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Lopinavir/ritonavir tablets

DESCRIPTIONLopinavir 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 CYP3Amediatedmetabolism 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 inisopropanol 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. Itsmolecular formula is C37H48N4O5, and its molecular weight is 628.80. Lopinavir has the followingstructural 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-thiazolylmethylester, [5S-(5R*, 8R*, 10R*, 11R*)]. Its molecular formula is C37H48N6O5S2, and its molecularweight is 720.95. Ritonavir has the following structural formula:

Lopinavir/ritonavir film coated tablets are available for oral adminstration in a strength of 200 mg oflopinavir 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 PuertoRico: 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, colloidalanhydrous silica, macrogols type 3350, red ferric oxide E172, and polysorbate 80.

CLINICAL PHARMACOLOGY

Microbiology

Mechanism of action Lopinavir, an inhibitor of the HIV-1 and HIV-2 proteases, prevents cleavage of the gag-polpolyprotein, 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 wasevaluated in acutely infected lymphoblastic cell lines and peripheral blood lymphocytes,respectively. In the absence of human serum, the mean 50% effective concentration (EC50) oflopinavir against five different HIV-1laboratory strains ranged from 10 to 27 nM (0.006 to 0.017mcg/mL, 1 mcg/mL equals 1.6 microM) and ranged from 4 to 11nM (0.003 to 0.007 mcg/mL) againstseveral HIV-1 clinical isolates (n equals 6). In the presence of 50% human serum, the mean EC50of 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 otherprotease 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 ofritonavir 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 yetbeen 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 atweek 24, 32, 40 and/or 48 were analyzed. No evidence of genotypic or phenotypic resistance tolopinavir/ritonavir was observed in 37 evaluable lopinavir/ritonavir - treated patients (0%). Evidenceof genotypic resistance to nelfinavir, defined as the presence of the D30N and/or L90M mutation inHIV protease, was observed in 25/76 (33%) of evaluable nelfinavir treated patients. The selection ofresistance to lopinavir/ritonavir in atiretroviral treatment naive pediatric patients (Study 940) appearsto be consistent with that seen in adult patients (Study 863).

Resistance to lopinavir/ritonavir has been noted to emerge in patients treated with other proteaseinhibitor prior to lopinavir/ritonavir therapy. In Phase II studies of 227 antiretroviral treatment naiveand protease inhibitors experienced patients, isolates from 4 of 23 patients with quantifiable (greaterthan 400 copies/mL) viral RNA following treatment with lopinavir/ritonavir for 12 to 100 weeksdisplayed significantly reduced susceptibility to lopinavir compared to the corresponding baselineviral isolates. Three of these patients had previously received treatment with a single proteaseinhibitor (nelfinavir, indinavir, or saquinavir) and one patient had received treatment with multipleprotease inhibitors (indinavir, saquinavir and ritonavir). All four of these patients had at least fourmutations associated with protease inhibitor resistance immediately prior to lopinavir/ritonavirtherapy. Following viral rebound, isolates from these patients all contained additional mutations,some of which are recognized to be associated with protease inhibitor resistance. However, thereare insufficient data at this time to identify lopinavir associated mutational patterns in isolates frompatients 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

activity of lopinavir against clinical isolates from patients previously treated with a single proteaseinhibitor was determined. Isolates that displayed greater than 4-fold reduced susceptibility tonelfinavir (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 frompatients previously treated with two or more protease inhibitors showed greater reductions insusceptibility to lopinavir, as decribed in the clinical section below (Clinical Studies: AntiviralActivity 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 withlopinavir/ritonavir. Isolates from four patients previously treated with one or more protease inhibitorsthat developed increased lopinavir phenotypic resistance during lopinavir/ritonavir therapy eitherremained cross-resistant or developed cross-resistance to ritonavir, indinavir, and nelfinavir. Allrebound viruses either remained fully sensitive or demonstrated modestly reduced sysceptibility toamprenavir (up to 8.5-fold concurrent with 99-fold resistance to lopinavir). The rebound isolates fromthe two subjects with no prior saquinavir treatment remained fully sensitive to saquinavir.

Genotypic Correlates of Reduced Phenotypic Susceptibility to Lopinavir in Viruses Selected ByOther Protease Inhibitors

The in vitro antiviral activity of lopinavir against 112 clinical isolates taken from patients with HIVRNA greater than 1000 copies/mL despite previous therapy with one or more protease inhibitorswas assassed. Within this panel, the following mutations in HIV protease were associated withreduced 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 thenumber of the above mutations is shown in Figure1 below. The 16 viruses that displayed greaterthan 20-fold change in susceptibility all contained mutation sat positions 10, 54, 63 plus 82 and/or84. 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 byassessing the virologic response to lopinavir/ritonavir therapy, with respect to baseline viral

genotype and phenotype, in 56 NNRTI-naive patients with HIV RNA greater than 1000 copies/mLdespite 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 receiveone of two doses of lopinavir/ritonavir in combination with efavirenz and nucleoside reversetranscriptase inhibitors. The EC50 values of lopinavir against the 56 baseline viral isolates rangedfrom 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 reducedsusceptibility to lopinavir. These 31 isolates had a mean reduction in lopinavir susceptibility of 27.9-fold.

After 48 weeks of treatment with lopinavir/ritonavir, efavirenz and nucleoside reverse transcriptaseinhibitors, 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 byVirologic; genotype also performed by Virologic. Plasma HIV RNA less than or equal to 50copies/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), ofpatients whose baseline viral isolates contained up to and including five mutations recognized to beassociated with protease inhibitor resistance. Thirteen of those 23 isolates contained proteasemutations at positions 82, 84, and/or 90. Plasma HIV RNA less than or equal to 400 copies/mL wasobserved 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 lessthan or equal to 50 copies/mL was observed in 83% (19/23) and 52% (14/27) in the groups ofpatients whose baseline isolates contained less than or equal to five and greater than five of theabove mutations, respectively.

There are insufficient data at this time to identify lopinavir-associated mutational patterns in isolatesfrom patients on lopinavir/ritonavir therapy. Further studies are needed to assess the associationbetween specific mutational patterns and virologic response rates.

Pharmacokinetics

The pharmacokinetic properties of lopinavir co-administered with ritonavir have been evaluated inhealthy adult volunteers and in HIV-infected patients; no substantial differences were observedbetween 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-statelopinavir 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 mgB.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 afterlopinavir/ritonavir 400/100 mgB.I.D. with food for three weeks from a pharmacokinetic study in HIV-infected adult subjects (n=19).

Figure 2

Mean Steady-State Plasma Concentrations with 95% Confidence Intervals (CL) for HIVInfected

Adult Subjects (N = 19)

Plasma concentrations of lopinavir and ritonavir after administration of two 200/50 mg tablets areequivalent 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 mglopinavir/ritonavir B.I.D with food for three weeks produced a mean ± SD lopinavir peak plasmaconcentration (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 andminimum 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 co-formulated with ritonavir in humans has not been established.

Effects of Food on Oral AbsorptionAdministration of a single 400/100 mg dose of lopinavir/ritonavir tablets under fed conditions (high-fat, 872 kcal, 56% from fat) compared to the fasted state was associated with no significant changesin 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 mealconditions compared to the lopinavir/ritonavir capsule.

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

Metabolism In vitro experiments with human hepatic microsomes indicate that lopinavir primarily undergoesoxidative metabolism. Lopinavir is extensively metabolized by the hepatic cytochrome P450 system,almost exclusively by the CYP3A isozyme. Ritonavir is potent CYP3A inhibitor, which inhibits themetabolism of lopinavir, and therefore increases plasma levels of lopinavir. A 14Clopinavir study in

humans showed that 89% of the plasma radioactivity after a single 400/100 mg lopinavir/ritonavirdose was due to parent drug. At least 13 lopinavir oxidative metabolites have been identified inman. Ritonavir has been shown to induce metabolic enzymes, resulting in the induction of its ownmetabolism. Pre-dose lopinavir concentrations decline with time during multiple dosing, stabilizingafter 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% ofan administered dose of 14C-lopinavir can be accounted for in urine and feces, respectively, aftereight days. Unchanged lopinavir accounted for approximately 2.2 and 19.8% of the administereddose in urine and feces, respectively. After multiple dosing, less than 3% of the lopinavir dose isexcreted unchanged in the urine. The apparent oral clearance (CL/F) of lopinavir is 5.98 +/- 5.75L/hr (mean +/- SD, N=19).

