COMPOSITION:
Each tablet contains:
Ritonavir 100mg

DESCRIPTION:
Ritonavir inhibits HIV protease and renders the enzyme incapable of processing of polyprotein precursor which leads to production of noninfectious immature HIV particles.

PHARMACOLOGICAL:
Ritonavir was originally developed as an inhibitor of HIV protease. It is now rarely used for its own antiviral activity, but remains widely used as a booster of other protease inhibitors. More specifically, ritonavir is used to inhibit a particular liver enzyme that normally metabolizes protease inhibitors, cytochrome P450-3A4 (CYP3A4). The drug's molecular structure inhibits CYP3A4, so a low dose can be used to enhance other protease inhibitors.

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

Absorption
The absolute bioavailability of ritonavir has not been determined. After a 600 mg dose of oral solution, peak concentrations of ritonavir were achieved approximately 2 hours and 4 hours after dosing under fasting and non-fasting (514 KCal; 9% fat, 12% protein, and 79% carbohydrate) conditions, respectively.

Effect of Food on Oral Absorption
When the oral solution was given under non-fasting conditions, peak ritonavir concentrations decreased 23% and the extent of absorption decreased 7% relative to fasting conditions. Dilution of the oral solution, within one hour of administration, with 240 mL of chocolate milk, Advera® or Ensure® did not significantly affect the extent and rate of ritonavir absorption. After a single 600 mg dose under non-fasting conditions, in two separate studies, the soft gelatin capsule (n = 57) and oral solution (n = 18) formulations yielded mean ± SD areas under the plasma concentration-time curve (AUCs) of 121.7 ± 53.8 and 129.0 ± 39.3 μg.h/mL, respectively. Relative to fasting conditions, the extent of absorption of ritonavir from the soft gelatin capsule formulation was 13% higher when administered with a meal (615 KCal; 14.5% fat, 9% protein, and 76% carbohydrate).

Metabolism
Nearly all of the plasma radioactivity after a single oral 600 mg dose of 14C-ritonavir oral solution (n = 5) was attributed to unchanged ritonavir. Five ritonavir metabolites have been identified in human urine and feces. The isopropylthiazole oxidation metabolite (M-2) is the major metabolite and has antiviral activity similar to that of parent drug; however, the concentrations of this metabolite in plasma are low. In vitro studies utilizing human liver microsomes have demonstrated that cytochrome P450 3A (CYP3A) is the major isoform involved in ritonavir metabolism, although CYP2D6 also contributes to the formation of M-2.

Elimination
In a study of five subjects receiving a 600 mg dose of 14C-ritonavir oral solution, 11.3 ± 2.8% of the dose was excreted into the urine, with 3.5 ± 1.8% of the dose excreted as unchanged parent drug. In that study, 86.4 ± 2.9% of the dose was excreted in the feces with 33.8 ± 10.8% of the dose excreted as unchanged parent drug. Upon multiple dosing, ritonavir accumulation is less than predicted from a single dose possibly due to a time and dose-related increase in clearance.

INDICATIONS:
Treatment of HIV infection; should always be used as part of a multidrug regimen (at least three antiretroviral agents).

DOSAGE AND ADMINISTRATION:
Ritonavir is used for the treatment of HIV infection. The recommended dose for adults is 600 mg twice daily. To reduce the occurrence of side effects, ritonavir should be started at 300 mg twice daily and increased every 2-3 days by 100 mg twice daily. The recommended dose for children is 400 mg/m2 two times a day and should not exceed 600 mg two times daily. Treatment should be started at 250 mg/m2 and increased every 2-3 days by 50 mg/m2 two times daily. Ritonavir should be administered with meals.

CONTRAINDICATIONS:
Hypersensitivity to ritonavir or any component of the formulation; concurrent amiodarone, bepridil, cisapride, dihydroergotamine, ergonovine, ergotamine, flecainide, lovastatin, methylergonovine, midazolam, pimozide, propafenone, quinidine, simvastatin, St John's wort, triazolam, and voriconazole

WARNINGS AND PRECAUTIONS:
Use caution in patients with hepatic insufficiency; safety and efficacy have not been established in children <2 years of age; use caution with benzodiazepines, rifabutin, sildenafil, and certain analgesics (meperidine, piroxicam, propoxyphene). Selected HMG-CoA reductase inhibitors are contraindicated; atorvastatin should be used at the lowest possible dose, while fluvastatin or pravastatin may be safer alternatives. Ritonavir may interact with many medications. Careful review is required. Dosage adjustment is required for combination therapy with amprenavir and ritonavir; in addition, the risk of hyperlipidemia may be increased during concurrent therapy. Warn patients that redistribution of fat may occur.

PREGNANCY:
Use of ritonavir during pregnancy has not been adequately evaluated. It is not known whether ritonavir is secreted in breast milk. Nevertheless, HIV-infected

NURSING MOTHERS:
mothers should not breast-feed because of the potential risk of transmitting HIV to an infant that is not infected.

SIDE EFFECTS:
The most serious side effects are liver failure, and failure of the pancreas (pancreatitis). Ritonavir also may elevate blood glucose, triglyceride and cholesterol levels. Common symptomatic side effects of ritonavir include weakness, diarrhea, abdominal discomfort, and nausea. Less frequent effects include numbness around the mouth or in the extremities, and abnormal taste sensation.

DRUG INTERACTIONS:
Ritonavir interacts with many drugs. Some of the important interactions are mentioned below. Viewers should consult their healthcare provider before combining any drugs with ritonavir.

Ritonavir should not be used together with amiodarone, quinidine, triazolam, midazolam, pimozide, propafenone and flecainide because ritonavir increases the blood levels of these drugs and may lead to serious side effects.

Ritonavir also increases the concentrations in blood of rifabutin and sildenafil. Therefore, the doses of rifabutin and sildenafil should be reduced. The blood concentrations of oral contraceptives, methadone and theophylline are reduced by ritonavir, and this could reduce the effectiveness of these drugs. Ritonavir decreases the concentration of meperidine and increases the buildup of meperidine's toxic breakdown product in the body. Therefore, ritonavir reduces the beneficial effect of meperidine while increasing its side effects.

Ritonavir may increase the blood concentration of lovastatin, simvastatin, atorvastatin and cerivastatin. This may result in increased occurrence of myopathy (muscle pain) or rhabdomyolysis (muscle breakdown). St. John's wort and rifampin decrease the concentration of ritonavir in the body and this could reduce the effectiveness of ritonavir. Clarithromycin, ketoconazole, fluconazole and fluoxetine may increase blood concentrations of ritonavir and result in increased side effects from ritonavir.

OVERDOSAGE:
Human experience is limited; there is no specific antidote for overdose with ritonavir. Dialysis is unlikely to be beneficial in significant removal of the drug. Charcoal or gastric lavage may be useful to remove unabsorbed drug.

STORAGE CONDITIONS:
Store in a cool & dry place, protected from light.
Keep out of reach of children.

PRESENTATION:
1x60’s in HDPE containers.
1x84’s in HDPE containers.