Norvir Tablets

Name: Norvir Tablets

Norvir Tablets Dosage and Administration

General Dosing and Administration Recommendations

  • NORVIR must be used in combination with other antiretroviral agents.
  • NORVIR is administered orally. Norvir Tablets should be swallowed whole, and not chewed, broken or crushed. Take NORVIR with meals.
  • Patients may improve the taste of NORVIR oral solution by mixing with chocolate milk, Ensure®, or Advera® within one hour of dosing.
  • NORVIR oral powder should be mixed with soft food such as apple sauce or vanilla pudding, or mixed with liquid such as water, chocolate milk, or infant formula [see Dosage and Administration (2.4) and Instructions for Use]. The bitter aftertaste of NORVIR oral powder may be lessened if administered with food.

Because NORVIR oral solution contains ethanol, it is not recommended for use with polyurethane feeding tubes due to potential incompatibility.

General Dosing Guidelines

Patients who take the 600 mg twice daily soft gel capsule NORVIR dose may experience more gastrointestinal side effects such as nausea, vomiting, abdominal pain or diarrhea when switching from the soft gel capsule to the tablet formulation because of greater maximum plasma concentration (Cmax) achieved with the tablet formulation relative to the soft gel capsule [see Clinical Pharmacology (12.3)]. Patients should also be aware that these adverse events (gastrointestinal or paresthesias) may diminish as therapy is continued.

Recommended Adult Dosage

Recommended Dosage for Treatment of HIV-1:

The recommended dosage of NORVIR is 600 mg twice daily by mouth to be taken with meals. Use of a dose titration schedule may help to reduce treatment-emergent adverse events while maintaining appropriate ritonavir plasma levels. NORVIR should be started at no less than 300 mg twice daily and increased at 2 to 3 day intervals by 100 mg twice daily. The maximum dose of 600 mg twice daily should not be exceeded upon completion of the titration.

Pregnant Women

NORVIR oral solution is not recommended during pregnancy due to its ethanol content. NORVIR oral solution contains the excipients ethanol (approx. 43% v/v) and propylene glycol (approx. 27% w/v) [see Use in Specific Populations (8.1)].

Recommended Pediatric Dosage

NORVIR must be used in combination with other antiretroviral agents [see Dosage and Administration (2)]. The recommended dosage of NORVIR in pediatric patients older than 1 month is 350 to 400 mg per m2 twice daily by mouth to be taken with meals and should not exceed 600 mg twice daily. NORVIR should be started at 250 mg per m2 twice daily and increased at 2 to 3 day intervals by 50 mg per m2 twice daily. If patients do not tolerate 400 mg per 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.

Pediatric Dosage Guidelines for Oral Solution

NORVIR oral solution should not be administered to neonates before a postmenstrual age (first day of the mother’s last menstrual period to birth plus the time elapsed after birth) of 44 weeks has been attained [see Warnings and Precautions (5.2)].

NORVIR oral solution contains the excipients ethanol (approx. 43% v/v) and propylene glycol (approx. 27% w/v). Special attention should be given to accurate calculation of the dose of NORVIR, transcription of the medication order, dispensing information and dosing instructions to minimize the risk for medication errors, and overdose. This is especially important for young children. Total amounts of ethanol and propylene glycol from all medicines that are to be given to pediatric patients 1 to 6 months of age should be taken into account in order to avoid toxicity from these excipients [see Warnings and Precautions (5.2) and Overdosage (10)]. When possible, dose should be administered using a calibrated dosing syringe.

