gout flares: If the original colchicine regimen was 0.6 mg twice daily, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.3 mg twice daily, the regimen should be adjusted to 0.3 mg once every other day.
Treatment of Familial Mediterranean fever (FMF): Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Anti-infective:
clarithromycin↑ clarithromycinFor patients with renal impairment, the following dosage adjustments should be considered:
• For patients with CLCR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%.
• For patients with CLCR < 30 mL/min the dose of clarithromycin should be reduced by 75%.
No dose adjustment for patients with normal renal function is necessary.
Antimycobacterial:
rifabutin↑ rifabutin and rifabutin metabolite
↓ ritonavir
Dosage reduction of rifabutin by at least three-quarters of the usual dose of 300 mg/day is recommended (e.g. 150 mg every other day or three times a week). Further dosage reduction may be necessary.
rifampin↑ ritonavirMay lead to loss of virologic response. Alternate antimycobacterial agents such as rifabutin should be considered. See (Antimycobacterial: rifabutin) for dose reduction recommendations.
Antiparasitics:
atovaquone↓ atovaquonePlasma concentrations of atovaquone are expected to decrease by co-administration with NORVIR. Use with caution, dose increase of atovaquone may be needed.
quinine↑ quininePlasma concentrations of quinine are expected to increase by co-administration with NORVIR. Use with caution, dose reduction of quinine may be needed.
Antipsychotics:
quetiapine↑ quetiapineNORVIR should not be used in combination with quetiapine. Due to CYP3A inhibition by NORVIR, concentrations of quetiapine are expected to increase, which can result in serious and/or life-threatening adverse reactions.
Beta-blockers:
metoprolol, timolol↑ beta-blockersPlasma concentrations of these drugs are expected to increase by co-administration with NORVIR. Use with caution, dose reduction of these drugs may be needed.
Bronchodilator:
theophylline↓ theophyllineIncreased dosage of theophylline may be required; therapeutic monitoring should be considered.
Calcium channel blockers:
diltiazem, nifedipine, verapamil↑ calcium channel blockersPlasma concentrations of these drugs are expected to increase by co-administration with NORVIR. Use with caution, dose reduction of these drugs may be needed.
Corticosteroids:
fluticasone propionate, budesonide↑ fluticasoneConcomitant use of NORVIR and fluticasone propionate or other glucocorticoids that are metabolized by CYP3A4 is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid side effects, including Cushing`s syndrome and adrenal suppression. Consider alternatives to fluticasone propionate or budesonide, particularly for long-term use. See (WARNINGS AND PRECAUTIONS, Endocrine and Metabolism, Corticosteroids).
dexamethasone↑dexamethasone
↓ ritonavir
Dexamethasone, which increases CYP3A activity, would be expected to increase the clearance of NORVIR resulting in decreased ritonavir plasma concentrations.
prednisone↑ prednisonePlasma concentrations of dexamethasone and prednisone are expected to increase by co-administration with NORVIR. Use with caution, dose adjustment of these drugs may be needed.
Digoxin↑ digoxinA literature report has shown that co-administration of NORVIR (300 mg every 12 hours) and digoxin resulted in significantly increased digoxin levels. Caution should be exercised when co-administrating NORVIR and digoxin, with appropriate monitoring of serum levels.
Endothelin receptor antagonist:
bosentan↑ bosentanCo-administration of bosentan in patients already on NORVIR for at least 10 days: Start at 62.5 mg once daily or every other day based upon individual tolerability.
Coadministration of NORVIR in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of NORVIR. After at least 10 days following the initiation of NORVIR, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
PDE5 Inhibitors:
sildenafil↑ sildenafilSildenafil should be used with caution and should not exceed a maximum single dose of 25 mg in a 48-hour period. See (WARNINGS AND PRECAUTIONS). Concomitant use of sildenafil with NORVIR is contraindicated in patients with pulmonary arterial hypertension. See (CONTRAINDICATIONS) and (WARNINGS AND PRECAUTIONS).
tadalafil↑ tadalafilUse tadalafil for the treatment of erectile dysfunction with caution at reduced doses of no more than 10 mg every 72 hours with increased monitoring for adverse events. See (WARNINGS AND PRECAUTIONS, Sexual Function/Reproduction, PDE5 Inhibitors).
Coadministration of NORVIR and tadalafil for the treatment of pulmonary arterial hypertension is not recommended.
vardenafil↑ vardenafilConcomitant use of vardenafil with NORVIR is contraindicated. See (CONTRAINDICATIONS).
Hypolipidemics, HMG- CoA Reductase Inhibitors:
atorvastatin↑ atorvastatinCo-administration with lovastatin and simvastatin is not recommended. See (CONTRAINDICATIONS) and (WARNINGS AND PRECAUTIONS, General, HMG-CoA Reductase Inhibitors). Use the lowest possible dose of atorvastatin or rosuvastatin with careful monitoring or consider other HMG-CoA reductase inhibitors such as pravastatin or fluvastatin in combination with NORVIR.
rosuvastatin↑ rosuvastatin
Immunosuppressants :
cyclosporine, everolimus, tacrolimus, rapamycin↑ immunosuppressantsTherapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with NORVIR.
Neuroleptics:
perphenazine, risperidone, thioridazine↑ neurolepticsPlasma concentrations of these drugs are expected to increase by co-administration with NORVIR. Use with caution, dose reduction of these drugs may be needed.
Oral Contraceptive or Patch Contraceptive:
ethinyl estradiol↓ ethinyl estradiolDosage increase or alternate contraceptive measures should be considered.
Sedative/hypnotics:
buspirone, clorazepate, diazepam, estazolam, flurazepam, zolpidem↑ sedative/hypnoticsPlasma concentrations of these drugs are expected to increase by co-administration with NORVIR. Use with caution, dose reduction of these drugs may be needed.
Stimulants:
methamphetamine↑ methamphetaminePlasma concentrations of these drugs are expected to increase by co-administration with NORVIR. Use with caution, dose reduction of these drugs may be needed.

