ALUVIA TM. Lopinavir/ritonavir tablets

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1 ALUVIA TM Lopinavir/ritonavir tablets DESCRIPTION Lopinavir is a co-formulation of lopinavir and ritonavir. Lopinavir is an inhibitor of the HIV-1 and HIV- 2 proteases. As co-formulated in lopinavir/ritonavir, ritonavir inhibits the CYP3Amediated metabolism of lopinavir, thereby providing increased plasma levels of lopinavir. Lopinavir is a white to light tan powder. It is freely soluble in methanol and ethanol, soluble in isopropanol and practically insoluble in water. Lopionavir is chemically designated as [1S-[1R*, (R*), 3R*, 4R*]]-N-[4-[[2,6-dimethylphenoxy)acetyl]amino]-3-hydroxy-5-phenyl-1- (phenylmethyl)pentyl]tetrahydro-alpha-(1-methylethyl)-2-oxo-1(2h)-pyrimidineacetamide. Its molecular formula is C37H48N4O5, and its molecular weight is Lopinavir has the following structural formula: Ritonavir is chemically designated as 10-Hydroxy-2-methyl-5-(1-methylethyl)-1-[2-(1-methylethyl)-4- thiazolyl]-3,6-dioxo-8,11-bis(phenylmethyl)-2,4,7,12-tetraazatridecan-13-oic acid, 5-thiazolylmethyl ester, [5S-(5R*, 8R*, 10R*, 11R*)]. Its molecular formula is C37H48N6O5S2, and its molecular weight is Ritonavir has the following structural formula: Lopinavir/ritonavir film coated tablets are available for oral adminstration in a strength of 200 mg of lopinavir and 50 mg of ritonavir with the following inactive ingredients: copovidone, sorbitan laurate (for U.S. and Puerto Rico: sorbitan monolaurate), colloidal anhydrous silica (for U.S. and Puerto Rico: colloidal silicon dioxide), and sodium stearyl fumarate. The following are the ingredients in the film coating: Red tablet: Hypromellose, titanium dioxide, macrogols type 400, hydroxypropyl cellulose, talc, colloidal anhydrous silica, macrogols type 3350, red ferric oxide E172, and polysorbate 80.

2 CLINICAL PHARMACOLOGY Microbiology Mechanism of action Lopinavir, an inhibitor of the HIV-1 and HIV-2 proteases, prevents cleavage of the gag-pol polyprotein, resulting in the production of immature, non infectious virus. Antiviral activity in vitro The in vitro antiviral activity of lopinavir against laboratory HIV strains and clinical HIV isolates was evaluated in acutely infected lymphoblastic cell lines and peripheral blood lymphocytes, respectively. In the absence of human serum, the mean 50% effective concentration (EC50) of lopinavir against five different HIV-1laboratory strains ranged from 10 to 27 nm (0.006 to mcg/ml, 1 mcg/ml equals 1.6 microm) and ranged from 4 to 11nM (0.003 to mcg/ml) against several HIV-1 clinical isolates (n equals 6). In the presence of 50% human serum, the mean EC50 of lopinavir against these five laboratory strains ranged from 65 to 289 nm (0.04 to 0.18 mcg/ml), representing a 7-to 11-fold attenuation. Combination drug activity studies with lopinavir and other protease inhibitors or reverse transcriptase inhibitors have not been completed. Resistance HIV-1 isolates with reduced susceptibility to lopinavir have been selected in vitro. The presence of ritonavir does not appear to influence the selection of lopinavir-resistant viruses in-vitro. The selection of resistance to lopinavir/ritonavir in antiretroviral treatment naive patients has not yet been characterized. In a Phase III study of 653 antiretroviral treatment naive patients (Study 863), plasma viral isolates from each patient on treatment with plasma HIV greater than 400 copies/ml at week 24, 32, 40 and/or 48 were analyzed. No evidence of genotypic or phenotypic resistance to lopinavir/ritonavir was observed in 37 evaluable lopinavir/ritonavir - treated patients (0%). Evidence of genotypic resistance to nelfinavir, defined as the presence of the D30N and/or L90M mutation in HIV protease, was observed in 25/76 (33%) of evaluable nelfinavir treated patients. The selection of resistance to lopinavir/ritonavir in atiretroviral treatment naive pediatric patients (Study 940) appears to be consistent with that seen in adult patients (Study 863). Resistance to lopinavir/ritonavir has been noted to emerge in patients treated with other protease inhibitor prior to lopinavir/ritonavir therapy. In Phase II studies of 227 antiretroviral treatment naive and protease inhibitors experienced patients, isolates from 4 of 23 patients with quantifiable (greater than 400 copies/ml) viral RNA following treatment with lopinavir/ritonavir for 12 to 100 weeks displayed significantly reduced susceptibility to lopinavir compared to the corresponding baseline viral isolates. Three of these patients had previously received treatment with a single protease inhibitor (nelfinavir, indinavir, or saquinavir) and one patient had received treatment with multiple protease inhibitors (indinavir, saquinavir and ritonavir). All four of these patients had at least four mutations associated with protease inhibitor resistance immediately prior to lopinavir/ritonavir therapy. Following viral rebound, isolates from these patients all contained additional mutations, some of which are recognized to be associated with protease inhibitor resistance. However, there are insufficient data at this time to identify lopinavir associated mutational patterns in isolates from patients on lopinavir/ritonavir therapy. The assessment of these mutational patterns is under study. Cross-resistance Preclinical Studies Varying degrees of cross-resistance have been observed among protease inhibitors. The invitro

