Ritonavir

Ritonavir oral solution is the preferred formulation for patients requiring doses less than 100 mg or incremental doses between 100 mg intervals. 6 Dose Modification due to Drug Interaction Dose reduction of ritonavir tablet is necessary when used with other protease inhibitors: atazanavir, darunavir, fosamprenavir, saquinavir, and tipranavir.

1) , and Drug Interactions (7) ].

Vomiting, diarrhea, and skin rash/allergy were the only drug-related clinical adverse events of moderate to severe intensity observed in greater than or equal to 2% of pediatric patients enrolled in ritonavir clinical trials. Laboratory Abnormalities in Pediatric Patients The following Grade 3 to 4 laboratory abnormalities occurred in greater than 3% of pediatric patients who received treatment with ritonavir either alone or in combination with reverse transcriptase inhibitors: neutropenia (9%), hyperamylasemia (7%), thrombocytopenia (5%), anemia (4%), and elevated AST (3%).

2 Postmarketing Experience The following adverse events (not previously mentioned in the labeling) 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.

Body as a Whole Dehydration, usually associated with gastrointestinal symptoms, and sometimes resulting in hypotension, syncope, or renal insufficiency has been reported. Syncope, orthostatic hypotension, and renal insufficiency have also been reported without known dehydration.

Co-administration of ritonavir with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm and ischemia of the extremities and other tissues including the central nervous system. 6) ] .

Cardiac and neurologic events have been reported when ritonavir has been co-administered with disopyramide, mexiletine, nefazodone, fluoxetine, and beta blockers. The possibility of drug interaction cannot be excluded. Endocrine System Cushing’s syndrome and adrenal suppression have been reported when ritonavir has been co­-administered with fluticasone propionate or budesonide.

Nervous System There have been postmarketing reports of seizure. Also, see Cardiovascular System. Renal and Urinary Disorders Nephrolithiasis Skin and subcutaneous tissue disorders Toxic epidermal necrolysis (TEN) has been reported.

See Table 4 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 ritonavir therapy; review concomitant medications during ritonavir therapy, and monitor for the adverse reactions associated with the concomitant medications [see Contraindications (4) and Drug Interactions (7) ].

2 Toxicity in Preterm Neonates Ritonavir oral solution contains the excipients ethanol and propylene glycol. 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.

Ritonavir oral solution should not be used in preterm neonates in the immediate postnatal period because of possible toxicities. However, if the benefit of using ritonavir 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 ritonavir 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.

4) and Overdosage (10) ]. 3 Hepatotoxicity 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 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 diseases, liver enzyme abnormalities, or hepatitis.

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. 4 Pancreatitis Pancreatitis has been observed in patients receiving ritonavir therapy, including those who developed hypertriglyceridemia.

In some cases fatalities have been observed. 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 ritonavir therapy should be discontinued if a diagnosis of pancreatitis is made. 5 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. 6 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. Ritonavir 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.

3) ] . 1) ] . Triglyceride 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, taking into account any potential drug-drug interactions with ritonavir and HMG CoA reductase inhibitors [see Contraindications (4) and Drug Interactions (7) ] .

8 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 ritonavir.

9 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in HIV-infected patients treated with combination antiretroviral therapy, including ritonavir. 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.

10 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. 11 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.

12 Resistance/Cross-resistance Varying degrees of cross-resistance among protease inhibitors have been observed. 4) ] . 13 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 ritonavir therapy and at periodic intervals or if any clinical signs or symptoms occur during therapy.