Table 1. Pediatric Dosage Guidelines for Oral Solution*
Body Surface Area (m2) Twice Daily Dose
250 mg per m2
Twice Daily Dose
300 mg per m2
Twice Daily Dose
350 mg per m2
Twice Daily Dose
400 mg per m2
0.20 0.6 mL (50 mg) 0.75 mL (60 mg) 0.9 mL (70 mg) 1.0 mL (80 mg)
0.25 0.8 mL (62.5 mg) 0.9 mL (75 mg) 1.1 mL (87.5 mg) 1.25 mL (100 mg)
0.50 1.6 mL (125 mg) 1.9 mL (150 mg) 2.2 mL (175 mg) 2.5 mL (200 mg)
0.75 2.3 mL (187.5 mg) 2.8 mL (225 mg) 3.3 mL (262.5 mg) 3.75 mL (300 mg)
1.00 3.1 mL (250 mg) 3.75 mL (300 mg) 4.4 mL (350 mg) 5 mL (400 mg)
1.25 3.9 mL (312.5 mg) 4.7 mL (375 mg) 5.5 mL (437.5 mg) 6.25 mL (500 mg)
1.50 4.7 mL (375 mg) 5.6 mL (450 mg) 6.6 mL (525 mg) 7.5 mL (600 mg)
*The concentration of the oral solution is 80 mg per mL.

Body surface area (BSA) can be calculated as follows1:

Pediatric Dosage Guidelines for Oral Powder

NORVIR oral powder should be used only for dosing increments of 100 mg. NORVIR powder should not be used for doses less than 100 mg or for incremental doses between 100 mg intervals. NORVIR oral solution is the preferred formulation for patients requiring doses less than 100 mg or incremental doses between 100 mg intervals.

When NORVIR oral powder is used with other protease inhibitors (e.g. atazanavir, darunavir, fosamprenavir, or tipranavir), prescribers should consult the full prescribing information and clinical study information of these protease inhibitors [see Warnings and Precautions (5.1), and Drug Interactions (7)]. When NORVIR oral powder is used as the sole protease inhibitor in a regimen, refer to Table 1 for dosing recommendations.

Preparation of Norvir Oral Powder

For details on the preparation and administration of NORVIR oral powder (see Instructions for Use). NORVIR oral powder should only be used for dosing increments of 100 mg.

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

The prescribed dose of NORVIR oral powder can be administered via a feeding tube after being mixed with water (see Instructions for Use). Follow the instructions for the feeding tube to administer the medicine.

Dose Modification due to Drug Interaction

Dose reduction of NORVIR is necessary when used with other protease inhibitors: atazanavir, darunavir, fosamprenavir, saquinavir, and tipranavir.

Prescribers should consult the full prescribing information and clinical study information of these protease inhibitors if they are co-administered with a reduced dose of ritonavir [see Warnings and Precautions (5.1), and Drug Interactions (7)].

Warnings and Precautions

Risk of Serious Adverse Reactions Due to Drug Interactions

Initiation of NORVIR, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving NORVIR, may increase plasma concentrations of medications metabolized by CYP3A. Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of NORVIR, respectively. These interactions may lead to:

  • Clinically significant adverse reactions, potentially leading to severe, life-threatening, or fatal events from greater exposures of concomitant medications.
  • Clinically significant adverse reactions from greater exposures of NORVIR.
  • Loss of therapeutic effect of NORVIR and possible development of resistance.

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

See Table 5 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations [see Drug Interactions (7)]. Consider the potential for drug interactions prior to and during NORVIR therapy; review concomitant medications during NORVIR therapy, and monitor for the adverse reactions associated with the concomitant medications [see Contraindications (4) and Drug Interactions (7)].

Toxicity in Preterm Neonates

NORVIR oral solution contains the excipients ethanol (approx. 43% v/v) and propylene glycol (approx. 27% w/v) . When administered concomitantly with propylene glycol, ethanol competitively inhibits the metabolism of propylene glycol, which may lead to elevated concentrations. Preterm neonates may be at an increased risk of propylene glycol-associated adverse events due to diminished ability to metabolize propylene glycol, thereby leading to accumulation and potential adverse events. Postmarketing life-threatening cases of cardiac toxicity (including complete AV block, bradycardia, and cardiomyopathy), lactic acidosis, acute renal failure, CNS depression and respiratory complications leading to death have been reported, predominantly in preterm neonates receiving lopinavir/ritonavir oral solution which also contains the excipients ethanol and propylene glycol.

