Norvir 100 mg

Lopinavir/ritonavir has been shown to increase tenofovir concentrations. Higher tenofovir concentrations could potentiate tenofovir-associated adverse events, including renal disorders. Patients receiving ritonavir and tenofovir disoproxil fumarate should be monitored for tenofovir-associated adverse events. Refer to the VIREAD (tenofovir) Product Monograph for more information.

Based on results of a drug interaction study with ketoconazole, another potent inhibitor of CYP3A4, and alfuzosin, a significant increase in alfuzosin exposure is expected in the presence of ritonavir (600 mg twice daily). Therefore, alfuzosin should not be co-administered with ritonavir.

A literature report has shown that co-administration of ritonavir (300 mg every 12 hours) and digoxin resulted in significantly increased digoxin levels. Caution should be exercised when co-administrating ritonavir and digoxin, with appropriate monitoring of serum levels.

Agents which increase CYP3A activity (e.g., phenobarbital, carbamazepine, dexamethasone, phenytoin, rifampin, and rifabutin) would be expected to increase the clearance of ritonavir resulting in decreased ritonavir plasma concentrations. Tobacco use is associated with an 18% decrease in the AUC of ritonavir.

Ritonavir can produce large increases in plasma concentrations of certain highly metabolized drugs. Ritonavir has a high affinity for several cytochrome P450 (CYP) isoforms with the following rank order: CYP3A > CYP2D6 > CYP2C9, CYP2C19 >> CYP2A6, CYP1A2, CYP2E1. There is some evidence that ritonavir may increase the activity of glucuronosyltransferases; thus, loss of therapeutic effects from directly glucuronidated agents during ritonavir therapy may signify the need for dosage alteration of these agents.

A systematic review of over 200 medications prescribed to HIV-infected patients was performed to identify potential drug interactions with ritonavir. 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 and Precautions and Contraindications), 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 Drug Interactions, Table 7 (Predicted Drug Interactions: Use with Caution, Dose Decrease May Be Needed).

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 Drug Interactions, Table 7 [Predicted Drug Interactions: Use with Caution, Dose Increase May Be Needed]).

In healthy volunteers receiving 500 mg ritonavir twice daily with efavirenz 600 mg once daily, the steady state AUC was increased by 21%. An associated increase in the AUC of ritonavir of 17% was observed.

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

It is recommended that ritonavir be taken with meals, if possible. Refer to Action and Clinical Pharmacology, Absorption for information on the effect of food of ritonavir pharmacokinetics.

Established Drug Interactions: Alteration in Dose or Regimen Recommended Based on Drug Interaction Studies or Predicted Interaction (see Drug Interactions, Table 4 and Table 5 for Magnitude of Interaction)

Interactions with laboratory tests have not been established.

Literature reports have shown that concentrations of the HIV-protease inhibitor, amprenavir, are increased when co-administered with ritonavir.

Table 4 and Table 5 summarize the effects on AUC and C_max with 95% confidence intervals (95% CI) around the mean differences, of the co-administration of ritonavir with a variety of drugs. For information about clinical recommendations, see Drug Interactions, Table 6 and Table 7.

The recommended dosage of ritonavir is 600 mg (6 capsules or 7.5 mL) twice daily orally. Some patients experience nausea upon initiation of 600 mg twice daily dosing. 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 by 100 mg twice daily increments up to 600 mg twice daily. The titration period should not exceed 14 days.

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 ritonavir and other antiretroviral agents may improve gastrointestinal tolerance by initiating ritonavir alone and subsequently adding the other antiretroviral agents before completing two weeks of ritonavir monotherapy. The long-term effects of dose escalation on efficacy have not been established.

NORVIR (ritonavir oral solution) and NORVIR SEC (ritonavir soft elastic capsules) are administered orally. It is recommended that ritonavir be taken with meals if possible. Patients may improve the taste of ritonavir oral solution by mixing with chocolate milk or ENSURE within one hour of dosing. The effects of antacids on the absorption of ritonavir have not been studied.

The ritonavir solution dosage cup should be cleaned immediately with hot water and dish soap after use. When cleaned immediately, drug residue is removed. The dosage cup must be dry prior to use.

If a dose of ritonavir is missed, patients should take the dose as soon as possible and then return to their normal schedule. However, if a dose is skipped, the patient should not double the next dose.

Menorrhagia has been reported.

The following adverse events have been reported during post-marketing use of ritonavir. 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 ritonavir exposure.