Drug-Food Interactions

It is recommended that NORVIR be taken with meals, if possible. Refer to( ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics, Absorption) and to (CLINICAL TRIALS, Pivotal Comparative Bioavailability Studies) for information on the effect of food on ritonavir pharmacokinetics.

Drug-Herb Interactions

St-John`s Wort

Concomitant use of NORVIR and St. John`s wort (Hypericum perforatum) or products containing St. John`s wort is not recommended. Co-administration of protease inhibitors, including NORVIR, with St. John`s wort is expected to substantially decrease protease inhibitor concentrations and may result in sub-optimal levels of ritonavir and lead to loss of virologic response and possible resistance to NORVIR or to the class of protease inhibitors. See (CONTRAINDICATIONS).

Drug-Laboratory Interactions

Interactions with laboratory tests have not been established.

Dosage and Administration

General Dosing Guidelines

Prescribers should consult the Product Monograph and clinical study information of protease inhibitors if they are co-administered with a reduced dose of NORVIR (ritonavir) film-coated tablets or NORVIR (ritonavir) oral solution.

Dosing Considerations

Patients should be aware that frequently observed adverse events, such as mild to moderate gastrointestinal disturbances and paresthesias, may diminish as therapy is continued. In addition, patients initiating combination regimens with NORVIR and other antiretroviral agents may improve gastrointestinal tolerance by initiating NORVIR alone and subsequently adding the other antiretroviral agents before completing two weeks of NORVIR monotherapy. The long-term effects of dose escalation on efficacy have not been established.

Recommended Dose and Dosage Adjustment

Adult Patients

NORVIR Film-coated Tablets

The recommended dose of NORVIR tablets is 600 mg (six tablets) twice daily orally and should be taken with a meal. NORVIR tablets should be swallowed whole with water and not chewed, broken or crushed.

NORVIR Oral Solution

The recommended dosage of NORVIR is 600 mg (6 capsules or 7.5 mL) twice daily orally. Some patients experience nausea upon initiation of 600 mg twice daily dosing. Use of a dose titration schedule may help to reduce treatment-emergent adverse events while maintaining appropriate ritonavir plasma levels. NORVIR should be started at no less than 300 mg twice daily and increased by 100 mg twice daily increments up to 600 mg twice daily. The titration period should not exceed 14 days.