Once Daily Dosing The pharmacokinetics of once daily lopinavir/ritonavir has been evaluated in HIV-infected subjectsnaive to antiretroviral treatment. Lopinavir/ritonavir 800/200 mg was administered in combinationwith 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 amean ± SD lopinavir peak plasma concentration (Cmax) of 11.8 ± 3.7 µg/mL, occuringapproximately 6 hours after administration. The mean steady-state lopinavir trough concentrationprior to the morning dose was 3.2 ± 2.1 µg/mL and minimum concentration within a dosing intervalwas 1.7 ± 1.6 µg/mL. Lopinavir AUC over a 24-hour dosing interval averaged 154.1 ± 61.4 µg·h/mL

Special Population

Gender, Race and Age

Lopinavir pharmacokinetics have not been studied in elderly patients. No gender relatedpharmacokinetic differences have been observed in adult patients. No clinically importantpharmacokinetic 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. havebeen studied in a total of 53 pediatric patients, ranging in age from six months to 12 years. The230/57.5 mg/m2 B.I.D. regimen without nevirapine and the 300/75 mg/m2 B.I.D. regimen withnevirapine provided lopinavir plasma concentrations similar to those obtained in adult patientsreceiving the 400/100 mg B.I.D. regimen (without nevirapine). Lopinavir/ritonavir once daily has notbeen evaluated in pediatric patients. The lopinavir mean steady-state AUC, Cmax, and Cmin were 72.6 ± 31.1mcg·h/mL, 8.2 ± 2.9 and3.4 ± 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 300/75mg/m2 B.I.D. with nevirapine (n=12). The nevirapine regimen was 7 mg/kg B.I.D. (six months toeight 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

expected in patients with renal insufficiency.

Hepatic Impairment

Lopinavir is principally metabolized and eliminated by the liver. Multiple dosing of lopinavir/ritonavir400/100 mg twice daily to HIV and HCV co-infected patients with mild to moderate hepaticimpairment resulted in a 30% increase in lopinavir AUC and 20% increase Cmax compared to HIV-infected subjects with normal hepatic function. Additionally, the plasma protein binding of lopinavirwas lower in both mild and moderate hepatic impairment compared to controls (99.09 vs. 99.31%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 oflopinavir/ritonavir and drugs primarily metabolized by CYP3A may result in increased plasmaconcentrations 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 atclinically relevant concentrations. Lopinavir/ritonavir has been shown in vivo to induce its own metabolism and to increase thebiotransformation of some drugs metabolized by cytochrome P450 enzymes and byglucuronidation.

Lopinavir/ritonavir is metabolized by CYP3A. Drugs that induce CYP3A activity would be expectedto increase the clearance of lopinavir, resulting in lowered plasma concentrations of lopinavir.Although not noted with concurrent ketoconazole, coadministration of lopinavir/ritonavir and otherdrugs that inhibit CYP3A may increase lopinavir plasma concentrations.

Drug interaction studies were performed with lopinavir/ritonavir and other drugs likely to becoadministered 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 inTable1 (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 thoseobserved with lopinavir (if lopinavir concentrations are decreased, ritonavir concentrations aredecreased) unless otherwise indicated in the table footnotes. For information regarding clinicalrecommendations, 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)

Co-administered

Drug

Dose of Co-administered

Drug (mg)

Dose oflopinavir/ritonavir

(mg)n

Ratio (with/without coadministereddrug) of Lopinavir Pharmacokinetic

Parameters (90% CI); No Effect = 1.00

Cmax AUC Cmin

Amprenavir750 B.I.D.;10 d

400/100 capsuleB.I.D,21 d

120.72

(0.65, 0.79)0.62

(0.56, 0.70)0.43

(0.34, 0.56)

Atorvastotin20 QD;4 d


120.90

(0.78, 1.06)0.90

(0.79, 1.02)0.92

(0.78, 1.10)

Efavirenz1

600 QHS;9 d


117*

0.97(0.78, 1.22)

0.81(0.64, 1.03)

0.61(0.38, 0.97)

600 QHS;9 d


231.36

(1.28 - 1.44)

1.36(1.28 - ,1.44)

1.32(1.21, 1.44)

Ketoconazole200 singledose


120.89

(0.80, 0.99)0.87

(0.75, 1.00)0.75

(0.55, 1.00)

Nelfinavir100 B.I.D.;10 d


130.79

(0.70, 0.89)0.73

(0.63, 0.85)0.62

(0.49, 0.78)

Nevirapine

200 BID,steady-state(>1 yr)2

400/100 capsuleB.I.D,steady-state (> 1yr) 300/75 mg/m2

oral solution B.I.D,3 wk

2219*

0.81(0.62, 1.05)

0.73(0.53, 0.98)

0.49(0.28, 0.74)

7 mg/kg or 4mg/kg QD, 2wk; B.I.D. 1wk3

1215*

0.86(0.64, 1.16)

0.78(0.56, 1.09)

0.45(0.25, 0.81)

Omeprazole 40 QD, 5 d

400/100 tabletB.I.D., 10 d

121.08

(0.99, 1.17)1.07

(0.99, 1.15)1.03

(0.90, 1.18)

800/200 tabletQ.D., 10 d

120.94

(0.88, 1.00)0.92

(0.86, 0.99)0.71

(0.57, 0.89)

Pravastin 20 QD; 4 d400/100 capsuleB.I.D., 14 d

120.98

(0.89, 1.08)0.95

(0.85, 1.05)0.88

(0.77, 1.02)

Ranitidine150 singledose

400/100 tabletB.I.D., 10 d

120.98

(0.95, 1.02)0.98

(0.94, 1.01)0.93

(0.89, 0.98)

800/200 tabletQ.D., 10 d

110.98

(0.95, 1.01)0.96

(0.90, 1.02)0.85

(0.67, 1.08)

Rifabutin150 QD;10 d

400/100 capsuleB.I.D., 20 d

141.08

(0.97, 1.19)1.17

(1.04, 1.31)1.20

(0.96, 1.65)

Rifampin

600 QD, 10 d400/100 capsuleB.I.D., 20 d

220.45

(0.40, 0.51)0.25

(0.21, 0.29)0.01

(0.01, 0.02)

600 QD, 14 d800/200 capsuleB.I.D., 9 d4

101.02

(0.85, 1.23)0.84

(0.64, 1.10)0.43

(0.19, 0.96)

600 QD, 14 d400/400 capsuleB.I.D., 9 d5

90.93

(0.81, 1.07)0.98

(0.81, 1.17)1.03

(0.68, 1.56)

Co-administration oflopinavir/ritonavir and

rifampin is notrecommended. (seePRECAUTIONS)

Ritonavir2100 B.I.D.;3 to 4 wk

400/100 capsuleB.I.D., 3 to 4 wk

821*

1.28(0.94, 1.76)

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)

Co-administered

Drug

Dose of Co-administered

Drug (mg)

Dose oflopinavir/ritonavir

(mg)n

Ratio (with/without lopinavir/ritonavir)of Coadministered Drug

Pharmacokinetic Parameters (90% CI);

No Effect = 1.00

Cmax AUC Cmin

Amprenavir1

750 BID, 10 dcombo vs.1200 BID,14 d alone


111.12

(0.91, 1.39)1.72

(1.41, 2.09)4.57

(3.51, 5.95)

Atorvastatin20 QD;4 d


124.67

(3.35, 6.51)5.88

(4.69, 7.37)2.28

(1.91, 2.71)

Desipramine2 100 singledose


150.91

(0.84, 0.97)1.05

(0.96, 1.16)NA

Efavirenz600 QHS;9 d


1112*

0.91(0.72, 1.15)

0.84(0.62, 1.15)

0.84(0.58, 1.20)

EthinylEstradiol

35 mcg QD;21 d (OrthoNovum®)


120.59

(0.52, 0.66)0.58

(0.54, 0.62)0.42

(0.36, 0.49)

Indinavir1

600 BID, 10 dcombononfasting vs.800 TID, 5 dalone fasting


130.71

(0.63, 0.81)0.91

(0.75, 1.10)3.47

(2.60, 4.64)

