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:

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 soft gelatin capsules are available for oral administration in a strength of 100 mg ritonavir with the following inactive ingredients: Butylated hydroxytoluene, ethanol, gelatin, iron oxide, oleic acid, polyoxyl 35 castor oil, and titanium dioxide.

NORVIR oral solution is available for oral administration as 80 mg/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.

NORVIR is indicated in combination with other antiretroviral agents for the treatment of HIV-infection. This indication is based on the results from a study in patients with advanced HIV disease that showed a reduction in both mortality and AIDS-defining clinical events for patients who received NORVIR either alone or in combination with nucleoside analogues. Median duration of follow-up in this study was 13.5 months.

NORVIR is administered orally. It is recommended that NORVIR be taken with meals if possible. Patients may improve the taste of NORVIR oral solution by mixing with chocolate milk, Ensure®, or Advera® within one hour of dosing. The effects of antacids on the absorption of ritonavir have not been studied.

Adults

Recommended Dosage: The recommended dosage of ritonavir is 600 mg twice daily by mouth. 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.

Pediatric Patients

Ritonavir should be used in combination with other antiretroviral agents (see General Dosing Guidelines). The recommended dosage of ritonavir in children > 1 month is 350 to 400 mg/m² twice daily by mouth 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.

Pediatric Dosage Guidelines¹

General Dosing Guidelines

Patients should be aware that frequently observed adverse events, such as mild to moderate gastrointestinal disturbances and paraesthesias, may diminish as therapy is continued. In addition, patients initiating combination regimens with NORVIR and reverse transcriptase inhibitors may improve gastrointestinal tolerance by initiating NORVIR alone and subsequently adding reverse transcriptase inhibitors before completing two weeks of NORVIR monotherapy.

NORVIR (ritonavir capsules) soft gelatin are white capsules imprinted with the corporate logo a, 100 and the Abbo-Code DS, available in the following package size:

Bottles of 120 capsules each................................... (NDC 0074-6633-22).
Bottles of 30 capsules each..................................... (NDC 0074-6633-30).

Recommended Storage: Store soft gelatin capsules in the refrigerator between 36-46°F (2-8°C) until dispensed. Refrigeration of NORVIR soft gelatin capsules by the patient is recommended, but not required if used within 30 days and stored below 77°F (25°C). Protect from light. Avoid exposure to excessive heat.

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/mL) in the following size:

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

Recommended Storage: Store NORVIR oral solution at room temperature 68°F to 77°F (20°C to 25°C). 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.

REFERENCES

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

2. Bertz RJ and Granneman GR. Use of in vitro and in vivo data to estimate the likelihood of metabolic pharmacokinetic interactions. Clin Pharmacokinet 1997; 32(3):210-258. (Nos. 1940 and 6633)

Rev. May, 2007. Abbott Laboratories North Chicago, IL 60064, U.S.A. FDA rev date: 5/16/2008

Adults

The safety of NORVIR alone and in combination with nucleoside reverse transcriptase inhibitors was studied in 1270 adult patients. Table 7 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 inhibitornaive, 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 7: Percentage of Patients with Treatment-emergent Adverse Events¹ of Moderate or Severe Intensity Occurring in ≥ 2% of Adult Patients Receiving NORVIR

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.

Post-Marketing Experience: The following adverse events have been reported during post-marketing use of NORVIR. Because these reactions are reported voluntarily from a population of unknown size, it is not possible to reliably estimate their frequency or establish a causal relationship to NORVIR exposure.

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. Redistribution/accumulation of body fat has been reported (see PRECAUTIONS-Fat Redistribution).

Cardiovascular System: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.

Hemic and Lymphatic System: There have been reports of increased bleeding in patients with hemophilia A or B (see PRECAUTIONS-Hemophilia).

Nervous System:There have been postmarketing reports of seizure. Also, see Cardiovascular System.

Laboratory Abnormalities

Table 8 shows the percentage of adult patients who developed marked laboratory abnormalities.

Table 8: Percentage of Adult Patients, by Study and Treatment Group, with Chemistry and Hematology Abnormalities Occurring in > 3% of Patients Receiving NORVIR

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%).

Ritonavir has been found to be an inhibitor of cytochrome P450 3A (CYP3A) both in vitro and in vivo(Table 3). Agents that are extensively metabolized by CYP3A and have high first pass metabolism appear to be the most susceptible to large increases in AUC ( > 3-fold) when co-administered with ritonavir. 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 as well as other enzymes, including glucuronosyl transferase, CYP1A2, and possibly CYP2C9.

