RITONAVIR (Generic for NORVIR)

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
-Dosage titration may help to reduce treatment-related side effects.
-Take with meals.
Oral Solid Formulations
-When switching from the capsule to the tablet, patients may experience more gastrointestinal side effects, which may diminish over time.

Tablets
-Tablets should be swallowed whole. Do not chew, break, or crush.

Oral Liquid Formulations
Oral solution
-Shake well before each use.
-Administer using a calibrated dosing syringe. Pay close attention to dosage of the oral solution, especially in young children, to ensure appropriate administration and to avoid overdosage.
-The oral solution contains 43.2% (v/v) alcohol and 26.57% (w/v) propylene glycol; caution is advised when administering to infants 1 to 6 months of age.
-To improve the taste, the oral solution may be mixed with milk, chocolate milk, Ensure, or Advera and given within one hour after mixing.
-Because the oral solution contains ethanol and propylene glycol, it is not recommended for use with polyurethane feeding tubes due to potential incompatibility. Feeding tubes compatible with ethanol and propylene glycol, such as silicone and polyvinyl chloride (PVC), can be used for administration of ritonavir oral solution. Follow instructions for use of the feeding tube to administer the medication.

Oral powder for solution
-Ritonavir oral powder should only be used for dosing increments of 100 mg. It should not be used for doses less than 100 mg or for incremental doses between 100 mg intervals. Use ritonavir oral solution for patients requiring doses less than 100 mg or incremental doses between 100 mg intervals.
-Prepare the dose using the required number of 100 mg packets.
-Pour and mix the entire contents of each packet over soft food or mix in 4 ounces of liquid and administer. If there is any powder left in the container, add more soft food or liquid and mix; administer again.
-Feeding tube: Mix contents of packet with water and administer via feeding tube.
-The mixture should be administered within 2 hours of preparation; discard mixture if not given within 2 hours of preparation and prepare new dose.

The FDA-approved product labeling states that the adverse event profile observed during pediatric clinical trials (n = 265, ages 1 month to 21 years) was similar to that of adult patients. Gastrointestinal events and skin rash were the only drug-related adverse events of moderate to severe intensity that were observed in >= 2% of pediatric patients enrolled in these trials.

Gastrointestinal (GI) effects are some of the most common adverse reactions associated with ritonavir use. Vomiting and diarrhea of moderate to severe intensity occurred in >= 2% of patients during pediatric clinical trials. In some cases, ritonavir-associated diarrhea may be severe enough to cause clinically significant electrolyte disturbances. Common GI adverse events during adult clinical trials included diarrhea (67.9%), nausea (57.4%), vomiting (31.9%), abdominal pain (26.4%), dysgeusia (16.2%), dyspepsia (11.5%), flatulence (8.1%), and gastroesophageal reflux disease (GERD); similar effects are seen in children. Nausea, vomiting, and abdominal pain may also be symptoms of inflammation of the pancreas; if a patient experiences significant or persistent abdominal symptoms, carefully evaluate to rule out a more serious condition. Cases of dehydration, usually associated with gastrointestinal symptoms, have been reported during post-marketing use.

Pancreatitis, in some cases fatal, has been observed in patients receiving treatment with ritonavir. In pediatric clinical trials, 7% of patients developed hyperamylasemia. Marked triglyceride elevations are a risk factor for development of pancreatitis; marked triglyceride elevations with the development of pancreatitis have occurred with ritonavir. Patients with advanced HIV disease may be at increased risk of elevated triglycerides and pancreatitis, and patients with a history of pancreatitis may be at increased risk for recurrence. If clinical symptoms (nausea/vomiting, abdominal pain) or lab abnormalities (elevated amylase or serum lipase) suggestive of pancreatitis occur, evaluate the patient and hold ritonavir and/or other antiretroviral therapy as clinically appropriate; discontinue ritonavir if the diagnosis of pancreatitis is made.