Ketoconazole200 singledose


121.13

(0.91, 1.40)3.04

(2.44, 3.79)NA

Methadone 5 single dose400/100 capsuleB.I.D,10 d

110.55

(0.48, 0.64)0.47

(0.42, 0.53)NA

Nelfinavir11000 BID, 10d combo vs.1250 BID, 14dalone


13

0.93(0.82, 1.05)

1.07(0.95, 1.19)

1.86(1.57, 2.22)

M8 metabolite2.36

(1.91, 2.91)3.46

(2.78, 4.31)7.49

(5.85, 9.58)

Nevirapine200 QD, 14 d;B.I.D., 6 d


5.6*1.05

(0.72, 1.52)1.08

(0.72, 1.64)1.15

(0.71, 1.86)

Norethindrone1 QD, 21 d (OrthoNovum®)


12*0.84

(0.75, 0.94)0.83

(0.73, 0.94)0.68

(0.54, 0.85)

Pravastin 20 QD; 4 d400/100 capsuleB.I.D., 14 d

121.26

(0.87, 1.83)1.33

(0.91, 1.94)NA

Rifabutin

150 QD 10 dcombo vs. 300QD, 10 d; alone


12

2.12(1.89, 2.38)

3.03(2.79, 3.30)

4.90(3.18, 5.76)

25-Odesacetylrifabutin

23.6(13.7, 25.3)

47.5(29.3, 51.8)

94.9(74.0, 122)

Rifabutin + 25-O-desacetylrifabutin3

3.46(3.07, 3.91)

5.73(5.08, 6.46)

9.53(7.56, 12.01)

Saquinavir1

800 BID, 10 dcombo vs.1200 TID, 5 dalone


146.34

(5.32, 7.55)

9.62(8.05,11.49)

16.74(13.73,20.42)

1200 BID, 5 dcombo vs.1200 TID 5 dalone


106.44

(5.59, 7.41)

9.91(8.28,11.86)

16.54(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 fordose. 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 activemetabolite *Parallel group design; n for lopinavir/ritonavir + coadministered drug, n for coadministered drugalone

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 withfocal degeneration. While exposure eliciting these changes were comparable to human clinical exposure, dosages inanimals were over 6-fold the recommended clinical dose. Mild renal tubular degeneration was confined to mice exposed with at least twice the recommendedhuman exposure; the kidney was unaffected in rats and dogs. Reduced serum thyroxine led to anincreased 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 miceand dogs. Coombs-negative anisocytosis and poikilocytosis were observed in rats, but not in miceor dogs. Enlarged spleens with histiocytosis were seen in rats but not other species. Serumcholesterol 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 ofHIV-infection as a second line treatment. This indication is based on analyses of plasma HIV RNAlevels and CD4 cell counts in a controlled study of lopinavir/ritonavir of 48 weeks duration, and insmaller uncontrolled dose-ranging studies of lopinavir/ritonavir of 144-360 weeks duration. Atpresent, there are no results from controlled trials evaluating the effect of Lopinavir/ritonavir onclinical progression of HIV.

Once daily administration of lopinavir/ritonavir has not been studied in therapy-experiencedpatients.

Description of Clinical Studies

Patients Without Prior Antiretroviral Therapy

Study M98-863: lopinavir/ritonavir B.I.D. + stavudine + lamivudine compared to nelfinavir TID +stavudine + lamivudine.

Study M98-863 is an ongoing, randomized, double -blind, multicenter trial comparing treatment withlopinavir/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 meanage of 38 years (range: 19 to 84), 57% were Caucasian, and 80% were male. Mean baseline CD4cell count was 259 cells/mm3 (range: 2 to 949 cells/mm3) and mean baseline plasma HIV-1 RNAwas 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 3Treatment Response Through 48 Weeks* (Study 863)

*Proportion of patients at each time point who achieved and maintained HIV RNA less than 400copies/mL, are on their original study medication, and have not experienced a new CDC Class Cevent

Table 3 Outcomes of Randomized Treatment Through Week 48 (Study 863)

Outcomelopinavir/ritonavir

+ d4T +3TC(N=326)

Nelfinavir + d4T +3TC(N=327)

Responder1 75% 62%

Virologic failure2 9% 25%

Rebound 7% 15%

Never suppressed through Week 48 2% 9%

Death 2% 1%

Discontinued due to adverse event 4% 4%

Discontinued for other reasons3 10% 8%

1 Corresponds to rates at week 48 in Figure 3.

2 Patients achieved and maintained confirmed HIV RNA <400 copies/mLthrough Week 48

3

Includes confirmed viral rebound and failure to achieve confirmed <400 copies/mL through Week 48>Includes lost to follow-up, patient'swithdrawal, non compliance, protocol violation and other reasonsOverall discontinuation through week 48, including patients who discontinuedsubsequent to virologic failure, was 17% in the lopinavir/ritonavir arm and24% in the nelfinavir arm

Through 48 weeks of therapy, there was a statistically significantly higher proportion of patients inthe 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.

BaselineViral Load

(HIV-1RNA

copies/mL)

Lopinavir/ritonavir + d4T + 3TC Nelfinavir + d4T + 3TC

<400copies/mL1 <50copies/mL2 n <400copies/mL1 <50copies/mL2 n

<30,000 74% 71% 82 79% 72% 87

=30,000 to<100,000

81% 73% 79 67% 54% 79

=100,000 to<250,000

75% 64% 83 60% 47% 72

=250,000 72% 60% 82 44% 33% 891 Patients achieved and mantained confirmed HIV RNA <400 copies/mL through Week 48. 2 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 207cells/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 timeof treatment failure was defined as the earliest time a patient experienced virologic failure (twoconsecutive HIV RNA values demonstrating rebound above 400 copies/mL), a new CDC Class Cevent, or premature discontinuation from the study.

Figure 4Time to Treatment Failure (Study 863)

Study M97-720: lopinavir/ritonavir B.I.D. + Stavudine + lamivudine Study M97-720 was a randomized, blinded, multicenter trial evaluating treatment withlopinavir/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 mgB.I.D.) in 100 patients. All patients were converted to open label lopinavir/ritonavir at the 400/100mg 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 338cells/mm3 (range: 3 to 918 cells/mm3) and mean baseline plasma HIV-1 RNA was 4.9 log10copies/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 cellcount 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 virologicresponse (two consecutive rebound HIV-1 RNA values above 400 copies/mL, one rebound HIV-1RNA value followed by discontinuation, or failure to achieve HIV RNA <400 copies/mL. Genotypicanalysis of viral isolates was conducted on these patients and 10 additional patients with isolatedHIV-1 RNA values >400 copies/mL after week 24. Results were available from 19 patients andconfirmed 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 toLopinavir/ritonavir twice daily + tenofovir DF + emtricitabine

Study 418 was a randomized, open label, multicenter trial comparing treatment withLopinavir/ritonavir 800/200 mg once-daily plus tenofovir DF and emtricitabine versusLopinavir/ritonavir 400/100 mg twice-daily plus tenofovir DF and emtricitabine in 190 antiretroviraltreatment naive patients. Patients had a mean age of 39 years (range: 19 to 75), 54% wereCaucasian, and 78% were male. Mean baseline CD4 cell count was 260 cells/mm3 (range: 3 to1006 cells/mm3) and mean baseline plasma HIV-1 RNA was 4.8 log10 copies/mL (range: 2.6 to 6.4log10 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)

Outcome

Lopinavir/ritonavironce daily

+ TDF +FTC(n=115)

Lopinavir/ritonavirtwice daily

+ TDF +FTC(n=75)

Responder1 71% 65%


Rebound 6% 5%


Death 0% 1%



1 Patients achieved and maintained confirmed HIV RNA < 50 copies/mL through Week 48

2 Includes confirmed viral rebound and failure to achieve confirmed < 50 copies/mL through Week48

3 Includes lost to follow-up, patient's withdrawal, non compliance, protocol violation and otherreasons

Through 48 weeks of therapy, 71% in the lopinavir/ritonavir once daily arm and 65% in thelopinavir/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 48were 185 cells/mm3 for the lopinavir/ritonavir once daily arm and 196 cells/mm3 for thelopinavir/ritonavir twice daily arm.

