NORVIR tablet, film coated

Norvir by

Drug Labeling and Warnings

Norvir by is a Prescription medication manufactured, distributed, or labeled by RedPharm Drug, Inc.. Drug facts, warnings, and ingredients follow.

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BOXED WARNIING

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

Co-administration of NORVIR 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 NORVIR on the hepatic metabolism of certain drugs. Review medications taken by patients prior to prescribing NORVIR or when prescribing other medications to patients already taking NORVIR [see Contraindications (4), Warnings and Precautions (5.1), Drug Interactions (7), and Clinical Pharmacology (12.3)].

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use NORVIR safely and effectively. See full prescribing information for NORVIR.

NORVIR (ritonavir) tablet, for oral use
NORVIR (ritonavir) solution, for oral use
Initial U.S. Approval: 1996

WARNING: DRUG-DRUG INTERACTIONS LEADING TO POTENTIALLY SERIOUS AND/OR LIFE THREATENING REACTIONS
SEE FULL PRESCRIBING INFORMATION FOR COMPLETE BOXED WARNING

Co-administration of NORVIR 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 NORVIR on the hepatic metabolism of certain drugs. Review medications taken by patients prior to prescribing NORVIR or when prescribing other medications to patients already taking NORVIR [see Contraindications (4), Warnings and Precautions (5.1), Drug Interactions (7), and Clinical Pharmacology (12.3)].

RECENT MAJOR CHANGES

Dosage and Administration (2.1) 12/2016
Contraindications (4) 11/2016
Warnings and Precautions
Diabetes Mellitus/Hyperglycemia (5.8) 11/2016

INDICATIONS AND USAGE

NORVIR is an HIV protease inhibitor indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection (1)

DOSAGE AND ADMINISTRATION

Dose modification for NORVIR is necessary when used with other protease inhibitors (2)
Adult patients: 600 mg twice-day with meals (2.1)
Pediatrics patients: The recommended twice daily dose for children greater than one month of age is based on body surface area and should not exceed 600 mg twice daily with meals (2.2)
NORVIR oral solution should not be administered to neonates before a postmenstrual age (first day of the mother’s last menstrual period to birth plus the time elapsed after birth) of 44 weeks has been attained (2.2, 5.2)

DOSAGE FORMS AND STRENGTHS

Tablet: 100 mg ritonavir (3)
Oral solution: 80 mg ritonavir per milliliter (3)

CONTRAINDICATIONS

NORVIR is contraindicated in patients with known hypersensitivity to ritonavir (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome) or any of its ingredients (4)
Co-administration with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations may be associated with serious and/or life-threatening events (4)
Co-administration with drugs that significantly reduce ritonavir (4)

WARNINGS AND PRECAUTIONS

The following have been observed in patients receiving NORVIR:

The concomitant use of NORVIR and certain other drugs may result in known or potentially significant drug interactions. Consult the full prescribing information prior to and during treatment for potential drug interactions. (5.1, 7.2)
Toxicity in preterm neonates: NORVIR oral solution should not be used in preterm neonates in the immediate postnatal period because of possible toxicities. A safe and effective dose of NORVIR oral solution in this patient population has not been established (2.2,5.2)
Hepatic Reactions: Fatalities have occurred. Monitor liver function before and during therapy, especially in patients with underlying hepatic disease, including hepatitis B and hepatitis C, or marked transaminase elevations (5.3, 8.6)
Pancreatitis: Fatalities have occurred; suspend therapy as clinically appropriate (5.4)
Allergic Reactions/Hypersensitivity: Allergic reactions have been reported and include anaphylaxis, toxic epidermal necrolysis, Stevens-Johnson syndrome, bronchospasm and angioedema. Discontinue treatment if severe reactions develop (5.5, 6.2)
PR interval prolongation may occur in some patients. Cases of second and third degree heart block have been reported. Use with caution with patients with preexisting conduction system disease, ischemic heart disease, cardiomyopathy, underlying structural heart disease or when administering with other drugs that may prolong the PR interval (5.6, 12.3)
Total cholesterol and triglycerides elevations: Monitor prior to therapy and periodically thereafter (5.7)
Patients may develop new onset or exacerbations of diabetes mellitus, hyperglycemia (5.8)
Patients may develop immune reconstitution syndrome (5.9)
Patients may develop redistribution/accumulation of body fat (5.10)
Hemophilia: Spontaneous bleeding may occur, and additional factor VIII may be required (5.11)

ADVERSE REACTIONS

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 (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc. at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

Co-administration of NORVIR can alter the concentrations of other drugs. The potential for drug-drug interactions must be considered prior to and during therapy (4, 5.1, 7, 12.3)

USE IN SPECIFIC POPULATIONS

Lactation: Women infected with HIV should be instructed not to breastfeed due to the potential for HIV transmission (8.2).

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 12/2016

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: DRUG-DRUG INTERACTIONS LEADING TO POTENTIALLY SERIOUS AND/OR LIFE THREATENING REACTIONS
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Adult Patients
2.2 Pediatric Patients
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Risk of Serious Adverse Reactions Due to Drug Interactions
5.2 Toxicity in Preterm Neonates
5.3 Hepatic Reactions
5.4 Pancreatitis
5.5 Allergic Reactions/Hypersensitivity
5.6 PR Interval Prolongation
5.7 Lipid Disorders
5.8 Diabetes Mellitus/Hyperglycemia
5.9 Immune Reconstitution Syndrome
5.10 Fat Redistribution
5.11 Patients with Hemophilia
5.12 Resistance/Cross-resistance
5.13 Laboratory Tests
6 ADVERSE REACTIONS
6.1 Clinical Trial Experience
6.2 Postmarketing Experience
7 DRUG INTERACTIONS
7.1 Potential for NORVIR to Affect Other Drugs
7.2 Established and Other Potentially Significant Drug Interactions
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Lactation
8.3 Females and Males of Reproductive Potential
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Hepatic Impairment
10 OVERDOSAGE
10.1 Acute Overdosage - Human Overdose Experience
10.2 Management of Overdosage
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.3 Pharmacokinetics
12.4 Microbiology
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
14.1 Advanced Patients with Prior Antiretroviral Therapy
14.2 Patients without Prior Antiretroviral Therapy
15 REFERENCES
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 NORVIR Tablets, 100 mg Ritonavir
16.2 NORVIR Oral Solution, 80 mg per mL Ritonavir
17 PATIENT COUNSELING INFORMATION

*
Sections or subsections omitted from the full prescribing information are not listed.

1 INDICATIONS AND USAGE

NORVIR is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection.

2 DOSAGE AND ADMINISTRATION

NORVIR is administered orally. NORVIR tablets should be swallowed whole, and not chewed, broken or crushed. Take NORVIR with meals. Patients may improve the taste of NORVIR oral solution by mixing with chocolate milk, Ensure®, or Advera® within one hour of dosing.

General Dosing Guidelines

Patients who take the 600 mg twice daily soft gel capsule NORVIR dose may experience more gastrointestinal side effects such as nausea, vomiting, abdominal pain or diarrhea when switching from the soft gel capsule to the tablet formulation because of greater maximum plasma concentration (Cmax) achieved with the tablet formulation relative to the soft gel capsule [see Clinical Pharmacology (12.3)]. Patients should also be aware that these adverse events (gastrointestinal or paresthesias) may diminish as therapy is continued.

Dose Modification for NORVIR

Dose reduction of NORVIR is necessary when used with other protease inhibitors: atazanavir, darunavir, fosamprenavir, saquinavir, and tipranavir.

Prescribers should consult the full prescribing information and clinical study information of these protease inhibitors if they are co-administered with a reduced dose of ritonavir [see Warnings and Precautions (5.1), and Drug Interactions (7)].

2.1 Adult Patients

Recommended Dosage for Treatment of HIV-1:

The recommended dosage of ritonavir is 600 mg twice daily by mouth to be taken with meals. Use of a dose titration schedule may help to reduce treatment-emergent adverse events while maintaining appropriate ritonavir plasma levels. Ritonavir should be started at no less than 300 mg twice daily and increased at 2 to 3 day intervals by 100 mg twice daily. The maximum dose of 600 mg twice daily should not be exceeded upon completion of the titration.

Pregnant Women

NORVIR oral solution is not recommended during pregnancy due to its alcohol content. NORVIR oral solution contains the excipients alcohol (43.2% v/v) and propylene glycol (26.57% w/v) [see Use in Specific Populations (8.1)].

2.2 Pediatric Patients

Ritonavir should be used in combination with other antiretroviral agents [see Dosage and Administration (2)]. The recommended dosage of ritonavir in children greater than 1 month is 350 to 400 mg per m2 twice daily by mouth to be taken with meals and should not exceed 600 mg twice daily. Ritonavir should be started at 250 mg per m2 twice daily and increased at 2 to 3 day intervals by 50 mg per m2 twice daily. If patients do not tolerate 400 mg per m2 twice daily due to adverse events, the highest tolerated dose may be used for maintenance therapy in combination with other antiretroviral agents, however, alternative therapy should be considered. When possible, dose should be administered using a calibrated dosing syringe.

NORVIR oral solution should not be administered to neonates before a postmenstrual age (first day of the mother’s last menstrual period to birth plus the time elapsed after birth) of 44 weeks has been attained [see Warnings and Precautions (5.2)].

NORVIR oral solution contains 43.2% (v/v) alcohol and 26.57% (w/v) propylene glycol. Special attention should be given to accurate calculation of the dose of NORVIR, transcription of the medication order, dispensing information and dosing instructions to minimize the risk for medication errors, and overdose. This is especially important for young children. Total amounts of alcohol and propylene glycol from all medicines that are to be given to pediatric patients 1 to 6 months of age should be taken into account in order to avoid toxicity from these excipients [see Warnings and Precautions (5.2) and Overdosage (10)].

Table 1. Pediatric Dosage Guidelines
Body Surface Area (m2) Twice Daily Dose
250 mg per m2 Twice Daily Dose
300 mg per m2 Twice Daily Dose
350 mg per m2 Twice Daily Dose
400 mg per m2
0.20 0.6 mL (50 mg) 0.75 mL (60 mg) 0.9 mL (70 mg) 1.0 mL (80 mg)
0.25 0.8 mL (62.5 mg) 0.9 mL (75 mg) 1.1 mL (87.5 mg) 1.25 mL (100 mg)
0.50 1.6 mL (125 mg) 1.9 mL (150 mg) 2.2 mL (175 mg) 2.5 mL (200 mg)
0.75 2.3 mL (187.5 mg) 2.8 mL (225 mg) 3.3 mL (262.5 mg) 3.75 mL (300 mg)
1.00 3.1 mL (250 mg) 3.75 mL (300 mg) 4.4 mL (350 mg) 5 mL (400 mg)
1.25 3.9 mL (312.5 mg) 4.7 mL (375 mg) 5.5 mL (437.5 mg) 6.25 mL (500 mg)
1.50 4.7 mL (375 mg) 5.6 mL (450 mg) 6.6 mL (525 mg) 7.5 mL (600 mg)

Body surface area (BSA) can be calculated as follows1:

[norvir equation]

3 DOSAGE FORMS AND STRENGTHS

NORVIR Tablets

White film-coated ovaloid tablets debossed with the "a" logo and the code NK providing 100 mg ritonavir.