3 activity of lopinavir against clinical isolates from patients previously treated with a single protease inhibitor was determined. Isolates that displayed greater than 4-fold reduced susceptibility to nelfinavir (n=13) and saquinavir (n=4), displayed less than 4-fold reduced susceptibility to lopinavir. Isolates with greater than 4-fold reduced susceptibility to indinavir (n=16) and ritonavir (n=3) displayed a mean of 5.7- and 8.3-fold reduced susceptibility to lopinavir, respectively. Isolates from patients previously treated with two or more protease inhibitors showed greater reductions in susceptibility to lopinavir, as decribed in the clinical section below (Clinical Studies: Antiviral Activity of lopinavir/ritonavir in Patients With Previous Protease Inhibitor Therapy). Cross-Resistance During lopinavir/ritonavir Therapy Little information is available on the cross-resistance of viruses selected during therapy with lopinavir/ritonavir. Isolates from four patients previously treated with one or more protease inhibitors that developed increased lopinavir phenotypic resistance during lopinavir/ritonavir therapy either remained cross-resistant or developed cross-resistance to ritonavir, indinavir, and nelfinavir. All rebound viruses either remained fully sensitive or demonstrated modestly reduced sysceptibility to amprenavir (up to 8.5-fold concurrent with 99-fold resistance to lopinavir). The rebound isolates from the two subjects with no prior saquinavir treatment remained fully sensitive to saquinavir. Genotypic Correlates of Reduced Phenotypic Susceptibility to Lopinavir in Viruses Selected By Other Protease Inhibitors The in vitro antiviral activity of lopinavir against 112 clinical isolates taken from patients with HIV RNA greater than 1000 copies/ml despite previous therapy with one or more protease inhibitors was assassed. Within this panel, the following mutations in HIV protease were associated with reduced in vitro susceptibility to lopinavir: (L10F/I/R/V, K20M/R, L241, M461/L, F53L, I54L/T/V, L63P, A71I/L/T/V, V82A/F/T, I84V and L90M). The median EC50 of lopinavir as a function of the number of the above mutations is shown in Figure1 below. The 16 viruses that displayed greater than 20-fold change in susceptibility all contained mutation sat positions 10, 54, 63 plus 82 and/or 84. In addition, they contained a median of three mutations at amino acid positions 20, 24, 46, 53, 71 and 90. Figure 1 Clinical Studies Antiviral Activity of lopinavir/ritonavir in Patients With Previous Protease Inhibitor Therapy The clinical relevance of reduced in vitro susceptibility to lopinavir has been examined by assessing the virologic response to lopinavir/ritonavir therapy, with respect to baseline viral

4 genotype and phenotype, in 56 NNRTI-naive patients with HIV RNA greater than 1000 copies/ml despite previous therapy with at least two protease inhibitors selected from nelfinavir, indinavir, saquinavir, and ritonavir (Study M98-957). In this study, patients were initially randomized to receive one of two doses of lopinavir/ritonavir in combination with efavirenz and nucleoside reverse transcriptase inhibitors. The EC50 values of lopinavir against the 56 baseline viral isolates ranged from 0.5- to 96-fold higher than the EC50. against wild-type HIV. Fifty-five percent (31/56) of these baseline isolates displayed a greater than 4-fold reduced susceptibility to lopinavir. These 31 isolates had a mean reduction in lopinavir susceptibility of fold. After 48 weeks of treatment with lopinavir/ritonavir, efavirenz and nucleoside reverse transcriptase inhibitors, plasma HIV RNA less than or equal to 400 copies/ml was observed in 93% (25/27), 73% (11/15), and 25% (2/8) of patients with less than or equal to 10-fold, greater than 10 and less than 40 -fold, and greater than or equal to 40-fold reduced susceptibility to lopinavir at baseline, respectively. Lopinavir susceptibility was determined by recombinat phenotypic technology performed by Virologic; genotype also performed by Virologic. Plasma HIV RNA less than or equal to 50 copies/ml was observed in 81% (22/27), 60% (9/15), and 25% (2/8) in the above groups of patients, respectively. In addition, plasma HIV RNA less than or equal to 400 copies/ml was observed in 91% (21/23), of patients whose baseline viral isolates contained up to and including five mutations recognized to be associated with protease inhibitor resistance. Thirteen of those 23 isolates contained protease mutations at positions 82, 84, and/or 90. Plasma HIV RNA less than or equal to 400 copies/ml was observed in 63% (17/27) of patients whose baseline viral isolates contained six or more mutations, including those at positions 82, 84, and/or 90 plus multiple other mutations. Plasma HIV RNA less than or equal to 50 copies/ml was observed in 83% (19/23) and 52% (14/27) in the groups of patients whose baseline isolates contained less than or equal to five and greater than five of the above mutations, respectively. There are insufficient data at this time to identify lopinavir-associated mutational patterns in isolates from patients on lopinavir/ritonavir therapy. Further studies are needed to assess the association between specific mutational patterns and virologic response rates. 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, threby increasing the plasma levels of lopinavir. Across studies, administration of lopinavir/ritonavir 400/100 mg B.I.D. 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 B.I D.. The in vitro antiviral EC50 of lopinavir is approximately 10-fold lower than that of ritonavir. Therefore, the antiviral activity of Kaletra is due to lopinavir. Figure 2 displays the mean steady-state plasma concentrations of lopinavir and ritonavir after lopinavir/ritonavir 400/100 mgb.i.d. with food for three weeks from a pharmacokinetic study in HIVinfected adult subjects (n=19). Figure 2

5 Mean Steady-State Plasma Concentrations with 95% Confidence Intervals (CL) for HIV Infected Adult Subjects (N = 19) Plasma concentrations of lopinavir and ritonavir after administration of two 200/50 mg tablets are equivalent to three 133/33 mg capsules under fed conditions with less pharmacokinetic variability. Absorption In a pharmacokinetic study in HIV-positive subjects (n=19), multiple dosing with 400/100 mg lopinavir/ritonavir B.I.D with food for three weeks produced a mean ± SD lopinavir peak plasma concentration (Cmax) 0f 9.8 ± 3.7 mcg/ml, occuring approximately four hours after administration. The mean steady-state trough concentration prior to the morning dose was 7.1 ± 2.9 mcg/ml and minimum concentration within a dosing interval was 5.5 ± 2.7 mcg/ml. Lopinavir AUC over a 12- hour dosing interval averaged 92.6 ± 36.7 mcg h/ml. The absolute bioavailability of lopinavir coformulated with ritonavir in humans has not been established. Effects of Food on Oral Absorption Administration of a single 400/100 mg dose of lopinavir/ritonavir tablets under fed conditions (highfat, 872 kcal, 56% from fat) compared to the fasted state was associated with no significant changes in Cmax and AUCinf, therefore, lopinavir/ritonavir tablets may be taken with or without food. Lopinavir/ritonavir tablets have also shown less pharmacokinetic variability under all meal conditions compared to the lopinavir/ritonavir capsule. Distribution At steady state, lopinavir is approximately 98 to 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 lopinavir/ritonavir B.I.D., and is similar between healthy volunteers and HIVpositive patients. Metabolism In vitro experiments with human hepatic microsomes indicate that lopinavir primarily undergoes oxidative metabolism. Lopinavir is extensively metabolized by the hepatic cytochrome P450 system, almost exclusively by the CYP3A isozyme. Ritonavir is potent CYP3A inhibitor, which inhibits the metabolism of lopinavir, and therefore increases plasma levels of lopinavir. A 14 Clopinavir study in