Patients with Prior Antiretroviral Therapy

Study M98-888: Lopinavir / ritonavir B.I.D. + nevirapine + NRTIs compared to investigatorselectedprotease 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 versusinvestigator-selected protease inhibitor(s) plus nevirapine and nucleoside reverse transcriptaseinhibitors in 288 single protease inhibitor-experienced, non-nucleoside reverse transcriptaseinhibitor (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/mm3 (range: 10 to 1059 cells/mm3) and mean baselineplasma HIV-1 RNA was 4.1 log10 copies/mL (range: 2.6 to 6.0 log10 copies/mL).

Treatment response and outcomes of randomized treatment through Week 48 are presented inFigure 5 and table 6 respectively.

Figure 5Virologic Response Through Week 48, Study 888*†

*Roche AMPLICHOR HIV-1 MONITOR Assay.† Responders at each visit are patients who had achieved and maintained HIV-1 RNA <400copies/mL without discontinuation by that visit. >

Table 6Outcome of Randomized Treatment Through Week 48 (Study 888)

Outcome

Lopinavir/ritonavir +nevirapine

+ NRTIs(n=148)

Investigator-SelectedProtease Inhibitor(s)+ nevirapine + NRTIs

(n=140)

Responder*1 57% 33%


Rebound 11% 19%


Death 1% 2%



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 M97-765 is an ongoing, randomized, blinded, multicenter trial evaluating treatment withlopinavir/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 reversetranscriptase inhibitor (NNRTI) naive patients. Patients had a mean age of 40 years (range 22 to66), 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).

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 cellcount 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 M98-940

Study M-98-940 was an open-label, multicenter trial evaluating the pharmacokinetic profile,tolerability, safety and efficacy of lopinavir/ritonavir oral solution containing lopinavir 80 mg/mL andritonavir 20 mg/mL in 100 antiretroviral naive (44%) and experienced (56%) pediatric patients. Allpatients were non-nucleoside reverse transcriptase inhibitor naive. Patients were randomized toeither 230 mg lopinavir/57.5 mg ritonavir per m2 or 300 mg lopinavir/75 mg ritonavir per m2. Naivepatients also received lamivudine and stavudine. Experienced patients received nevirapine plus upto two nucleoside reverse transcriptase inhibitors.

Safety, efficacy and pharmacokinetic profiles of the two dose regimens were assessed after threeweeks of therapy in each patient. After analysis of these data, all patients were continued on the 300mg lopinavir/75 mg ritonavir per m2 dose. Patients had a mean age of five years (range six monthsto 12 years) with 14% less than two years. Mean baseline CD4 cell count was 838 cells/mm3 andmean 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 RNAless than 400 copies/mL was 80% for antiretroviral naive patients and 71% for antiretroviral-experienced patients. The mean increase from baseline in CD4 cell count was 404 cells/mm3 forantiretroviral naive and 284 cells/mm3 for antiretroviral-experienced patients treated through 48weeks. Premature discontinuations were noted in 2 (2%) subjects prior to week 48. One of thesewas considered by the investigator to be "unrelated" to study drug, the second "possibly" related tostudy drug.

Dose selection for patients 6 months to 12 years of age was based on the following results. The230/57.5 mg/m2 BID regimen without nevirapine and the 300/75 mg/m2 BID regimen withnevirapine provided lopinavir plasma concentrations similar to those obtained in adult patientsreceiving the 400/100 mg BID regimen (without nevirapine).

CONTRAINDICATION

Lopinavir/ritonavir is contraindicated in patients with known hypersensitivity to lopinavir, ritonavir, orany excipients.

Lopinavir/ritonavir should not be coadministered concurrently with drugs that are highly dependenton CYP3A for clearance and for which elevated plasma concentrations are associated with seriousand/or life-threatening events. These drugs are listed in Table 7.

Table 7

Drugs which should not be coadministered withlopinavir/ritonavir

Drug Class Drug Within Class Not to beCoadministered

Benzodiazepines Midazolam, Triazolam

Ergot derivativesErgotamine, Dihydroergotamine,ergonovine, Methylergonovine

Neuroleptics Pimozide

GI motility agent Cisapride

Antihistamines Astemizole, Terfenadine

Patients with severe hepatic insufficiency.

Herbal preparations containing St. John's Word (Hypericum perforatum) must not be used whiletaking lopinavir and ritonavir due to the risk of decreased plasma concentrations and reducedcliniacl effects of lopinavir and ritonavir.

Rifampicin should not be used in combination with lopinavir/ritonavir because co-administrationmay cause large decreases in lopinavir concentrations which may in turn significantly decrease thelopinavir therapeutic effect.

WARNINGS

Drug Interactions

Lopinavir/ritonavir is an inhibitor of the P450 isoform CYP3A. Coadministration of lopinavir/ritonavirand drugs primarily metabolized by CYP3A or may result increased plasma concentrations of theother drug that could increase or prolong its therapeutic and adverse effects (seePharmacokinetics: Drug-Drug Interactions, CONTRAINDICATIONS-Table 7: Drugs whichshould not be coadministered with lopinavir/ritonavir, and PRECAUTIONS).

Anti-mycobacterial

Lopinavir/ritonavir should not be coadministered with rifampin because large decrease in lopinavirconcentrations may significantly decrease the therapeutic effect (see PRECAUTIONS: DrugInteractions).

Corticosteroids Concomitant use of lopinavir/ritonavir (lopinavir/ritonavir) and fluticasone propionate cansignificantly increase fluticasone propionate plasma concentrations and reduce serum cortisolconcentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenalsuppression have been reported when ritonavir has been co-administered with inhaled orintranasally administered fluticasonepropionate. Similar findings with concomitant administration oflopinavir/ritonavir and other inhaled corticosteroids that are metabolized similary to fluticasone, suchas budesonide, cannot be excluded. Particular caution should be used when administeringlopinavir/ritonavir and any of these inhaled or intranasally administered glucorticoids (seePRECAUTIONS: Drug Interactions)

Erectile Dysfunction Agents Particular caution should be used when prescribing sildenafil, tadalafil or vardenafil in patientsreceiving lopinavir/ritonavir. Coadministration of lopinavir/ritonavir with these drugs is expected tosubstantially increase their concentrations and may result in increased associated adverse eventssuch as hypotension, and prolonged erection (see PRECAUTIONS: Drug Interactions).

Herbal Products Patients on lopinavir/ritonavir should not use products containing St. Jhon's Wort (Hypericumperforatum) because coadministration may be expected to reduce plasma concentrations ofprotease inhibitors. This may result in loss of therapeutic effect and development of resistance tolopinavir or to the therapeutic class of protease inhibitors (see PRECAUTIONS: DrugInteractions).

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 usedconcurently with other HMG-CoA reductase inhibitors that are also metabolized by the CYP3A4pathway (e.g., atorvastatin), as this may increase the potential for serious reactions such asmyopathy, icluding rhabdomyolysis (see PRECAUTIONS: Drug Interactions).

Tipranavir In a clinical study of dual-boosted protease inhibitor combination therapy in multiple-treatmentexperienced 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 oflopinavir/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 hyperglycemiahave been reported during post-marketing surveillance in HIV-infected patients receiving proteaseinhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oralhypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis hasoccured. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted insome cases. Because these events have been reported voluntarily during clinical practice,estimates of frequency cannot be made and a causal relationship between protease inhibitortherapy and these events has not been established.

Pancreatitis

Pancreatitis has been observed in patients receiving lopionavir/ritonavir therapy, including thosewho developed marked triglyceride elevations. In some cases, fatalities have been obeserved.Although a causal relationship to lopinavir/ritonavir has not been established, marked triglycerideelevations 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 andpancreatitis, and patients with a history of pancreatitis may be at increased risk for recurrence duringlopinavir/ritonavir therapy. Pancreatitis should be considered if clinical symptoms (nausea, vomiting, abdominal pain) orabnormalities in laboratory values (such as increased serum lipase or amylase values)suggestive of pancreatitis should occur. Patients who exhibit these signs or symptomsshould be evaluated and lopinavir/ritonavir and/or other antiretroviral therapy should besuspended as clinically appropriate.