Hyperlipidemia, with large increases in total cholesterol and triglyceride concentrations, has been reported during treatment with ritonavir. Measure triglyceride and cholesterol concentrations prior to initiating ritonavir treatment and periodically thereafter. In adult clinical trials, hypercholesterolemia (> 240 mg/dL) was reported in 30.7-65.2% of patients. Hypertriglyceridemia (> 800 mg/dL) was reported in 9.6-33.6% of adult patients; triglyceride elevations > 1500 mg/dL were reported in 1.8-12.6% of patients. Marked triglyceride elevations are a risk factor for development of pancreatitis; marked triglyceride elevations with the development of pancreatitis have occurred with ritonavir. Lipid disorders should be managed as clinically appropriate, taking potential drug interactions into account.

Metabolic adverse reactions reported in adult patients receiving ritonavir during clinical trials include edema and peripheral edema (6.3%) and gout (1.4%).

Increased bleeding, including spontaneous skin hematoma and hemarthrosis, has been reported in HIV infected patients with hemophilia (type A and B) being treated with protease inhibitors, such as ritonavir. The majority of the patients have been able to continue taking their protease inhibitor therapy in spite of the bleeding events; some patients received additional coagulation factor. More serious bleeding episodes, such as GI bleeding, were reported in 2.3% of adult patients receiving treatment with ritonavir in phase II/IV clinical trials.

A lipodystrophy syndrome consisting of redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, accumulation of facial fat, lipomas, breast enlargement, gynecomastia and other cushingoid features has been reported in patients receiving long-term highly active antiretroviral therapy (HAART) that includes protease inhibitors such as ritonavir. This syndrome may be associated with metabolic complications such as insulin resistance and dyslipidemia, but not always. Some studies indicate that up to 5-30% of patients receiving protease inhibitors may develop lipodystrophy. The mechanism and long-term consequences are not known. A casual relationship has not been established. Changes in HAART to reverse lipodystrophy should probably be avoided unless the patient finds the changes in body fat intolerable and more conservative interventions fail.

New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported during post-marketing use of protease inhibitors, including ritonavir. Diabetic ketoacidosis has also occurred. Initiation or adjustment of hypoglycemic therapy is required in some patients after beginning protease inhibitor treatment. In some patients who have discontinued protease inhibitor therapy, hyperglycemia has persisted. A causal relationship between these events and protease inhibitors has not been established.

Elevated hepatic enzymes (exceeding 5 times the upper limit of normal), hepatitis, and jaundice have been reported in patients receiving ritonavir. There have been post-marketing reports of hepatic dysfunction, including some fatalities, which have generally occurred in patients with advanced AIDS taking multiple concomitant medications. Elevations in AST (3% of pediatric patients) and ALT, hepatitis (8.7% of adults), and hyperbilirubinemia, including jaundice (1.4% of adults), were reported in clinical trials. Patients with underlying hepatitis B or C may be at increased risk for developing further transaminase elevations or hepatic decompensation; increased monitoring should be considered in these patients, especially during the first few months of therapy.

During clinical trials with ritonavir, rash (unspecified) was reported in >= 2% of pediatric patients. The types of rash reported in general include maculopapular rash and erythematous rash. Other dermatologic adverse reactions reported in adult patients during clinical trials include pruritus (12.2%) and acne vulgaris (3.8%). Allergic-type reactions including angioedema, bronchospasm, urticaria, and mild skin eruptions have been reported in 8.2% of adult patients during clinical trials; rare cases of anaphylactoid reactions, toxic epidermal necrolysis, and Stevens-Johnson syndrome have also been reported. Instruct patients to discontinue therapy and seek immediate medical attention if severe reactions develop.

Increased urinary frequency was reported by 4.2% of adult patients receiving ritonavir during clinical trials. Cases of nephrolithiasis and renal insufficiency, with or without known dehydration, have been reported during postmarketing use. Due to the voluntary nature of postmarketing reports, neither a frequency nor a definitive causal relationship can be established.

Arthralgia and back pain (18.6%), myalgia (8.9%), myopathy (3.8%), and increased creatine phosphokinase (> 1000 international units/L; 9.1-12.1%) were the most common musculoskeletal adverse reactions associated with ritonavir therapy during adult clinical trials.