Drugs that are contraindicated specifically due to the expected magnitude of interaction and potential for serious adverse events are listed both in CONTRAINDICATIONS: Table 4 and under Drugs That Should Not Be Co-administered with NORVIR in Table 5.

Those drug interactions that have been established based on drug interaction studies are listed with the pharmacokinetic results in CLINICAL PHARMACOLOGY:Table 2 and Table 3. The clinical recommendations based on the results of these studies are listed in Table 6. Established and Other Potentially Significant Drug Interactions.

A systematic review of over 200 medications prescribed to HIV-infected patients was performed to identify potential drug interactions with ritonavir.2 There are a number of agents in which CYP3A or CYP2D6 partially contribute to the metabolism of the agent. In these cases, the magnitude of the interaction and therapeutic consequences cannot be predicted with any certainty.

When co-administering ritonavir with calcium channel blockers, immunosuppressants, some HMG-CoA reductase inhibitors (see WARNINGS, Drug Interactions), some steroids, or other substrates of CYP3A; or most antidepressants, certain antiarrhythmics, and some narcotic analgesics which are partially mediated by CYP2D6 metabolism, it is possible that substantial increases in concentrations of these other agents may occur, possibly requiring a dosage reduction ( > 50%); examples are listed in Table 6. Established and Other Potentially Significant Drug Interactions.

When co-administering ritonavir with any agent having a narrow therapeutic margin, such as anticoagulants, anticonvulsants, and antiarrhythmics, special attention is warranted. With some agents, the metabolism may be induced, resulting in decreased concentrations (see Table 6. Established and Other Potentially Significant Drug Interactions).

Table 5: Drugs that Should Not be Co-administered with NORVIR

Table 6: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen Recommended Based on Drug Interaction Studies or Predicted Interaction (see CLINICAL PHARMACOLOGY: Table 2 and Table 3 for Magnitude of Interaction)

ALERT: Find out about medicines that should NOT be taken with NORVIR. This statement is included on the product's bottle label.

Drug Interactions

Ritonavir is an inhibitor of cytochrome P450 3A (CYP3A) both in vitro and in vivo. Ritonavir also inhibits CYP2D6 in vitro, but to a lesser extent than CYP3A. Co-administration of ritonavir and drugs primarily metabolized by CYP3A or CYP2D6 may result in increased plasma concentrations of other drugs that could increase or prolong its therapeutic and adverse effects (see Pharmacokinetics: Drug-Drug Interactions:, CONTRAINDICATIONS - Table 4: Drugs that are Contraindicated with NORVIR, PRECAUTIONS - Table 5: Drugs That Should Not be Co-Administered with NORVIR, Table 6: Established and Other Potentially Significant DRUG INTERACTIONS).

The magnitude of the interactions and therapeutic consequences between ritonavir and some of the drugs listed in Table 6: Established and Other Potentially Significant Drug Interactions cannot be predicted with any certainty. When co-administering ritonavir with any agent listed in this table special attention is warranted. Refer to PRECAUTIONS: DRUG INTERACTIONS for additional information.

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

Particular caution should be used when prescribing PDE5 inhibitors for erectile dysfunction (eg, sildenafil, tadalafil, or vardenafil) for patients receiving protease inhibitors, including NORVIR. Co-administration of NORVIR with a PDE5 inhibitor is expected to substantially increase PDE5 inhibitor concentrations and may result in an increase in sildenafil-associated adverse events, including hypotension, syncope, visual changes, and prolonged erection (see PRECAUTIONS, Table 6. Established and Other Potentially Significant DRUG INTERACTIONS and the complete prescribing information for sildenafil, tadalafil and vardenafil).

Concomitant use of NORVIR with lovastatin or simvastatin is not recommended. Caution should be exercised if HIV protease inhibitors, including NORVIR, are used concurrently with other HMG-CoA reductase inhibitors that are also metabolized by the CYP3A4 pathway (e.g., atorvastatin or cerivastatin). The risk of myopathy including rhabdomyolysis may be increased when HIV protease inhibitors, including NORVIR, are used in combination with these drugs.