Redistribution/accumulation of body fat has been reported (see Warnings and Precautions). 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.

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

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.

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

There have been post-marketing reports of seizure. Cause and effect relationship has not been established.

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.

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

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.

Myocardial infarction has 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.

Hyperglycemia has been reported in individuals with and without a known history of diabetes.

Cushing's syndrome and adrenal suppression have been reported when ritonavir has been co-administered with fluticasone propionate.

Percentage of Adult Patients, by Study and Treatment Group, with Chemistry and Hematology Abnormalities Occurring in ≥2% of Patients Receiving NORVIR

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.

Adverse events occurring in less than 2% of adult patients receiving ritonavir 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.

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

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

There have been reports of increased bleeding in patients with hemophilia A or B (see Warnings and Precautions, Hematologic).

Clinical studies of ritonavir did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, appropriate caution should be exercised in the administration and monitoring of ritonavir in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

The safety and effectiveness of ritonavir in pediatric patients below the age of 2 years have not been established. Although the database in HIV-infected patients age 2 to 16 years is much smaller, the adverse event profile seen during a clinical trial and post-marketing experience was similar to that observed for adult patients.

Human Overdose Experience: Human experience of acute overdose with NORVIR (ritonavir oral solution) and NORVIR SEC (ritonavir soft elastic capsules) is limited. One patient in clinical trials took ritonavir 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.

Administration of activated charcoal may be used to aid in removal of unabsorbed drug. Treatment of overdose with ritonavir 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 ritonavir. 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 Centre should be consulted for up-to-date information on the management of overdose with ritonavir.

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.

Each white, oblong, soft elastic capsule, imprinted with the Abbott logo, 100, and the Abbo-Code DS, contains: ritonavir 100 mg. Nonmedicinal ingredients: black opacode ink (iron oxide), butylated hydroxytoluene, ethanol, gelatin, glycerin, oleic acid, polyoxyl 35 castor oil, purified water, sorbitol and titanium dioxide. HDPE bottles of 120.

Each mL of orange-colored oral solution, in a peppermint and caramel-flavored vehicule, contains: ritonavir 80 mg. Nonmedicinal ingredients: anhydrous citric acid (to adjust pH), creamy caramel flavoring, ethanol, FD&C Yellow No. 6, peppermint oil, polyoxyl 35 castor oil, propylene glycol, saccharin sodium and water. Amber-colored, multidose bottles of 240 mL with marked dosage cup of 7.5 mL (600 mg/7.5 mL).

Saquinavir/ritonavir should not be given together with rifampin, due to the risk of severe hepatotoxicity (presenting as increased hepatic transaminases) if the three drugs are given together.

Co-administration of tipranavir with 200 mg ritonavir has been associated with reports of clinical hepatitis and hepatic decompensation including some fatalities (see Drug Interactions). Refer to the APTIVUS (tipranavir) Product Monograph for more information.

Extra vigilance is warranted in patients with chronic hepatitis B or hepatitis C co-infection, as these patients have an increased risk of hepatotoxicity.

Ritonavir is principally metabolized by the liver. Pre-clinical studies have identified the liver as a toxicity target. Therefore, appropriate tests should be performed at treatment initiation and at periodic intervals to assess hepatic function.

Caution should be exercised when administering ritonavir to patients with impaired hepatic function.

The safety and effectiveness of ritonavir in pediatric patients below the age of 2 years have not been established. Although the database in HIV-infected patients age 2 to 16 years is much smaller, the adverse event profile seen during a clinical trial and post-marketing experience was similar to that observed for adult patients.

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 ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects (see Drug Interactions).

Ritonavir has been shown to cause asymptomatic prolongation of the PR interval in some patients. Reports of second or third degree atrioventricular block in patients with underlying structural heart disease and preexisting conduction system abnormalities or in patients receiving drugs known to prolong the PR interval (such as verapamil or atazanavir) have been reported in patients receiving ritonavir. Ritonavir should be used with caution in such patients. (See Action and Clinical Pharmacology, Pharmacodynamics, Effects on the Electrocardiogram.)

Hepatic transaminase elevations exceeding 5 times the upper limit of normal, clinical hepatitis, and jaundice have occurred in patients receiving ritonavir alone or in combination with other antiretroviral drugs (see Adverse Reactions, Table 3). There may be an increased risk for transaminase elevations in patients with underlying hepatitis B or C. Therefore, caution should be exercised when administering ritonavir to patients with pre-existing liver disease, liver enzyme abnormalities, or hepatitis.

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

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.

