Norvir Tablets

Dosage Form: tablet, oral solution
FULL PRESCRIBING INFORMATION

WARNING:

Co-administration of NORVIR with 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 [see Contraindications (4) and Warnings and Precautions (5.1)].

Indications and Usage for Norvir Tablets

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

Norvir Tablets 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: amprenavir, 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) and Table 5, Established and Other Potentially Significant Drug Interactions].

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.

Pediatric Patients

Ritonavir should be used in combination with other antiretroviral agents [see Dosage and Administration (2)]. The recommended dosage of ritonavir in children > 1 month is 350 to 400 mg/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/m2 and increased at 2 to 3 day intervals by 50 mg/m2 twice daily. If patients do not tolerate 400 mg/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.

Table 1. Pediatric Dosage Guidelines

Body Surface Area (m2)	Twice Daily Dose 250 mg/m2	Twice Daily Dose 300 mg/m2	Twice Daily Dose 350 mg/m2	Twice Daily Dose 400 mg/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:

Dosage Forms and Strengths

• Norvir Tablets

White film-coated ovaloid tablets debossed with the corporate Abbott "A" logo and the Abbo-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/mL).

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.


• Co-administration of NORVIR is contraindicated with the drugs listed in Table 2 because ritonavir mediated CYP3A inhibition can result in serious and/or life-threatening reactions. Voriconazole and St. John’s Wort are exceptions in that co-administration of NORVIR and voriconazole results in a significant decrease in plasma concentrations of voriconazole, and co-administration of NORVIR with St. John’s Wort may result in decreased ritonavir plasma concentrations.

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.
Antiarrhythmics	Amiodarone, flecainide, propafenone, quinidine	Potential for cardiac arrhythmias.
Antifungal	Voriconazole	Coadministration of voriconazole with ritonavir 400 mg every 12 hours significantly decreases voriconazole plasma concentrations and may lead to loss of antifungal response. Voriconazole is contraindicated with ritonavir doses of 400 mg every 12 hours or greater [see Drug Interactions (7.2)].
Ergot Derivatives	Dihydroergotamine, ergonovine, 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.
Neuroleptic	Pimozide	Potential for cardiac arrhythmias.
PDE5 enzyme inhibitor	Sildenafil* (Revatio®) only when used for the treatment of pulmonary arterial hypertension (PAH)	A safe and effective dose has not been established when used with ritonavir. There is an increased potential for sildenafil-associated adverse events, including visual abnormalities, hypotension, prolonged erection, and syncope [see Drug Interactions (7)].
Sedative/hypnotics	Oral midazolam, triazolam	Prolonged or increased sedation or respiratory depression [see Drug Interactions (7.2)].
*see Drug Interactions (7), Table 5 for coadministration of sildenafil in patients with erectile dysfunction. ** For additional information for these contraindicated drugs, see also Drug Interactions (7), Table 5.

Warnings and Precautions

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

Drug Interactions

NORVIR is a CYP3A inhibitor. Initiating treatment with NORVIR in patients receiving medications metabolized by CYP3A or initiating medications metabolized by CYP3A in patients already maintained on NORVIR may result in increased plasma concentrations of concomitant medications. Higher plasma concentrations of concomitant medications can result in increased or prolonged therapeutic or adverse effects, potentially leading to severe, life-threatening or fatal events. The potential for drug-drug interactions must be considered prior to and during therapy with NORVIR. Review of other medications taken by patients and monitoring of patients for adverse effects is recommended during therapy with NORVIR.

See Table 2 for a listing of drugs that are contraindicated with NORVIR due to potentially life-threatening adverse events, significant drug interactions, or loss of virologic activity. Also, see Table 5 for a listing of drugs with established and other significant drug interactions [see Contraindications (4) and Drug Interactions (7)].

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.

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 (5.8)]. 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.

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.

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 Clinical Pharmacology (12.3)].

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)].

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.

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.

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.

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.

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 Clinical Pharmacology (12.4)].

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. For comprehensive information concerning laboratory test alterations associated with reverse transcriptase inhibitors, physicians should refer to the complete product information for each of these drugs.

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 (5.2)]


• Pancreatitis [see Warnings and Precautions (5.3)]


• Allergic Reactions/Hypersensitivity [see Warnings and Precautions (5.4)]

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.

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

Adults — Clinical Trials Experience

The safety of NORVIR alone and in combination with nucleoside reverse transcriptase inhibitors was studied in 1270 adult patients. Table 3 lists treatment-emergent adverse events (at least possibly related and of at least moderate intensity) that occurred in 2% or greater of adult patients receiving NORVIR alone or in combination with nucleoside reverse transcriptase inhibitors in Study 245 or Study 247 and in combination with saquinavir in study 462. In that study, 141 protease inhibitor-naive, HIV-infected patients with mean baseline CD4 of 300 cells/μL were randomized to one of four regimens of NORVIR + saquinavir, including NORVIR 400 mg twice-daily + saquinavir 400 mg twice-daily. Overall the most frequently reported clinical adverse events, other than asthenia, among adult patients receiving NORVIR were gastrointestinal and neurological disturbances including nausea, diarrhea, vomiting, anorexia, abdominal pain, taste perversion, and circumoral and peripheral paresthesias. Similar adverse event profiles were reported in adult patients receiving ritonavir in other trials.