6 humans showed that 89% of the plasma radioactivity after a single 400/100 mg lopinavir/ritonavir dose was due to parent drug. At least 13 lopinavir oxidative metabolites have been identified in man. Ritonavir has been shown to induce metabolic enzymes, resulting in the induction of its own metabolism. Pre-dose lopinavir concentrations decline with time during multiple dosing, stabilizing after approximately 10 to 16 days. Elimination Following a 400/100 mg 14C-lopinavir/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 eight 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 / L/hr (mean +/- SD, N=19). Once Daily Dosing The pharmacokinetics of once daily lopinavir/ritonavir has been evaluated in HIV-infected subjects naive to antiretroviral treatment. Lopinavir/ritonavir 800/200 mg was administered in combination with emtricitabine 200 mg and tenofovir DF 300 mg as part of once daily regimen. Multiple dosing of 800/200 mg lopinavir/ritonavir once daily for 4 weeks with food (n=24) produced a mean ± SD lopinavir peak plasma concentration (Cmax) of 11.8 ± 3.7 µg/ml, occuring approximately 6 hours after administration. The mean steady-state lopinavir trough concentration prior to the morning dose was 3.2 ± 2.1 µg/ml and minimum concentration within a dosing interval was 1.7 ± 1.6 µg/ml. Lopinavir AUC over a 24-hour dosing interval averaged ± 61.4 µg h/ml Special Population Gender, Race and Age Lopinavir pharmacokinetics have not been studied in elderly patients. No gender related pharmacokinetic differences have been observed in adult patients. No clinically important pharmacokinetic differences due to race have been identified. Pediatric Patients The pharmacokinetics of lopinavir/ritonavir 300/75 mg/m2 B.I.D. and 230/57.5 mg/m2 B.I.D. have been studied in a total of 53 pediatric patients, ranging in age from six months to 12 years. The 230/57.5 mg/m2 B.I.D. regimen without nevirapine and the 300/75 mg/m2 B.I.D. regimen with nevirapine provided lopinavir plasma concentrations similar to those obtained in adult patients receiving the 400/100 mg B.I.D. regimen (without nevirapine). Lopinavir/ritonavir once daily has not been evaluated in pediatric patients. The lopinavir mean steady-state AUC, Cmax, and Cmin were 72.6 ± 31.1mcg h/ml, 8.2 ± 2.9 and 3.4 ± 2.1 mcg/ml, respectively after lopinavir/ritonavir 230/57.5 mg/m2 B.I.D. without nevirapine (n=12), and were 85.8 ± 36.9 mcg h/ml, 10.0 ± 3.3 and 3.6 ± 3.5 mcg/ml, respectively after 300/75 mg/m2 B.I.D. with nevirapine (n=12). The nevirapine regimen was 7 mg/kg B.I.D. (six months to eight years) or 4 mg/kg B.I.D. (greater than eight years). Renal Insufficiency Lopinavir pharmacokinetics have not been studied in patients with renal insufficiency; however, since the renal clearance of lopinavir is negligible, a decrease in total body clearance is not

7 expected in patients with renal insufficiency. Hepatic Impairment Lopinavir is principally metabolized and eliminated by the liver. Multiple dosing of lopinavir/ritonavir 400/100 mg twice daily to HIV and HCV co-infected patients with mild to moderate hepatic impairment resulted in a 30% increase in lopinavir AUC and 20% increase Cmax compared to HIVinfected subjects with normal hepatic function. Additionally, the plasma protein binding of lopinavir was lower in both mild and moderate hepatic impairment compared to controls (99.09 vs % respectively). Lopinavir/ritonavir has not been studied in patients with severe hepatic impairment (see PRECAUTIONS). Drug-Drug Interactions (See also CONTRAINDICATIONS, WARNINGS and PRECAUTIONS: Drug Interactions.) Lopinavir/ritonavir is an inhibitor of the P450 isoform CYP3A in vitro. Coadministration of lopinavir/ritonavir and drugs primarily metabolized by CYP3A may result in increased plasma concentrations of the other drug, which could increase or prolong its therapeutic and adverse effects (see CONTRAINDICATIONS). Lopinavir/ritonavir does not inhibit CYP2D6, CYP2C9, CYP2C19, CYP2E1, CYP2B6 or CYP1A2 at clinically relevant concentrations. Lopinavir/ritonavir has been shown in vivo to induce its own metabolism and to increase the biotransformation of some drugs metabolized by cytochrome P450 enzymes and by glucuronidation. Lopinavir/ritonavir is metabolized by CYP3A. Drugs that induce CYP3A activity would be expected to increase the clearance of lopinavir, resulting in lowered plasma concentrations of lopinavir. Although not noted with concurrent ketoconazole, coadministration of lopinavir/ritonavir and other drugs that inhibit CYP3A may increase lopinavir plasma concentrations. Drug interaction studies were performed with lopinavir/ritonavir and other drugs likely to be coadministered and some drugs commonly used as probes for pharmacokinetic interactions. The effects of coadministration of lopinavir/ritonavir on the AUC, Cmax and Cmin are summarized in Table1 (effect of other drugs on lopinavir) and Table 2 (effect of lopinavir/ritonavir on other drugs). The effect of other drugs on ritonavir are not shown since they generally correlate with those observed with lopinavir (if lopinavir concentrations are decreased, ritonavir concentrations are decreased) unless otherwise indicated in the table footnotes. For information regarding clinical recommendations, see PRECAUTIONS. Table 1 Drug interactions Pharmacokinetic Parameters for Lopinavir in the Presence of the Coadministered Drug (see PRECAUTIONS for Recommended Alterations in Dose or Regimen)