Pediatric Patients (2 to 16 years of age)

NORVIR should be used in combination with other antiretroviral agents. The recommended dosage of NORVIR oral solution is 400 mg/m2 of body surface area twice daily by mouth and should not exceed 600 mg twice daily (Table 6). NORVIR oral solution should be started at 250 mg/m2 twice daily and increased at 2- to 3-day intervals by 50 mg/m2 twice daily, as tolerated. If patients do not tolerate 400 mg/m2 twice daily due to adverse events, the highest tolerated dose should be used for maintenance therapy in combination with other antiretroviral agents. Doses of oral solution should be administered using a calibrated dosing syringe.

Table 6. Pediatric Dosage Guidelines for NORVIR Oral Solution
Body Surface Area* (m2)Twice Daily Dose 250 mg/m2Twice Daily Dose 300 mg/m2Twice Daily Dose 350 mg/m2Twice Daily Dose 400 mg/m2
0.250.8 mL (62.5 mg)0.9 mL (75 mg)1.1 mL (87.5 mg)1.25 mL (100 mg)
0.51.6 mL (125 mg)1.9 mL (150 mg)2.2 mL (175 mg)2.5 mL (200 mg)
0.752.3 mL (187.5 mg)2.8 mL (225 mg)3.3 mL (262.5 mg)3.75 mL (300 mg)
1.003.1 mL (250 mg)3.75 mL (300 mg)4.4 mL (350 mg)5 mL (400 mg)
1.253.9 mL (312.5 mg)4.7 mL (375 mg)5.5 mL (437.5 mg)6.25 mL (500 mg)
1.504.7 mL (375 mg)5.6 mL (450 mg)6.6 mL (525 mg)7.5 mL (600 mg)

* Body surface area can be calculated with the following equation:



Total amounts of alcohol and propylene glycol from all medicines, including ritonavir oral solution, that are to be given to children should be taken into account in order to avoid toxicity from these excipients. See [WARNINGS AND PRECAUTIONS, Special Populations, Pediatrics (2 to 16 years of age), Toxicity in Preterm Neonates] and (OVERDOSAGE, Management of Overdosage).

Missed Dose

If a dose of this medication has been missed, it should be taken as soon as possible. However, if it is almost time for the next dose, skip the missed dose and go back to the regular dosing schedule. Do not double doses.

Administration

NORVIR (ritonavir) film-coated tablets and NORVIR (ritonavir) oral solution are administered orally. It is recommended that NORVIR oral solution be taken with meals if possible. Patients may improve the taste of NORVIR oral solution by mixing with chocolate milk or ENSURE within one hour of dosing. The effects of antacids on the absorption of NORVIR have not been studied.

The NORVIR oral solution dosage cup should be cleaned immediately with hot water and dish soap after use. When cleaned immediately, drug residue is removed. The dosage cup must be dry prior to use.

Overdosage

For management of a suspected drug overdose, contact your regional Poison Control Centre.

Acute Overdosage

Human Overdose Experience

Human experience of acute overdose with NORVIR (ritonavir) film-coated tablets and NORVIR (ritonavir) oral solution is limited. One patient in clinical trials took NORVIR 1500 mg/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 NORVIR overdose.

Management of Overdosage

Administration of activated charcoal may be used to aid in removal of unabsorbed drug. 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. 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. However, dialysis can remove both alcohol and propylene glycol in the case of overdose with NORVIR oral solution.

NORVIR oral solution contains 43.2% alcohol by volume and 26.57% propylene glycol by weight. Accidental ingestion of the product by a young child could result in significant alcohol- and propylene glycol-related toxicity and could approach the potential lethal dose of alcohol.

Action and Clinical Pharmacology

Mechanism of Action

NORVIR is an inhibitor of HIV protease with activity against the Human Immunodeficiency Virus (HIV).

Ritonavir is an orally active peptidomimetic inhibitor of both the HIV-1 and HIV-2 proteases. Inhibition of HIV protease renders the enzyme incapable of processing the gag-pol polyprotein precursor which leads to the production of HIV particles with immature morphology that are unable to initiate new rounds of infection. Ritonavir has selective affinity for the HIV protease and has little inhibitory activity against human aspartyl proteases.