NORVIR Oral Solution

Orange-colored liquid containing 600 mg ritonavir per 7.5 mL marked dosage cup (80 mg per mL).

4 CONTRAINDICATIONS

When co-administering NORVIR with other protease inhibitors, see the full prescribing information for that protease inhibitor including contraindication information.
NORVIR is contraindicated in patients with known hypersensitivity (e.g., toxic epidermal necrolysis (TEN) or Stevens-Johnson syndrome) to ritonavir or any of its ingredients.
NORVIR is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening reactions.
NORVIR is contraindicated with drugs that are potent CYP3A inducers where significantly reduced lopinavir plasma concentrations may be associated with the potential for loss of virologic response and possible resistance and cross-resistance.

Table 2. Drugs that are Contraindicated with NORVIR
Drug Class Drugs Within Class That Are Contraindicated With NORVIR** Clinical Comments
Alpha1-adrenoreceptor antagonist Alfuzosin HCL Potential for hypotension.
Antiarrhythmic Amiodarone, dronedarone, flecainide, propafenone, quinidine Potential for cardiac arrhythmias.
Antifungal Voriconazole Voriconazole is contraindicated with ritonavir doses of 400 mg every 12 hours or greater due to the potential for loss of antifungal response.
Anti-gout Colchicinea Potential for serious and/or life-threatening reactions in patients with renal and/or hepatic impairment.
Antipsychotics Lurasidone


Pimozide Potential for serious and/or life-threatening reactions.

Potential for serious and/or life‑threatening reactions such as cardiac arrhythmias.
Ergot Derivatives Dihydroergotamine, ergotamine, methylergonovine Potential for acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system.
GI Motility Agent Cisapride Potential for cardiac arrhythmias.
Herbal Products St. John's Wort (hypericum perforatum) May lead to loss of virologic response and possible resistance to NORVIR or to the class of protease inhibitors.
HMG-CoA Reductase Inhibitors Lovastatin, simvastatin Potential for myopathy including rhabdomyolysis.
PDE5 inhibitor Sildenafilb (Revatio®) when used for the treatment of pulmonary arterial hypertension (PAH) Potential for sildenafil-associated adverse events, including visual abnormalities, hypotension, prolonged erection, and syncope.
Sedative/hypnotics Oral midazolamc, triazolam Prolonged or increased sedation or respiratory depression.
a see Drug Interactions (7), TABLE 5 for colchicine doses in patients with normal hepatic and renal function.
b see Drug Interactions (7), TABLE 5 for co-administration of sildenafil in patients with erectile dysfunction.
c see Drug Interactions (7), TABLE 5 for parenterally administered midazolam.

5 WARNINGS AND PRECAUTIONS

5.1 Risk of Serious Adverse Reactions Due to Drug Interactions

Initiation of NORVIR, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving NORVIR, may increase plasma concentrations of medications metabolized by CYP3A. Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of NORVIR, respectively. These interactions may lead to:

Clinically significant adverse reactions, potentially leading to severe, life-threatening, or fatal events from greater exposures of concomitant medications.
Clinically significant adverse reactions from greater exposures of NORVIR.
Loss of therapeutic effect of NORVIR and possible development of resistance.

When co-administering NORVIR with other protease inhibitors, see the full prescribing information for that protease inhibitor including important Warnings and Precautions.

See Table 5 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations [see Drug Interactions (7)]. Consider the potential for drug interactions prior to and during NORVIR therapy; review concomitant medications during NORVIR therapy, and monitor for the adverse reactions associated with the concomitant medications [see Contraindications(4) and Drug Interactions (7)].

5.2 Toxicity in Preterm Neonates

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. Postmarketing life-threatening cases of cardiac toxicity (including complete AV block, bradycardia, and cardiomyopathy), lactic acidosis, acute renal failure, CNS depression and respiratory complications leading to death have been reported, predominantly in preterm neonates receiving lopinavir/ritonavir oral solution which also contains the excipients alcohol and propylene glycol.

NORVIR oral solution should not be used in preterm neonates in the immediate postnatal period because of possible toxicities. However, if the benefit of using NORVIR oral solution to treat HIV infection in infants immediately after birth outweighs the potential risks, infants should be monitored closely for increases in serum osmolality and serum creatinine, and for toxicity related to NORVIR 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 [see Dosage and Administration (2.2) and Overdosage (10)].

5.3 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 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 diseases, liver enzyme abnormalities, or hepatitis. Increased AST/ALT monitoring should be considered in these patients, especially during the first three months of NORVIR treatment [see Use in Specific Populations (8.6)].

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

5.4 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 [see Warnings and Precautions (5.7)]. 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.

5.5 Allergic Reactions/Hypersensitivity

Allergic reactions including urticaria, mild skin eruptions, bronchospasm, and angioedema have been reported. Cases of anaphylaxis, toxic epidermal necrolysis (TEN), and Stevens-Johnson syndrome have also been reported. Discontinue treatment if severe reactions develop.

5.6 PR Interval Prolongation

Ritonavir prolongs the PR interval in some patients. Post marketing cases of second or third degree atrioventricular block have been reported in patients.

NORVIR should be used with caution in patients with underlying structural heart disease, preexisting conduction system abnormalities, ischemic heart disease, cardiomyopathies, as these patients may be at increased risk for developing cardiac conduction abnormalities.

The impact on the PR interval of co-administration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers, beta-adrenergic blockers, digoxin and atazanavir) has not been evaluated. As a result, co-administration of ritonavir with these drugs should be undertaken with caution, particularly with those drugs metabolized by CYP3A. Clinical monitoring is recommended [see Drug Interactions (7), and Clinical Pharmacology (12.3)].

5.7 Lipid Disorders

Treatment with NORVIR therapy alone or in combination with saquinavir has resulted in substantial increases in the concentration of total cholesterol and triglycerides [see Adverse Reactions (6.1)]. Triglyceride 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, taking into account any potential drug-drug interactions with NORVIR and HMG CoA reductase inhibitors [see Contraindications (4)and Drug Interactions (7)].

5.8 Diabetes Mellitus/Hyperglycemia

New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during postmarketing 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.Consider monitoring for hyperglycemia, new onset diabetes mellitus, or an exacerbation of diabetes mellitus in patients treated with NORVIR.

5.9 Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in HIV-infected patients treated with combination antiretroviral therapy, including NORVIR. During the initial phase of combination antiretroviral treatment, patients whose immune system responds 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.

5.10 Fat Redistribution

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.

5.11 Patients with Hemophilia

There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis, in patients with hemophilia type A and 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 reintroduced. A causal relationship between protease inhibitor therapy and these events has not been established.

5.12 Resistance/Cross-resistance

Varying degrees of cross-resistance among protease inhibitors have been observed. Continued administration of ritonavir 600 mg twice daily following loss of viral suppression may increase the likelihood of cross-resistance to other protease inhibitors [see Microbiology (12.4)].

5.13 Laboratory Tests

Ritonavir has been shown to increase triglycerides, cholesterol, SGOT (AST), SGPT (ALT), GGT, CPK, 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.

6 ADVERSE REACTIONS

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

Drug Interactions [see Warnings and Precautions (5.1)]
Hepatotoxicity [see Warnings and Precautions (5.3)]
Pancreatitis [see Warnings and Precautions (5.4)]
Allergic Reactions/Hypersensitivity [see Warnings and Precautions (5.5)]

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

6.1 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 3 lists treatment-emergent Adverse Reactions (with possible or probable relationship to study drug) occurring in greater than or equal to 1% of adult patients receiving NORVIR in combined Phase II/IV studies.

The most frequently reported adverse drug reactions among patients receiving NORVIR alone or in combination with other antiretroviral drugs were gastrointestinal (including diarrhea, nausea, vomiting, abdominal pain (upper and lower)), neurological disturbances (including paresthesia and oral paresthesia), rash, and fatigue/asthenia.

Table 3. Treatment-Emergent Adverse Reactions (With Possible or Probable Relationship to Study Drug) Occurring in greater than or equal to 1% of Adult Patients Receiving NORVIR in Combined Phase II/IV Studies (N = 1,755)
Adverse Reactions n %
Eye disorders
Blurred vision 113 6.4
Gastrointestinal disorders
Abdominal Pain (upper and lower)* 464 26.4
Diarrhea including severe with electrolyte imbalance* 1,192 67.9
Dyspepsia 201 11.5
Flatulence 142 8.1
Gastrointestinal hemorrhage* 41 2.3
Gastroesophageal reflux disease (GERD) 19 1.1
Nausea 1,007 57.4
Vomiting* 559 31.9
General disorders and administration site conditions
Fatigue including asthenia* 811 46.2
Hepatobiliary disorders
Blood bilirubin increased (including jaundice)* 25 1.4
Hepatitis (including increased AST, ALT, GGT)* 153 8.7
Immune system disorders
Hypersensitivity including urticaria and face edema* 114 8.2
Metabolism and nutrition disorders
Edema and peripheral edema* 110 6.3
Gout* 24 1.4
Hypercholesterolemia* 52 3.0
Hypertriglyceridemia* 158 9.0
Lipodystrophy acquired* 51 2.9
Musculoskeletal and connective tissue disorders
Arthralgia and back pain* 326 18.6
Myopathy/creatine phosphokinase increased* 66 3.8
Myalgia 156 8.9
Nervous system disorders
Dizziness* 274 15.6
Dysgeusia* 285 16.2
Paresthesia (including oral paresthesia)* 889 50.7
Peripheral neuropathy 178 10.1
Syncope* 58 3.3
Psychiatric disorders
Confusion* 52 3.0
Disturbance in attention 44 2.5
Renal and urinary disorders
Increased urination* 74 4.2
Respiratory, thoracic and mediastinal disorders
Coughing* 380 21.7
Oropharyngeal Pain* 279 15.9
Skin and subcutaneous tissue disorders
Acne* 67 3.8
Pruritus* 214 12.2
Rash (includes erythematous and maculopapular)* 475 27.1
Vascular disorders
Flushing, feeling hot* 232 13.2
Hypertension* 58 3.3
Hypotension including orthostatic hypotension* 30 1.7
Peripheral coldness* 21 1.2
* Represents a medical concept including several similar MedDRA PTs

Laboratory Abnormalities in Adults

Table 4 shows the percentage of adult patients who developed marked laboratory abnormalities.