Asthenia and fatigue (46.2%), paresthesias (including oral paresthesia; 50.7%), dizziness (15.6%), peripheral neuropathy (10.1%), confusion (3%), and attention disturbance (2.5%) were the most frequently reported neurologic adverse events in adult patients receiving ritonavir during clinical trials. Seizures have been reported during post-marketing surveillance of ritonavir.

Flushing (13.2%), syncope (3.3%), and hypertension (3.3%) were the most common cardiovascular adverse reactions reported with ritonavir therapy during adult clinical trials. Other adverse cardiovascular reactions that were reported include hypotension and orthostatic hypotension (1.7%) and peripheral coldness (1.2%). In some cases, syncope and orthostatic hypotension were secondary to dehydration.

Cough (21.7%) and oropharyngeal pain or throat irritation (15.9%) were reported by adult patients who received ritonavir during clinical trials.

Laboratory abnormalities have been reported after ritonavir use in both adult and pediatric populations. During clinical trials, pediatric recipients of ritonavir have experienced adverse hematologic events including neutropenia (9%), thrombocytopenia (5%), and anemia (4%). Other laboratory abnormalities occurring during clinical trials included elevated gamma-glutamyl transpeptidase (1.8-19.6% adults), hyperamylasemia (7% pediatrics), and hyperuricemia (1.4-3.8%).

Ritonavir has been associated with QT prolongation. Postmarketing cases of PR prolongation with second or third degree AV block and right bundle-branch block have also been reported. Use caution when administering ritonavir in patients at risk for developing cardiac conduction abnormalities.

Blurred vision was reported by 6.4% of adult patients receiving ritonavir during clinical trials.

Unplanned antiretroviral therapy interruption may be necessary in specific situations, such as serious drug toxicity, intercurrent illness or surgery precluding oral intake, or drug non-availability. If short-term treatment interruption is necessary (i.e., < 1-2 days), in general, it is recommended that all antiretroviral agents be discontinued simultaneously, especially if the interruption is because of serious toxicity. However, if a short-term treatment interruption is anticipated in the case of elective surgery, the pharmacokinetic properties and food requirements of specific drugs should be considered. When the antiretroviral regimen contains drugs with differing half-lives, stopping all drugs simultaneously may result in functional monotherapy of the drug with the longest half-life. For example, after discontinuation, the duration of detectable drug concentrations of efavirenz and nevirapine ranges from < 1 week to > 3 weeks. Simultaneously stopping all drugs in a regimen containing these agents may result in functional monotherapy with the NNRTI and may increase the risk of NNRTI-resistant mutations. Planned long-term treatment interruptions are not recommended due to the potential for HIV disease progression (i.e., declining CD4 counts, viral rebound, acute viral syndrome), development of minor HIV-associated manifestations or serious non-AIDS complications, development of drug resistance, increased risk of HIV transmission, and increased risk for opportunistic infections. If therapy must be discontinued, counsel patient on the potential risks and closely monitor for any clinical or laboratory abnormalities.

Due to its potent inhibition of the CYP3A4 enzyme system, ritonavir coadministration with other drugs should be done with extreme caution. Specifically, the administration of certain non-sedating antihistamines, sedative hypnotics, antiarrhythmics, and ergot alkaloids to patients receiving ritonavir can result in serious and potentially life-threatening adverse reactions due to inhibited metabolism and, hence, increased concentrations of the coadministered drug. See the Interactions section for more specific information.

Ritonavir should be used with caution in patients with pre-existing hepatic disease, liver enzyme abnormalities, jaundice, or hepatitis due to an increased risk for transaminase elevations during ritonavir therapy. Frequent monitoring of hepatic enzymes should be considered in these patients, especially during the first 3 months of therapy. Ritonavir should be used with caution in patients with moderate to severe hepatic impairment; dosage adjustment is not needed in patients with mild hepatic impairment. All patients presenting with HIV-infection should be screened for hepatitis B virus (HBV) coinfection to assure appropriate treatment. Patients with hepatitis B and HIV coinfection who require treatment for either infection should be started on a fully suppressive antiretroviral regimen that contains NRTIs with activity against both viruses. Avoid using single-drug therapy to treat HBV (i.e., lamivudine, emtricitabine, or tenofovir as the only active agent) due to the risk of developing resistant strains of HIV. The HIV guidelines recommend that coinfected pediatric patients >= 2 years receive an antiretroviral regimen that contains tenofovir in combination with either lamivudine or emtricitabine as the dual NRTI backbone. If tenofovir cannot be used, another agent with anti-HBV activity should be used in combination with lamivudine or emtricitabine to assure adequate treatment of HBV infection. Management of HIV should be continued with the goal of maximal suppression.