Antiviral Activity in vitro

The activity of ritonavir was assessed in vitro in acutely infected lymphoblastoid cell lines and in peripheral blood lymphocytes. The concentration of drug that inhibits 50% (EC50) of viral replication ranged from 3.8 to 153 nM depending upon the HIV-1 isolate and the cells employed. The average EC50 for low passage clinical isolates was 22 nM (n = 13). In MT4 cells, ritonavir demonstrated additive effects against HIV-1 in combination with either zidovudine (ZDV) or didanosine (ddI). Studies which measured cytotoxicity of ritonavir on several cell lines showed that > 20 microM was required to inhibit cellular growth by 50% resulting in an in vitro therapeutic index of at least 1000.

Resistance

HIV-1 isolates with reduced susceptibility to ritonavir have been selected in vitro. The clinical relevance of phenotypic and genotypic changes associated with NORVIR therapy has not been established. See (WARNINGS AND PRECAUTIONS) and (MICROBIOLOGY).

Cross-resistance to Other Antiretrovirals

Among protease inhibitors variable cross-resistance has been recognized. See (WARNINGS AND PRECAUTIONS) and (MICROBIOLOGY).

Cross-resistance between ritonavir and reverse transcriptase inhibitors is unlikely because of the different enzyme targets involved. One ZDV-resistant HIV isolate tested in vitro retained full susceptibility to ritonavir.

Pharmacodynamics

In vitro data indicate that ritonavir is active against all strains of HIV tested in a variety of transformed and primary human cell lines. The concentration of drug that inhibits 50% and 90% (EC50, EC90) of viral replication is approximately 0.02 and 0.11 microM, respectively. Studies which measured direct cell toxicity of ritonavir on several cell lines showed no direct toxicity at concentrations up to 25 microM, with a resulting in vitro therapeutic index of at least 1000.

Effects on the Electrocardiogram

QTcF interval was evaluated in a randomized, placebo and active (moxifloxacin 400 mg once daily) controlled cross-over study in 45 healthy adults, with 10 measurements over 12 hours on Day 3. The maximum mean (95% upper confidence bound) difference in QTcF from placebo was 5.5 (7.6) msec for 400 mg twice daily NORVIR. The Day 3 NORVIR exposure was approximately 1.5 fold higher than that observed with the 600 mg twice daily dose at steady state. No subject experienced an increase in QTcF of ≥ 60 msec from baseline or a QTcF interval exceeding the potentially clinically relevant threshold of 500 msec.

Mean change from baseline in PR interval of 11.0 to 24.0 msec was also noted in subjects receiving NORVIR in the same study on Day 3. Maximum PR interval was 252 msec and no second or third degree heart block was observed. See (WARNINGS and PRECAUTIONS).

Pharmacokinetics

The pharmacokinetics of ritonavir have been studied in healthy volunteers and HIV-infected patients (CD4 ≥ 50 cells/microliter). See Table 7 for ritonavir pharmacokinetic characteristics.

Table 7. Ritonavir Pharmacokinetic Characteristics
Parameter n Values (Mean ± SD)
Cmax SS1 10 11.2 ± 3.6 mcg/mL
Ctrough SS1 10 3.7 ± 2.6 mcg/mL
Vβ/F2 91 0.41 ± 0.25 L/kg
t1/2 3 to 5 h
CL/F SS1 10 8.8 ± 3.2 L/h
CL/F2 91 4.6 ± 1.6 L/h
CLR 62 < 0.1 L/h
RBC/Plasma Ratio 0.14
Percent Bound3 98 to 99%

1: SS = steady state; patients taking NORVIR 600 mg every 12h.

2: Single NORVIR 600 mg dose.

3: Primarily bound to human serum albumin and alpha-1 acid glycoprotein over the ritonavir concentration range of 0.01 to 30 mcg/mL.

Absorption

The absolute bioavailability of NORVIR has not been determined. After a 600 mg dose of oral solution, peak concentrations of ritonavir were achieved approximately 2 hours and 4 hours after dosing under fasting and non-fasting (514 KCal; 9% fat, 12% protein, and 79% carbohydrate) conditions, respectively.