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

There are 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.

In rat fertility studies, hepatic toxicity precluded drug exposures equal to those achieved with the proposed human therapeutic dose. No effects on fertility in rats were produced at drug exposures approximately 40% (male) and 60% (female) of that achieved with the proposed human therapeutic dose.

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.

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.

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 which 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.

Immune reconstitution syndrome has been reported in HIV-infected patients treated with combination antiretroviral therapy, including ritonavir. During the initial phase of treatment, patients responding to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as M. avium infection, cytomegalovirus, P. carinii pneumonia, or tuberculosis), which may necessitate further evaluation and treatment.

Clinical studies of ritonavir did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, appropriate caution should be exercised in the administration and monitoring of ritonavir in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis, in patients with Hemophilia Type A and Type 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 re-introduced. There is no proven relationship between protease inhibitors and such bleeding, however, the frequency of bleeding episodes should be closely monitored in patients on ritonavir.

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.

CNS penetration of ritonavir has not been established.

Co-administration of NORVIR (ritonavir oral solution) or NORVIR SEC (ritonavir soft elastic capsules) with certain nonsedating antihistamines, sedative hypnotics, or antiarrhythmics may result in potentially serious and/or life-threatening adverse events due to possible effects of ritonavir on the hepatic metabolism of certain drugs. See Contraindications and 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 Contraindications, Table 1 and Drug Interactions, Table 4, Table 5 and Table 6).

The magnitude of the interactions and therapeutic consequences between ritonavir and the drugs listed in Drug Interactions, Table 7 (Predicted Drug Interactions: Use with Caution) cannot be predicted with any certainty. When co-administering ritonavir with any agent listed in Table 7, special attention is warranted.

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

There have been post-marketing reports of drug interactions, including increased itraconazole levels, when ritonavir and itraconazole were co-administered.

Particular caution should be used when prescribing sildenafil or tadalafil in patients receiving ritonavir. Co-administration of ritonavir with these drugs is expected to substantially increase their concentrations and may result in increased associated adverse events, such as hypotension, syncope, visual changes, and prolonged erection. Vardenafil should not be administered with ritonavir. (See Drug Interactions, Table 6.)

Ritonavir has been associated with elevations in cholesterol, triglycerides, AST, ALT, GGT, CK, and uric acid. Appropriate laboratory testing should be performed prior to initiating ritonavir therapy and at periodic intervals or if any clinical signs or symptoms occur during therapy. For comprehensive information concerning laboratory test alterations associated with other antiretroviral agents, physicians should refer to the complete product information for each of these drugs.

Pancreatitis has been observed in patients receiving ritonavir 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 ritonavir therapy should be discontinued if a diagnosis of pancreatitis is made.

New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus and hyperglycemia have been reported during post-marketing 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 discontinue 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.

Toxicological studies in laboratory animals identified various organs as targets for toxicity at drug exposures below or approaching those achieved in patients participating in clinical trials with ritonavir. Because no safety margin or a small safety margin has been demonstrated in long-term studies, these organs should be assessed periodically or if clinical signs and symptoms occur during therapy.

Concomitant use of ritonavir with lovastatin and simvastatin is not recommended (see Contraindications). Caution should be exercised if HIV protease inhibitors, including ritonavir, are used concurrently with other HMG-CoA reductase inhibitors that are also metabolized by the CYP3A4 pathway (e.g., atorvastatin). While rosuvastatin elimination is not dependent on CYP3A, an elevation of rosuvastatin exposure has been reported with ritonavir coadministration. The risk of myopathy including rhabdomyolysis may be increased when HIV protease inhibitors, including ritonavir, are used in combination with these drugs.

Treatment with ritonavir therapy alone or in combination with saquinavir has resulted in substantial increases in the concentration of total triglycerides and cholesterol (see Adverse Reactions, Abnormal Hematologic and Clinical Chemistry Findings). Triglycerides and cholesterol testing should be performed prior to initiating ritonavir therapy and at periodic intervals during therapy. Lipid disorders should be managed as clinically appropriate.

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 or NORVIR SEC.

Store NORVIR (ritonavir oral solution) at room temperature, between 20 and 25°C. Do not refrigerate. Shake well before each use. Product must be stored and dispensed in the original container. Avoid exposure to excessive heat. Keep cap tightly closed. Use by product expiration date.

The ritonavir oral solution dosage cup should be cleaned immediately with hot water and dish soap after use. When cleaned immediately, drug residue is removed. The dosage cup must be dry prior to use.