PRECAUTIONS

Hepatic Impairment

Lopinavir/ritonavir is principally metabolized by the liver. Therefore, caution should be exercised

when administering this drug to patients with impaired hepatic function. Lopinavir/ritonavir has notbeen studied in patients with severe hepatic impairment. Pharmacokinetic data suggest increasesin lopinavir plasma concentrations of approximately 30% as well as decreases in plasma proteinbinding in HIV and HCV co-infected patients with mild to moderate hepatic impairment (seeCLINICAL PHARMACOLOGY: Pharmacokinetic). Patients with underlying hepatitis B or C ormarked elevations in transaminases prior to treatment may be at increased risk for developingfurther transaminase elevations. There have been postmarketing reports of hepatic dysfunction,including some fatalities. These have generally occurred in patients with advanced HIV diseasetaking multiple concomitant medications in the setting of underlying chronic hepatitis or cirrhosis. Acausal relationship with lopinavir/ritonavir therapy has not been established. Increased AST/ALT monitoring should be considered in these patients, especially during the firstseveral months of lopinavir/ritonavir treatment.

Resistance/Cross-Resistance

Various degrees of cross-resistance among protease inhibitors have been observed. The effect oflopinavir/ritonavir therapy on the efficacy of subsequently administered protease inhibitors is underinvestigation (see Microbiology).

Hemophilia

There have been reports of increased bleeding, including spontaneous skin hematomas andhemarthrosis, in patients with hemophilia type A and B treated with protease inhibitors. In somepatients additional factor VIII was given. In more than half of the reported cases, treatment withprotease inhibitors was continued or reintroduced. Neither a causal relationship or a mechanism ofaction 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 "cushingoidappearance" have been observed in patients receiving antiretroviral therapy. The mechanism andlong-term consequences of these events are currently unknown. A causal relationship has not beenestablished.

Lipid Elevations

Treatment with lopinavir/ritonavir has resulted in increase in the concentration of total cholesteroland tryglycerides (see ADVERSE REACTIONS-Tables 10 and 11). Triglyceride and cholesteroltesting should be performed prior to initiating lopinavir/ritonavir therapy and at periodic intervalsduring therapy. Lipid disorders should be managed as clinically appropiate. See WARNINGS andPRECAUTIONS: HMG-CoA Reductase Inhibitors for additional information on potential druginteractions with lopinavir/ritonavir and HMG CoA reductase inhibitors.

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in HIV-infected patients treated withcombination antiretroviral therapy, including lopinavir/ritonavir. During the initial phase ofcombination antiretroviral treatment when the immune system responds, patients may develop aninflammatory response to asymptomatic or residual opportunistic infections (such as Mycobacteriumavium infection, cytomegalovirus, Pneumocystis carinii pneumonia, or tuberculosis), which maynecessitate further evaluation and treatment.

When initiating treatment with lopinavir/ritonavir in therapy-naive patients, it should be notedthat the incidence of diarrhoea was greater for lopinavir/ritonavir once-daily compared tolopinavir/ritonavir twice-daily in Study 418 (57% vs 35% - events of all grades and probably orpossibly related to drug; 16% vs 5% -events of at least moderate severity and probablyrelated to drug).

Liver disease

The safety and efficacy of lopinavir/ritonavir has not been established in patients withsignificant underlying liver disorders. Lopinavir/ritonavir is contraindicated in patients withsevere liver impairment. Patients with chronic hepatitis B or C and treated with combinationantiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverseevents. In case of concomitant antiviral therapy for hepatitis B or C, please refer to therelevant product information for these medicinal products.

Osteonecrosis

Although the etiology is considered to multifactorial (including corticosteroid use, alcoholconsumption, severe immunosuppression, higher body mass index), cases of osteonecrosishave been reported particularly in patients with advanced HIV-disease and/or long-termexposure to combination antiretroviral therapy (CART). Patients should be advised to seekmedical advice if they experience joint aches and pain, joint stiffness or difficulty inmovement.

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, immunosuppressantsand sildenafil) may result in increased plasma concentrations of the other drugs that could increaseor prolong their therapeutic and adverse effects (see PRECAUTIONS). Agents that are extensivelymetabolized by CYP3A and have gigh first pass metabolism appear to be the most susceptible tolarge increases in AUC (greater than 3-fold) when coadministered with lopinavir/ritonavir. Drugs thatare contraindicated specifically due to the expected magnitude of interaction and potential forserious adverse events are listed in Table 7 under CONTRAINDICATIONS. Lopinavir/ritonavir is metabolized by CYP3A. Co-administration of lopinavir/ritonavir and drugs thatinduce CYP3A may decrease lopinavir plasma concentrations and reduce its therapeutic effect (seePRECAUTIONS). Although not noted with concurrent ketoconazole, coadministration oflopinavir/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 givenalone or in combination with stavudine and lamivudine.

Didanosine it is recommended that didanosine be administered on an empty stomach; therefore, didanosinemay be coadministered with lopinavir/ritonavir tablets without food.

Zidovudine and Abacavir Lopinavir/ritonavir induces glucuronidation, therefore lopinavir/ritonavir has the potential to reducezidovudine and abacavir plasma concentrations. The clinical significance of this potentialinteraction is unknown.

Tenofovir A study has shown lopinavir/ritonavir increases tenofovir concentrations. The mechanism of thisinteraction is unknown. Patients receiving lopinavir/ritonavir and tenofovir should be monitored fortenofovir-associated adverse events.

All Increased CPK, myalgia, myositis, and rarely, rhabdomyolysis have been reported with Pls,particularly in combination with NRTIs.

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTs)

Nevirapine

No change in the pharmacokinetics of lopinavir was apparent in healthy adult subjects duringnevirapine and lopinavir/ritonavir coadministration. Results from a study in HIV-positive pediatricsubjects revealed a decrease in lopinavir concentrations during nevirapine coadministration. The effect of nevirapine in HIV-positive adults is expected to be similar to that in pediatric subjectsand lopinavir concentrations may be decreased. The clinical significance of the pharmacokineticinteraction is unknown. Lopinavir/ritonavir should not be administered once daily in combinationwith nevirapine.

Efavirenz Increasing the dose of lopinavir/ritonavir tablets to 600/150 (three (3) tablets) BID coadministeredwith efavirenz significantly increased the lopinavir plasma concentrations approximately 36% andritonavir concentrations approximately 56% to 92% compared to lopinavir/ritonavir tablets 400/100mg BID without efavirenz (see Dosage and Administration).

NOTE: Efavirenz and nevirapine induce the activity of CYP3A and thus have the potential todecrease plasma concentrations of other protease inhibitors when used in combination withlopinavir/ritonavir. Lopinavir/ritonavir should not be administered once daily in combination with efavirenz.

Delavirdine Delavirdine has the potential to increase concentrations of lopinavir.

Protease Inhibitors (Pls)

Amprenavir Lopinavir/ritonavir is expected to increase concentrations of amprenavir (amprenavir 750 mg BIDplus lopinavir/ritonavir produces increased AUC, similar Cmax, increased Cmin, relative toamprenavir 1200 mg BID). Co-administration of lopinavir/ritonavir and amprenavir result indecreased concentrations of lopinavir (see Dosage and Administeration). Lopinavir/ritanovir shouldnot be administered once daily in combination with amprenavir.

Fosamprenavir A study has shown that coadministration of lopinavir/ritonavir with fosamprenavir lowers amprenavirand lopinavir concentrations. Appropriate doses of the combination of fosamprenavir and

lopinavir/ritonavir with respect to safety and efficacy have not been established.

Indinavir Lopinavir/ritonavir is expected to increase concentrations of indinavir (indinavir 600 mg BID pluslopinavir/ritonavir produces similar AUC, decreased Cmax, increased Cmin relative to indinavir 800mg TID. The dose of indinavir may need to be decreased during co-administration of lopinavir/ritonavir400/100 mg BID (see CLINICAL PHARMACOLOGY: Table 2). Lopinavir/ritonavir once daily has notbeen studied in combination with indinavir.

Nelfinavir Lopinavir/ritonavir is expected to increase concentrations of nelfinavir and increased M8 metaboliteof nelfinavir (nelfinavir 1000 mg BID plus lopinavir/ritonavir produces similar AUC, similar C max,increased Cmin relative to nelfinavir 1250 mg BID). Co-administration of lopinavir/ritonavir andnelfinavir result in decreased concentrations of lopinavir (see Dosage and Administration).Lopinavir/ritonavir should not be administered once daily in combination with nelfinavir.