Table 4. Percentage of Adult Patients, by Study and Treatment Group, with Chemistry and Hematology Abnormalities Occurring in greater than 3% of Patients Receiving NORVIR
Study 245
Naive Patients Study 247
Advanced Patients Study 462 PI-Naive Patients
Variable Limit NORVIR plus ZDV NORVIR ZDV NORVIR Placebo NORVIR plus Saquinavir
Chemistry High
Cholesterol > 240 mg/dL 30.7 44.8 9.3 36.5 8.0 65.2
CPK > 1000 IU/L 9.6 12.1 11.0 9.1 6.3 9.9
GGT > 300 IU/L 1.8 5.2 1.7 19.6 11.3 9.2
SGOT (AST) > 180 IU/L 5.3 9.5 2.5 6.4 7.0 7.8
SGPT (ALT) > 215 IU/L 5.3 7.8 3.4 8.5 4.4 9.2
Triglycerides > 800 mg/dL 9.6 17.2 3.4 33.6 9.4 23.4
Triglycerides > 1500 mg/dL 1.8 2.6 - 12.6 0.4 11.3
Triglycerides Fasting > 1500 mg/dL 1.5 1.3 - 9.9 0.3 -
Uric Acid > 12 mg/dL - - - 3.8 0.2 1.4
Hematology Low
Hematocrit < 30% 2.6 - 0.8 17.3 22.0 0.7
Hemoglobin < 8.0 g/dL 0.9 - - 3.8 3.9 -
Neutrophils ≤ 0.5 x 109/L - - - 6.0 8.3 -
RBC < 3.0 x 1012/L 1.8 - 5.9 18.6 24.4 -
WBC < 2.5 x 109/L - 0.9 6.8 36.9 59.4 3.5
- Indicates no events reported.

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%).

6.2 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 [see Warnings and Precautions (5.6)].

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. Also, see Cardiovascular System.

Skin and subcutaneous tissue disorders

Toxic epidermal necrolysis (TEN) has been reported.

7 DRUG INTERACTIONS

See also Contraindications (4), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)

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.

7.1 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 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.

7.2 Established and Other Potentially Significant Drug Interactions

Table 5 provides a list of established or potentially clinically significant drug interactions. Alteration in dose or regimen may be recommended based on drug interaction studies or predicted interaction [see Clinical Pharmacology (12.3)] for magnitude of interaction.

Table 5. Established and Other Potentially Significant Drug Interactions
Concomitant Drug Class:
Drug Name Effect on Concentration of Ritonavir or Concomitant Drug Clinical Comment
HIV-Antiviral Agents
HIV-1 Protease Inhibitor:
atazanavir
darunavir
fosamprenavir ↑ amprenavir
↑ atazanavir
↑ darunavir See the complete prescribing information for fosamprenavir, atazanavir, darunavir for details on co-administration with ritonavir.
HIV-1 Protease Inhibitor:
indinavir ↑ indinavir Appropriate doses for this combination, with respect to efficacy and safety, have not been established.
HIV-1 Protease Inhibitor:
saquinavir ↑ saquinavir See the complete prescribing information for saquinavir for details on co-administration of saquinavir and ritonavir.
Saquinavir/ritonavir in combination with rifampin is not recommended due to the risk of severe hepatotoxicity (presenting as increased hepatic transaminases) if the three drugs are given together.
HIV-1 Protease Inhibitor:
tipranavir ↑ tipranavir See the complete prescribing information for tipranavir for details on co-administration of tipranavir and ritonavir.
Non-Nucleoside Reverse Transcriptase Inhibitor:
delavirdine ↑ ritonavir Appropriate doses of this combination with respect to safety and efficacy have not been established.
HIV-1 CCR5 – antagonist: maraviroc ↑ maraviroc See the complete prescribing information for maraviroc for details on co-administration of maraviroc and ritonavir-containing protease inhibitors.
Integrase Inhibitor:
raltegravir ↓ raltegravir The effects of ritonavir on raltegravir with ritonavir dosage regimens greater than 100 mg twice daily have not been evaluated, however raltegravir concentrations may be decreased with ritonavir coadministration.
Other Agents
Analgesics, Narcotic:
tramadol,
propoxyphene,
methadone,
fentanyl ↑ analgesics




↓ methadone

↑ fentanyl A dose decrease may be needed for these drugs when co-administered with ritonavir.



Dosage increase of methadone may be considered.

Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with NORVIR.
Anesthetic:
meperidine ↓ meperidine/ ↑ normeperidine (metabolite) Dosage increase and long-term use of meperidine with ritonavir are not recommended due to the increased concentrations of the metabolite normeperidine which has both analgesic activity and CNS stimulant activity (e.g., seizures).
Antialcoholics:
disulfiram/ metronidazole Ritonavir formulations contain alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).
Antiarrhythmics:
disopyramide, lidocaine, mexiletine ↑ antiarrhythmics For contraindicated antiarrhythmics [see Contraindications (4)].
Caution is warranted and therapeutic concentration monitoring is recommended for antiarrhythmics when co-administered with ritonavir, if available.
Anticancer Agents:
dasatinib, nilotinib,
vincristine, vinblastine ↑ anticancer agents For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when ritonavir is administered concurrently with vincristine or vinblastine. Clinicians should be aware that if the ritonavir containing regimen is withheld for a prolonged period, consideration should be given to altering the regimen to not include a CYP3A or P-gp inhibitor in order to control HIV-1 viral load.
A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as NORVIR. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions.
Anticoagulant:
warfarin ↑↓ warfarin Initial frequent monitoring of the INR during ritonavir and warfarin co-administration is recommended.
Anticoagulant:
rivaroxaban ↑ rivaroxaban Avoid concomitant use of rivaroxaban and ritonavir. Co-administration of ritonavir and rivaroxaban may lead to risk of increased bleeding.
Anticonvulsants:
carbamazepine, clonazepam, ethosuximide ↑ anticonvulsants A dose decrease may be needed for these drugs when co-administered with ritonavir and therapeutic concentration monitoring is recommended for these anticonvulsants, if available.
Anticonvulsants:
divalproex, lamotrigine, phenytoin ↓ anticonvulsants A dose increase may be needed for these drugs when co-administered with ritonavir and therapeutic concentration monitoring is recommended for these anticonvulsants, if available.
Antidepressants:
nefazodone,
selective serotonin
reuptake inhibitors
(SSRIs): e.g.
fluoxetine,
paroxetine,
tricyclics: e.g.
amitriptyline,
nortriptyline ↑ antidepressants A dose decrease may be needed for these drugs when co-administered with ritonavir.
Antidepressant:
bupropion ↓ bupropion
↓ active metabolite, hydroxybupropion Patients receiving ritonavir and bupropion concurrently should be monitored for an adequate clinical response to bupropion.
Antidepressant:
desipramine ↑ desipramine Dosage reduction and concentration monitoring of desipramine is recommended.
Antidepressant:
trazodone ↑ trazodone Adverse events of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and NORVIR. A lower dose of trazodone should be considered.
Antiemetic:
dronabinol ↑ dronabinol A dose decrease of dronabinol may be needed when co-administered with ritonavir.
Antifungals:
ketoconazole
itraconazole
voriconazole ↑ ketoconazole
↑ itraconazole
↓ voriconazole

For contraindicated antifungals, [see Contraindications (4)].

High doses of ketoconazole or itraconazole (greater than 200 mg per day) are not recommended.

Co-administration of voriconazole and ritonavir doses of 400 mg every 12 hours or greater is contraindicated [see Contraindications (4)]. Co-administration of voriconazole and ritonavir 100 mg should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole.

Anti-gout:
colchicine ↑ colchicine

Concomitant administration with colchicine is contraindicated in patients with renal and/or hepatic impairment [see Contraindications (4)].

For patients with normal renal or hepatic function:

Treatment of gout flares-co-administration of colchicine in patients on ritonavir:

0.6 mg (one tablet) for one dose, followed by 0.3 mg (half tablet) one hour later. Dose to be repeated no earlier than three days.

Prophylaxis of gout flares-co-administration of colchicine in patients on ritonavir:

If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.

If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.

Treatment of familial Mediterranean fever (FMF)-co-administration of colchicine in patients on ritonavir:

Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Anti-infective:
clarithromycin ↑ clarithromycin For patients with renal impairment, adjust clarithromycin dose as follows:

For patients with CLCR 30 to 60 mL per min the dose of clarithromycin should be reduced by 50%.
For patients with CLCR less than 30 mL per min the dose of clarithromycin should be decreased by 75%.

No dose adjustment for patients with normal renal function is necessary.
Antimycobacterial:
bedaquiline ↑ bedaquiline Bedaquiline should only be used with ritonavir if the benefit of co-administration outweighs the risk.
Antimycobacterial:
rifabutin ↑ rifabutin and rifabutin metabolite Dosage reduction of rifabutin by at least three-quarters of the usual dose of 300 mg per day is recommended (e.g., 150 mg every other day or three times a week). Further dosage reduction may be necessary.
Antimycobacterial:
rifampin ↓ ritonavir May lead to loss of virologic response. Alternate antimycobacterial agents such as rifabutin should be considered.
Antiparasitic:
atovaquone ↓ atovaquone Clinical significance is unknown; however, increase in atovaquone dose may be needed.
Antiparasitic:
quinine ↑ quinine A dose decrease of quinine may be needed when co-administered with ritonavir.
Antipsychotics:
perphenazine,
risperidone,
thioridazine ↑ antipsychotics For contraindicated antipsychotics, [see Contraindications (4)].
A dose decrease may be needed for these drugs when co-administered with ritonavir.
Antipsychotics:
quetiapine ↑ quetiapine

Initiation of NORVIR in patients taking quetiapine:

Consider alternative antiretroviral therapy to avoid increases in quetiapine exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring.

Initiation of quetiapine in patients taking NORVIR:

Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.
β-Blockers:
metoprolol, timolol ↑ beta-blockers Caution is warranted and clinical monitoring of patients is recommended. A dose decrease may be needed for these drugs when co-administered with ritonavir.
Bronchodilator:
theophylline ↓ theophylline Increased dosage of theophylline may be required; therapeutic monitoring should be considered.
Calcium channel blockers:
diltiazem, nifedipine, verapamil ↑ calcium channel blockers Caution is warranted and clinical monitoring of patients is recommended. A dose decrease may be needed for these drugs when co-administered with ritonavir.
Digoxin ↑ digoxin Concomitant administration of ritonavir with digoxin may increase digoxin levels. Caution should be exercised when co-administering ritonavir with digoxin, with appropriate monitoring of serum digoxin levels.
Endothelin receptor antagonists: bosentan ↑ bosentan

Co-administration of bosentan in patients on ritonavir:

In patients who have been receiving ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

Co-administration of ritonavir in patients on bosentan:

Discontinue use of bosentan at least 36 hours prior to initiation of ritonavir.