NORVIR oral solution should not be used in preterm neonates in the immediate postnatal period because of possible toxicities. However, if the benefit of using NORVIR oral solution to treat HIV infection in infants immediately after birth outweighs the potential risks, infants should be monitored closely for increases in serum osmolality and serum creatinine, and for toxicity related to NORVIR oral solution including: hyperosmolality, with or without lactic acidosis, renal toxicity, CNS depression (including stupor, coma, and apnea), seizures, hypotonia, cardiac arrhythmias and ECG changes, and hemolysis. Total amounts of ethanol and propylene glycol from all medicines that are to be given to infants should be taken into account in order to avoid toxicity from these excipients [see Dosage and Administration (2.2) and Overdosage (10)].

Hepatotoxicity

Hepatic transaminase elevations exceeding 5 times the upper limit of normal, clinical hepatitis, and jaundice have occurred in patients receiving NORVIR alone or in combination with other antiretroviral drugs (see Table 4). There may be an increased risk for transaminase elevations in patients with underlying hepatitis B or C. Therefore, caution should be exercised when administering NORVIR to patients with pre-existing liver diseases, liver enzyme abnormalities, or hepatitis. Increased AST/ALT monitoring should be considered in these patients, especially during the first three months of NORVIR treatment [see Use in Specific Populations (8.6)].

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

Pancreatitis

Pancreatitis has been observed in patients receiving NORVIR therapy, including those who developed hypertriglyceridemia. In some cases fatalities have been observed. Patients with advanced HIV disease may be at increased risk of elevated triglycerides and pancreatitis [see Warnings and Precautions (5.7)]. Pancreatitis should be considered if clinical symptoms (nausea, vomiting, abdominal pain) or abnormalities in laboratory values (such as increased serum lipase or amylase values) suggestive of pancreatitis should occur. Patients who exhibit these signs or symptoms should be evaluated and NORVIR therapy should be discontinued if a diagnosis of pancreatitis is made.

Allergic Reactions/Hypersensitivity

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

PR Interval Prolongation

Ritonavir prolongs the PR interval in some patients. Post marketing cases of second or third degree atrioventricular block have been reported in patients.

NORVIR should be used with caution in patients with underlying structural heart disease, preexisting conduction system abnormalities, ischemic heart disease, cardiomyopathies, as these patients may be at increased risk for developing cardiac conduction abnormalities.

The impact on the PR interval of co-administration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers, beta-adrenergic blockers, digoxin and atazanavir) has not been evaluated. As a result, co-administration of ritonavir with these drugs should be undertaken with caution, particularly with those drugs metabolized by CYP3A. Clinical monitoring is recommended [see Drug Interactions (7) and Clinical Pharmacology (12.3)].

Lipid Disorders

Treatment with NORVIR therapy alone or in combination with saquinavir has resulted in substantial increases in the concentration of total cholesterol and triglycerides [see Adverse Reactions (6.1)]. Triglyceride and cholesterol testing should be performed prior to initiating NORVIR therapy and at periodic intervals during therapy. Lipid disorders should be managed as clinically appropriate, taking into account any potential drug-drug interactions with NORVIR and HMG CoA reductase inhibitors [see Contraindications (4)and Drug Interactions (7)].

Diabetes Mellitus/Hyperglycemia

New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in HIV-infected patients receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease inhibitor therapy and these events has not been established.Consider monitoring for hyperglycemia, new onset diabetes mellitus, or an exacerbation of diabetes mellitus in patients treated with NORVIR.

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in HIV-infected patients treated with combination antiretroviral therapy, including NORVIR. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia, or tuberculosis), which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment.

