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. A

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) ] .

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

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 (C) 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]..

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.

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/m twice daily by mouth to be taken with meals and should not exceed 600 mg twice daily. Ritonavir should be started at 250 mg/m and increased at 2 to 3 day intervals by 50 mg/m twice daily. If patients do not tolerate 400 mg/m 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.

White film-coated ovaloid tablets debossed with the corporate Abbott "A" logo and the Abbo-Code NK providing 100 mg ritonavir.

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

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

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 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 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 eva luated and NORVIR therapy should be discontinued if a diagnosis of pancreatitis is made.

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

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 eva luated. 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)].

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)].

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 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 eva luation and treatment.

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.

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.

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)].

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.

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

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.

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 CD 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.

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.

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

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.

Adrenal cortex insufficiency and diabetes mellitus.

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

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

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

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.

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

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.

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.

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.

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

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.

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%).

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.

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.

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)].

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Manufacturer

Abbott Laboratories

Active Ingredients

Source

• U.S. National Library of Medicine
• DailyMed
•  Last Updated: 2nd of March 2011