Consider patient specific factors, such as preexisting hyperlipidemia, when selecting an antiretroviral treatment regimen. Hyperlipidemia is a recognized side effect of protease inhibitor-based regimens. Obtain a random or fasting lipid profile at entry of care, initiation or modification of antiretroviral therapy, every 12 months, and as clinically indicated. Possible interventions for patients who develop hyperlipidemia during treatment with ritonavir include dietary modification, use of lipid lowering agents, or switching to a regimen with a more favorable lipid profile. Clinicians should be aware of the potential for drug interactions with certain cholesterol-lowering drugs.

Patients with diabetes mellitus or hyperglycemia may experience an exacerbation of their condition during ritonavir treatment. In some cases, diabetic ketoacidosis has occurred. Further, reports of new onset diabetes mellitus have been associated with protease inhibitor therapy. Some patients may require either initiation or dose adjustments of insulin or oral hyperglycemic agents. Patients should be monitored closely for new onset diabetes mellitus, diabetic ketoacidosis, or hyperglycemia.

Protease inhibitors such as ritonavir should be used cautiously in patients with hemophilia A or B due to reports of spontaneous bleeding episodes requiring treatment with additional factor VIII. In many cases, treatment with protease inhibitors was continued or restarted. A casual relationship has not been established.

Testing for human immunodeficiency virus (HIV) infection resistance is recommended in all antiretroviral treatment-naive patients at the time of HIV diagnosis, regardless of whether treatment will be initiated. Additionally, perform resistance testing prior to initiating or changing any HIV treatment regimen. Transmission of drug-resistant HIV strains has been both well documented and associated with suboptimal virologic response to initial antiretroviral therapy. Therefore, resistance testing at baseline can help optimize treatment and, thus, virologic response. In the absence of therapy, resistant viruses may decline over time to less than the detection limit of standard resistance tests, but may still increase the risk of treatment failure when therapy is eventually initiated. Thus, if therapy is deferred, resistance testing should still be performed during acute HIV infection with the genotypic resistance test results kept in the patient's medical record until they become clinically useful. Additionally, because of the possibility of acquisition of another drug-resistant virus before treatment initiation, repeat resistance testing at the time therapy is initiated would be prudent. Varying degrees of cross-resistance among protease inhibitors have been observed. Continued administration of ritonavir following loss of viral suppression may increase the likelihood of antimicrobial resistance to other protease inhibitors. In studies of indinavir with ritonavir, saquinavir, and amprenavir, the extent and spectrum of cross-resistance varied with the specific HIV mutational patterns observed; the degree of cross-resistance typically increased with the accumulation of resistance-associated amino acid substitutions. Within a panel of 29 viral isolates from indinavir-treated patients that exhibited measurable phenotypic resistance to indinavir, all were resistant to ritonavir and of the indinavir-resistant HIV isolates, 63% showed resistance to saquinavir and 81% to amprenavir.

The safety and efficacy of ritonavir in neonates (i.e., younger than 1 month of age) have not been established. Administering ritonavir oral solution to neonates before a postmenstrual age of 44 weeks (first day of the mother's last menstrual period to birth plus the time since birth) may result in significant alcohol and propylene glycol-related toxicities; use is not recommended. Premature neonates are especially at risk as they have a diminished ability to metabolize propylene glycol and ethanol may additionally competitively inhibit propylene glycol metabolism. If the benefit of using the oral solution in a neonate immediately after birth outweighs the potential risk, monitor for increases in serum osmolarity, serum creatinine, and for adverse events such as hyperosmolarity, lactic acidosis, renal toxicity, CNS depression (stupor, coma, apnea), seizures, hypotonia, cardiac arrhythmias (ECG changes), and hemolysis. When dosing and administering the oral solution to any pediatric patient, use caution to avoid an overdosage. The solution contains 43.2% (v/v) alcohol and 26.57% (w/v) propylene glycol; an accidental overdosage by a young child could result in significant propylene glycol or alcohol-related toxicities including death. For infants between 1 to 6 months of age, health care providers are advised to calculate the total amounts of alcohol and propylene glycol from all medications that are being administered to the patient. The oral powder for solution does not contain alcohol or propylene glycol and may be a safer alternative in pediatric patients.