8 Coadministered Drug Dose of Coadministered Drug (mg) Dose of lopinavir/ritonavir (mg) n Ratio (with/without coadministered drug) of Lopinavir Pharmacokinetic Parameters (90% CI); No Effect = 1.00 C max AUC C min Amprenavir 750 B.I.D.; 10 d B.I.D, 21 d (0.65, 0.79) 0.62 (0.56, 0.70) 0.43 (0.34, 0.56) Atorvastotin 20 QD; 4 d B.I.D, 14 d (0.78, 1.06) 0.90 (0.79, 1.02) 0.92 (0.78, 1.10) Efavirenz QHS; 9 d 600 QHS; 9 d B.I.D, 9 d 600/150 capsule B.I.D, 10 d 11 7* (0.78, 1.22) 1.36 ( ) 0.81 (0.64, 1.03) 1.36 (1.28 -, 1.44) 0.61 (0.38, 0.97) 1.32 (1.21, 1.44) Ketoconazole 200 single dose B.I.D, 16 d (0.80, 0.99) 0.87 (0.75, 1.00) 0.75 (0.55, 1.00) Nelfinavir 100 B.I.D.; 10 d B.I.D, 21 d (0.70, 0.89) 0.73 (0.63, 0.85) 0.62 (0.49, 0.78) Nevirapine 200 BID, steady-state (>1 yr) 2 B.I.D, 7 mg/kg or 4 mg/kg QD, 2 wk; B.I.D. 1 wk 3 steady-state (> 1 yr) 300/75 mg/m 2 oral solution B.I.D, 3 wk 22 19* 12 15* 0.81 (0.62, 1.05) 0.86 (0.64, 1.16) 0.73 (0.53, 0.98) 0.78 (0.56, 1.09) 0.49 (0.28, 0.74) 0.45 (0.25, 0.81) Omeprazole 40 QD, 5 d 400/100 tablet B.I.D., 10 d 800/200 tablet Q.D., 10 d (0.99, 1.17) 0.94 (0.88, 1.00) 1.07 (0.99, 1.15) 0.92 (0.86, 0.99) 1.03 (0.90, 1.18) 0.71 (0.57, 0.89) Pravastin 20 QD; 4 d B.I.D., 14 d (0.89, 1.08) 0.95 (0.85, 1.05) 0.88 (0.77, 1.02) Ranitidine 150 single dose 400/100 tablet B.I.D., 10 d 800/200 tablet Q.D., 10 d (0.95, 1.02) 0.98 (0.95, 1.01) 0.98 (0.94, 1.01) 0.96 (0.90, 1.02) 0.93 (0.89, 0.98) 0.85 (0.67, 1.08)

9 Rifabutin Rifampin Ritonavir QD; 10 d 600 QD, 10 d 600 QD, 14 d 600 QD, 14 d 100 B.I.D.; 3 to 4 wk B.I.D., 20 d B.I.D., 20 d /200 capsule B.I.D., 9 d /400 capsule B.I.D., 9 d 5 9 B.I.D., 3 to 4 wk 8 21* 1.08 (0.97, 1.19) 0.45 (0.40, 0.51) 1.02 (0.85, 1.23) 0.93 (0.81, 1.07) 1.28 (0.94, 1.76) 1.17 (1.04, 1.31) 0.25 (0.21, 0.29) 0.84 (0.64, 1.10) 0.98 (0.81, 1.17) 1.20 (0.96, 1.65) 0.01 (0.01, 0.02) 0.43 (0.19, 0.96) 1.03 (0.68, 1.56) Co-administration of lopinavir/ritonavir and rifampin is not recommended. (see PRECAUTIONS) 1.46 (1.04, 2.06) 2.16 (1.29, 3.62) All interaction studies conducted in healthy, HIV-negative subjects unless otherwise indicated. 1. The pharmacokinetics of ritonavir are unaffected by concurrent efavirenz. 2. Study conducted in HIV-positive adult subjects 3. Study conducted in HIV-positive pediatric subjects ranging in age from 6 months to 12 years 4. Titrated to 800/200 B.I.D as 533/133 BID x 1 d, 667/167 BID x 1 d, then 800/200 BID x 7 d, compared to 400/100 BID x 10 days alone. 5. Titrated to 400/400 BID as 400/200 BID x 1 d, 400/300 BID x 1 d, then 400/400 BID x 7 d, compared to 400/100 BID x 10 days alone. *Parallel group design; n for lopinavir/ritonavir + coadministered drug, n for lopinavir/ritonavir alone Table 2 Drug interactions Pharmacokinetic Parameters for Coadministered Drug in the Presence of lopinavir/ritonavir (see PRECAUTIONS for Recommended Alterations in Dose or Regimen) Coadministered Drug Dose of Coadministered Drug (mg) Dose of lopinavir/ritonavir (mg) n Ratio (with/without lopinavir/ritonavir) of Coadministered Drug Pharmacokinetic Parameters (90% CI); No Effect = 1.00 C max AUC C min Amprenavir BID, 10 d combo vs BID, 14 d alone B.I.D, 21 d (0.91, 1.39) 1.72 (1.41, 2.09) 4.57 (3.51, 5.95)

10 Atorvastatin 20 QD; 4 d B.I.D, 14 d (3.35, 6.51) 5.88 (4.69, 7.37) 2.28 (1.91, 2.71) Desipramine single dose B.I.D, 10 d (0.84, 0.97) 1.05 (0.96, 1.16) NA Efavirenz 600 QHS; 9 d B.I.D, 9 d 11 12* 0.91 (0.72, 1.15) 0.84 (0.62, 1.15) 0.84 (0.58, 1.20) Ethinyl Estradiol 35 mcg QD; 21 d (Ortho Novum ) B.I.D, 14 d (0.52, 0.66) 0.58 (0.54, 0.62) 0.42 (0.36, 0.49) Indinavir BID, 10 d combo nonfasting vs. 800 TID, 5 d alone fasting B.I.D, 15 d (0.63, 0.81) 0.91 (0.75, 1.10) 3.47 (2.60, 4.64) Ketoconazole 200 single dose B.I.D, 16 d (0.91, 1.40) 3.04 (2.44, 3.79) NA Methadone 5 single dose B.I.D, 10 d (0.48, 0.64) 0.47 (0.42, 0.53) NA Nelfinavir BID, 10 d combo vs BID, 14 M8 metabolite d alone B.I.D, 21 d (0.82, 1.05) 2.36 (1.91, 2.91) 1.07 (0.95, 1.19) 3.46 (2.78, 4.31) 1.86 (1.57, 2.22) 7.49 (5.85, 9.58) Nevirapine 200 QD, 14 d; B.I.D., 6 d B.I.D, 20 d 5.6* 1.05 (0.72, 1.52) 1.08 (0.72, 1.64) 1.15 (0.71, 1.86) Norethindrone 1 QD, 21 d (Ortho Novum ) B.I.D., 20 d 12* 0.84 (0.75, 0.94) 0.83 (0.73, 0.94) 0.68 (0.54, 0.85) Pravastin 20 QD; 4 d B.I.D., 14 d (0.87, 1.83) 1.33 (0.91, 1.94) NA Rifabutin 25- Odesacetyl rifabutin 150 QD 10 d combo vs. 300 QD, 10 d; alone B.I.D., 10 d (1.89, 2.38) 23.6 (13.7, 25.3) 3.03 (2.79, 3.30) 47.5 (29.3, 51.8) 4.90 (3.18, 5.76) 94.9 (74.0, 122)