Store NORVIR SEC (soft elastic capsules) in the refrigerator between 2 and 8°C until dispensed. Refrigeration of NORVIR SEC by the patient is recommended, but not required if used within 30 days and stored below 25°C. Protect from light. Avoid exposure to excessive heat. Product must be stored and dispensed in the original container.

The protein binding of ritonavir in human plasma was noted to be approximately 98 to 99%. Ritonavir binds to both human α-1-acid glycoprotein (AAG) and human serum albumin (HSA) with comparable affinities. Total plasma protein binding is constant over the concentration range of 1-100 µg/mL.

Tissue distribution studies with ¹⁴C-labeled ritonavir in rats showed the liver, adrenals, pancreas, kidneys and thyroid to have the highest concentrations of drug. Tissue to plasma ratios of approximately one, measured in rat lymph nodes, suggests that ritonavir distributes into lymphatic tissue. Ritonavir penetrates minimally into the brain.

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.

QTcF interval was evaluated in a randomized, placebo and active (moxifloxacin 400 mg once-daily) controlled cross-over study in 45 healthy adults, with 10 measurements over 12 hours on Day 3. The maximum mean (95% upper confidence bound) difference in QTcF from placebo was 5.5 (7.6) msec for 400 mg twice-daily ritonavir. The Day 3 ritonavir exposure was approximately 1.5 fold higher than that observed with the 600 mg twice-daily dose at steady state. No subject experienced an increase in QTcF of ≥60 msec from baseline or a QTcF interval exceeding the potentially clinically relevant threshold of 500 msec.

Mean change from baseline in PR interval of 11.0-24.0 msec was also noted in subjects receiving ritonavir in the same study on Day 3. Maximum PR interval was 252 msec and no second or third degree heart block was observed. (See Warnings and Precautions.)

Among protease inhibitors variable cross-resistance has been recognized (see Warnings and Precautions).

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.

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.

A study of ritonavir pharmacokinetics in healthy males and females showed no statistically significant differences in the pharmacokinetics of ritonavir.

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 isopropyl thiazole 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. 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.

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 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 capsule (n=21) and oral solution (n=18) formulations yielded mean±SD areas under the plasma concentration-time curve (AUCs) of 129.5±47.1 and 129.0±39.3 µg·h/mL, respectively. Relative to fasting conditions, the extent of absorption of ritonavir from the capsule formulation was 15% higher when administered with a meal (771 KCal; 46% fat, 18% protein, and 37% carbohydrate).

In vitro data indicate that ritonavir is active against all strains of HIV tested in a variety of transformed and primary human cell lines. The concentration of drug that inhibits 50% and 90% (EC₅₀, EC₉₀) of viral replication is approximately 0.02 and 0.11 µM, respectively. Studies which measured direct cell toxicity of ritonavir on several cell lines showed no direct toxicity at concentrations up to 25 µM, with a resulting in vitro therapeutic index of at least 1000.

The pharmacokinetic profile of ritonavir in pediatric patients below the age of 2 years has not been established. 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. Across dose groups, ritonavir steady-state oral clearance (CL/F/m²) was approximately 1.5 times faster in pediatric patients than in adult subjects. Ritonavir concentrations obtained after 350 to 400 mg/m² twice daily in pediatric patients were comparable to those obtained in adults receiving 600 mg (approximately 330 mg/m²) twice daily.

HIV-1 isolates with reduced susceptibility to ritonavir have been selected in vitro. The clinical relevance of phenotypic and genotypic changes associated with ritonavir therapy has not been established (see Warnings and Precautions).

In six HIV-infected adult subjects with mild hepatic insufficiency dosed with ritonavir 400 mg twice daily, ritonavir exposures were similar to control subjects dosed with 500 mg twice daily. Results indicate that dose adjustment is not required in patients with mild hepatic impairment. Adequate pharmacokinetic data are not available for patients with moderate hepatic impairment. Protein binding of ritonavir was not statistically significantly affected by mild or moderately impaired hepatic function.

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

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

Ritonavir is an orally active 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 the production of HIV particles with immature morphology that are unable to initiate new rounds of infection. Ritonavir has selective affinity for the HIV protease and has little inhibitory activity against human aspartyl proteases.

Pharmacokinetic differences due to race have not been identified.

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.

Because ritonavir is highly protein bound it is unlikely that ritonavir will be significantly removed by dialysis (see Overdosage).

Ritonavir pharmacokinetic parameters were not statistically significantly associated with body weight or lean body mass.

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.