Ritonavir When lopinavir/ritonavir was coadministered with an additional 100 mg ritonavir twice daily,lopinavir AUC increased 33% and Cmin increased 64% as compared to lopinavir/ritonavir 400/100mg (three (3) soft gel capsules) twice daily.

Saquinavir Lopinavir/ritonavir is expected to increase concentrations of saquinavir (saquinavir 800 mg BID pluslopinavir/ritonavir produces increased AUC, increased Cmax, increased Cmin relative to saquinavir1200 mg TID). The dose of saquinavir may need to be decreased when coadministered withlopinavir/ritonavir 400/100 mg BID (see CLINICAL PHARMACOLOGY:Table 2). Lopinavir/ritonavironce daily has not been studied in combination with saquinavir.

Other drugs

Antiarrhythmics (amiodarone, bepridil, systemic lidocaine and quinidine): Concentrations may beincreased when coadministered with lopinavir/ritonavir. Caution is warranted and therapeuticconcentration monitoring is recommended when available.

Digoxin: A literature report has shown that coadministration of ritonavir (300 mg every 12 hours)and digoxin resulted in significantly increased digoxin levels. Caution should be exercised whencoadministering lopinavir/ritonavir with digoxin, with appropriate monitoring of serum digoxin levels.

Anticoagulant: Warfarin concentrations may be affected when coadministered withlopinavir/ritonavir. It is recommended that INR (International Normalized Ratio) be monitored.

Antidepressants Trazadone: Concomitant use of ritonavir and trazadone may increase concentrations of trazadone.Adverse events of nausea, dizziness, hypotension and syncope have been observed. If trazadoneis used with a CYP3A4 inhibitor such as lopinavir/ritonavir, the combination should be used withcaution and a lower dose of trazadone should be considered.

Anticonvulsants(Phenobarbital, phenytoin, carbamazepine):These drugs are known to induced CYP3A4 and maydecrease lopinavir concentrations. Lopinavir/ritonavir should not be administered once daily incombination with phenobarbital, phenytoin, or carbamazepine.

Antifungals Ketoconazole and itraconazole may have serum concentrations increased by lopinavir/ritonavir.High doses of ketoconazole and itraconazole (greater than 200 mg/day) are not recommended.

Voriconazole: A study has shown that co-administration of ritonavir 400 mg every 12 hoursdecreased voriconazole steady state AUC by an average of 82%; therefore, co-administration oflopinavir/ritonavir and voriconazole is not recommended.

Anti-infectiveModerate increases clarithomycin AUC are expected when coadministered with lopinavir/ritonavir.For patients with renal or hepatic impairment dose reduction of clarithomycin should be considered.

Anti-mycobacterialWhen rifabutin and lopinavir/ritonavir were coadministered for ten days, rifabutin (parent drug andactive 25-O-desacetyl metabolite) Cmax and AUC were increased by 3.5- and 5.7-fold, respectively.On the basis of these data, a rifabutin dose reduction of 75% (i.e. 150 mg every other day or threetimes per week) is recommended when administered with lopinavir/ritonavir. Further dose reductionof rifabutin may be necessary.Due to large decreases in lopinavir concentrations, rifampin should not be used in combination withlopinavir/ritonavir (see WARNINGS: Drug Interactions). The use of rifampin with lopinavir/ritonavir,may lead to loss of virologic response and possible resistance to lopinavir.riotonavir or to the classof protease inhibitors or other co-administered antiretroviral agents. A study evaluated combinationof rifampin 600 mg QD, with lopinavir/ritonavir 800/200 BID or lopinavir/ritonavir 400/100 mg +ritonavir 300 mg BID. Pharmacokinetic and safety result from this study do not allow for a doserecomendation. Nine subjects (28%) experienced a greater than or equal to grade 2 increase inALT/AST, of which seven (21%) prematurely discontinued study per protocol. Based on the studydesign, it is not possible to determine whether the frequency or magnitude of the ALT/ASTelevations observed is higher than would be seen with rifampin alone. (See CLINICALPHARMACOLOGY for magtitude of interaction, Table 1).

AntiparasiticDecreases in the therapeutic concentration of atovaquone are possible when coadministered withlopinavir/ritonavir. Increases in atovaquone doses may be necessary.

Corticosteroids

Dexamethasone may incluce CYP3A4 and may decrease lopinavir concentrations.

Fluticasone propionate: Concomitant use of fluticasone propionate and lopinavir/ritonavir(lopinavir/ritonavir) may increase concentrations of fluticasone propionate. Use with caution.Consider alternatives to fluticasone propionate, particularly for long-term use (see WARNINGS:Drug Interactions)

Dihydropyridines Calcium Channel Blockers(e.g. felodipine, nifedipine, nicardipine,): May have their serum concentrations increased bylopinavir/ritonavir.

Erectile Dysfunction AgentsSildenafil: Use sildenafil with caution at reduced doses of 25 mg every 48 hours with increasedmonitoring for adverse events (see WARNINGS: Drug Interactions).

Tadalafil: Use tadalafil with caution at reduced doses of no more than 10 mg every 72 hours with

increased monitoring for adverse events (see WARNINGS: Drug Interactions).

Vardenafil: Use vardenafil with caution at reduced doses of no more than 2.5 mg every 72 hourswith increased monitoring for adverse events (see WARNINGS: Drug Interactions).

Herbal ProductsPatients on lopinavir/ritonavir should not use products containing ST John Wort concomitantly,since this combination may be expected to result in reduced plasma concentrations oflopinavir/ritonavir. This effect may be due to an induction of CYP3A4 and may result in the loss oftherapeutic effect and development of resistance (see WARNINGS: Drug Interactions).

HMG-CoA Reductase Inhibitors

HMG Co-A reductase inhibitors, which are highly dependent on CYP3A4 metabolism, such aslovastatin and simvastatin, are expected to have markedly increase plasma concentration whencoadministered with lopinavir/ritonavir. Since increased concentrations of HMG-CoA reductaseinhibitors may cause myopathy, including rhabdomyolysis, the combination of these drugs withlopinavir/ritonavir is not recommended. Atorvastatin is less dependent on CYP3A for metabolism.When atorvastatin was given concurrently with lopinavir/ritonavir, a mean 4.7-fold and 5.9-foldincreae in atorvastatin Cmax and AUC, respectively, was observed. When used withlopinavir/ritonavir, the lowest possible doses of atorvastatin should be administered. Result from adrug interaction study with lopinavir/ritonavir and pravastatin reveal no clinically significantinteraction. The metabolism of pravastatin and fluvastatin is not dependent on CYP3A4, andinteractions are not expected with lopinavir/ritonavir. If treatment with a HMG-CoA redectaseinhibitor is indicated, pravastatin or fluvastatin is recommended (see WARNINGS: DrugInteractions).

Immunosuppressants

Concentrations of these drugs (e.g. cyclosporin, tacrolimus and sirolimus (rapamycin)) may beincreased when coadministered with lopinavir/ritonavir. More frequent therapeutic concentrationmonitoring is recommended until blood levels of these products have stabilized.

MethadoneLopinavir/ritonavir was demonstrated to lower plasma concentrations of methadone. Monitoringplasma concentrations of methadone is recommended.

Oral Contaceptives or Patch ContraceptivesSince levels of ethinyl estradiol may be decreased, alternative or additional contraceptive measuresare to be used when estrogen-based oral contraceptives or patch contraceptives andlopinavir/ritonavir are coadministered.

Clinically Significant Drug Interactions Are Not ExpectedDrug interaction studies reveal no clinically significant interaction between desipramine (CYP2D6probe), omeprazole or ranitidine.Based on known metabolic profiles, clinically significant drug interactions are not expected betweenKaletra and fluvastatin, dapsone, trimethoprim/sulfamethoxazole, azithromycin, or fluconazole inpatients with normal renal and hepatic function.

Carcinogenesis and MutagenesisLong-term carcinogenicity studies of lopinavir/ritonavir in mice revealed a non-genotoxic, mitogenicinduction of liver tumors, generally considered to have little relevance to human risk.

Carcinogenicity studies in rats revealed no tumorigenic findings. Lopinavir was not found to bemutagenic or clastogenic in a battery of in vitro assays including the Ames bacterial reversemutation assay, the mouse lymphoma assay, and chromosomal aberration assays in humanlymphocytes. Lopinavir/ritonavir was not found to be mutagenic or clastogenic in in vivo assaysusing the mouse micronucleus assay.