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

A drug interaction study in healthy subjects has shown that ritonavir significantly increases plasma fluticasone propionate exposures, resulting in significantly decreased serum cortisol concentrations. Systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression have been reported during postmarketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Therefore, co-administration of fluticasone propionate and NORVIR is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects (see PRECAUTIONS: DRUG INTERACTIONS).

Tipranavir co-administered with 200 mg of ritonavir has been associated with reports of clinical hepatitis and hepatic decompensation including some fatalities. Extra vigilance is warranted in patients with chronic hepatitis B or hepatitis C co-infection, as these patients have an increased risk of hepatotoxicity.

Allergic Reactions

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

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 8). 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.

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.

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.

General

Ritonavir is principally metabolized by the liver. Therefore, caution should be exercised when administering this drug to patients with impaired hepatic function (see WARNINGS and CLINICAL PHARMACOLOGY: Hepatic Insufficiency).

Resistance/Cross-resistance

Varying degrees of cross-resistance among protease inhibitors have been observed. Continued administration of ritonavir therapy following loss of viral suppression may increase the likelihood of cross-resistance to other protease inhibitors (see Microbiology).

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 has not been established.

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.

Lipid Disorders

Treatment with NORVIR therapy alone or in combination with saquinavir has resulted in substantial increases in the concentration of total triglycerides and cholesterol. 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. See PRECAUTIONS: Table 5 and Table 6 for additional information on potential drug interactions with NORVIR and HMG CoA reductase inhibitors.

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.

Information For Patients

A statement to patients and health care providers is included on the product's bottle label: ALERT: Find out about medicines that should NOT be taken with NORVIR. A Patient Package Insert (PPI) for Norvir is available for patient information.

Patients should be informed that NORVIR is not a cure for HIV infection and that they may continue to acquire illnesses associated with advanced HIV infection, including opportunistic infections.

Patients should be told that the long-term effects of NORVIR are unknown at this time. They should be informed that NORVIR therapy has not been shown to reduce the risk of transmitting HIV to others through sexual contact or blood contamination.

Patients should be advised to take NORVIR with food, if possible.

Patients should be informed to take NORVIR every day as prescribed. Patients should not alter the dose or discontinue NORVIR without consulting their doctor. If a dose is missed, patients should take the next dose as soon as possible. However, if a dose is skipped, the patient should not double the next dose.

Patients should be informed that 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.

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.

Patients receiving PDE5 inhibitors for erectile dysfunction (eg, sildenafil, tadalafil, or vardenafil) should be advised that they may be at an increased risk of associated adverse events including hypotension, visual changes, and sustained erection, and should promptly report any symptoms to their doctor.

Patients receiving estrogen-based hormonal contraceptives should be instructed that additional or alternate contraceptive measures should be used during therapy with NORVIR.

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.

Carcinogenesis and Mutagenesis

Carcinogenicity studies in mice and rats have been carried out on ritonavir. In male mice, at levels of 50, 100 or 200 mg/kg/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/kg/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. However, ritonavir was found to be negative for mutagenic or clastogenic activity in a battery of 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.

Pregnancy, Fertility, and Reproduction

Pregnancy Category B

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.

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

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

There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

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

Nursing Mothers

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

Pediatric Use

In HIV-infected patients age > 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.

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.

Acute Overdosage

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

Management of Overdosage

NORVIR oral solution contains 43% alcohol by volume. Accidental ingestion of the product by a young child could result in significant alcohol-related toxicity and could approach the potential lethal dose of alcohol.

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 emesis or 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. A Certified Poison Control Center should be consulted for up-to-date information on the management of overdose with NORVIR.

NORVIR is contraindicated in patients with known hypersensitivity to ritonavir or any of its ingredients.

Co-administration of NORVIR is contraindicated with the drugs listed in Table 4 (also see PRECAUTIONS: Table 5: Drugs that Should Not be Co-Administered with NORVIR) because competition for primarily CYP3A by ritonavir could result in inhibition of the metabolism of these drugs and create the potential for serious and/or life-threatening reactions such as cardiac arrhythmias, prolonged or increased sedation, and respiratory depression. Voriconazole is an exception in that co-administration of Norvir and Voriconazole results in a significant decrease in plasma concentrations of Voriconazole.

Table 4: Drugs that are Contraindicated with NORVIR

Microbiology

Mechanism of action

Ritonavir is a peptidomimetic inhibitor of both the HIV-1 and HIV-2 proteases. Inhibition of HIV protease renders the enzyme incapable of processing the gag-pol polyprotein precursor which leads to production of non-infectious immature HIV particles.