Fat Redistribution

Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

Patients with Hemophilia

There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis, in patients with hemophilia type A and B treated with protease inhibitors. In some patients additional factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced. A causal relationship between protease inhibitor therapy and these events has not been established.

Resistance/Cross-resistance

Varying degrees of cross-resistance among protease inhibitors have been observed. Continued administration of ritonavir 600 mg twice daily following loss of viral suppression may increase the likelihood of cross-resistance to other protease inhibitors [see Microbiology (12.4)].

Laboratory Tests

Ritonavir has been shown to increase triglycerides, cholesterol, SGOT (AST), SGPT (ALT), GGT, CPK, and uric acid. Appropriate laboratory testing should be performed prior to initiating NORVIR therapy and at periodic intervals or if any clinical signs or symptoms occur during therapy.

Overdosage

Acute Overdosage - Human Overdose Experience

Human experience of acute overdose with NORVIR is limited. One patient in clinical trials took NORVIR 1500 mg per 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 approx. 43% ethanol (v/v) and approx. 27% (w/v) propylene glycol. Ingestion of the product over the recommended dose by a young child could result in significant toxicity and could potentially be lethal.

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 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. However, dialysis can remove both ethanol and propylene glycol in the case of overdose with ritonavir oral solution. A Certified Poison Control Center should be consulted for up-to-date information on the management of overdose with NORVIR.

Clinical Studies

The activity of NORVIR as monotherapy or in combination with nucleoside reverse transcriptase inhibitors has been evaluated in 1446 patients enrolled in two double-blind, randomized trials.

Advanced Patients with Prior Antiretroviral Therapy

Study 247 was a randomized, double-blind trial (with open-label follow-up) conducted in HIV-infected patients with at least nine months of prior antiretroviral therapy and baseline CD4 cell counts less than or equal to 100 cells per μL. NORVIR 600 mg twice-daily or placebo was added to each patient's baseline antiretroviral therapy regimen, which could have consisted of up to two approved antiretroviral agents. The study accrued 1,090 patients, with mean baseline CD4 cell count at study entry of 32 cells per μL. After the clinical benefit of NORVIR therapy was demonstrated, all patients were eligible to switch to open-label NORVIR for the duration of the follow-up period. Median duration of double-blind therapy with NORVIR and placebo was 6 months. The median duration of follow-up through the end of the open-label phase was 13.5 months for patients randomized to NORVIR and 14 months for patients randomized to placebo.

The cumulative incidence of clinical disease progression or death during the double-blind phase of Study 247 was 26% for patients initially randomized to NORVIR compared to 42% for patients initially randomized to placebo. This difference in rates was statistically significant.

Cumulative mortality through the end of the open-label follow-up phase for patients enrolled in Study 247 was 18% (99/543) for patients initially randomized to NORVIR compared to 26% (142/547) for patients initially randomized to placebo. This difference in rates was statistically significant. However, since the analysis at the end of the open-label phase includes patients in the placebo arm who were switched from placebo to NORVIR therapy, the survival benefit of NORVIR cannot be precisely estimated.

During the double-blind phase of Study 247, CD4 cell counts increases from baseline for patients randomized to NORVIR at Week 2 and Week 4 were observed. From Week 4 and through Week 24, mean CD4 cell counts for patients randomized to NORVIR appeared to plateau. In contrast, there was no apparent change in mean CD4 cell counts for patients randomized to placebo at any visit between baseline and Week 24 of the double-blind phase of Study 247.

Patients without Prior Antiretroviral Therapy

In Study 245, 356 antiretroviral-naive HIV-infected patients (mean baseline CD4 = 364 cells per μL) were randomized to receive either NORVIR 600 mg twice-daily, zidovudine 200 mg three-times-daily, or a combination of these drugs.

During the double-blind phase of study 245, greater mean CD4 cell count increases were observed from baseline to Week 12 in the NORVIR-containing arms compared to the zidovudine arms. Mean CD4 cell count changes subsequently appeared to plateau through Week 24 in the NORVIR arm, whereas mean CD4 cell counts gradually diminished through Week 24 in the zidovudine and NORVIR plus zidovudine arms.