Pregnancy, Fertility and ReproductionLopinavir in combination with ritonavir at a 2 to1 ratio produced no effects on fertility in male andfemale rats at maximum achievable doses producing drug exposures which were comparable to orslightly less than those achieved with the recommended therapeutic dose. levels of 10/5, 30/15 or100/50 mg/kg/day. Based on AUC measurements, the exposures in rats at the high doses wereapproximately 0.7-fold for lopinavir and 1.8-fold for ritonavir of the exposures in humans at therecommended therapeuic dose (400/100 mg BID).

No treatment-related malformations were observed when lopinavir/ritonavir was administered topregnant rats or rabbits. Embryonic and fetal developmental toxicity observed in rats (earlyresorption, decreased fetal viability, decreased fetal body weight, increased incidence of skeletalvariations and skeletal ossification delays) occured in rats at a maternally toxic dosage (100/50mg/kg/day). Based on AUC measurements, the drug exposures in rats at 100/50 mg/kg/day wereapproximately 0.7-fold for lopinavir and 1.8-fold for ritonavir for males and females that of theexposures in humans at the recommended therapeuic 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) occured at 40/20 mg/kg/day and greater.

No embryonic and fetal developmental toxicity was observed in rabbits at a maternally toxic dosage(80/40 mg/kg/day). Based on AUC measurements the drug exposures in rabbit at 80/40 mg/kg/daywere approximately 0.6-fold for lopinavir and 1.0-fold for ritonavir that of the exposures in humans atthe recommended therapeutic dose (400/100 mg BID). There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not alwayspredictive of human response, lopinavir/ritonavir should be used during pregnancy only if thepotential benefits justifies the potential risks to the fetus.

Nursing WomenBecause of both the potential for HIV transmission and the potential for serious adverse reactions innursing infants, mothers should be instructed not to breast-feed if they are receivinglopinavir/ritonavir. Studies in rats have demonstrated that lopinavir is secreted in milk. It is notknown whether lopinavir is secreted in human milk.

Geriatric UseClinical studies of lopinavir/ritonavir did not include sufficient numbers of subjects aged 65 and overto determine whether they respond differently from younger subjects. In general, appropiate cautionshould be exercised in the administration and monitoring of lopinavir/ritonavir in elderly patientsreflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitantdisease or other drug therapy.

Pediatric UseThe safety and pharmacokinetic profiles of lopinavir/ritonavir in pediatric patient below the age of sixmonths have not been established. In HIV-infected patients age six month to 12 years, the adverseevent profile seen during clinical trial was similar to that for adult patients. The evaluation of theantiviral activity of lopinavir/ritonavir in pediatric patients in clinical trials ongoing (see Descriptionof Clinical Studies section following INDICATIONS AND USAGE). Lopinavir/ritonavir once daily

has not been evaluated in pediatric patients.

ADVERSE REACTIONS

Adults

Treatment-Emergent Adverse EventsLopinavir/ritonavir has been studied in 891 patients as combination theraphy in Phase I/II andPhase III clinical trials. The most common adverse event associated with lopinavir/ritonavir therapywas diarrhea, which was generally of mild to moderate severity. Rates of discontinuation ofrandomized therapy due to adverse events, including death, were 5.8% in lopinavir/ritonavir -treatedand 4.9% in nelfinavir-treated patients in Study 863. The incidence of diarrhea was greater forlopinavir/ritonavir capsules once daily compared to lopinavir/ritonavir capsules twice daily in Study418 (see Table 8).

Treatment-emergent clinical adverse events of moderate or severe intensity in greater than or equalto 2% of patients treated with combination therapy including lopinavir/ritonavir for up to 48 weeks(Study M98-863) and for up to 360weeks (phase I/II) are presentes in Table 8 and Table 9. For otherinformation regarding observed or potentially serious adverse events, please see WARNINGS andPRECAUTIONS.

Table 8 Percentage of Patients with Selected Treatment-Emergent1 Adverse Events of Moderate or Severe

IntensityReported in ≥ 2% of Adult Antiretroviral-Naive Patients

Study 863(48 weeks)

Study 418(48 weeks)

Study 720(360 weeks)

Lopinavir/ritonavir400/100 mg BID +

d4T + 3TC (N=326)

Nelfinavir750 mgTID +d4T +3TC

(N=327)

Lopinavir/ritonavir800/200 mg QD +

TDF + FTC (N=115)


TDF + FTC (N=75)

Lopinavir/ritonavirBID2 + d4T + 3TC

(N=100)

Gastrointestinal disorders

Abdomenenlarged

0.3% 0.6% 0.9% 0.0% 4.0%

Abdominalpain

4.0% 3.1% 2.6% 2.7% 11.0%

Abdominalstools

0.0% 0.3% 0.0% 0.0% 8.0%

Diarrhea 15.6% 17.1% 15.7% 5.3% 28.0%

Dyspepsia 2.1% 0.3% 0.0% 1.3% 6.0%

Flatulence 1.5% 1.2% 1.7% 1.3% 4.0%

Nausea 6.7% 4.6% 8.7% 8.0% 16.0%

Vomiting 2.5% 2.4% 3.5% 4.0% 6.0%

General disorder and administration site conditions

Asthenia 4.0% 3.4% 0.0% 0.0% 9.0%

Pain 0.6% 0.0% 0.0% 0.0% 3.0%

Nervous system disorders

Headache 2.5% 1.8% 2.6% 2.7% 6.0%

Insomnia 1.5% 1.2% 0.0% 0.0% 3.0%

Parasthesia 0.9% 0.9% 0.0% 0.0% 2.0%

Psychiatric disorders

Libidodecreased

0.3% 0.3% 0.0% 1.3% 2.0%

Depression 0.6% 1.5% 1.0% 0.0% 0.0%

Vascular disorders

Vasculardisorder

0.0% 0.0% 0.0% 0.0% 3.0%

Skin and subcutaneous disorders

Lipodystrophy 0.6% 0.6% 0.0% 0.0% 12.0%

Rash 0.6% 1.5% 0.9% 0.0% 5.0%

Musculoskeletal and connective tissue disorders

Myalgia 0.6% 0.9% 0.0% 0.0% 2.0%

Infections and infestations

Brochitis 0.0% 0.0% 0.0% 0.0% 2.0%

Endocrine disorders

Hipogonadismmale

0.0% 0.0% 0.0% 0.0% 2.1%

Metabolism and nutrition disorders

Anorexia 0.9% 0.3% 0.9% 1.3% 2.0%

Weight loss 0.6% 0.3% 0.0% 0.0% 2.0%

Reproductive system and breast disorders

Amenorrhea 0.0% 0.0% 4.5% 0.0% 0.0%

1 Includes adverse events of possible, probable, or unknown relationship to study drug2 Includes adverse event data from dose group I (200/100mg BID [N = 16] and 400/100 mg BID only [N=16]) and dosegroup II (400/100 mg BID [N=35] and 400/200 mg BID [N=33]). Within dosing groups, moderate to severe nausea of probable/possile relationshipto Lopinavir/ritonavir occured at a higher rate in the 400/200 mg dose arm compared to the 400/100 mg dose arm in group II

Table 9 Percentage of Patients with Selected Treatment-Emergent1 Adverse Events of Moderate or Severe Intensity

Reported in ≥ 2% of Adult of Adult Protease Inhibitor-Experience Patients

Study 888 (48 weeks) Study 9572 and Study 7653

(84-1444 Weeks)

Lopinavir/ritonavir 400/100

mg BID + NVP + NRTIs (N=148)

Ivestigator-selectedprotease inhibitor(s) +

NVP + NRTIs(N=140)

Lopinavir/ritonavir BID +NNRTI + NRTIs

(N=127)