After at least 10 days following the initiation of ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Hepatitis C direct acting antiviral:
simeprevir ↑simeprevir It is not recommended to co-administer ritonavir with simeprevir.
HMG-CoA Reductase Inhibitor:
atorvastatin
rosuvastatin ↑ atorvastatin

↑ rosuvastatin For contraindicated HMG-CoA reductase inhibitors, [see Contraindications (4)].
Titrate atorvastatin and rosuvastatin dose carefully and use the lowest necessary dose.
If NORVIR is used with another protease inhibitor, see the complete prescribing information for the concomitant protease inhibitor for details on co-administration with atorvastatin and rosuvastatin.
Immunosuppressants:
cyclosporine, tacrolimus, sirolimus (rapamycin) ↑ immunosuppressants Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with ritonavir.
Inhaled or Intranasal
Steroid: e.g.
fluticasone
budesonide ↑ glucocorticoids

Concomitant use of ritonavir and fluticasone or other glucocorticoids that are metabolized by CYP3A is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects. Concomitant use may result in increased steroid concentrations and reduced serum cortisol concentrations.

Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during postmarketing use in patients when ritonavir has been coadministered with fluticasone propionate or budesonide.

Long-acting beta-adrenoceptor agonist: salmeterol ↑ salmeterol Concurrent administration of salmeterol and ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Oral Contraceptives or Patch Contraceptives:
ethinyl estradiol ↓ ethinyl estradiol Alternate methods of contraception should be considered.
PDE5 Inhibitors:
avanafil
sildenafil,
tadalafil,
vardenafil ↑ avanafil
↑ sildenafil
↑ tadalafil
↑ vardenafil For contraindicated PDE5 inhibitors, [see Contraindications (4)].
Do not use ritonavir with avanafil because a safe and effective avanafil dosage regimen has not been established.

Particular caution should be used when prescribing sildenafil, tadalafil or vardenafil in patients receiving ritonavir. Coadministration of ritonavir with these drugs may result in an increase in PDE5 inhibitor associated adverse events, including hypotension, syncope, visual changes, and prolonged erection.

Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH):

Sildenafil (Revatio®) is contraindicated [see Contraindications (4)].

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

Co-administration of ADCIRCA in patients on ritonavir:

In patients receiving ritonavir for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Co-administration of ritonavir in patients on ADCIRCA:

Avoid use of ADCIRCA during the initiation of ritonavir. Stop ADCIRCA at least 24 hours prior to starting ritonavir. After at least one week following the initiation of ritonavir, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Use of PDE5 inhibitors for the treatment of erectile dysfunction:

It is recommended not to exceed the following doses:

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

Use with increased monitoring for adverse events.

Sedative/hypnotics:
buspirone, clorazepate, diazepam, estazolam, flurazepam, zolpidem ↑ sedative/hypnotics A dose decrease may be needed for these drugs when co-administered with ritonavir.
Sedative/hypnotics: Parenteral midazolam
↑ midazolam For contraindicated sedative/hypnotics, [see Contraindications (4)].
Co-administration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered.
Steroids (systemic): e.g.
budesonide, dexamethasone, prednisone ↑ glucocorticoids Concomitant use of glucocorticoids that are metabolized by CYP3A is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects. This may increase the risk for development of systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression.
Stimulant:
methamphetamine ↑ methamphetamine Use with caution. A dose decrease of methamphetamine may be needed when co-administered with ritonavir.

8 USE IN SPECIFIC POPULATIONS

When co-administering NORVIR with other protease inhibitors, see the full prescribing information for the co-administered protease inhibitor including important information for use in special populations.

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to NORVIR during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1–800–258–4263.

Risk Summary

Prospective pregnancy data from the Antiretroviral Pregnancy Registry (APR) are not sufficient to adequately assess the risk of birth defects or miscarriage. Available data from the APR show no difference in the rate of overall birth defects for ritonavir compared to the background rate for major birth defects of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) [see Data ].

In animal reproduction studies, no evidence of adverse developmental outcomes was observed with oral administration of ritonavir to pregnant rats and rabbits. During organogenesis in the rat and rabbit, systemic exposure (AUC) was approximately 1/3 lower than human exposure at the recommended daily dose. In the rat pre- and post-natal developmental study, maternal systemic exposure to ritonavir was approximately 1/2 of the exposure in humans at the recommended daily dose, based on a body surface area conversion factor [see Data].

NORVIR oral solution is not recommended during pregnancy because there is no known safe level of alcohol exposure during pregnancy [see Clinical Considerations, Dosage and Administration (2.1) and Warnings and Precautions (5.2)].

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Dose Adjustments During Pregnancy and the Postpartum Period

NORVIR oral solution contains 43.2% alcohol and 26.57% propylene glycol and is not recommended during pregnancy because there is no known safe level of alcohol exposure during pregnancy [see Dosage and Administration (2.1) and Warnings and Precautions (5.2)].

Data

Human Data

Based on prospective reports to the APR of approximately 6100 live births following exposure to ritonavir-containing regimens (including over 2800 live births exposed in the first trimester and over 3200 live births exposed in the second and third trimesters), there was no difference in the rate of overall birth defects for ritonavir compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of birth defects in live births was 2.3% (95% CI: 1.7%-2.9%) following first-trimester exposure to ritonavir-containing regimens and 2.9% (95% CI: 2.3%-3.5%) following second and third trimester exposure to ritonavir-containing regimens.

While placental transfer of ritonavir and fetal ritonavir concentrations are generally low, detectable levels have been observed in cord blood samples and neonate hair.

Animal Data

Ritonavir was administered orally to pregnant rats (at 0, 15, 35, and 75 mg/kg/day) and rabbits (at 0, 25, 50, and 110 mg/kg/day) during organogenesis (on gestation days 6 through 17 and 6 through 19, respectively). No evidence of teratogenicity due to ritonavir was observed in rats and rabbits at doses producing systemic exposures (AUC) equivalent to approximately 1/3 lower than human exposure at the recommended daily dose. Developmental toxicity observed in rats (early resorptions, decreased fetal body weight and ossification delays and developmental variations) occurred at a maternally toxic dose, at an exposure equivalent to approximately 1/3 lower than human exposure at the recommended daily dose. A slight increase in the incidence of cryptorchidism was also noted in rats (at a maternally toxic dose) at an exposure approximately 1/5 lower than human exposure at the recommended daily dose. Developmental toxicity was observed in rabbits (resorptions, decreased litter size and decreased fetal weights) at maternally toxic doses approximately 1.8 times higher than the recommended daily dose, based on a body surface area conversion factor. In pre-and postnatal development study in rats, ritonavir was administered at doses of 0, 15, 35, and 60 mg/kg/day from gestation day 6 through postnatal day 20. At doses of 60 mg/kg/day, no developmental toxicity was noted with ritonavir dosage equivalent to 1/2 of the recommended daily dose, based on a body surface area conversion factor.

8.2 Lactation

Risk Summary

The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV.

Limited published data reports that ritonavir is present in human milk.

There is no information on the effects of ritonavir on the breastfed infant or the effects of the drug on milk production. Because of the potential for (1) HIV transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants) and (3) serious adverse reactions in a breastfed infant, instruct mothers not to breastfeed if they are receiving NORVIR.

8.3 Females and Males of Reproductive Potential

Contraception

Use of NORVIR may reduce the efficacy of combined hormonal contraceptives. Advise patients using combined hormonal contraceptives to use an effective alternative contraceptive method or an additional barrier method of contraception [see Drug Interactions (7.3)].

8.4 Pediatric Use

In HIV-infected patients age greater than 1 month to 21 years, the antiviral activity and adverse event profile seen during clinical trials and through postmarketing experience were similar to that for adult patients.

8.5 Geriatric Use

Clinical studies of NORVIR did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

8.6 Hepatic Impairment

No dose adjustment of ritonavir is necessary for patients with either mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. No pharmacokinetic or safety data are available regarding the use of ritonavir in subjects with severe hepatic impairment (Child-Pugh Class C), therefore, ritonavir is not recommended for use in patients with severe hepatic impairment [see Warnings and Precautions (5.3), Clinical Pharmacology (12.3)].

10 OVERDOSAGE

10.1 Acute Overdosage - Human Overdose Experience

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

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

10.2 Management of Overdosage

NORVIR oral solution contains 43.2% (v/v) alcohol and 26.57% (w/v) propylene glycol. Ingestion of the product over the recommended dose by a young child could result in significant toxicity and could potentially be lethal.

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

11 DESCRIPTION

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

Ritonavir is chemically designated as 10-Hydroxy-2-methyl-5-(1-methylethyl)-1- [2-(1-methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-bis(phenylmethyl)-2,4,7,12- tetraazatridecan-13-oic acid, 5-thiazolylmethyl ester, [5S-(5R*,8R*,10R*,11R*)]. Its molecular formula is C37H48N6O5S2, and its molecular weight is 720.95. Ritonavir has the following structural formula:

[norvir chem structure]

Ritonavir is a white-to-light-tan powder. Ritonavir has a bitter metallic taste. It is freely soluble in methanol and ethanol, soluble in isopropanol and practically insoluble in water.

NORVIR tablets are available for oral administration in a strength of 100 mg ritonavir with the following inactive ingredients: copovidone, anhydrous dibasic calcium phosphate, sorbitan monolaurate, colloidal silicon dioxide, and sodium stearyl fumarate. The following are the ingredients in the film coating: hypromellose, titanium dioxide, polyethylene glycol 400, hydroxypropyl cellulose, talc, polyethylene glycol 3350, colloidal silicon dioxide, and polysorbate 80.

NORVIR oral solution is available for oral administration as 80 mg per mL of ritonavir in a peppermint and caramel flavored vehicle. Each 8-ounce bottle contains 19.2 grams of ritonavir. NORVIR oral solution also contains ethanol, water, polyoxyl 35 castor oil, propylene glycol, anhydrous citric acid to adjust pH, saccharin sodium, peppermint oil, creamy caramel flavoring, and FD&C Yellow No. 6.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Ritonavir is an antiretroviral drug [see Microbiology (12.4)].

12.3 Pharmacokinetics

The pharmacokinetics of ritonavir have been studied in healthy volunteers and HIV-infected patients (CD4 greater than or equal to 50 cells per μL). See Table 6 for ritonavir pharmacokinetic characteristics.

Absorption

The absolute bioavailability of ritonavir 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 -↑39%).