Greater mean reductions in plasma HIV-1 RNA levels were observed from baseline to Week 2 for the NORVIR-containing arms compared to the zidovudine arm. After Week 2 and through Week 24, mean plasma HIV-1 RNA levels either remained stable in the NORVIR and zidovudine arms or gradually rebounded toward baseline in the NORVIR plus zidovudine arm.

References

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

For Healthcare Professionals

Applies to ritonavir: oral capsule, oral solution, oral tablet

General

The most frequently reported side effects associated with this drug alone and in combination with other antiretrovirals were gastrointestinal (including nausea, diarrhea, vomiting, upper and lower abdominal pain), neurological disturbances (including paresthesia, oral paresthesia), rash, and fatigue/asthenia.

When used as a pharmacokinetic enhancer, side effects were dependent on the coadministered protease inhibitor. The manufacturer product information for the coadministered protease inhibitor should be consulted.[Ref]

Gastrointestinal

Pancreatitis (including some fatalities) has been reported in patients using this drug, including those who developed hypertriglyceridemia.

Limit for high chemistry included amylase greater than 2 times the upper limit of normal (2 x ULN).[Ref]

Very common (10% or more): Diarrhea (including severe with electrolyte imbalance; up to 67.9%), nausea (up to 57.4%), vomiting (up to 31.9%), upper and lower abdominal pain (up to 26.4%), dyspepsia (up to 11.5%)
Common (1% to 10%): Flatulence, gastrointestinal (GI) hemorrhage, gastroesophageal reflux disease, mouth ulcer, pancreatitis, increased amylase, constipation, circumoral paresthesia, local throat irritation
Frequency not reported: Abnormal stools, bloody diarrhea, cheilitis, colitis, dry mouth, dysphagia, eructation, esophagitis, esophageal ulcer, fecal incontinence, gastritis, gastroenteritis, GI disorder, GI symptoms, gingivitis, ileitis, ileus, melena, oral moniliasis, periodontal abscess, pseudomembranous colitis, rectal disorder, rectal hemorrhage, sialadenitis, stomatitis, tenesmus, tongue edema, ulcerative colitis[Ref]

Metabolic

Very common (10% or more): Increased cholesterol (up to 65.2%), increased triglycerides (up to 33.6%)
Common (1% to 10%): Increased fasting triglycerides, hypertriglyceridemia, increased uric acid, hypercholesterolemia, increased glucose, gout, dehydration, anorexia, increased alkaline phosphatase, decreased potassium, decreased calcium
Uncommon (0.1% to 1%): Diabetes mellitus, increased magnesium, increased LDH, increased chloride, increased potassium, decreased sodium, decreased chloride, decreased magnesium
Rare (0.01% to 0.1%): Hyperglycemia
Frequency not reported: Alcohol intolerance, avitaminosis, enzymatic abnormality, xanthomatosis, redistribution/accumulation of body fat

Antiretroviral therapy:
-Frequency not reported: Redistribution/accumulation of body fat (including central obesity, dorsocervical fat enlargement, peripheral wasting, facial wasting, breast enlargement, "cushingoid appearance"), increased blood lipid levels, increased glucose levels

Protease inhibitor therapy:
-Postmarketing reports: New onset diabetes mellitus, exacerbation of preexisting diabetes mellitus, hyperglycemia, diabetic ketoacidosis[Ref]

Limits for high chemistry included cholesterol greater than 240 mg/dL, triglycerides greater than 800 mg/dL, triglycerides greater than 1500 mg/dL (greater than 16.9 mmol/L), fasting triglycerides greater than 1500 mg/dL (greater than 16.9 mmol/L), uric acid greater than 12 mg/dL (greater than 0.7 mmol/L), glucose greater than 13.8 mmol/L, alkaline phosphatase greater than 550 units/L, LDH greater than 1170 units/L, chloride greater than 122 mmol/L, and potassium greater than 6 mmol/L. Limits for low chemistry included potassium 3 mmol/L, calcium less than 3.45 mmol/L, chloride less than 84 mmol/L, magnesium less than 1 mmol/L, and sodium less than 123 mmol/L.