NORVIR tablets are not bioequivalent to NORVIR capsules. Under moderate fat conditions (857 kcal; 31% fat, 13% protein, 56% carbohydrates), when a single 100 mg NORVIR dose was administered as a tablet compared with a capsule, AUC(0-∞) met equivalence criteria but mean Cmax was increased by 26% (92.8% confidence intervals: +15% to +39%).

No information is available comparing NORVIR tablets to NORVIR capsules or NORVIR oral solution under fasting conditions.

Effect of Food on Oral Absorption

When the oral solution was given under non-fasting conditions, peak ritonavir concentrations decreased 23% and the extent of absorption decreased 7% relative to fasting conditions. Dilution of oral solution, within one hour of administration, with 240 mL of chocolate milk, ADVERA or ENSURE did not significantly affect the extent and rate of ritonavir absorption. After a single 600 mg dose under non-fasting conditions, in two separate studies, the capsule (n = 21) and oral solution (n = 18) formulations yielded mean ± SD areas under the plasma concentration-time curve (AUCs) of 129.5 ± 47.1 and 129.0 ± 39.3 mcg·h/mL, respectively. Relative to fasting conditions, the extent of absorption of ritonavir from the capsule formulation was 15% higher when administered with a meal (771 KCal; 46% fat, 18% protein, and 37% carbohydrate).

A food effect is observed for NORVIR tablets. Food decreased the bioavailability of the ritonavir tablets when a single 100 mg dose of NORVIR was administered. Under high fat conditions (907 kcal; 52% fat, 15% protein, 33% carbohydrates), a 23% decrease in mean AUC(0-∞) [90% confidence intervals: -30% to -15%], and a 23% decrease in mean Cmax [90% confidence intervals: -34% to -11%] was observed relative to fasting conditions. Under moderate fat conditions, a 21% decrease in mean AUC(0-∞) [90% confidence intervals: -28% to -13%], and a 22% decrease in mean Cmax [90% confidence intervals: -33% to -9%] was observed relative to fasting conditions.

However, the type of meal administered did not change ritonavir tablet bioavailability when high fat was compared to moderate fat meals.

Distribution

The protein binding of ritonavir in human plasma was noted to be approximately 98 to 99%. Ritonavir binds to both human α-1-acid glycoprotein (AAG) and human serum albumin (HSA) with comparable affinities. Total plasma protein binding is constant over the concentration range of 1 to 100 mcg/mL.

Tissue distribution studies with 14C-labeled ritonavir in rats showed the liver, adrenals, pancreas, kidneys and thyroid to have the highest concentrations of drug. Tissue to plasma ratios of approximately one, measured in rat lymph nodes, suggest that ritonavir distributes into lymphatic tissue. Ritonavir penetrates minimally into the brain.

Metabolism

Nearly all of the plasma radioactivity after a single oral 600 mg dose of 14C-ritonavir oral solution (n = 5) was attributed to unchanged ritonavir. Five ritonavir metabolites have been identified in human urine and feces. The isopropyl thiazole oxidation metabolite (M-2) is the major metabolite and has antiviral activity similar to that of parent drug; however, the concentrations of this metabolite in plasma are low. Studies utilizing human liver microsomes have demonstrated that cytochrome P450 3A (CYP3A) is the major isoform involved in ritonavir metabolism, although CYP2D6 also contributes to the formation of M-2.

Excretion

In a study of five subjects receiving a 600 mg dose of 14C-ritonavir oral solution, 11.3 ± 2.8% of the dose was excreted into the urine, with 3.5 ± 1.8% of the dose excreted as unchanged parent drug. In that study, 86.4 ± 2.9% of the dose was excreted in the feces with 33.8 ± 10.8% of the dose excreted as unchanged parent drug. Upon multiple dosing, ritonavir accumulation is less than predicted from a single dose possibly due to a time and dose-related increase in clearance.