No information is available comparing NORVIR tablets to NORVIR capsules 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 the 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. Administration of a single 600 mg dose oral solution under non-fasting conditions yielded mean ± SD areas under the plasma concentration-time curve (AUCs) of 129.0 ± 39.3 mgh per mL.

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%-↓15%], and a 23% decrease in mean Cmax [90% confidence intervals: ↓34%-↓11%]) was observed relative to fasting conditions. Under moderate fat conditions, a 21% decrease in mean AUC(0-∞) [90% confidence intervals: ↓28%-↓13%], and a 22% decrease in mean Cmax [90% confidence intervals: ↓33%-↓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.

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 isopropylthiazole 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. In vitro 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.

Elimination

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.

Table 6. Ritonavir Pharmacokinetic Characteristics
Parameter N Values (Mean ± SD)
Vβ/F‡ 91 0.41 ± 0.25 L/kg
t½ 3 - 5 h
CL/F SS† 10 8.8 ± 3.2 L/h
CL/F‡ 91 4.6 ± 1.6 L/h
CLR 62 < 0.1 L/h
RBC/Plasma Ratio 0.14
Percent Bound* 98 to 99%
† SS = steady state; patients taking ritonavir 600 mg q12h.
‡ Single ritonavir 600 mg dose.
* Primarily bound to human serum albumin and alpha-1 acid glycoprotein over the ritonavir concentration range of 0.01 to 30 µg/mL.

Effects on Electrocardiogram

QTcF interval was evaluated in a randomized, placebo and active (moxifloxacin 400 mg once-daily) controlled crossover study in 45 healthy adults, with 10 measurements over 12 hours on Day 3. The maximum mean (95% upper confidence bound) time-matched difference in QTcF from placebo after baseline correction was 5.5 (7.6) milliseconds (msec) for 400 mg twice-daily ritonavir. Ritonavir 400 mg twice daily resulted in Day 3 ritonavir exposure that was approximately 1.5 fold higher than observed with ritonavir 600 mg twice-daily dose at steady state.

PR interval prolongation was also noted in subjects receiving ritonavir in the same study on Day 3. The maximum mean (95% confidence interval) difference from placebo in the PR interval after baseline correction was 22 (25) msec for 400 mg twice-daily ritonavir [see Warnings and Precautions (5.6)].

Special Populations

Gender, Race and Age

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

A study of ritonavir pharmacokinetics in healthy males and females showed no statistically significant differences in the pharmacokinetics of ritonavir. Pharmacokinetic differences due to race have not been identified.

Pediatric Patients

Steady-state pharmacokinetics were evaluated in 37 HIV-infected patients ages 2 to 14 years receiving doses ranging from 250 mg per m2 twice-daily to 400 mg per m2 twice-daily in PACTG Study 310, and in 41 HIV-infected patients ages 1 month to 2 years at doses of 350 and 450 mg per m2 twice-daily in PACTG Study 345. Across dose groups, ritonavir steady-state oral clearance (CL/F/m2) was approximately 1.5 to 1.7 times faster in pediatric patients than in adult subjects. Ritonavir concentrations obtained after 350 to 400 mg per m2 twice-daily in pediatric patients greater than 2 years were comparable to those obtained in adults receiving 600 mg (approximately 330 mg per m2) twice-daily. The following observations were seen regarding ritonavir concentrations after administration with 350 or 450 mg per m2 twice-daily in children less than 2 years of age. Higher ritonavir exposures were not evident with 450 mg per m2 twice-daily compared to the 350 mg per m2twice-daily. Ritonavir trough concentrations were somewhat lower than those obtained in adults receiving 600 mg twice-daily. The area under the ritonavir plasma concentration time curve and trough concentrations obtained after administration with 350 or 450 mg per m2 twice-daily in children less than 2 years were approximately 16% and 60% lower, respectively, than that obtained in adults receiving 600 mg twice daily.

Renal Impairment

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

Hepatic Impairment

Dose-normalized steady-state ritonavir concentrations in subjects with mild hepatic impairment (400 mg twice-daily, n = 6) were similar to those in control subjects dosed with 500 mg twice-daily. Dose-normalized steady-state ritonavir exposures in subjects with moderate hepatic impairment (400 mg twice-daily, n= 6) were about 40% lower than those in subjects with normal hepatic function (500 mg twice-daily, n = 6). Protein binding of ritonavir was not statistically significantly affected by mild or moderately impaired hepatic function. No dose adjustment is recommended in patients with mild or moderate hepatic impairment. However, health care providers should be aware of the potential for lower ritonavir concentrations in patients with moderate hepatic impairment and should monitor patient response carefully. Ritonavir has not been studied in patients with severe hepatic impairment.

Pregnancy

Based on evaluation of the published literature, ritonavir exposures are reduced during pregnancy relative to postpartum.

Drug Interactions

[see also Contraindications (4), Warnings and Precautions (5.1), and Drug Interactions (7)]

Table 7 and Table 8 summarize the effects on AUC and Cmax, with 95% confidence intervals (95% CI), of co-administration of ritonavir with a variety of drugs. For information about clinical recommendations see Table 5 in Drug Interactions (7).

Table 7. Drug Interactions - Pharmacokinetic Parameters for Ritonavir in the Presence of the Co-administered Drug
Co-administered Drug Dose of Co-administered Drug (mg) Dose of NORVIR (mg) N AUC % (95% CI) Cmax(95% CI) Cmin (95% CI)
Clarithromycin 500 q12h, 4 d 200 q8h, 4 d 22 ↑ 12% (2, 23%) ↑ 15% (2, 28%) ↑ 14% (-3, 36%)
Didanosine 200 q12h, 4 d 600 q12h, 4 d 12 ↔ ↔ ↔
Fluconazole 400 single dose, day 1; 200 daily, 4 d 200 q6h, 4 d 8 ↑ 12% (5, 20%) ↑ 15% (7, 22%) ↑ 14% (0, 26%)
Fluoxetine 30 q12h, 8 d 600 single dose, 1 d 16 ↑ 19% (7, 34%) ↔ ND
Ketoconazole 200 daily, 7 d 500 q12h, 10 d 12 ↑ 18% (-3, 52%) ↑ 10% (-11, 36%) ND
Rifampin 600 or 300 daily, 10 d 500 q12h, 20 d 7, 9* ↓ 35% (7, 55%) ↓ 25% (-5, 46%) ↓ 49% (-14, 91%)
Voriconazole 400 q12h, 1 d; then 200 q12h, 8 d 400 q12h, 9 d ↔ ↔ ND
Zidovudine 200 q8h, 4 d 300 q6h, 4 d 10 ↔ ↔ ↔

Table 8. Drug Interactions - Pharmacokinetic Parameters for Co-administered Drug in the Presence of NORVIR
Co-administered Drug Dose of Co-administered Drug (mg) Dose of NORVIR (mg) N AUC % (95% CI) Cmax(95% CI) Cmin (95% CI)
Alprazolam 1, single dose 500 q12h, 10 d 12 ↓ 12% (-5, 30%) ↓ 16% (5, 27%) ND
Avanafil 50, single dose 600 q12h 146 ↑ 13-fold ↑ 2.4-fold ND
Clarithromycin

14-OH clarithromycin metabolite 500 q12h, 4 d 200 q8h, 4 d 22 ↑ 77% (56, 103%)

↓ 100% ↑ 31% (15, 51%)

↓ 99% ↑ 2.8-fold (2.4, 3.3X)

↓ 100%
Desipramine

2-OH desipramine metabolite 100, single dose 500 q12h, 12 d 14 ↑ 145% (103, 211%)

↓ 15% (3, 26%) ↑ 22% (12, 35%)

↓ 67% (62, 72%) ND

ND
Didanosine 200 q12h, 4 d 600 q12h, 4 d 12 ↓ 13% (0, 23%) ↓ 16% (5, 26%) ↔
Ethinyl estradiol 50 µg single dose 500 q12h, 16 d 23 ↓ 40% (31, 49%) ↓ 32% (24, 39%) ND
Fluticasone propionate aqueous nasal spray 200 mcg qd, 7 d 100 mg q12h, 7 d 18 ↑ approximately 350-fold5 ↑ approximately 25-fold5
Indinavir1
Day 14
Day 15 400 q12h, 15 d 400 q12h, 15 d 10
↑ 6% (-14, 29%)
↓ 7% (-22, 28%)
↓ 51% (40, 61%)
↓ 62% (52, 70%) ↑ 4-fold (2.8, 6.8X)
↑ 4-fold (2.5, 6.5X)
Ketoconazole 200 daily, 7 d 500 q12h, 10 d 12 ↑ 3.4-fold (2.8, 4.3X) ↑ 55% (40, 72%) ND
Meperidine

Normeperidine metabolite 50 oral single dose 500 q12h, 10 d 8

6 ↓ 62% (59, 65%)

↑ 47% (-24, 345%) ↓ 59% (42, 72%)

↑ 87% (42, 147%) ND

ND
Methadone2 5, single dose 500 q12h, 15 d 11 ↓ 36% (16, 52%) ↓ 38% (28, 46%) ND
Raltegravir 400, single dose 100 q12h, 16 d 10 ↓ 16% (-30, 1%) ↓ 24% (-45, 4%) ↓ 1% (-30, 40%)
Rivaroxaban 10, single dose
(days 0 and 7) 600 q12h
(days 2 to 7) 12 ↑ 150% (130-170%)7 ↑ 60% (40-70%)7 ND
Rifabutin
25-O-desacetyl rifabutin metabolite 150 daily, 16 d 500 q12h, 10 d 5,


11* ↑ 4-fold (2.8, 6.1X)

↑ 38-fold (28, 56X) ↑ 2.5-fold (1.9, 3.4X)

↑ 16-fold (13, 20X) ↑ 6-fold (3.5, 18.3X)

↑ 181-fold (ND)
Sildenafil 100, single dose 500 twice daily, 8 d 28 ↑ 11-fold ↑ 4-fold ND
Simeprevir 200 mg qd, 7 d 100 mg bid,15 d 12 ↑ 618% (463%-815%)8 ↑370% (284%-476%)8 ↑1335% (929%-1901%)8
Sulfamethoxazole3 800, single dose 500 q12h, 12 d 15 ↓ 20% (16, 23%) ↔ ND
Tadalafil 20 mg, single dose 200 mg q12h ↑ 124% ↔ ND
Theophylline 3 mg/kg q8h, 15 d 500 q12h, 10 d 13, 11* ↓ 43% (42, 45%) ↓ 32% (29, 34%) ↓ 57% (55, 59%)
Trazodone 50 mg, single dose 200 mg q12h, 4 doses 10 ↑ 2.4-fold ↑ 34%
Trimethoprim3 160, single dose 500 q12h, 12 d 15 ↑ 20% (3, 43%) ↔ ND
Vardenafil 5 mg 600 q12h ↑ 49-fold ↑ 13-fold ND
Voriconazole 400 q12h, 1 d; then 200 q12h, 8 d 400 q12h, 9 d ↓ 82% ↓ 66%
400 q12h, 1 d; then 200 q12h, 8 d 100 q12h, 9 d ↓ 39% ↓ 24%
Warfarin
S-Warfarin
R-Warfarin 5, single dose 400 q12h, 12d 12 ↑ 9% (-17, 44%)4
↓ 33% (-38, -27%)4 ↓ 9% (-16, -2%)4
↔ ND