11 Rifabutin + 25-Odesacetyl rifabutin 3 Saquinavir BID, 10 d combo vs TID, 5 d alone 1200 BID, 5 d combo vs TID 5 d alone B.I.D., 15 d B.I.D., 20 d (3.07, 3.91) 6.34 (5.32, 7.55) 6.44 (5.59, 7.41) 5.73 (5.08, 6.46) 9.62 (8.05, 11.49) 9.91 (8.28, 11.86) 9.53 (7.56, 12.01) (13.73, 20.42) (10.91, 25.08) All interaction studies conducted in healthy, HIV-negative subjects unless otherwise indicated. 1. Ratio of parameters for amprenavir, indinavir, nelfinavir, and saquinavir are not normalized for dose. 2. Desipramine is a probe substrate for assessing effects on CYP2D6-mediated metabolism. 3. Effect on the dose-normalized sum of rifabutin parent and 25-O-desacetyl rifabutin active metabolite *Parallel group design; n for lopinavir/ritonavir + coadministered drug, n for coadministered drug alone TOXICOLOGY Acute, Subacute and Chronic Toxicity Repeat-dose toxicity studies in rodents and dogs identified major target organs as the liver, kidney, thyroid, spleen and circulating red blood cells. Hepatic changes indicated cellular swelling with focal degeneration. While exposure eliciting these changes were comparable to human clinical exposure, dosages in animals were over 6-fold the recommended clinical dose. Mild renal tubular degeneration was confined to mice exposed with at least twice the recommended human exposure; the kidney was unaffected in rats and dogs. Reduced serum thyroxine led to an increased release of TSH with resultant follicular cell hypertrophy in the thyroid glands of rats. These changes were reversible with withdrawal of the active substance and were absent in mice and dogs. Coombs-negative anisocytosis and poikilocytosis were observed in rats, but not in mice or dogs. Enlarged spleens with histiocytosis were seen in rats but not other species. Serum cholesterol was elevated in rodents but not dogs, while triglycerides were elevated only in mice. INDICATIONS AND USAGE Lopinavir/ritonavir is indicated in combination with other antiretroviral agents for the treatment of HIV-infection as a second line treatment. This indication is based on analyses of plasma HIV RNA levels and CD4 cell counts in a controlled study of lopinavir/ritonavir of 48 weeks duration, and in smaller uncontrolled dose-ranging studies of lopinavir/ritonavir of weeks duration. At present, there are no results from controlled trials evaluating the effect of Lopinavir/ritonavir on clinical progression of HIV. Once daily administration of lopinavir/ritonavir has not been studied in therapy-experienced patients. Description of Clinical Studies

12 Patients Without Prior Antiretroviral Therapy Study M98-863: lopinavir/ritonavir B.I.D. + stavudine + lamivudine compared to nelfinavir TID + stavudine + lamivudine. Study M is an ongoing, randomized, double -blind, multicenter trial comparing treatment with lopinavir/ritonavir (400/100 mg B.I.D.) plus stavudine and lamivudine versus nelfinavir (750 mg TID) plus stavudine and lamivudine in 653 antiretroviral treatment naive patients. Patients had a mean age of 38 years (range: 19 to 84), 57% were Caucasian, and 80% were male. Mean baseline CD4 cell count was 259 cells/mm3 (range: 2 to 949 cells/mm3) and mean baseline plasma HIV-1 RNA was 4.9 log10 copies/ml (range: 2.6 to 6.8 log10 copies/ml). Treatment response and outcomes of randomized treatment are presented in Figure 3 and Table 3, respectively. Figure 3 Treatment Response Through 48 Weeks* (Study 863) *Proportion of patients at each time point who achieved and maintained HIV RNA less than 400 copies/ml, are on their original study medication, and have not experienced a new CDC Class C event Table 3 Outcomes of Randomized Treatment Through Week 48 (Study 863) Outcome lopinavir/ritonavir + d4t +3TC (N=326) Nelfinavir + d4t + 3TC(N=327) Responder 1 75% 62% Virologic failure 2 9% 25% Rebound 7% 15% Never suppressed through Week 48 2% 9% Death 2% 1% Discontinued due to adverse event 4% 4%

13 Discontinued for other reasons 3 10% 8% 1 Corresponds to rates at week 48 in Figure Patients achieved and maintained confirmed HIV RNA <400 copies/ml through Week 48 Includes confirmed viral rebound and failure to achieve confirmed <400 copies/ml through Week 48>Includes lost to follow-up, patient's withdrawal, non compliance, protocol violation and other reasons Overall discontinuation through week 48, including patients who discontinued subsequent to virologic failure, was 17% in the lopinavir/ritonavir arm and 24% in the nelfinavir arm Through 48 weeks of therapy, there was a statistically significantly higher proportion of patients in the lopinavir/ritonavir arm compared to the nefinavir arm with HIV RNA less than 400 copies/ml (75% vs. 62%, respectively) and HIV RNA less than 50 copies/ml (67% vs. 52%, respectively). Treatment response by baseline HIV RNA level subgroups is presented in Table 4. Baseline Viral Load (HIV-1 RNA copies/ml) Lopinavir/ritonavir + d4t + 3TC Nelfinavir + d4t + 3TC <400copies/mL 1 <50copies/mL 2 n <400copies/mL 1 <50copies/mL 2 n <30,000 74% 71% 82 79% 72% 87 =30,000 to <100,000 =100,000 to <250,000 81% 73% 79 67% 54% 79 75% 64% 83 60% 47% 72 =250,000 72% 60% 82 44% 33% 89 1 Patients achieved and mantained confirmed HIV RNA <400 copies/ml through Week Patients achieved HIV RNA <50 copies/ml at Week 48 Through 48 weeks of therapy, the mean increase from baseline in CD4 cell count was 207 cells/mm3 for the lopinavir/ritonavir arm and 195 cells/mm3 for the nelfinavir arm. Figure 4 displays the Kaplan-Meier estimates of the time to treatment failure in Study 863. The time of treatment failure was defined as the earliest time a patient experienced virologic failure (two consecutive HIV RNA values demonstrating rebound above 400 copies/ml), a new CDC Class C event, or premature discontinuation from the study. Figure 4 Time to Treatment Failure (Study 863)