Increases of 30% to 40% from baseline have been reported for cholesterol levels and 200% to 300% for triglycerides.

Dehydration (usually associated with GI symptoms, and sometimes resulting in hypotension, syncope, or renal insufficiency) has been reported (including during postmarketing experience); orthostatic hypotension, syncope, and renal insufficiency have also been reported without known dehydration.

Hyperglycemia has also been reported during postmarketing experience in patients with and without known history of diabetes.

New onset diabetes mellitus, exacerbation of preexisting diabetes mellitus, and hyperglycemia have been reported in HIV-infected patients receiving protease inhibitors; in some cases, diabetic ketoacidosis occurred. No causal relationship has been established.[Ref]

Nervous system

Very common (10% or more): Paresthesia (including oral and peripheral paresthesia; up to 50.7%), dysgeusia (16.2%), dizziness (up to 15.6%), taste perversion (up to 15.5%), peripheral neuropathy (10.1%), headache
Common (1% to 10%): Syncope, seizure, somnolence
Frequency not reported: Abnormal gait, amnesia, aphasia, ataxia, coma, convulsion, dementia, grand mal convulsion, hearing impairment, hyperesthesia, hyperkinesia, hypoesthesia, incoordination, migraine, neuralgia, neuropathy, paralysis, peripheral neuropathic pain, peripheral sensory neuropathy, sleep disorder, speech disorder, stupor, subdural hematoma, tinnitus, tremor, vertigo, vestibular disorder, cerebral ischemia, cerebral venous thrombosis, taste loss
Postmarketing reports: Neurologic events[Ref]

Syncope and seizure have also been reported during postmarketing experience.

Cardiac and neurologic events have been reported during postmarketing experience when this drug was used with disopyramide, mexiletine, nefazodone, fluoxetine, and beta blockers. Possible drug interaction could not be excluded.[Ref]

Other

Very common (10% or more): Fatigue (including asthenia; 46.2%), asthenia (up to 14.2%), flushing/feeling hot (13.2%)
Common (1% to 10%): Edema, peripheral edema, peripheral coldness, fever, weight loss, malaise
Uncommon (0.1% to 1%): Decreased albumin
Frequency not reported: Breast pain, enlarged abdomen, accidental injury, cachexia, chest pain, chills, facial edema, facial pain, influenza syndrome, hypothermia, neck pain, neck rigidity, pain (unspecified), pelvic pain, substernal chest pain, ear pain, increased cerumen, parosmia, thirst
Postmarketing reports: Acute ergot toxicity (characterized by vasospasm, ischemia of extremities and other tissues [including the central nervous system])

Antiretroviral therapy:
-Frequency not reported: Increased weight[Ref]

Limit for low chemistry included albumin less than 20 g/L.

Acute ergot toxicity has been reported when this drug was used with ergotamine or dihydroergotamine.[Ref]

Hematologic

Limits for low hematology included WBCs less than 2.5 x 10(9)/L, RBCs less than 3 x 10(12)/L, hematocrit less than 30% (less than 0.3), neutrophils up to 0.5 x 10(9)/L, hemoglobin less than 8 g/dL, and platelet count less than 2 x 10(9)/L. Limits for high hematology included eosinophils greater than 1 x 10(9)/L, neutrophils greater than 20 x 10(9)/L, WBCs greater than 25 x 10(9)/L, and prothrombin time greater than 1.5 x ULN.