ND
Zidovudine 200 q8h, 4 d 300 q6h, 4 d 9 ↓ 25% (15, 34%) ↓ 27% (4, 45%) ND
1 Ritonavir and indinavir were co-administered for 15 days; Day 14 doses were administered after a 15%-fat breakfast (757 Kcal) and 9%-fat evening snack (236 Kcal), and Day 15 doses were administered after a 15%-fat breakfast (757 Kcal) and 32%-fat dinner (815 Kcal). Indinavir Cminwas also increased 4-fold. Effects were assessed relative to an indinavir 800 mg q8h regimen under fasting conditions.
2 Effects were assessed on a dose-normalized comparison to a methadone 20 mg single dose.
3 Sulfamethoxazole and trimethoprim taken as single combination tablet.
4 90% CI presented for R- and S-warfarin AUC and Cmax ratios.
5 This significant increase in plasma fluticasone propionate exposure resulted in a significant decrease (86%) in plasma cortisol AUC.
6 For the reference arm: N=14 for Cmax and AUC(0-inf), and for the test arm: N=13 for Cmax and N=4 for AUC(0-inf).
7 90% CI presented for rivaroxaban
8 90% CI presented for simeprevir (change in exposure presented as percentage increase)
↑ Indicates increase.
↓ Indicates decrease.
↔ Indicates no change.
* Parallel group design; entries are subjects receiving combination and control regimens, respectively.

12.4 Microbiology

Mechanism of Action

Ritonavir is a peptidomimetic inhibitor of the HIV-1 protease. Inhibition of HIV protease renders the enzyme incapable of processing the Gag-Pol polyprotein precursor which leads to production of non-infectious immature HIV particles.

Antiviral Activity in Cell Culture

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

Resistance

HIV-1 isolates with reduced susceptibility to ritonavir have been selected in cell culture. Genotypic analysis of these isolates showed mutations in the HIV-1 protease gene leading to amino acid substitutions I84V, V82F, A71V, and M46I. Phenotypic (n = 18) and genotypic (n = 48) changes in HIV-1 isolates from selected patients treated with ritonavir were monitored in phase I/II trials over a period of 3 to 32 weeks. Substitutions associated with the HIV–1 viral protease in isolates obtained from 43 patients appeared to occur in a stepwise and ordered fashion at positions V82A/F/T/S, I54V, A71V/T, and I36L, followed by combinations of substitutions at an additional 5 specific amino acid positions (M46I/L, K20R, I84V, L33F and L90M). Of 18 patients for whom both phenotypic and genotypic analysis were performed on free virus isolated from plasma, 12 showed reduced susceptibility to ritonavir in cell culture. All 18 patients possessed one or more substitutions in the viral protease gene. The V82A/F substitution appeared to be necessary but not sufficient to confer phenotypic resistance. Phenotypic resistance was defined as a greater than or equal to 5-fold decrease in viral sensitivity in cell culture from baseline.

Cross-Resistance to Other Antiretrovirals

Among protease inhibitors variable cross-resistance has been recognized. Serial HIV-1 isolates obtained from six patients during ritonavir therapy showed a decrease in ritonavir susceptibility in cell culture but did not demonstrate a concordant decrease in susceptibility to saquinavir in cell culture when compared to matched baseline isolates. However, isolates from two of these patients demonstrated decreased susceptibility to indinavir in cell culture (8-fold). Isolates from 5 patients were also tested for cross-resistance to amprenavir and nelfinavir; isolates from 3 patients had a decrease in susceptibility to nelfinavir (6- to 14-fold), and none to amprenavir. Cross-resistance between ritonavir and reverse transcriptase inhibitors is unlikely because of the different enzyme targets involved. One ZDV-resistant HIV-1 isolate tested in cell culture retained full susceptibility to ritonavir.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Carcinogenicity studies in mice and rats have been carried out on ritonavir. In male mice, at levels of 50, 100 or 200 mg per kg per day, there was a dose dependent increase in the incidence of both adenomas and combined adenomas and carcinomas in the liver. Based on AUC measurements, the exposure at the high dose was approximately 0.3-fold for males that of the exposure in humans with the recommended therapeutic dose (600 mg twice-daily). There were no carcinogenic effects seen in females at the dosages tested. The exposure at the high dose was approximately 0.6-fold for the females that of the exposure in humans. In rats dosed at levels of 7, 15 or 30 mg per kg per day there were no carcinogenic effects. In this study, the exposure at the high dose was approximately 6% that of the exposure in humans with the recommended therapeutic dose. Based on the exposures achieved in the animal studies, the significance of the observed effects is not known.

Mutagenesis

However, ritonavir was found to be negative for mutagenic or clastogenic activity in a battery of in in vitro and in vivo assays including the Ames bacterial reverse mutation assay using S. typhimurium and E. coli, the mouse lymphoma assay, the mouse micronucleus test and chromosomal aberration assays in human lymphocytes.

Impairment of Fertility

Ritonavir produced no effects on fertility in rats at drug exposures approximately 40% (male) and 60% (female) of that achieved with the proposed therapeutic dose. Higher dosages were not feasible due to hepatic toxicity.

14 CLINICAL STUDIES

The activity of NORVIR as monotherapy or in combination with nucleoside reverse transcriptase inhibitors has been evaluated in 1446 patients enrolled in two double-blind, randomized trials.

14.1 Advanced Patients with Prior Antiretroviral Therapy

Study 247 was a randomized, double-blind trial (with open-label follow-up) conducted in HIV-infected patients with at least nine months of prior antiretroviral therapy and baseline CD4 cell counts less than or equal to 100 cells per μL. NORVIR 600 mg twice-daily or placebo was added to each patient's baseline antiretroviral therapy regimen, which could have consisted of up to two approved antiretroviral agents. The study accrued 1,090 patients, with mean baseline CD4 cell count at study entry of 32 cells per μL. After the clinical benefit of NORVIR therapy was demonstrated, all patients were eligible to switch to open-label NORVIR for the duration of the follow-up period. Median duration of double-blind therapy with NORVIR and placebo was 6 months. The median duration of follow-up through the end of the open-label phase was 13.5 months for patients randomized to NORVIR and 14 months for patients randomized to placebo.

The cumulative incidence of clinical disease progression or death during the double-blind phase of Study 247 was 26% for patients initially randomized to NORVIR compared to 42% for patients initially randomized to placebo. This difference in rates was statistically significant.

Cumulative mortality through the end of the open-label follow-up phase for patients enrolled in Study 247 was 18% (99/543) for patients initially randomized to NORVIR compared to 26% (142/547) for patients initially randomized to placebo. This difference in rates was statistically significant. However, since the analysis at the end of the open-label phase includes patients in the placebo arm who were switched from placebo to NORVIR therapy, the survival benefit of NORVIR cannot be precisely estimated.

During the double-blind phase of Study 247, CD4 cell counts increases from baseline for patients randomized to NORVIR at Week 2 and Week 4 were observed. From Week 4 and through Week 24, mean CD4 cell counts for patients randomized to NORVIR appeared to plateau. In contrast, there was no apparent change in mean CD4 cell counts for patients randomized to placebo at any visit between baseline and Week 24 of the double-blind phase of Study 247.

14.2 Patients without Prior Antiretroviral Therapy

In Study 245, 356 antiretroviral-naive HIV-infected patients (mean baseline CD4 = 364 cells per μL) were randomized to receive either NORVIR 600 mg twice-daily, zidovudine 200 mg three-times-daily, or a combination of these drugs.

During the double-blind phase of study 245, greater mean CD4 cell count increases were observed from baseline to Week 12 in the NORVIR-containing arms compared to the zidovudine arms. Mean CD4 cell count changes subsequently appeared to plateau through Week 24 in the NORVIR arm, whereas mean CD4 cell counts gradually diminished through Week 24 in the zidovudine and NORVIR plus zidovudine arms.

Greater mean reductions in plasma HIV-1 RNA levels were observed from baseline to Week 2 for the NORVIR-containing arms compared to the zidovudine arm. After Week 2 and through Week 24, mean plasma HIV-1 RNA levels either remained stable in the NORVIR and zidovudine arms or gradually rebounded toward baseline in the NORVIR plus zidovudine arm.

15 REFERENCES

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

16 HOW SUPPLIED/STORAGE AND HANDLING

NORVIR (ritonavir) tablets and NORVIR (ritonavir) oral solution are available in the following strengths and package sizes:

16.1 NORVIR Tablets, 100 mg Ritonavir

NORVIR (ritonavir) tablets are white film-coated ovaloid tablets debossed with the "a" logo and the code NK.

Bottles of 30 tablets each (NDC: 0074-3333-30).

Recommended Storage

Store at or below 30°C (86°F). Exposure to temperatures up to 50°C (122°F) for seven days permitted. Dispense in original container or USP equivalent tight container (60 mL or less). For patient use: exposure of this product to high humidity outside the original or USP equivalent tight container (60 mL or less) for longer than 2 weeks is not recommended.

16.2 NORVIR Oral Solution, 80 mg per mL Ritonavir

NORVIR (ritonavir) oral solution is an orange-colored liquid, supplied in amber-colored, multi-dose bottles containing 600 mg ritonavir per 7.5 mL marked dosage cup (80 mg per mL).

240 mL bottles (NDC: 0074-1940-63).

Recommended Storage

Store NORVIR oral solution at room temperature 20°-25°C (68°-77°F). Do not refrigerate. Shake well before each use. Use by product expiration date.

Product should be stored and dispensed in the original container.

Avoid exposure to excessive heat. Keep cap tightly closed.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information)

Patients or parents of patients should be informed that:

General Information

 They should pay special attention to accurate administration of their dose to minimize the risk of accidental overdose or underdose of NORVIR.

 They should inform their healthcare provider if their children’s weight changes in order to make sure that the child’s NORVIR dose is the correct one.

 Take NORVIR with meals.

 For adult patients taking NORVIR tablets, the maximum dose of 600 mg twice daily by mouth with meals should not be exceeded.