Table 3. Percentage of Patients with Treatment-emergent Adverse Events1 of Moderate or Severe Intensity Occurring in ≥ 2% of Adult Patients Receiving NORVIR

Adverse Events	Study 245 Naive Patients2			Study 247 Advanced Patients3		Study 462 PI-Naive Patients4
	NORVIR + ZDV n = 116	NORVIR n = 117	ZDV n = 119	NORVIR n = 541	Placebo n = 545	NORVIR + Saquinavir n= 141
Body as a Whole
Abdominal Pain	5.2	6.0	5.9	8.3	5.1	2.1
Asthenia	28.4	10.3	11.8	15.3	6.4	16.3
Fever	1.7	0.9	1.7	5.0	2.4	0.7
Headache	7.8	6.0	6.7	6.5	5.7	4.3
Malaise	5.2	1.7	3.4	0.7	0.2	2.8
Pain (unspecified)	0.9	1.7	0.8	2.2	1.8	4.3
Cardiovascular
Syncope	0.9	1.7	0.8	0.6	0.0	2.1
Vasodilation	3.4	1.7	0.8	1.7	0.0	3.5
Digestive
Anorexia	8.6	1.7	4.2	7.8	4.2	4.3
Constipation	3.4	0.0	0.8	0.2	0.4	1.4
Diarrhea	25.0	15.4	2.5	23.3	7.9	22.7
Dyspepsia	2.6	0.0	1.7	5.9	1.5	0.7
Fecal Incontinence	0.0	0.0	0.0	0.0	0.0	2.8
Flatulence	2.6	0.9	1.7	1.7	0.7	3.5
Local Throat Irritation	0.9	1.7	0.8	2.8	0.4	1.4
Nausea	46.6	25.6	26.1	29.8	8.4	18.4
Vomiting	23.3	13.7	12.6	17.4	4.4	7.1
Metabolic and Nutritional
Weight Loss	0.0	0.0	0.0	2.4	1.7	0.0
Musculoskeletal
Arthralgia	0.0	0.0	0.0	1.7	0.7	2.1
Myalgia	1.7	1.7	0.8	2.4	1.1	2.1
Nervous
Anxiety	0.9	0.0	0.8	1.7	0.9	2.1
Circumoral Paresthesia	5.2	3.4	0.0	6.7	0.4	6.4
Confusion	0.0	0.9	0.0	0.6	0.6	2.1
Depression	1.7	1.7	2.5	1.7	0.7	7.1
Dizziness	5.2	2.6	3.4	3.9	1.1	8.5
Insomnia	3.4	2.6	0.8	2.0	1.8	2.8
Paresthesia	5.2	2.6	0.0	3.0	0.4	2.1
Peripheral Paresthesia	0.0	6.0	0.8	5.0	1.1	5.7
Somnolence	2.6	2.6	0.0	2.4	0.2	0.0
Thinking Abnormal	2.6	0.0	0.8	0.9	0.4	0.7
Respiratory
Pharyngitis	0.9	2.6	0.0	0.4	0.4	1.4
Skin and Appendages
Rash	0.9	0.0	0.8	3.5	1.5	0.7
Sweating	3.4	2.6	1.7	1.7	1.1	2.8
Special Senses
Taste Perversion	17.2	11.1	8.4	7.0	2.2	5.0
Urogenital
Nocturia	0.0	0.0	0.0	0.2	0.0	2.8
1   Includes those adverse events at least possibly related to study drug or of unknown relationship and excludes concurrent HIV conditions. 2   The median duration of treatment for patients randomized to regimens containing NORVIR in Study 245 was 9.1 months. 3   The median duration of treatment for patients randomized to regimens containing NORVIR in Study 247 was 9.4 months. 4   The median duration of treatment for patients in Study 462 was 48 weeks.

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

Body as a Whole

Abdomen enlarged, accidental injury, allergic reaction, back pain, cachexia, chest pain, chills, facial edema, facial pain, flu syndrome, hormone level altered, hypothermia, kidney pain, neck pain, neck rigidity, pelvic pain, photosensitivity reaction, and substernal chest pain.

Cardiovascular System

Cardiovascular disorder, cerebral ischemia, cerebral venous thrombosis, hypertension, hypotension, migraine, myocardial infarct, palpitation, peripheral vascular disorder, phlebitis, postural hypotension, tachycardia and vasospasm.