Increased bleeding (including spontaneous skin hematomas and hemarthrosis) in patients with hemophilia type A or B treated has been associated with protease inhibitors. In many of the reported cases, treatment with protease inhibitors was continued or restarted and some patients required additional factor VIII. A causal relationship between protease inhibitor therapy and these episodes has not been established.[Ref]

Very common (10% or more): Decreased WBCs (up to 36.9%), decreased RBCs (up to 18.6%), decreased hematocrit (up to 17.3%)
Common (1% to 10%): Decreased neutrophils, decreased hemoglobin, thrombocytopenia, increased eosinophils, increased neutrophils, increased WBCs
Uncommon (0.1% to 1%): Increased prothrombin time, decreased platelet count
Frequency not reported: Acute myeloblastic leukemia, anemia, ecchymosis, leukopenia, lymphadenopathy, lymphocytosis, myeloproliferative disorder

Protease inhibitor therapy:
-Frequency not reported: Increased bleeding (including spontaneous skin hematomas, hemarthrosis) in hemophiliacs[Ref]

Dermatologic

Toxic epidermal necrolysis has also been reported during postmarketing experience.

Alopecia has been reported in patients using indinavir or atazanavir plus this drug.[Ref]

Very common (10% or more): Rash (including erythematous rash, maculopapular rash; up to 27.1%), pruritus (up to 12.2%)
Common (1% to 10%): Acne, acquired lipodystrophy, sweating
Rare (0.01% to 0.1%): Stevens-Johnson syndrome, toxic epidermal necrolysis
Frequency not reported: Contact dermatitis, dry skin, eczema, erythema multiforme, exfoliative dermatitis, folliculitis, fungal dermatitis, furunculosis, maculopapular rash, molluscum contagiosum, onychomycosis, photosensitivity reaction, psoriasis, pustular rash, seborrhea, skin discoloration, skin disorder, skin hypertrophy, skin melanoma, urticaria, vesiculobullous rash, alopecia[Ref]

Respiratory

Very common (10% or more): Coughing (21.7%), oropharyngeal pain (15.9%), pharyngitis
Frequency not reported: Asthma, bronchitis, increased cough, dyspnea, epistaxis, hiccup, hypoventilation, interstitial pneumonia, larynx edema, lung disorder, rhinitis, sinusitis[Ref]

Hepatic

Limits for high chemistry included GGT greater than 300 international units/L, AST greater than 180 international units/L, ALT greater than 215 international units/L, and total bilirubin greater than 61 mcmol/L.

Hepatic dysfunction (including some fatalities) has been reported, generally in patients taking multiple concurrent medications and/or with advanced AIDS.[Ref]

Very common (10% or more): Increased GGT (up to 19.6%)
Common (1% to 10%): Increased AST, increased ALT, hepatitis (including increased AST, ALT, GGT), increased blood bilirubin (including jaundice), increased total bilirubin
Frequency not reported: Exacerbation of chronic liver disease, cholangitis, cholestatic jaundice, hepatic coma, hepatomegaly, hepatosplenomegaly, liver damage, liver function tests abnormal, hepatic transaminase elevations exceeding 5 x ULN, clinical hepatitis, jaundice
Postmarketing reports: Hepatic dysfunction (including some fatalities)[Ref]

Musculoskeletal

Very common (10% or more): Arthralgia and back pain (18.6%), increased creatine phosphokinase (CPK; up to 12.1%)
Common (1% to 10%): Myalgia, myopathy/increased CPK, myositis, rhabdomyolysis
Frequency not reported: Arthritis, arthrosis, bone disorder, bone pain, extraocular palsy, joint disorder, leg cramps, muscle cramps, muscle weakness, twitching, osteonecrosis[Ref]

Limit for high chemistry included CPK greater than 1000 international units/L.