 Advise pregnant women that use of NORVIR oral solution during pregnancy is not recommended due to its alcohol content [see Dosage and Administration (2.1) and Use in Specific Population (8.1)].

 Patients should remain under the care of a physician while using NORVIR. Patients should be advised to take NORVIR and other concomitant antiretroviral therapy every day as prescribed. NORVIR must always be used in combination with other antiretroviral drugs. Patients should not alter the dose or discontinue therapy without consulting with their doctor. If a dose of NORVIR is missed patients should take the dose as soon as possible and then return to their normal schedule. However, if a dose is skipped the patient should not double the next dose.

 NORVIR is not a cure for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients should remain under the care of a physician when using NORVIR.

Patients should be advised to avoid doing things that can spread HIV-1 infection to others.

Do not share needles or other injection equipment.
Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
Do not have any kind of sex without protection. Always practice safe sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.
Do not breastfeed. Instruct women with HIV-1 infection not breastfeed because HIV-1 can be passed to the infant in the breast milk [see Use in Specific Populations (8.2)].

 Sustained decreases in plasma HIV-1 RNA have been associated with a reduced risk of progression to AIDS and death.

Drug Interactions

 NORVIR may interact with some drugs; therefore, patients should be advised to report to their doctor the use of any other prescription, non-prescription medication or herbal products, particularly St. John's Wort.

 Instruct patients receiving combined hormonal contraception to use an effective alternative contraceptive method or an additional barrier method during therapy with NORVIR because hormonal levels may decrease [see Drug Interactions (7.3), Use in Specific Populations (8.3)].

Potential Adverse Effects

 Pre-existing liver disease including Hepatitis B or C can worsen with use of NORVIR. This can be seen as worsening of transaminase elevations or hepatic decompensation. Patients should be advised that their liver function tests will need to be monitored closely especially during the first several months of NORVIR treatment and that they should notify their healthcare provider if they develop the signs and symptoms of worsening liver disease including loss of appetite, abdominal pain, jaundice, and itchy skin.

 Pancreatitis, including some fatalities, has been observed in patients receiving NORVIR therapy. Your patients should let you know of signs and symptoms (nausea, vomiting, and abdominal pain) that might be suggestive of pancreatitis.

 Skin rashes ranging in severity from mild to Stevens-Johnson syndrome have been reported in patients receiving NORVIR. Patients should be advised to contact their healthcare provider if they develop a rash while taking NORVIR. The healthcare provider will determine if treatment should be continued or an alternative antiretroviral regimen used.

 Pregnancy Exposure Registry

Inform patients that there is an antiretroviral pregnancy registry that monitors fetal outcomes of pregnant women exposed to NORVIR [see Use in Specific Populations (8.1)].

 NORVIR may produce changes in the electrocardiogram (e.g., PR prolongation). Patients should consult their physician if they experience symptoms such as dizziness, lightheadedness, abnormal heart rhythm or loss of consciousness.

 Treatment with NORVIR therapy can result in substantial increases in the concentration of total cholesterol and triglycerides.

 New onset of diabetes or exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported. Patients should be advised to notify their healthcare provider if they develop the signs and symptoms of diabetes mellitus including frequent urination, excessive thirst, extreme hunger or unusual weight loss and/or an increased blood sugar while on NORVIR as they may require a change in their diabetes treatment or new treatment.

 Immune reconstitution syndrome has been reported in HIV-infected patients treated with combination antiretroviral therapy, including NORVIR.

 Redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long term health effects of these conditions are not known at this time.

 Patients with hemophilia may experience increased bleeding when treated with protease inhibitors such as NORVIR.

 If they are receiving avanafil, sildenafil, tadalafil, or vardenafil for the treatment of erectile dysfunction, they may be at an increased risk of associated adverse reactions including hypotension, visual changes, and sustained erection, and should promptly report any symptoms to their doctor. They should seek medical assistance immediately if they develop a sustained penile erection lasting more than 4 hours while taking NORVIR and a PDE 5 Inhibitor such as Stendra®, Viagra®, Cialis® or Levitra®. If they are currently using or planning to use avanafil or tadalafil (for the treatment of pulmonary arterial hypertension) they should ask their doctor about potential adverse reactions these medications may cause when taken with NORVIR. The doctor may choose not to keep them on avanafil, or may adjust the dose of tadalafil while initiating treatment with NORVIR. Concomitant use of Revatio® (sildenafil) with NORVIR is contraindicated in patients with pulmonary arterial hypertension (PAH).

 Continued NORVIR therapy at a dose of 600 mg twice daily following loss of viral suppression may increase the likelihood of cross-resistance to other protease inhibitors.

NORVIR tablets and oral solution are manufactured by:

AbbVie Inc.

North Chicago, IL 60064 USA

© 2016 AbbVie Inc. All rights reserved.

03-B455

PATIENT PACKAGE INSERT

Patient Information

NORVIR® (NOR-VEER)

(ritonavir)

Tablet

NORVIR® (NOR-VEER)

(ritonavir)

Oral Solution

Read this Patient Information before you start taking NORVIR and each time you get a refill. There may be new information. This information does not take the place of talking to your doctor about your medical condition or your treatment.

What is the most important information I should know about NORVIR?

NORVIR can interact with other medicines and cause serious side effects. It is important to know the medicines that should not be taken with NORVIR. See the section “Who should not take NORVIR?”

What is NORVIR?

NORVIR is a prescription anti-HIV medicine used with other anti-HIV medicines to treat people with human immunodeficiency virus (HIV) infection. NORVIR is a type of anti-HIV medicine called a protease inhibitor. HIV is the virus that causes AIDS (Acquired Immune Deficiency Syndrome).

When used with other HIV medicines, NORVIR may reduce the amount of HIV in your blood (called “viral load”). NORVIR may also help to increase the number of CD4 (T) cells in your blood which help fight off other infections. Reducing the amount of HIV and increasing the CD4 (T) cell count may improve your immune system. This may reduce your risk of death or infections that can happen when your immune system is weak (opportunistic infections). Patients who took NORVIR in clinical studies had significant reductions in both death and AIDS defining diseases; however NORVIR may not have these effects in all patients.

NORVIR does not cure HIV infection or AIDS and you may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. You should remain under the care of a doctor when using NORVIR.

Avoid doing things that can spread HIV-1 infection.

Do not share needles or other injection equipment.
Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
Do not have any kind of sex without protection. Always practice safe sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.

Who should not take NORVIR?

Do not take NORVIR if you are allergic to ritonavir or any of the ingredients in NORVIR. See the end of this leaflet for a complete list of ingredients in NORVIR.

Do not take NORVIR with any of the following medicines:

alfuzosin (Uroxatral)
amiodarone (Cordarone, Nexterone, Pacerone), dronedarone (Multaq), flecainide (Tambocor), propafenone (Rythmol) or quinidine (Nuedext, Quinaglute, Cardioquin, Quinidex, and others)
colchicine (Colcrys, Col-Probenecid, Probenecid and Colchine), if you have kidney and/or liver problems
voriconazole (VFend) if NORVIR dose is 400 mg every 12 hours or greater
dihydroergotamine (D.H.E. 45, Embolex, Migranal), ergotamine (Cafergot, Ergomar) methylergonovine (Methergine)
cisapride (Propulsid)
St. John’s Wort (Hypericum perforatum)
the cholesterol lowering medicines lovastatin (Mevacor, Altoprev, Advicor) or simvastatin (Zocor, Simcor, Vytorin)
lurasidone (Latuda), pimozide (Orap)
sildenafil (Revatio) only when used for the treatment of pulmonary arterial hypertension
oral midazolam or triazolam (Halcion)

Serious problems can happen if you or your child takes any of these medicines with NORVIR.

What should I tell my doctor before taking NORVIR?

Before taking NORVIR, tell your doctor if you:

have liver problems, including Hepatitis B or Hepatitis C.
have heart problems.
have high blood sugar (diabetes).
have bleeding problems or hemophilia.
are pregnant or plan to become pregnant.

Pregnancy Registry: There is a pregnancy registry for women who take antiviral medicines during pregnancy. The purpose of the registry is to collect information about the health of you and your baby. Talk to your doctor about how you can take part in this registry.

are breastfeeding. Do not breastfeed if you take NORVIR

You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.
It is not known if NORVIR passes into your breast milk.
Talk to your doctor about the best way to feed your baby.

Tell your doctor about all the medicines you take including prescription and nonprescription medicines, vitamins, and herbal supplements. Taking NORVIR and certain other medicines may affect each other causing serious side effects. NORVIR may affect the way other medicines work and other medicines may affect how NORVIR works.

Especially tell your doctor if you take:

medicine to treat HIV
estrogen-based contraceptives (birth control). NORVIR might reduce the effectiveness of estrogen-based contraceptives. You must take additional precautions for birth control such as a condom.
medicine for pain such as tramadol (Ryzolt, Ultracet, Conzip, Ultram), propoxyphene, or meperidine (Demerol)
medicine to treat alcohol abuse such as disulfiram (Antabuse)
medicine for your heart such as disopyramide (Norpace), lidocaine (Xylocaine Viscous), mexiletine, digoxin (Lanoxin), nifedipine (Procardia, Adalat, Afeditab CR), diltiazem (Cardizem, Dilacor, Cartia, Diltzac, Dilt, Taztia, Tiazac) or verapamil (Calan, Covera, Isoptin, Tarka, Verelan)
medicines for panic disorder or anxiety such as buspirone, clorazepate, diazepam, estazolam, flurazepam, and zolpidem
medicine for cancer such as dasatinib (Sprycel), nilotinib (Tasigna) vincristine, or vinblastine
warfarin (Coumadin, Jantoven), rivaroxaban (Xarelto)
medicine for seizures such as carbamazepine (Carbatrol, Equetro, Tegretol, Epitol), clonazepam (Klonopin), ethosuximide (Zarontin, Ethosuximide), divalproex (Depakote, Divalproex Sodium), lamotrigine (Lamictal) or phenytoin (Dilantin, Phenytek)
medicine for depression such as nefazodone, bupropion (Wellbutrin, Aplenzin, Zyban), desipramine (Norpramin) or trazadone, fluoxetine (Prozac), paroxetine (Paxil), amitriptyline, or nortriptyline
medicine for nausea and vomiting such as dronabinol (Marinol) or perphenazine
medicine for fungal infections such as ketoconazole (Nizoral), itraconazole (Sporanox, Onmel) or voriconazole (VFend)
colchicine (Colcrys, Col-Probenecid, Probenecid and Colchine)
medicine for infections such as clarithromycin (Prevpac, Biaxin), rifabutin (Mycobutin), rifampin (Rimactane, Rifadin, Rifater, Rifamate), atovaquone (Mepron, Malarone), bedaquiline (Sirturo), quinine (Qualaquin) or metronidazole (Flagyl, Helidac, Metrocream)
medicine used to treat blood pressure, a heart attack, heart failure, or to lower pressure in the eye such as metoprolol (Lopressor, Toprol-XL), timolol (Cosopt, Betimol, Timoptic, Isatolol, Combigan)
medicine for lung disease such as theophylline and salmeterol (Serevent)
bosentan (Tracleer)
medicine to treat Hepatitis C such as simeprevir (Olysio)
medicine to prevent organ transplant failure such as cyclosporine (Gengraf, Sandimmune, Neoral), tacrolimus (Prograf,) sirolimus (Rapamune)
steroids such as dexamethasone, fluticasone (Advair Diskus, Veramyst, Flovent, Flonase), budesonide (Entocort EC, Pulmicort, Rhinocort), or prednisone
a narcotic medicine such as methadone (Methadose, Dolophine Hydrochloride) or fentanyl (Abstral, Actiq, Fentora, Lazanda, Onsolis, Duragesic)
medicine to treat schizophrenia such as risperidone (Risperdal) or thioridazine
medicine to treat psychosis such as quetiapine (Seroquel)
medicine to treat erectile dysfunction or pulmonary hypertension such as avanafil (Stendra), sildenafil (Viagra, Revatio), vardenafil (Levitra, Staxyn), tadalafil (Cialis, Adcirca). If you are taking avanafil (Stendra), your doctor may need to change it to a different medicine.
midazolam by injection
methamphetamine (Desoxyn)
cholesterol lowering medicine such as atorvastatin (Lipitor) or rosuvastatin (Crestor)