14 Study M97-720: lopinavir/ritonavir B.I.D. + Stavudine + lamivudine Study M was a randomized, blinded, multicenter trial evaluating treatment with lopinavir/ritonavir at three dose levels (Group I: 200/100 mg B.I.D. and 400/100 mg B.I.D.; Group II: 400/100 mg B.I.D. and 400/200 mg B.I.D.) plus lamivudine (150 mg B.I.D.) and stavudine (40 mg B.I.D.) in 100 patients. All patients were converted to open label lopinavir/ritonavir at the 400/100 mg B.I.D. dose between weeks 48 and 72 of the study. Patients had a mean age of 35 years (range: 21 to 59), 70% were Caucasian, and 96% were male. Mean baseline CD4 cell count was 338 cells/mm3 (range: 3 to 918 cells/mm3) and mean baseline plasma HIV-1 RNA was 4.9 log10 copies/ml (range: 3.3 to 6.3 log10 copies/ml). Through 360 weeks of treatment in study 720, the proportion of patients with HIV RNA less than 400 (less than 50) copies/ml was 61% (59%) [n=100], and the corresponding mean increase in CD4 cell count was 501 cells/mm3. Thirty-nine patients (39%) discontinued the study, including 15 (15%) discontinuations due to adverse events and 1 (1%) death. 18 patients demonstrated loss of virologic response (two consecutive rebound HIV-1 RNA values above 400 copies/ml, one rebound HIV-1 RNA value followed by discontinuation, or failure to achieve HIV RNA <400 copies/ml. Genotypic analysis of viral isolates was conducted on these patients and 10 additional patients with isolated HIV-1 RNA values >400 copies/ml after week 24. Results were available from 19 patients and confirmed no primary or active site mutations in protease (amino acids at positions 8, 30, 32, 36, 47, 48, 50, 82, 84 and 90) or protease inhibitor phenotypic resistance. Study M02-418: Lopinavir/ritonavir once daily + tenofovir DF + emtricitabine compared to Lopinavir/ritonavir twice daily + tenofovir DF + emtricitabine Study 418 was a randomized, open label, multicenter trial comparing treatment with Lopinavir/ritonavir 800/200 mg once-daily plus tenofovir DF and emtricitabine versus Lopinavir/ritonavir 400/100 mg twice-daily plus tenofovir DF and emtricitabine in 190 antiretroviral treatment naive patients. Patients had a mean age of 39 years (range: 19 to 75), 54% were Caucasian, and 78% were male. Mean baseline CD4 cell count was 260 cells/mm3 (range: 3 to 1006 cells/mm3) and mean baseline plasma HIV-1 RNA was 4.8 log10 copies/ml (range: 2.6 to 6.4 log10 copies/ml). Treatment response and outcomes of randomized treatment are presented in Table 5 Table 5 Outcomes of Randomized Treatment Through Week 48 (Study 418)

15 Outcome Lopinavir/ritonavir once daily + TDF +FTC (n=115) Lopinavir/ritonavir twice daily + TDF +FTC (n=75) Responder 1 71% 65% Virologic failure 2 10% 9% Rebound 6% 5% Never suppressed through Week 48 3% 4% Death 0% 1% Discontinued due to adverse event 12% 7% Discontinued for other reasons 3 7% 17% 1 Patients achieved and maintained confirmed HIV RNA < 50 copies/ml through Week Includes confirmed viral rebound and failure to achieve confirmed < 50 copies/ml through Week 48 Includes lost to follow-up, patient's withdrawal, non compliance, protocol violation and other reasons Through 48 weeks of therapy, 71% in the lopinavir/ritonavir once daily arm and 65% in the lopinavir/ritonavir twice daily arm achieved and maintained HIV RNA < 50 copies/ml (95% confidence interval for the difference, -7.6% to 19.5%). Mean CD4 cell count increases at Week 48 were 185 cells/mm3 for the lopinavir/ritonavir once daily arm and 196 cells/mm3 for the lopinavir/ritonavir twice daily arm. Patients with Prior Antiretroviral Therapy Study M98-888: Lopinavir / ritonavir B.I.D. + nevirapine + NRTIs compared to investigatorselected protease inhibitor(s) + nevirapine + NRTIs Study 888 a randomized, open-label, multicenter trial comparing treatment with lopinavir/ritonavir (400/100 mg BID) plus nevirapine and nucleoside reverse transcriptase inhibitors versus investigator-selected protease inhibitor(s) plus nevirapine and nucleoside reverse transcriptase inhibitors in 288 single protease inhibitor-experienced, non-nucleoside reverse transcriptase inhibitor (NNRTI)-naive patients. Patients had a mean age of 40 years (range: 18 to 74), 68% were Caucasian, and 86% were male. Mean baseline CD4 cell count was 322 cells/mm 3 (range: 10 to 1059 cells/mm 3 ) and mean baseline plasma HIV-1 RNA was 4.1 log 10 copies/ml (range: 2.6 to 6.0 log 10 copies/ml). Treatment response and outcomes of randomized treatment through Week 48 are presented in Figure 5 and table 6 respectively. Figure 5 Virologic Response Through Week 48, Study 888 *