Special Populations and Conditions

Pediatrics

The pharmacokinetic profile of NORVIR in pediatric patients below the age of 2 years has not been established. Steady-state pharmacokinetics were evaluated in 37 HIV-infected patients ages 2 to 14 years receiving doses ranging from 250 mg/m2 twice daily to 400 mg/m2 twice daily. Across dose groups, ritonavir steady-state oral clearance (CL/F/m2) was approximately 1.5 times faster in pediatric patients than in adult subjects. Ritonavir concentrations obtained after 350 to 400 mg/m2 twice daily in pediatric patients were comparable to those obtained in adults receiving 600 mg (approximately 330 mg/m2) twice daily.

Geriatrics

No age-related pharmacokinetic differences have been observed in adult patients (18 to 63 years). Ritonavir pharmacokinetics have not been studied in older patients.

Gender

A study of ritonavir pharmacokinetics in healthy males and females showed no statistically significant differences in the pharmacokinetics of ritonavir.

Race

Pharmacokinetic differences due to race have not been identified.

Weight

Ritonavir pharmacokinetic parameters were not statistically significantly associated with body weight or lean body mass.

Hepatic Insufficiency

In six HIV-infected adult subjects with mild hepatic insufficiency dosed with NORVIR 400 mg twice daily, ritonavir exposures were similar to control subjects dosed with 500 mg twice daily. Results indicate that dose adjustment is not required in patients with mild hepatic impairment.

Adequate pharmacokinetic data are not available for patients with moderate hepatic impairment. Protein binding of ritonavir was not statistically significantly affected by mildly or moderately impaired hepatic function.

Renal Insufficiency

Ritonavir pharmacokinetics have not been studied in patients with renal insufficiency; however, since renal clearance is negligible, a decrease in total body clearance is not expected in patients with renal insufficiency.

Because ritonavir is highly protein bound it is unlikely that it will be significantly removed by dialysis. See (OVERDOSAGE).

Storage and Stability

NORVIR Film-coated Tablets

Store NORVIR film-coated tablets between 15 and 30°C. Dispense in original container or USP equivalent container (60 mL or less). For patient use: exposure of the product to high humidity outside the original or USP equivalent tight container (60 mL or less) for longer than 2 weeks is not recommended.

NORVIR Oral Solution

Store NORVIR oral solution between 20 and 25°C (68 and 77°F). Do not refrigerate. SHAKE WELL BEFORE EACH USE. Product must be stored and dispensed in the original container. Avoid exposure to excessive heat. Keep cap tightly closed. Use by product expiration date.

The NORVIR oral solution dosage cup should be cleaned immediately with hot water and dish soap after use. When cleaned immediately, drug residue is removed. The dosage cup must be dry prior to use.

Dosage Forms, Composition and Packaging

NORVIR is available as:

  • 100 mg film-coated tablets
  • 80 mg/mL oral solution

NORVIR Film-coated Tablets

NORVIR (ritonavir) film-coated tablets are white oval tablets debossed with the Abbott logo and the Abbo-Code “NK” on the same side. NORVIR is available as 100 mg tablets. Each bottle contains 30 tablets.

Listing of Non-Medicinal Ingredients

Each white film-coated oval tablet contains 100 mg of ritonavir with the following non-medicinal ingredients: copovidone, colloidal silicon dioxide/colloidal anhydrous silica, dibasic calcium phosphate anhydrous/calcium hydrogen phosphate anhydrous, sorbitan monolaurate/sorbitan laurate, sodium stearyl fumarate. The film coating ingredients include: colloidal silicon dioxide/colloidal silica anhydrous, hydroxypropyl cellulose, hypromellose, polyethylene glycol 400/macrogol type 400, polyethylene glycol 3350/macrogol type 3350, polysorbate 80, talc and titanium dioxide E171.

NORVIR Oral Solution

NORVIR (ritonavir) oral solution is an orange-colored liquid supplied in amber-colored, multi-dose bottles. Each multi-dose bottle contains 600 mg ritonavir per 7.5 mL marked dosage cup (80 mg/mL) in the following size: 240 mL bottles.

Listing of Non-Medicinal Ingredients

Each mL of oral solution contains 80 mg of ritonavir in a peppermint and caramel-flavored vehicle with the following non-medicinal ingredients: anhydrous citric acid to adjust pH, creamy caramel flavouring, ethanol, FD&C Yellow No. 6, peppermint oil, polyoxyl 35 castor oil, propylene glycol, saccharin sodium and water.