Ritonavir prolongs the PR interval in some patients, and postmarketing cases of second or third degree AV block have been reported. Use ritonavir with caution in patients who may be at increased risk for developing cardiac conduction abnormalities (e.g., patients with congenital heart disease, underlying structural cardiac disease, preexisting conduction system abnormalities, coronary artery disease, and cardiomyopathy). The impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers, beta-adrenergic blockers, digoxin, and atazanavir) has not been evaluated; however, concomitant administration of ritonavir with these drugs should be undertaken with caution, particularly with those drugs metabolized by cytochrome P450 3A4 isoenzymes. Clinical monitoring is recommended.


Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. During the initial phase of HIV treatment, patients whose immune system responds to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as mycobacterium avium complex (MAC), cytomegalovirus (CMV), Pneumocystis carinii pneumonia (PCP), or tuberculosis (TB)), which may necessitate further evaluation and treatment. In addition, autoimmune disease (including Graves' disease, Guillain-Barre syndrome, and polymyositis) may also develop; the time to onset is variable and may occur months after treatment initiation.

Perform hepatitis C virus (HCV) screening in any child whose mother is known to have HCV infection and all HIV-infected adolescents. Treatment of HCV infection in children < 3 years is not usually recommended; however, treatment should be considered for all children >= 3 years and adolescents with hepatitis C and HIV coinfection who have no contraindications to treatment. For antiretroviral-naive adolescent patients with CD4 counts > 500 cells/mm3, consideration may be given to deferring ARV therapy until the hepatitis C treatment regimen has been completed. Conversely, for adolescent patients with CD4 counts < 200 cells/mm3, consider delaying initiation of the hepatitis C treatment regimen until the patient is stable on a fully suppressive ARV regimen. All HIV-infected children and adolescents, regardless of HIV and HCV status, should receive standard vaccination with hepatitis A and B vaccines. Additionally, HIV/HCV-coinfected adolescents should be counseled to avoid alcohol.

Description: Ritonavir is an antiretroviral protease inhibitor used for the treatment of HIV infection. Ritonavir is most often used as a pharmacokinetic enhancer or boosting agent in combination with another protease inhibitor for the treatment of HIV infection. It is rarely used as the primary protease inhibitor in combination therapy. Ritonavir has high affinity for the cytochrome P450 isoenzymes, especially CYP3A4, and may be involved in many drug-drug interactions. The oral solution contains alcohol and propylene glycol as additives; these may be toxic to young children, when used at higher than recommended doses or in overdose situations. The oral powder for solution does not contain alcohol or propylene glycol and may be a safer alternative in pediatric patients. Ritonavir is FDA-approved in pediatric patients as young as 1 month of age.

NOTE: Dose reduction of ritonavir is necessary when used with other protease inhibitors.

Initiation of HIV therapy
-Antiretroviral drug resistance testing (preferably genotypic testing) is recommended prior to initiation of therapy in antiretroviral treatment (ART)-naive patients and prior to changing therapy for treatment failure.
-Initiation of treatment immediately or within days after HIV diagnosis is recommended in all pediatric patients, except for patients with cryptococcal meningitis, disseminated Mycobacterium avium complex disease, or Mycobacterium tuberculosis disease. In these patients, initiate treatment for the opportunistic infection first, ahead of ART initiation. The urgency of rapid treatment initiation is especially critical for all patients younger than 1 year, who carry the highest risk of rapid disease progression and mortality. If therapy is deferred for certain circumstances, closely monitor the patient's virologic, immunologic, and clinical status at least every 3 to 4 months. If therapy is deferred, initiate treatment when HIV RNA concentrations increase, CD4 count or percentage values decline (i.e., approaching CDC Stage 2 or 3), the patient develops new HIV-related clinical symptoms, or the ability of the caregiver and patient to adhere to the prescribed regimen has improved.