Digestive System

Abnormal stools, bloody diarrhea, cheilitis, cholestatic jaundice, colitis, dry mouth, dysphagia, eructation, esophageal ulcer, esophagitis, gastritis, gastroenteritis, gastrointestinal disorder, gastrointestinal hemorrhage, gingivitis, hepatic coma, hepatitis, hepatomegaly, hepatosplenomegaly, ileus, liver damage, melena, mouth ulcer, pancreatitis, pseudomembranous colitis, rectal disorder, rectal hemorrhage, sialadenitis, stomatitis, tenesmus, thirst, tongue edema, and ulcerative colitis.

Endocrine System

Adrenal cortex insufficiency and diabetes mellitus.

Hemic and Lymphatic System

Acute myeloblastic leukemia, anemia, ecchymosis, leukopenia, lymphadenopathy, lymphocytosis, myeloproliferative disorder, and thrombocytopenia.

Metabolic and Nutritional Disorders

Albuminuria, alcohol intolerance, avitaminosis, BUN increased, dehydration, edema, enzymatic abnormality, glycosuria, gout, hypercholesteremia, peripheral edema, and xanthomatosis.

Musculoskeletal System

Arthritis, arthrosis, bone disorder, bone pain, extraocular palsy, joint disorder, leg cramps, muscle cramps, muscle weakness, myositis, and twitching.

Nervous System

Abnormal dreams, abnormal gait, agitation, amnesia, aphasia, ataxia, coma, convulsion, dementia, depersonalization, diplopia, emotional lability, euphoria, grand mal convulsion, hallucinations, hyperesthesia, hyperkinesia, hypesthesia, incoordination, libido decreased, manic reaction, nervousness, neuralgia, neuropathy, paralysis, peripheral neuropathic pain, peripheral neuropathy, peripheral sensory neuropathy, personality disorder, sleep disorder, speech disorder, stupor, subdural hematoma, tremor, urinary retention, vertigo, and vestibular disorder.

Respiratory System

Asthma, bronchitis, dyspnea, epistaxis, hiccup, hypoventilation, increased cough, interstitial pneumonia, larynx edema, lung disorder, rhinitis, and sinusitis.

Skin and Appendages

Acne, contact dermatitis, dry skin, eczema, erythema multiforme, exfoliative dermatitis, folliculitis, fungal dermatitis, furunculosis, maculopapular rash, molluscum contagiosum, onychomycosis, pruritus, psoriasis, pustular rash, seborrhea, skin discoloration, skin disorder, skin hypertrophy, skin melanoma, urticaria, and vesiculobullous rash.

Special Senses

Abnormal electro-oculogram, abnormal electroretinogram, abnormal vision, amblyopia/blurred vision, blepharitis, conjunctivitis, ear pain, eye disorder, eye pain, hearing impairment, increased cerumen, iritis, parosmia, photophobia, taste loss, tinnitus, uveitis, visual field defect, and vitreous disorder.

Urogenital System

Acute kidney failure, breast pain, cystitis, dysuria, hematuria, impotence, kidney calculus, kidney failure, kidney function abnormal, kidney pain, menorrhagia, penis disorder, polyuria, urethritis, urinary frequency, urinary tract infection, and vaginitis.

Laboratory Abnormalities

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 > 3% of Patients Receiving NORVIR

		Study 245 Naive Patients			Study 247 Advanced Patients		Study 462 PI-Naive Patients
Variable	Limit	NORVIR + ZDV	NORVIR	ZDV	NORVIR	Placebo	NORVIR + 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.

Pediatrics - Treatment-Emergent Adverse Events

NORVIR has been studied in 265 pediatric patients > 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 ≥ 2% of pediatric patients enrolled in NORVIR clinical trials.

Laboratory Abnormalities

The following Grade 3-4 laboratory abnormalities occurred in > 3% of pediatric patients who received treatment with NORVIR either alone or in combination with reverse transcriptase inhibitors: neutropenia (9%), hyperamylasemia (7%), thrombocytopenia (5%), anemia (4%), and elevated AST (3%).

Postmarketing Experience

The following adverse events (not previously mentioned in the labeling) have been reported during post-marketing use of NORVIR. Because these reactions are reported voluntarily from a population of unknown size, it is not possible to reliably estimate their frequency or establish a causal relationship to NORVIR exposure.

Body as a Whole

Dehydration, usually associated with gastrointestinal symptoms, and sometimes resulting in hypotension, 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 (5.5)].

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.

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.

Drug Interactions

See also Contraindications (4), Clinical Pharmacology (12.3)

When co-administering NORVIR with other protease inhibitors (amprenavir, atazanavir, darunavir, fosamprenavir, saquinavir, and tipranavir), see the full prescribing information for that protease inhibitor including important information for drug interactions.

Potential for NORVIR to Affect Other Drugs

Ritonavir has been found to be 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