COMPOSITION:

Each tablet contains:

Lopinavir Ritonavir 200mg 50mg

DESCRIPTION:

Lopinavir/ritonavir has demonstrated antiviral activity in the HIV-infected adult.

PHARMACOLOGY:
Lopinavir, an inhibitor of the HIV protease, prevents cleavage of the Gag-Pol polyprotein, resulting in the production of immature, non-infectious viral particles. 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 pharmacokinetic properties of lopinavir co-administered with ritonavir have been evaluated in healthy adult volunteers and in HIV-infected patients; no substantial differences were observed between the two groups. Lopinavir is essentially completely metabolized by CYP3A. Ritonavir inhibits the metabolism of lopinavir, thereby increasing the plasma levels of lopinavir. Across studies, administration of ARGA-L 400/100 mg BID yields mean steady-state lopinavir plasma concentrations 15- to 20-fold higher than those of ritonavir in HIV-infected patients. The plasma levels of ritonavir are less than 7% of those obtained after the ritonavir dose of 600 mg BID. The in vitro antiviral EC50 of lopinavir is approximately 10-fold lower than that of ritonavir. Therefore, the antiviral activity of ARGA-L is due to lopinavir.

Absorption
In a pharmacokinetic study in HIV-positive subjects (n=19), multiple dosing with 400/100 mg ARGA-LBID with food for 3 weeks produced a mean ± SD lopinavir peak plasma concentration (Cmax) of 9.8 ± 3.7 μg/mL, occurring approximately 4 hours after administration. The mean steady-state trough concentration prior to the morning dose was 7.1 ± 2.9 μg/mL and minimum concentration within a dosing interval was 5.5 ± 2.7 μg/mL. Lopinavir AUC over a 12 hour dosing interval averaged 92.6 ± 36.7 μg h/mL. The absolute bioavailability of lopinavir co-formulated with ritonavir in humans has not been established. Under nonfasting conditions (500 kcal, 25% from fat), lopinavir concentrations were similar following administration of ARGA-Lco-formulated capsules and liquid. When administered under fasting conditions, both the mean AUC and Cmax of lopinavir were 22% lower for the ARGA- Lliquid relative to the capsule formulation.

Distribution
At steady state, lopinavir is approximately 98-99% bound to plasma proteins. Lopinavir binds to both alpha-1-acid glycoprotein (AAG) and albumin; however, it has a higher affinity for AAG. At steady state, lopinavir protein binding remains constant over the range of observed concentrations after 400/100 mg ARGA-LBID, and is similar between healthy volunteers and HIV-positive patients.

Elimination
Following a 400/100 mg 14C-ARGA-L Ritonavir dose, approximately 10.4 ± 2.3% and 82.6 ± 2.5% of an administered dose of 14C-lopinavir can be accounted for in urine and feces, respectively, after 8 days. Unchanged Lopinavir accounted for approximately 2.2 and 19.8% of the administered dose in urine and feces, respectively. After multiple dosing, less than 3% of the lopinavir dose is excreted unchanged in the urine. The apparent oral clearance (CL/F) of lopinavir is 5.98 +/- 5.75 L/hr ( mean +/- SD, N=19)

INDICATIONS:
ARGA-L is indicated in combination with other antiretroviral agents for the treatment of HIV-infection. This indication is based on analyses of plasma HIV RNA levels and CD4 cell counts in controlled studies of ARGA-L of 48 weeks duration and in smaller uncontrolled dose-ranging studies of ARGA-L of 72 weeks duration.

DOSAGE AND ADMINISTRATION:
Adults The recommended dosage of ARGA-Lis 400/100 mg twice daily taken with food. Concomitant therapy: Efavirenz, nevirapine, amprenavir or nelfinavir: A dose increase of ARGA-L to 533/133 mg twice daily taken with food is recommended when used in combination with efavirenz, nevirapine, amprenavir or nelfinavir.

CONTRAINDICATIONS:
ARGA-L is contraindicated in patients with known hypersensitivity to any of its ingredients, including ritonavir. Co-administration of ARGA-L is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events. These drugs are listed in Table.Table : Drugs That Are Contraindicated With ARGA-LDrug Class Drugs Within Class That Are Contraindicated With ARGA-LAntihistamines Astemizole, Terfenadine Ergot Derivatives Dihydroergotamine, Ergonovine, Ergotamine, Methylergonovine GI motility agent Cisapride Neuroleptic Pimozide Sedative/hypnotics Midazolam, Triazolam

PRECAUTIONS:

Hepatic Impairment and Toxicity
ARGA-L is principally metabolized by the liver; therefore, caution should be exercised when administering this drug to patients with hepatic impairment, because lopinavir concentrations may be increased. Patients with underlying hepatitis B or C or marked elevations in transaminases prior to treatment may be at increased risk for developing further transaminase elevations or hepatic decomposition. There have been post marketing reports of hepatic dysfunction, including some fatalities.