Antiviral activity in vitro

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

Resistance

HIV-1 isolates with reduced susceptibility to ritonavir have been selected in vitro. Genotypic analysis of these isolates showed mutations in the HIV protease gene at amino acid positions 84 (Ile to Val), 82 (Val to Phe), 71 (Ala to Val), and 46 (Met to Ile). Phenotypic (n=18) and genotypic (n=44) changes in HIV isolates from selected patients treated with ritonavir were monitored in phase I/II trials over a period of 3 to 32 weeks. Mutations associated with the HIV viral protease in isolates obtained from 41 patients appeared to occur in a stepwise and ordered fashion; in sequence, these mutations were position 82 (Val to Ala/Phe), 54 (Ile to Val), 71 (Ala to Val/Thr), and 36 (Ile to Leu), followed by combinations of mutations at an additional 5 specific amino acid positions. Of 18 patients for whom both phenotypic and genotypic analysis were performed on free virus isolated from plasma, 12 showed reduced susceptibility to ritonavir in vitro. All 18 patients possessed one or more mutations in the viral protease gene. The 82 mutation appeared to be necessary but not sufficient to confer phenotypic resistance. Phenotypic resistance was defined as a ≥ 5-fold decrease in viral sensitivity in vitro from baseline. The clinical relevance of phenotypic and genotypic changes associated with ritonavir therapy has not been established.

Cross-resistance to other antiretrovirals

Among protease inhibitors variable cross-resistance has been recognized. Serial HIV isolates obtained from six patients during ritonavir therapy showed a decrease in ritonavir susceptibility in vitro but did not demonstrate a concordant decrease in susceptibility to saquinavir in vitro when compared to matched baseline isolates. However, isolates from two of these patients demonstrated decreased susceptibility to indinavir in vitro (8-fold). Isolates from 5 patients were also tested for cross-resistance to amprenavir and nelfinavir; isolates from 2 patients had a decrease in susceptibility to nelfinavir (12- 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 isolate tested in vitro retained full susceptibility to ritonavir.

Pharmacokinetics

The pharmacokinetics of ritonavir have been studied in healthy volunteers and HIV-infected patients (CD₄ ≥ 50 cells/µL).

See Table 1 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.

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. After a single 600 mg dose under non-fasting conditions, in two separate studies, the soft gelatin capsule (n=57) and oral solution (n=18) formulations yielded mean ± SD areas under the plasma concentration-time curve (AUCs) of 121.7 ± 53.8 and 129.0 ± 39.3 µg•h/mL, respectively. Relative to fasting conditions, the extent of absorption of ritonavir from the soft gelatin capsule formulation was 13% higher when administered with a meal (615 KCal; 14.5% fat, 9% protein, and 76% carbohydrate).

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 1: Ritonavir Pharmacokinetic Characteristics

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/m² twice-daily to 400 mg/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/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/m² twice-daily in pediatric patients > 2 years were comparable to those obtained in adults receiving 600 mg (approximately 330 mg/m²) twice-daily. The following observations were seen regarding ritonavir concentrations after administration with 350 or 450 mg/m² twice-daily in children < 2 years of age. Higher ritonavir exposures were not evident with 450 mg/m² twice-daily compared to the 350 mg/m² twice-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/m² twice-daily in children < 2 years were approximately 16% and 60% lower, respectively, than that obtained in adults receiving 600 mg twice-daily.

Renal Insufficiency

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

Hepatic Insufficiency

Dose-normalized steady-state ritonavir concentrations in subjects with mild hepatic insufficiency (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.

Drug-Drug Interactions

See also CONTRAINDICATIONS, WARNINGS and PRECAUTIONS: DRUG INTERACTIONS.

Table 2 and Table 3 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 PRECAUTIONS: DRUG INTERACTIONS.

Table 2: Drug Interactions Pharmacokinetic Parameters for Ritonavir in the Presence of the Co-administered Drug (See PRECAUTIONS: Table 6 for Recommended Alterations in Dose or Regimen)

Table 3: Drug Interactions Pharmacokinetic Parameters for Co-administered Drug in the Presence of NORVIR (See PRECAUTIONS: Table 6 for Recommended Alterations in Dose or Regimen)