Osteonecrosis has been reported, particularly in patients with advanced HIV disease, long-term combination antiretroviral therapy, or other risk factors (including corticosteroid use, alcohol use, severe immunosuppression, higher body mass index).[Ref]

Hypersensitivity

Common (1% to 10%): Hypersensitivity (including urticaria, face edema)
Rare (0.01% to 0.1%): Anaphylaxis
Frequency not reported: Allergic reactions (including urticaria, mild skin eruptions, bronchospasm, angioedema)[Ref]

Ocular

Common (1% to 10%): Blurred vision
Frequency not reported: Abnormal electrooculogram, abnormal electroretinogram, abnormal vision, amblyopia/blurred vision, blepharitis, conjunctivitis, diplopia, eye disorder, eye pain, iritis, photophobia, uveitis, visual field defect, vitreous disorder[Ref]

Genitourinary

Common (1% to 10%): Increased urination, menorrhagia
Frequency not reported: Albuminuria, cystitis, dysuria, glycosuria, hematuria, impotence, nocturia, penis disorder, polyuria, urethritis, urinary frequency, urinary retention, urinary tract infection, vaginitis[Ref]

Menorrhagia has also been reported during postmarketing experience.[Ref]

Cardiovascular

Common (1% to 10%): Hypertension, hypotension (including orthostatic hypotension), vasodilation
Uncommon (0.1% to 1%): Myocardial infarction
Frequency not reported: PR interval prolonged, cardiovascular disorder, palpitation, peripheral vascular disorder, phlebitis, postural hypotension, tachycardia, vasospasm, hemorrhage
Postmarketing reports: Orthostatic hypotension, first-degree atrioventricular (AV) block, second-degree AV block, third-degree AV block, right bundle branch block, cardiac events[Ref]

Myocardial infarction has also been reported during postmarketing experience.

Cardiac and neurologic events have been reported during postmarketing experience when this drug was used with disopyramide, mexiletine, nefazodone, fluoxetine, and beta blockers. Possible drug interaction could not be excluded.[Ref]

Psychiatric

Common (1% to 10%): Confusion, disturbance in attention, insomnia, anxiety, abnormal thinking
Frequency not reported: Abnormal dreams, depression, depersonalization, emotional lability, euphoria, agitation, hallucinations, decreased libido, manic reaction, nervousness, personality disorder

Renal

Common (1% to 10%): Renal impairment (e.g., oliguria, elevated creatinine)
Uncommon (0.1% to 1%): Acute renal failure, increased creatinine
Frequency not reported: Renal calculus, renal failure, abnormal kidney function, kidney pain, pyelonephritis, increased BUN
Postmarketing reports: Renal insufficiency[Ref]

Limit for high chemistry included creatinine greater than 0.3 mmol/L.

Renal insufficiency was reported in 3 AIDS patients receiving this drug. All cases occurred within 10 to 15 days after starting this drug and all were reversible upon discontinuation.[Ref]

Immunologic

Frequency not reported: Immune reconstitution syndrome, autoimmune disorders in the setting of immune reconstitution (e.g., Graves' disease, polymyositis, Guillain-Barre syndrome)

Endocrine

Cushing's syndrome and adrenal suppression have been reported when this drug was used with fluticasone or budesonide.[Ref]

Common (1% to 10%): Decreased free and total thyroxin
Frequency not reported: Adrenal cortex insufficiency, hormone level altered
Postmarketing reports: Cushing's syndrome, adrenal suppression[Ref]

Some side effects of ritonavir may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Precautions

US BOXED WARNING:
-DRUG INTERACTIONS LEADING TO POTENTIALLY SERIOUS AND/OR LIFE-THREATENING REACTIONS: Concomitant use of this drug with several drug classes (including sedative hypnotics, antiarrhythmics, ergot alkaloids) may lead to potentially serious and/or life-threatening reactions due to possible effects of this drug on the hepatic metabolism of some agents. Medications taken by patients should be reviewed before starting this drug or when adding medications in patients already taking this drug.

Safety and efficacy have not been established in patients younger than 1 month.

Consult WARNINGS section for additional precautions.

Dialysis

Data not available

Comments:
-Significant removal via dialysis is not likely (highly protein bound).

(web3)