Place in therapy for HIV
-Ritonavir is not recommended as a sole protease-inhibitor for the treatment of HIV; however, it is utilized as a pharmacokinetic enhancer (booster) of other protease inhibitors.
-For treatment-naive pediatric patients, a backbone of 2 nucleoside reverse transcriptase inhibitors (NRTIs) should be used in combination with a non-nucleoside reverse transcriptase inhibitor (NNRTI), protease inhibitor (PI), or integrase strand transfer inhibitor (INSTI). Specific recommendations vary depending on age.

Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: human immunodeficiency virus (HIV)
NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.

For the treatment of human immunodeficiency virus (HIV) infection in combination with other antiviral agents:
Oral dosage:
Neonates and Premature Infants with postmenstrual age less than 44 weeks: Safety and efficacy have not been established in neonates less than 1 month (postnatal age) and/or a postmenstrual age (first day of the mother's last menstrual period to birth plus the time since birth) of less than 44 weeks. Use in this patient population is not recommended due to potential for toxicities.
Infants, Children, and Adolescents: 350 to 400 mg/m2/dose (Max: 600 mg/dose) PO every 12 hours. To minimize nausea/vomiting, initiate at 250 mg/m2/dose PO every 12 hours and increase at 2 to 3 day intervals by 50 mg/m2/dose until 400 mg/m2/dose PO every 12 hours is reached. If a patient is unable to tolerate 400 mg/m2/dose every 12 hours because of adverse reactions, the highest tolerated dose should be used for maintenance therapy in combination with other antiretrovirals; however, alternative therapy should be considered. Ritonavir is not recommended as a sole protease inhibitor (PI) but is used at lower doses as a pharmacokinetic enhancer of other PIs; the recommended dose of ritonavir depends on the PI combination selected and age/weight of patient.

For human immunodeficiency virus (HIV) prophylaxis* after nonoccupational exposure:
NOTE: Higher risk exposures for which prophylaxis is recommended include exposure of vagina, rectum, eye, mouth, or other mucous membrane, nonintact skin, or percutaneous contact with blood, semen, vaginal secretions, rectal secretions, breast milk, or any body fluid that is visibly contaminated with blood when the source is known to be HIV-positive. Exposures to a source patient with unknown HIV status should be assessed on a case-by-case basis.
Oral dosage:
Children 3 years and older weighing 10 kg: 32 mg PO twice daily with darunavir 200 mg PO twice daily in combination with tenofovir and emtricitabine for 28 days is an alternative HIV post-exposure prophylaxis (PEP) regimen in children 3 to 12 years. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.
Children 3 years and older weighing 11 kg: 32 mg PO twice daily with darunavir 220 mg PO twice daily in combination with tenofovir and emtricitabine for 28 days is an alternative HIV post-exposure prophylaxis (PEP) regimen in children 3 to 12 years. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.
Children 3 years and older weighing 12 kg: 40 mg PO twice daily with darunavir 240 mg PO twice daily in combination with tenofovir and emtricitabine for 28 days is an alternative HIV post-exposure prophylaxis (PEP) regimen in children 3 to 12 years. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.
Children 3 years and older weighing 13 kg: 40 mg PO twice daily with darunavir 260 mg PO twice daily in combination with tenofovir and emtricitabine for 28 days is an alternative HIV post-exposure prophylaxis (PEP) regimen in children 3 to 12 years. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.
Children 3 years and older weighing 14 kg: 48 mg PO twice daily with darunavir 280 mg PO twice daily in combination with tenofovir and emtricitabine for 28 days is an alternative HIV post-exposure prophylaxis (PEP) regimen in children 3 to 12 years. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.
Children 3 years and older weighing 15 to 29 kg: 48 mg PO twice daily with darunavir 375 mg PO twice daily in combination with tenofovir and emtricitabine for 28 days is an alternative HIV post-exposure prophylaxis (PEP) regimen in children 3 to 12 years. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.
Children weighing 30 to 39 kg: 100 mg PO twice daily with darunavir 450 mg PO twice daily in combination with tenofovir and emtricitabine for 28 days is an alternative HIV post-exposure prophylaxis (PEP) regimen in children 3 to 12 years. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.
Children weighing 40 kg or more: 100 mg PO twice daily with darunavir 600 mg PO twice daily in combination with tenofovir and emtricitabine for 28 days is an alternative HIV post-exposure prophylaxis (PEP) regimen in children 3 to 12 years. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.
Adolescents: 100 mg PO once daily with darunavir 800 mg PO once daily in combination with tenofovir and emtricitabine or zidovudine and lamivudine (patients with renal dysfunction; CrCl 59 mL/minute or less) for 28 days is an alternative HIV post-exposure prophylaxis (PEP) regimen in adolescents. A 3-drug regimen is recommended for all cases when PEP is indicated; however, the use of a 2-drug regimen (2 NRTIs or a combination of a PI and a NNRTI) may be considered if tolerability or adherence is a concern. Begin prophylaxis as soon as possible after exposure; prophylaxis initiated more than 72 hours after exposure is unlikely to be effective.