Resistance/Cross-resistance
Various degrees of cross-resistance among protease inhibitors have been observed. The effect of ARGA-L therapy on the efficacy of subsequently administered protease inhibitors is under investigation.

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.

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.

Lipid Elevations
Treatment with ARGA-L has resulted in large increases in the concentration of total cholesterol and triglycerides. Triglyceride and cholesterol testing should be performed prior to initiating ARGA-L therapy and at periodic intervals during therapy. Lipid disorders should be managed as clinically appropriate. Established and Other Potentially Significant Drug Interactions for additional information on potential drug interactions with ARGA-Land HMG-CoA reductase inhibitors.

Pregnancy
No treatment-related malformations were observed when lopinavir in combination with ritonavir was administered to pregnant rats or rabbits. Embryonic and fetal developmental toxicities (early resorption, decreased fetal viability, decreased fetal body weight, increased incidence of skeletal variations and skeletal ossification delays) occurred in rats at a maternally toxic dosage (100/50 mg/kg/day). Based on AUC measurements, the drug exposures in rats at 100/50 mg/kg/day were approximately 0.7-fold for lopinavir and 1.8-fold for ritonavir for males and females that of the exposures in humans at the recommended therapeutic dose (400/100 mg BID). In a peri- and postnatal study in rats, a developmental toxicity (a decrease in survival in pups between birth and postnatal day 21) occurred at 40/20 mg/kg/day and greater.

No embryonic and fetal developmental toxicities were observed in rabbits at a maternally toxic dosage (80/40 mg/kg/day). Based on AUC measurements, the drug exposures in rabbits at 80/40 mg/kg/day were approximately 0.6- fold for lopinavir and 1.0-fold for ritonavir that of the exposures in humans at the recommended therapeutic dose (400/100 mg BID). There are, however, no adequate and well-controlled studies in pregnant women.

Nursing Mothers
The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV. Studies in rats have demonstrated that lopinavir is secreted in milk. It is not known whether lopinavir is secreted in human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving ARGA-L.

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

Pancreatitis has been observed in patients receiving ARGA-L, including those who developed marked triglyceride elevations; in some cases, fatalities have occurred. Although a causal relationship with ARGA-L has not been established, marked triglyceride elevation is a risk factor in the development of pancreatitis.

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 during ARGA-L therapy. Pancreatitis should be considered if clinical symptoms suggestive of pancreatitis occur, including nausea, vomiting, abdominal pain, or abnormal laboratory values such as increased serum lipase or amylase. Patients who exhibit these signs or symptoms should be evaluated and ARGA-Lor other antiretroviral therapy should be suspended.

DRUG INTERACTIONS:
ARGA-L can be administered with or without food. ARGA-L induces glucuronidation and has the potential to reduce plasma concentrations of zidovudine or abacavir concentrations if these drugs are taken concurrently. Concentrations of antiarrhythmic drugs (amiodarone, bepridil, lidocaine, and quinidine) may be increased if taken concurrently with ARGA-L; therapeutic monitoring of antiarrhythmic concentration may be necessary.

Concomitant use of ARGA-L with lipid lowering agents will result in an increase of concentrations of these agents. Levels of atorvastatin or cerivastatin should be lowered to the lowest possible level when used in combination with ARGA-L. Pravastatin or fluvastatin should be considered as substitutes for atorvastatin or cerivastatin.

Concomitant use of lovastatin or simvastatin with ARGA-Lis not recommended, as serious reactions such as myopathy, including rhabdomyolysis, may occur. Concurrent use of carbamazepine, dexamethasone, phenobarbital or phenytoin with ARGA-Lmay decrease concentrations of lopinavir and lead to decreased effectiveness of lopinavir.

Serum concentrations of clarithromycin may increase if administered concomitantly with ARGA-L. In patients concurrently taking clarithromycin, doses of ARGA-Lshould be decreased as necessary in patients with renal impairment.

Concentrations of cyclosporine, sirolimus, and tacrolimus may increase if administered concomitantly with ARGA-L. Therapeutic monitoring is recommended for patients taking any of these immunosuppressants concurrently with ARGA- L.

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

PRESENTATION:
1x60's in HDPE containers. 1x120's in HDPE containers.