Norvir

1 INDICATIONS AND USAGE NORVIR tablets are indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. NORVIR oral powder is indicated in combination with other antiretroviral agents for the treatment of pediatric patients with HIV-1 infection. NORVIR tablets are HIV protease inhibitors indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection NORVIR oral powder is indicated in combination with other antiretroviral agents for the treatment of pediatric patients with HIV-1 infection

Adult patients: 600 mg twice-day with meals 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 NORVIR oral powder can only be used for dosing increments of 100 mg Instructions for Use should be followed for preparation and administration of NORVIR oral powder Dose modification for NORVIR is necessary when used with other protease inhibitors

2.1General Administration Recommendations

NORVIR must be used in combination with other antiretroviral agents. NORVIR is administered orally. NORVIR tablets should be swallowed whole, and not chewed, broken or crushed. Take NORVIR with meals. NORVIR oral powder should be mixed with soft food such as apple sauce or vanilla pudding, or mixed with liquid such as water, chocolate milk, or infant formula . The bitter aftertaste of NORVIR oral powder may be lessened if administered with food. 2. 2 Dosage Recommendations in Adults Recommended Dosage for Treatment of HIV-1: The recommended dosage of NORVIR 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. NORVIR 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 . 2. 3 Dosage Recommendations in Pediatric Patients NORVIR must be used in combination with other antiretroviral agents . The recommended dosage of NORVIR in pediatric patients older than 1 month is 350 to 400 mg per m 2 twice daily by mouth to be taken with meals and should not exceed 600 mg twice daily.

NORVIR should be started at 250 mg per m 2 twice daily and increased at 2 to 3 day intervals by 50 mg per m 2 twice daily. If patients do not tolerate 400 mg per m 2 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 . 2. 4 Preparation of Norvir Oral Powder For details on the preparation and administration of NORVIR oral powder . NORVIR oral powder should only be used for dosing increments of 100 mg. Prepare the dose using the required number of packets.

For example, use one packet for doses of 100 mg and two packets for doses of 200 mg. Pour and mix the entire contents of each packet over soft food or liquid. All of the powder mixed with soft food or liquid should be administered within 2 hours of preparation. If not administered within 2 hours of preparation, the mixture should be discarded and a new dose prepared.

The prescribed dose of NORVIR oral powder can be administered via a feeding tube after being mixed with water . Follow the instructions for the feeding tube to administer the medicine. 2. 5 Dose Modification due to Drug Interaction 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 .

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 ) Hepatotoxicity: 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 ( 5.2 , 8.6 ) Pancreatitis: Fatalities have occurred; suspend therapy as clinically appropriate 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 ( 5.4 , 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 ( 5.5 , 12.3 ) Total cholesterol and triglycerides elevations: Monitor prior to therapy and periodically thereafter Patients may develop new onset or exacerbations of diabetes mellitus, hyperglycemia Patients may develop immune reconstitution syndrome Patients may develop redistribution/accumulation of body fat Hemophilia: Spontaneous bleeding may occur, and additional factor VIII may be required

5.1Risk 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 3 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations . 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 . 5. 2 Hepatotoxicity 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 . 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 . 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. 3 Pancreatitis Pancreatitis has been observed in patients receiving NORVIR therapy, including those who developed hypertriglyceridemia. In some cases fatalities have been observed. Patients with advanced HIV disease may be at increased risk of elevated triglycerides and pancreatitis . Pancreatitis should be considered if clinical symptoms (nausea, vomiting, abdominal pain) or abnormalities in laboratory values (such as increased serum lipase or amylase values) suggestive of pancreatitis should occur.

Patients who exhibit these signs or symptoms should be evaluated and NORVIR therapy should be discontinued if a diagnosis of pancreatitis is made. 5. 4 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. 5 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 . 5. 6 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 . 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 . 5. 7 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. 8 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. 9 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. 1 0 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. 1 1 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 . 5. 1 2 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.

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 . ○ Alpha 1- Adrenoreceptor Antagonist : alfuzosin ○ Antianginal: ranolazine ○ Antiarrhythmics: amiodarone, dronedarone, flecainide, propafenone, quinidine ○ Antifungal: voriconazole ○ Anti-gout: colchicine ○ Antipsychotics: lurasidone, pimozide ○ Ergot Derivatives: dihydroergotamine, ergotamine, methylergonovine ○ GI Motility Agent: cisapride ○ HMG-CoA Reductase Inhibitors: lovastatin, simvastatin ○ Microsomal triglyceride transfer protein (MTTP) Inhibitor: lomitapide ○ PDE5 Inhibitor: sildenafil (Revatio ® ) when used for the treatment of pulmonary arterial hypertension ○ Sedative/Hypnotics: triazolam, orally administered midazolam NORVIR is contraindicated with drugs that are potent CYP3A inducers where significantly reduced ritonavir plasma concentrations may be associated with the potential for loss of virologic response and possible resistance and cross-resistance . ○ Anticancer Agents: apalutamide ○ Herbal Products: St.