16 *Roche AMPLICHOR HIV-1 MONITOR Assay. Responders at each visit are patients who had achieved and maintained HIV-1 RNA <400 copies/ml without discontinuation by that visit. > Table 6 Outcome of Randomized Treatment Through Week 48 (Study 888) Outcome Lopinavir/ritonavir + nevirapine + NRTIs (n=148) Investigator-Selected Protease Inhibitor(s) + nevirapine + NRTIs (n=140) Responder *1 57% 33% Virologic failure 2 24% 41% Rebound 11% 19% Never suppressed through Week 48 13% 23% Death 1% 2% Discontinued due to adverse event 5% 11% Discontinued for other reasons 3 14% 13% Corresponds to rates at Week 48 in Figure 5 1 Patients achieved and maintained confirmed HIV RNA < 400 copies/ml through Week 48 2 Includes confirmed viral rebound and failure to achieve confirmed < 400 copies/ml through Week 48 3 Includes lost to follow-up, patient's withdrawal, non compliance, protocol violation and other reasons Study M97-765: Lopinavir/ritonavir B.I.D. + nevirapine + NRTIs Study M is an ongoing, randomized, blinded, multicenter trial evaluating treatment with lopinavir/ritonavir at two dose levels (400/100 mg B.I.D. and 400/200 mg B.I.D.) plus nevirapine (200 mg B.I.D.) and two NRTIs in 70 single protease inhibitor experienced, non-nucleoside reverse transcriptase inhibitor (NNRTI) naive patients. Patients had a mean age of 40 years (range 22 to 66), were 73% Caucasian, and were 90% male. Mean baseline CD4 cell count was 372 cells/mm3 (range 72 to 807 cells/mm3) and mean baseline-plasma HIV-1 RNA was 4.0 log10 copies/ml (range 2.9 to 5.8 log10 copies/ml).

17 Through 144 weeks of teatment in study 765, the proportion of patients with HIV RNA less than 400 (less than 50 copies/ml was 54% (50%) [n=70], and the corresponding mean increase in CD4 cell count was 212 cells/mm3. 27 patients (39%) discontinued the study, including 9 (13%) discontinuations secondary to adverse events and 2 (3%) deaths. Pediatric use Study M Study M was an open-label, multicenter trial evaluating the pharmacokinetic profile, tolerability, safety and efficacy of lopinavir/ritonavir oral solution containing lopinavir 80 mg/ml and ritonavir 20 mg/ml in 100 antiretroviral naive (44%) and experienced (56%) pediatric patients. All patients were non-nucleoside reverse transcriptase inhibitor naive. Patients were randomized to either 230 mg lopinavir/57.5 mg ritonavir per m 2 or 300 mg lopinavir/75 mg ritonavir per m 2. Naive patients also received lamivudine and stavudine. Experienced patients received nevirapine plus up to two nucleoside reverse transcriptase inhibitors. Safety, efficacy and pharmacokinetic profiles of the two dose regimens were assessed after three weeks of therapy in each patient. After analysis of these data, all patients were continued on the 300 mg lopinavir/75 mg ritonavir per m2 dose. Patients had a mean age of five years (range six months to 12 years) with 14% less than two years. Mean baseline CD4 cell count was 838 cells/mm3 and mean baseline plasma HIV-1 RNA was 4.7 log10 copies/ml. Through 48 weeks of therapy, tje proportion of patients who achieved and sustained an HIV RNA less than 400 copies/ml was 80% for antiretroviral naive patients and 71% for antiretroviralexperienced patients. The mean increase from baseline in CD4 cell count was 404 cells/mm3 for antiretroviral naive and 284 cells/mm3 for antiretroviral-experienced patients treated through 48 weeks. Premature discontinuations were noted in 2 (2%) subjects prior to week 48. One of these was considered by the investigator to be "unrelated" to study drug, the second "possibly" related to study drug. Dose selection for patients 6 months to 12 years of age was based on the following results. The 230/57.5 mg/m2 BID regimen without nevirapine and the 300/75 mg/m2 BID regimen with nevirapine provided lopinavir plasma concentrations similar to those obtained in adult patients receiving the 400/100 mg BID regimen (without nevirapine). CONTRAINDICATION Lopinavir/ritonavir is contraindicated in patients with known hypersensitivity to lopinavir, ritonavir, or any excipients. Lopinavir/ritonavir should not be coadministered concurrently 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 7. Table 7 Drugs which should not be coadministered with lopinavir/ritonavir Drug Class Drug Within Class Not to be Coadministered

18 Benzodiazepines Midazolam, Triazolam Ergot derivatives Neuroleptics GI motility agent Antihistamines Ergotamine, Dihydroergotamine, ergonovine, Methylergonovine Pimozide Cisapride Astemizole, Terfenadine Patients with severe hepatic insufficiency. Herbal preparations containing St. John's Word (Hypericum perforatum) must not be used while taking lopinavir and ritonavir due to the risk of decreased plasma concentrations and reduced cliniacl effects of lopinavir and ritonavir. Rifampicin should not be used in combination with lopinavir/ritonavir because co-administration may cause large decreases in lopinavir concentrations which may in turn significantly decrease the lopinavir therapeutic effect. WARNINGS Drug Interactions Lopinavir/ritonavir is an inhibitor of the P450 isoform CYP3A. Coadministration of lopinavir/ritonavir and drugs primarily metabolized by CYP3A or may result increased plasma concentrations of the other drug that could increase or prolong its therapeutic and adverse effects (see Pharmacokinetics: Drug-Drug Interactions, CONTRAINDICATIONS-Table 7: Drugs which should not be coadministered with lopinavir/ritonavir, and PRECAUTIONS). Anti-mycobacterial Lopinavir/ritonavir should not be coadministered with rifampin because large decrease in lopinavir concentrations may significantly decrease the therapeutic effect (see PRECAUTIONS: Drug Interactions). Corticosteroids Concomitant use of lopinavir/ritonavir (lopinavir/ritonavir) and fluticasone propionate can significantly increase fluticasone propionate plasma concentrations and reduce serum cortisol concentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported when ritonavir has been co-administered with inhaled or intranasally administered fluticasonepropionate. Similar findings with concomitant administration of lopinavir/ritonavir and other inhaled corticosteroids that are metabolized similary to fluticasone, such as budesonide, cannot be excluded. Particular caution should be used when administering lopinavir/ritonavir and any of these inhaled or intranasally administered glucorticoids (see PRECAUTIONS: Drug Interactions) Erectile Dysfunction Agents Particular caution should be used when prescribing sildenafil, tadalafil or vardenafil in patients receiving lopinavir/ritonavir. Coadministration of lopinavir/ritonavir with these drugs is expected to substantially increase their concentrations and may result in increased associated adverse events such as hypotension, and prolonged erection (see PRECAUTIONS: Drug Interactions).