Maximum Dosage Limits:
-Neonates
Use not recommended.
-Infants
Postmenstrual age < 44 weeks: Use not recommended.
>= 1 month: Refer to dosage recommendations when used as a pharmacokinetic enhancer (specific dose varies significantly depending on patient age/weight and concomitant protease inhibitor); 800 mg/m2/day PO when used as the sole protease inhibitor.
-Children
Refer to dosage recommendations when used as a pharmacokinetic enhancer (specific dose varies significantly depending on patient age/weight and concomitant protease inhibitor); 800 mg/m2/day PO (Max: 1200 mg/day) when used as the sole protease inhibitor.
-Adolescents
Refer to dosage recommendations when used as a pharmacokinetic enhancer (specific dose varies significantly depending on patient age/weight and concomitant protease inhibitor); 800 mg/m2/day PO (Max: 1200 mg/day) when used as the sole protease inhibitor.

Patients with Hepatic Impairment Dosing
Dosage adjustment is not needed in adult patients with mild to moderate hepatic impairment (Child-Pugh Class A and B). At this time there are insufficient data in adult patients with severe hepatic impairment (Child-Pugh Class C) and, therefore, it is not recommended for use. There are no specific pediatric recommendations.

Patients with Renal Impairment Dosing
Dosing in patients with renal impairment has not been studied. Approximately 3.5% of ritonavir is excreted unchanged in the urine.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Ritonavir is a competitive inhibitor of HIV protease, an enzyme involved in the replication of HIV. During the later stages of the HIV growth cycle, the gag and gag-pol gene products are first translated into polyproteins and become immature budding particles. Protease is responsible for cleaving these precursor molecules to produce the final structural proteins of a mature virion core and to activate reverse transcriptase for a new round of infection. Thus, protease is necessary for the production of mature virions. Protease inhibition renders the virus noninfectious. Ritonavir inhibits both HIV-1 and HIV-2 proteases. Because HIV protease inhibitors inhibit the HIV replication cycle after translation and before assembly, they are active in acutely and chronically infected cells, as well as in cells not normally affected by dideoxynucleoside reverse transcriptase inhibitors (i.e., monocytes and macrophages).

Pharmacokinetics: Ritonavir is administered orally as a tablet, capsule, or solution. Protein binding is approximately 98% to 99%, primarily to albumin and alpha1-acid glycoprotein over the concentration range of 0.01 to 30 mcg/mL. Ritonavir is metabolized in the liver, primarily by cytochrome P450 (CYP) 3A4 and to a lesser degree by CYP2D6. One (M-2) of five metabolites has antiviral activity similar to that of ritonavir, although plasma concentrations are low. Ritonavir is primarily eliminated in the feces (approximately 86%, 34% as unchanged parent drug), with minimal excretion in the urine (approximately 11%). The volume of distribution is approximately 0.41 +/- 0.25 L/kg, and the elimination half-life is about 3 to 5 hours in adults.

Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, CYP2D6, CYP1A2, CYP2C9, CYP2C19, CYP2B6, P-gp, glucuronosyl transferase
Ritonavir is metabolized by CYP and has affinity for several cytochrome isoforms; many clinically significant drug interactions are possible. Ritonavir is primarily metabolized by CYP3A4. It is also a potent CYP3A4 inhibitor; drugs metabolized by CYP3A4 are expected to have large (more than 3 times) increases in the AUC when coadministered with ritonavir. Ritonavir is a partial substrate and minor inhibitor of CYP2D6; drugs metabolized by CYP2D6 may display a 2-fold increase in AUC when coadministered. Ritonavir is also a substrate and inhibitor of P-glycoprotein (P-gp). Ritonavir also appears to induce CYP3A4 as well as other enzymes, including glucuronosyl transferase and CYP1A2. According to the manufacturer, it may possibly induce the CYP2C9, CYP2C19, and CYP2B6 isoenzymes. The magnitude and effect of ritonavir on the pharmacokinetics of the coadministered drug are difficult to predict due to various affected enzymes and potential for inducer and inhibitory effects, especially with substrates that are metabolized by multiple enzymes or have a low intrinsic clearance by CYP3A.


-Route-Specific Pharmacokinetics
Oral Route
The absolute oral bioavailability of ritonavir has not been determined; however, oral bioavailability may be approximately 75%. After oral solution administration, peak plasma concentrations occur at approximately 2 and 4 hours under fasting and non-fasting conditions, respectively. Ritonavir tablets are not bioequivalent to the capsules. Under moderate fat conditions, administration of a single 100 mg tablet dose or capsule dose resulted in equivalent AUC, but the mean Cmax was increased for the tablet dose by 26%. No information is available comparing the tablets to the capsules under fasting conditions. After administration of a single 100 mg dose under fed conditions, ritonavir oral powder had comparable bioavailability to the oral solution.

Effects of food
The bioavailability of ritonavir is decreased when given with food as compared with fasted conditions. After the administration of a single 100 mg tablet dose, the Cmax and AUC of ritonavir were decreased by 21% to 23% under moderate fat or high fat conditions compared to fasting conditions. After the administration of a single 600 mg oral solution dose, the Cmax and AUC of ritonavir were decreased by 23% and 7%, respectively, under non-fasting conditions compared to fasting conditions. The rate and extent of absorption were not significantly affected when the oral solution was diluted with 240 mL of chocolate milk, Advera, or Ensure and administered within 1 hour. After administration of a single 100 mg oral powder dose, the Cmax and AUC of ritonavir were decreased by 23% to 49% under moderate fat or high fat conditions compared to fasting conditions. The extent of absorption from the capsule formulation is increased by approximately 13% when given with a meal.


-Special Populations
Pediatrics
Infants, Children, and Adolescents
In pediatric patients (1 month to 14 years, n = 78), the clearance of ritonavir is approximately 1.5 to 1.7 times faster than observed in adult patients. Plasma concentrations after 350 to 400 mg/m2 twice daily in pediatric patients older than 2 years are comparable to plasma concentrations in adults receiving 600 mg (about 330 mg/m2) twice daily. However, in patients younger than 2 years of age receiving 350 to 450 mg/m2 twice daily, the AUC and trough concentrations are 16% and 60% lower, respectively, than those observed in adults receiving 600 mg twice daily. Pharmacokinetic parameters in infants younger than 1 month have not been established.

Hepatic Impairment
Patients with mild hepatic insufficiency were not found to have clinically significant changes in ritonavir pharmacokinetic parameters compared to normal controls. Dose-normalized steady-state exposures in patients with moderate hepatic impairment (400 mg PO twice daily, n = 6) were approximately 40% lower than those in patients with normal hepatic function (500 mg PO twice daily, n = 6). No dosage adjustment is recommended for patients with mild to moderate hepatic disease, although, health care providers should be aware that lower concentrations may be seen in patients with moderate hepatic impairment; patient response should be carefully monitored. Ritonavir has not been studied in patients with severe hepatic impairment.

Renal Impairment
Renal insufficiency is not expected to affect ritonavir clearance, and pharmacokinetic parameters have not been established in such patients.