This is not a complete list of medicines that you should tell your doctor that you are taking. Ask your doctor, provider or pharmacist if you are not sure if your medicine is one that is listed above.

Know the medicines you take. Keep a list of them to show your doctor or pharmacist when you get a new medicine. Do not start any new medicines while you are taking NORVIR without first talking with your doctor.

How should I take NORVIR?

Take NORVIR exactly as prescribed by your doctor.
You should stay under a doctor's care when taking NORVIR. Do not change your dose of NORVIR or stop your treatment without talking with your doctor first.
If your child is taking NORVIR, your child’s doctor will decide the right dose based on your child's height and weight. Tell your doctor if your child’s weight changes. Your child should take NORVIR with food. If your child does not tolerate NORVIR Oral Solution, ask your child’s doctor for advice.
Swallow NORVIR tablets whole. Do not chew, break, or crush tablets before swallowing. If you cannot swallow NORVIR tablets whole, tell your doctor. You may need a different medicine.
Take NORVIR with meals.
NORVIR Oral Solution is peppermint or caramel flavored. You can take it alone, or may improve the taste by mixing it with 8 ounces of chocolate milk, Ensure®, or Advera®. NORVIR Oral Solution should be taken within 1 hour if mixed with these fluids. Ask your doctor, nurse or pharmacist about other ways to improve the taste of NORVIR Oral Solution.
Do not run out of NORVIR. Get your NORVIR prescription refilled from you doctor or pharmacy before you run out.
If you miss a dose of NORVIR, take it as soon as possible and then take your next scheduled dose at its regular time. If it is almost time for your next dose, wait and take the next dose at the regular time. Do not double the next dose.
If you take too much NORVIR, call your local poison control center or go to the nearest hospital emergency room right away.

What are the possible side effects of NORVIR?

NORVIR can cause serious side effects including:

See “What is the most important information I should know about NORVIR?”
Liver disease. Some people taking NORVIR in combination with other anti-HIV medicines have developed liver problems which may be life-threatening. Your doctor should do regular blood tests during your combination treatment with NORVIR. If you have chronic hepatitis B or C infection, your doctor should check your blood tests more often because you have an increased chance of developing liver problems. Tell your doctor if you have any of the below signs and symptoms of liver problems:

loss of appetite
pain or tenderness on your right side below your ribs
yellowing of your skin or whites of your eyes
itchy skin

Swelling of your pancreas (Pancreatitis). NORVIR can cause serious pancreas problems, which may lead to death. Tell your doctor right away if you have signs or symptoms of pancreatitis such as:

nausea
vomiting
stomach (abdomen) pain

Allergic Reactions. Sometimes these allergic reactions can become severe and require treatment in a hospital. You should call your doctor right away if you develop a rash. Stop taking NORVIR and get medical help right away if you have any of the following symptoms of a severe allergic reaction:

trouble breathing
wheezing
dizziness or fainting
throat tightness or hoarseness
fast heartbeat or pounding in your chest (tachycardia)
sweating
swelling of your face, lips or tongue
muscle or joint pain
blisters or skin lesions
mouth sores or ulcers

Changes in the electrical activity of your heart called PR prolongation. PR prolongation can cause irregular heartbeats. Tell your doctor right away if you have symptoms such as:

dizziness
lightheadedness
feel faint or pass out
abnormal heart beat

Increase in cholesterol and triglyceride levels. Treatment with NORVIR may increase your blood levels of cholesterol and triglycerides. Your doctor should do blood tests before you start your treatment with NORVIR and regularly to check for an increase in your cholesterol and triglycerides levels.
Diabetes and high blood sugar (hyperglycemia). Some people who take protease inhibitors including NORVIR can get high blood sugar, develop diabetes, or your diabetes can get worse. Tell your doctor if you notice an increase in thirst or urinate often while taking NORVIR.
Changes in your immune system (Immune reconstitution syndrome) can happen when you start taking HIV medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Call your doctor right away if you start having new symptoms after starting your HIV medicine.
Change in body fat. These changes can happen in people who take antiretroviral therapy. The changes may include an increase amount of fat in the upper back and neck (“buffalo hump”), breast, and around the back and stomach area. Loss of fat from the legs, arms, and face may also happen. The exact cause and long-term health effects of these conditions are not known.
Increased bleeding for hemophiliacs. Some people with hemophilia have increased bleeding with protease inhibitors including NORVIR.

The most common side effects of NORVIR include:

diarrhea
nausea
vomiting
upper and lower stomach (abdomen) pain
tingling feeling or numbness in hands or feet or around the lips
rash
feeling weak or tired

NORVIR liquid contains a large amount of alcohol. If a toddler or young child accidentally drinks more than the recommended dose of NORVIR, it could make him/her sick from too much alcohol. Contact your local poison control center or emergency room immediately if this happens.

Tell your doctor if you have any side effect that bothers you or that does not go away.

These are not all of the possible side effects of NORVIR. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store NORVIR?

Store NORVIR Oral Solution at room temperature between 68°F to 77°F (20°C to 25°C).
Store NORVIR tablets below 30°C (86°F). Exposure to temperatures up to 50°C (122°F) for seven days permitted.
Do not refrigerate NORVIR Oral Solution.
Shake NORVIR Oral Solution well before each use.
Keep NORVIR Oral Solution away from heat.
Store NORVIR tablets and NORVIR oral solution in the original container given to you by the pharmacist.
Exposure of NORVIR tablets to high humidity outside the original container for longer than 2 weeks is not recommended.
Use NORVIR tablets and NORVIR Oral Solution by the expiration date on the bottle.

Keep NORVIR and all medicines out of the reach of children.

General information about NORVIR

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information Leaflet. Do not use this medicine for a condition for which it was not prescribed. Do not share this medicine with other people.

This leaflet summarizes the most important information about NORVIR. If you would like more information, talk to your doctor. You can ask your doctor or pharmacist for information about NORVIR that is written for healthcare professionals.

For more information, call 1-800-633-9110.

What are the ingredients in NORVIR?

Active ingredient: ritonavir

Inactive ingredients:

NORVIR Tablet: copovidone, anhydrous dibasic calcium phosphate, sorbitan monolaurate, colloidal silicon dioxide, and sodium stearyl fumarate. The film coating contains: hypromellose, titanium dioxide, polyethylene glycol 400, hydroxypropyl cellulose, talc, polyethylene glycol 3350, colloidal silicon dioxide, and polysorbate 80.

NORVIR Oral Solution: ethanol, water, polyoxyl 35 castor oil, propylene glycol, anhydrous citric acid to adjust pH, saccharin sodium, peppermint oil, creamy caramel flavoring, and FD&C Yellow No. 6.

This Patient Information has been approved by the U.S. Food and Drug Administration.

NORVIR tablets and oral solution are manufactured by:

AbbVie Inc.
North Chicago, IL 60064 USA

Revised: December 2016

The brands listed are trademarks of their respective owners and are not trademarks of AbbVie Inc. The makers of these brands are not affiliated with and do not endorse AbbVie Inc. or its products.

© 2016 AbbVie Inc. All rights reserved.

SPL UNCLASSIFIED SECTION

03-B455

PRINCIPAL DISPLAY PANEL

INGREDIENTS AND APPEARANCE

NORVIR 
norvir tablet, film coated

Product Information
Product Type	HUMAN PRESCRIPTION DRUG	Item Code (Source)	NDC: 67296-1234(NDC:0074-3333)
Route of Administration	ORAL

Active Ingredient/Active Moiety
Ingredient Name	Basis of Strength	Strength
RITONAVIR (UNII: O3J8G9O825) (RITONAVIR - UNII:O3J8G9O825)	RITONAVIR	100 mg

Inactive Ingredients
Ingredient Name	Strength
ANHYDROUS DIBASIC CALCIUM PHOSPHATE (UNII: L11K75P92J)
TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
POLYETHYLENE GLYCOL 3350 (UNII: G2M7P15E5P)
SILICON DIOXIDE (UNII: ETJ7Z6XBU4)
SORBITAN MONOLAURATE (UNII: 6W9PS8B71J)
SODIUM STEARYL FUMARATE (UNII: 7CV7WJK4UI)
POLYETHYLENE GLYCOL 400 (UNII: B697894SGQ)
POLYSORBATE 80 (UNII: 6OZP39ZG8H)
HYPROMELLOSES (UNII: 3NXW29V3WO)
HYDROXYPROPYL CELLULOSE (1600000 WAMW) (UNII: RFW2ET671P)
COPOVIDONE K25-31 (UNII: D9C330MD8B)
TALC (UNII: 7SEV7J4R1U)

Product Characteristics
Color	white	Score	no score
Shape	OVAL	Size	22mm
Flavor		Imprint Code	A;NK
Contains

Packaging
#	Item Code	Package Description	Marketing Start Date	Marketing End Date
1	NDC: 67296-1234-4	4 in 1 BOTTLE; Type 0: Not a Combination Product	05/06/2010

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA022417	05/06/2010

Labeler - RedPharm Drug, Inc. (828374897)

Establishment
Name	Address	ID/FEI	Business Operations
RedPharm Drug, Inc.		828374897	repack(67296-1234) , relabel(67296-1234)