19 Herbal Products Patients on lopinavir/ritonavir should not use products containing St. Jhon's Wort (Hypericum perforatum) because coadministration may be expected to reduce plasma concentrations of protease inhibitors. This may result in loss of therapeutic effect and development of resistance to lopinavir or to the therapeutic class of protease inhibitors (see PRECAUTIONS: Drug Interactions). HMG-CoA Reductase Inhibitors Concomitant use of lopinavir/ritonavir with lovastatin or simvastatin is not recommended. Caution should be exercised if HIV protease inhibitors, including lopinavir/ritonavir, are used concurently with other HMG-CoA reductase inhibitors that are also metabolized by the CYP3A4 pathway (e.g., atorvastatin), as this may increase the potential for serious reactions such as myopathy, icluding rhabdomyolysis (see PRECAUTIONS: Drug Interactions). Tipranavir In a clinical study of dual-boosted protease inhibitor combination therapy in multiple-treatment experienced HIV-positive adults, tipranavir (500 mg twice daily) with ritonavir (200 mg twice daily), co-administered with lopinavir/ritonavir (400/100 mg twice daily), resulted in a 47% and 70% reduction in lopinavir AUC and Cmin respectively. The concomitant administration of lopinavir/ritonavir and tipranavir with low dose ritonavir is therefore not recommended. Diabetes Mellitus/Hyperglycemia New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during post-marketing 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 occured. 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. Pancreatitis Pancreatitis has been observed in patients receiving lopionavir/ritonavir therapy, including those who developed marked triglyceride elevations. In some cases, fatalities have been obeserved. Although a causal relationship to lopinavir/ritonavir has not been established, marked triglyceride elevations is a risk factor for development of pancreatitis (see PRECAUTIONS: Lipid Elevations). 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 lopinavir/ritonavir therapy. 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 lopinavir/ritonavir and/or other antiretroviral therapy should be suspended as clinically appropriate. PRECAUTIONS Hepatic Impairment Lopinavir/ritonavir is principally metabolized by the liver. Therefore, caution should be exercised

20 when administering this drug to patients with impaired hepatic function. Lopinavir/ritonavir has not been studied in patients with severe hepatic impairment. Pharmacokinetic data suggest increases in lopinavir plasma concentrations of approximately 30% as well as decreases in plasma protein binding in HIV and HCV co-infected patients with mild to moderate hepatic impairment (see CLINICAL PHARMACOLOGY: Pharmacokinetic). 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. There have been postmarketing reports of hepatic dysfunction, including some fatalities. These have generally occurred in patients with advanced HIV disease taking multiple concomitant medications in the setting of underlying chronic hepatitis or cirrhosis. A causal relationship with lopinavir/ritonavir therapy has not been established. Increased AST/ALT monitoring should be considered in these patients, especially during the first several months of lopinavir/ritonavir treatment. Resistance/Cross-Resistance Various degrees of cross-resistance among protease inhibitors have been observed. The effect of lopinavir/ritonavir therapy on the efficacy of subsequently administered protease inhibitors is under investigation (see Microbiology). 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. Neither a causal relationship or a mechanism of action between protease inhibitor therapy and these events has 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 lopinavir/ritonavir has resulted in increase in the concentration of total cholesterol and tryglycerides (see ADVERSE REACTIONS-Tables 10 and 11). Triglyceride and cholesterol testing should be performed prior to initiating lopinavir/ritonavir therapy and at periodic intervals during therapy. Lipid disorders should be managed as clinically appropiate. See WARNINGS and PRECAUTIONS: HMG-CoA Reductase Inhibitors for additional information on potential drug interactions with lopinavir/ritonavir and HMG CoA reductase inhibitors. Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in HIV-infected patients treated with combination antiretroviral therapy, including lopinavir/ritonavir. During the initial phase of combination antiretroviral treatment when the immune system responds, patients may develop an inflammatory response to asymptomatic or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis carinii pneumonia, or tuberculosis), which may necessitate further evaluation and treatment.

21 When initiating treatment with lopinavir/ritonavir in therapy-naive patients, it should be noted that the incidence of diarrhoea was greater for lopinavir/ritonavir once-daily compared to lopinavir/ritonavir twice-daily in Study 418 (57% vs 35% - events of all grades and probably or possibly related to drug; 16% vs 5% -events of at least moderate severity and probably related to drug). Liver disease The safety and efficacy of lopinavir/ritonavir has not been established in patients with significant underlying liver disorders. Lopinavir/ritonavir is contraindicated in patients with severe liver impairment. Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse events. In case of concomitant antiviral therapy for hepatitis B or C, please refer to the relevant product information for these medicinal products. Osteonecrosis Although the etiology is considered to multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV-disease and/or long-term exposure to combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement. Drug Interactions Lopinavir/ritonavir is an inhibitor of CYP3A (cytochrome P450 3A) both in vitro and in vivo. Coadministration of lopinavir/ritonavir and drugs primarily metabolized by CYP3A (e.g., dihydropyridine calcium channel blockers, HMG-CoA reductase inhibitors, immunosuppressants and sildenafil) may result in increased plasma concentrations of the other drugs that could increase or prolong their therapeutic and adverse effects (see PRECAUTIONS). Agents that are extensively metabolized by CYP3A and have gigh first pass metabolism appear to be the most susceptible to large increases in AUC (greater than 3-fold) when coadministered with lopinavir/ritonavir. Drugs that are contraindicated specifically due to the expected magnitude of interaction and potential for serious adverse events are listed in Table 7 under CONTRAINDICATIONS. Lopinavir/ritonavir is metabolized by CYP3A. Co-administration of lopinavir/ritonavir and drugs that induce CYP3A may decrease lopinavir plasma concentrations and reduce its therapeutic effect (see PRECAUTIONS). Although not noted with concurrent ketoconazole, coadministration of lopinavir/ritonavir and other drugs that inhibit CYP3A may increase lopinavir plasma concentrations. Anti-HIV Agents Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Stavudine and Lamivudine No change in the pharmacokinetics of lopinavir was observed when lopinavir/ritonavir was given alone or in combination with stavudine and lamivudine. Didanosine it is recommended that didanosine be administered on an empty stomach; therefore, didanosine may be coadministered with lopinavir/ritonavir tablets without food.