John's Wort (hypericum perforatum) NORVIR is contraindicated in patients with known hypersensitivity to ritonavir (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome) or any of its ingredients 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 Co-administration with drugs that significantly reduce ritonavir

8.1Pregnancy 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) . 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 . 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. 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.

The following adverse reactions are discussed in greater detail in other sections of the labeling. Drug Interactions Hepatotoxicity Pancreatitis Allergic Reactions/Hypersensitivity When co-administering NORVIR with other protease inhibitors, see the full prescribing information for that protease inhibitor including adverse reactions. 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 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.

6.1Clinical 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 1 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 1. 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

6.4Gastrointestinal

disorders Abdominal Pain (upper and lower)* 464

26.4Diarrhea

including severe with electrolyte imbalance* 1,192

67.9Dyspepsia

201

11.5Flatulence

142

8.1Gastrointestinal

hemorrhage* 41

2.3Gastroesophageal

reflux disease (GERD) 19

1.1Nausea

1,007

57.4Vomiting*

559

31.9General

disorders and administration site conditions Fatigue including asthenia* 811

46.2Hepatobiliary

disorders Blood bilirubin increased (including jaundice)* 25

1.4Hepatitis

(including increased AST, ALT, GGT)* 153

8.7Immune

system disorders Hypersensitivity including urticaria and face edema* 114

8.2Metabolism and

nutrition disorders Edema and peripheral edema* 110

6.3Gout*

24

1.4Hypercholesterolemia*

52

3.0Hypertriglyceridemia*

158

9.0Lipodystrophy

acquired* 51

2.9Musculoskeletal and

connective tissue disorders Arthralgia and back pain* 326

18.6Myopathy/creatine

phosphokinase increased* 66

3.8Myalgia

156

8.9Nervous

system disorders Dizziness* 274

15.6Dysgeusia*

285

16.2Paresthesia

(including oral paresthesia)* 889

50.7Peripheral

neuropathy 178

10.1Syncope*

58

3.3Psychiatric

disorders Confusion* 52

3.0Disturbance in

attention 44

2.5Renal and

urinary disorders Increased urination* 74

4.2Respiratory,

thoracic and mediastinal disorders Coughing* 380

21.7Oropharyngeal Pain*

279

15.9Skin and

subcutaneous tissue disorders Acne* 67

3.8Pruritus*

214

12.2Rash

(includes erythematous and maculopapular)* 475

27.1Vascular

disorders Flushing, feeling hot* 232

13.2Hypertension*

58

3.3Hypotension

including orthostatic hypotension* 30

1.7Peripheral

coldness* 21 1.2 * Represents a medical concept including several similar MedDRA PTs Laboratory Abnormalities in Adults Table 2 shows the percentage of adult patients who developed marked laboratory abnormalities. Table 2. 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

65.2CPK

> 1000 IU/L 9.6 12.1 11.0 9.1 6.3

9.9GGT

> 300 IU/L 1.8 5.2 1.7 19.6 11.3

9.2SGOT

(AST) > 180 IU/L 5.3 9.5 2.5 6.4 7.0

7.8SGPT

(ALT) > 215 IU/L 5.3 7.8 3.4 8.5 4.4

9.2Triglycerides

> 800 mg/dL 9.6 17.2 3.4 33.6 9.4

23.4Triglycerides

> 1500 mg/dL 1.8 2.6 - 12.6 0.4

11.3Triglycerides Fasting

> 1500 mg/dL 1.5 1.3 - 9.9 0.3 - Uric Acid > 12 mg/dL - - - 3.8 0.2

1.4Hematology Low Hematocrit

< 30% 2.6 - 0.8 17.3 22.0

0.7Hemoglobin

< 8.0 g/dL 0.9 - - 3.8 3.9 - Neutrophils ≤ 0.5 x 10 9 /L - - - 6.0 8.3 - RBC < 3.0 x 10 12 /L 1.8 - 5.9 18.6 24.4 - WBC < 2.5 x 10 9 /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%).

6.2Postmarketing Experience The

following adverse events (not previously mentioned in the labeling) have been reported during post-marketing use of NORVIR. Because these reactions are reported voluntarily from a population of unknown size, it is not possible to reliably estimate their frequency or establish a causal relationship to NORVIR exposure. Body as a Whole Dehydration, usually associated with gastrointestinal symptoms, and sometimes resulting in hypotension, syncope, or renal insufficiency has been reported. Syncope, orthostatic hypotension, and renal insufficiency have also been reported without known dehydration.

Co-administration of ritonavir with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system. Cardiovascular System First-degree AV block, second-degree AV block, third-degree AV block, right bundle branch block have been reported . Cardiac and neurologic events have been reported when ritonavir has been co-administered with disopyramide, mexiletine, nefazodone, fluoxetine, and beta blockers. The possibility of drug interaction cannot be excluded.

Endocrine System Cushing's syndrome and adrenal suppression have been reported when ritonavir has been co-administered with fluticasone propionate or budesonide. Nervous System There have been postmarketing reports of seizure. Also, see Cardiovascular System. Renal and Urinary Disorders Nephrolithiasis Skin and subcutaneous tissue disorders Toxic epidermal necrolysis (TEN) has been reported.