Gastrointestinal disorders

Abdominal Pain 2.0% 2.1% 3.9%

Abnormal Stools 0.0% 0.0% 2.4%

Diarrhea 7.4% 9.3% 22.8%

Dyspepsia 1.4% 1.4% 1.6%

Dysphagia 2.0% 0.7% 0.0%

Flatulence 0.7% 2.1% 1.6%

Nausea 6.8% 16.4% 4.7%

Vomiting 4.1% 12.1% 1.6%

General disorder and administration site conditions

Asthenia 2.7% 6.4% 9.4%

Chills 2.0% 0.0% 0.0%

Fever 2.0% 1.4% 1.6%

Pain 0.0% 0.0% 3.9%

Nervous system disorders

Headache 2.0% 2.9% 2.4%

Insomnia 0.0% 2.1% 2.4%

Parasthesia 0.0% 1.4% 2.4%

Vascular disorders

Hypertension 0.0% 0.0% 2.4%

Metabolism and nutrition disorders

Anorexia 0.7% 2.9% 0.0%

Weight loss 0.0% 1.4% 3.1%

Skin and subcutaneous disorders

Lipodystrophy 0.7% 1.4% 6.3%

Rash 2.0% 1.4% 2.4%

Psychiatric disorders

Depression 0.7% 2.1% 3.1%

1 Includes adverse events of possible, probable, or unknown relationship to study drug.2 Includes adverse event data from patients receiving 400/100mg BID (n= 29) or 533/133 mg BID (n=28) for 84 weeks.Patients receiving LOPINAVIR/RITONAVIR in combination with NRTIs and efavirens.3 Includes adverse event data from patients receiving 400/100mg BID (n= 36) or 400/200 mg BID (n=34) for 144 weeks.Patients received LOPINAVIR/RITONAVIR in combination with NRTIs and nevirapine.

Treatment-emergent adverse events occurring in less than 2% of adult patients receivinglopinavir/ritonavir in all phase II/III clinical trials and considered at least possibly related or ofunknown relationship to treatment with lopinavir/ritonavir and of at least moderate intensity are listedbelow by body system.

Infections and infestationsFlu syndrome, furunculosis, gastroenteritis, infection bacterial, otitis media, pharyngitis, sialadenitis,sinusitis, and viral infection.

Neoplasms benign, malignant and unspecifiedCyst, neoplasm and skin benign neoplasm.

Blood and lymphatic system disordersAnemia, leukopenia, and lymphadenopathy.

Immune system disorders

Allergic reaction.

Endocrine disordersCushing's syndrom, and hypothyroidism.

Metabolism and nutrition disordersAvitaminosis, dehydration, diabetes mellitus, increased appetite, lactic acidosis, obesity, and weightgain.

Psychiatric disordersAbnormal dreams, agitation, anxiety, apathy, confusion, emotional lability, nervousness, andthinking abnormal, insomnia.

Nervous System disordersAmnesia, ataxia, cerebral infarct, convulsion, dizziness, dyskinesia, encephalopathy, extrapiramidalsyndrome, facial paralysis, hypertonia, migraine, neuropathy, peripheral neuritis, somnolence, tasteloss, taste perversion, and tremor, headache.

Eye disordersAbnormal vision, and eye disorder.

Ear and labyrinth disordersTinnitus and vertigo.

Cardiac disordersAtrial fibrillation, myocardial infarct, and palpitation.

Vascular disorderDeep vein thrombosis, postural hypotension, thrombophlebitis, varicose vein, and vasculitis.

Respiratory, thoracic, and mediastinal disordersAsthma, Cough increased, dyspnea, lung edema, and rhinitis.

Gastrointestinal disordersConstipation, dry mouth, enteritis, enterocolitis, eructation, esophagitis, fecal incontinence, gastritis,haemorrhagic colitis, mouth ulceration, pancreatitis, periodontitis, stomatitis, and ulcerativestomatitis.Diarrhoea, nausea, vomiting, abdominal pain, abnormal stress, dispepsia, flatulence,gastrointestinal disorders.

Hepatobiliary disordersCholangitis, cholecytitis, hepatitis, hepatomegaly, jaundice, liver fatty deposit, and liver tenderness.

Skin and subcutaneous tissue disordersAcne, alopecia, dry skin, eczema, exfoliative dermatitis, face edema, maculopapular rash, naildisorder, pruritus, seborrhea, skin discoloration, skin striae, skin ulcer, and sweating, rash,lypodystrophy.

Musculoskeletal and connective tissue disorderArthralgia, arthrosis, back pain, and bone necrosis, joint disorder, and myastenia.

Renal and urinary disorderKidney calculus, nephritis, and urine abnormality

Reproductive system disordersAbnormal ejaculation, breast enlargement, gynecomastia, and impotence.

General disorders and administration site conditionsChest pain, chest pain substernal, drug interaction, edema, hypertrophy, malaise, and peripheraledema, asthenia

InvestigationsDrug level increased, and glucose tolerance decreased.Increased trigliserides, increased total cholesterol, increased GGT, incerased SGOT/AST,increased SGPT/ALT, liver test abnormal.

Laboratory Abnormalities

The percentages of adult patients treated with combination therapy including lopinavir/ritonavir withGrade 3 to 4 laboratory abnormalities are presented in Table 10 and Table 11.

Table 10Grade 3-4 Laboratory Abnormalities Reported in ≥2% of Adult Antiretroviral-Naive Patients

Study 863(48 Weeks)

Study 418(48 Weeks)

Study 720(360 Weeks)

Variable Limit1


d4T + 3TC (N=326)

Nelfinavir750 mg TID+ d4T + 3TC

(N=327)

Lopinavir/ritonavir800/200 mg QD +

TDF + FTC (N=115)


TDF + FTC (N=75)

Lopinavir/ritonavirBID + d4T + 3TC

(N=100)

Chemistry High

Glucose >250mg/dL

2% 2% 3% 1% 4%

Uric Acid >12mg/dL

2% 2% 0% 3% 5%

SGOT/AST

>180U/L

2% 4% 5% 3% 10%

SGPT/ALT

>215U/L

4% 4% 4% 3% 11%

GGT >300U/L

N/A N/A N/A N/A 10%

TotalCholesterol

>300mg/dL

9% 5% 3% 3% 27%

Triglyserides >750mg/dL

9% 1% 5% 4% 29%

Amylase >2 xULN

3% 2% 7% 5% 4%

Hematology Low

Neutrophils

0.75 x109 /L

1% 3% 5% 1% 5%

1 ULN = upper limit of the normal range; N/a = Not Applicable

Table 11Grade 3-4 Laboratory Abnormalities Reported in ≥2% of Adult Protease Inhibitor-Esperienced Patients

Variable Limit1

Study 888(48 Weeks)

Study 9572 and Study1653

(84-144 Weeks)

Lopinavir/ritonavir400/100 mg BID +NVP

+ NRTIs(N=148)

Investigator-selectedprotease Inhibitor(s) +

NVP + NRTIs (N=140)

Lopinavir/ritonavir BID +NNRTI + NRTIs

(N=127)

Chemistry High Glucose >250 mg/dL 1% 2% 5% Total Billirubin >3.48 mg/dL 1% 3% 1% SGOT/AST >180 U/L 5% 11% 8% SGPT/ALT >215 U/L 6% 13% 10% GGT >300 U/L N/A N/A 29% Total Cholesterol >300 mg/dL 20% 21% 39% Triglyserides >750 mg/dL 25% 21% 36%

Amylase >2 x ULN 4% 8% 8%

Chemistry Low Inorganic Phosphorus < 1.5 mg/dL 1% 0% 2%Hematology Low Neutrophils 0.75 x 109 /L 1% 2% 4%

1 ULN = upper limit of the normal range; N/A = Not Applicable2 Includes clinical laboratory data from patients receiving 400/100 mg BID (n= 29) or 533/133 mg BID (n=28) for 84weeks. Patients received lopinavir/ritonavir in combination with NRTIs and efavirens.3 Includes clinical laboratory data from patients receiving 400/100mg BID (n= 36) or 400/200 mg BID (n=34) for 144weeks. Patients received lopinavir/ritonavir in combination with NRTIs and nevirapine.

PediatricsTreatment-Emergent Adverse Events

Lopinavir/ritonavir has been studied in 100 pediatric patients 6 months to 12 years of age. Theadverse event profile seen during a clinical trial was similar to that for adult patients.

Taste aversion, vomiting, and diarrhea were the most commonly reported drug related adverseevents of any severity in pediatrics patients treated with combination therapy includinglopinavir/ritonavir for up to 48 weeks in Study 940.A total of 8 children experienced moderate orsevere adverse event at least possibly related to lopinavir/ritonavir. Rash (reporeted in 3%) was theonly drug-related clinical adverse event of moderate to severe intensity observed in greater than orequal to 2% of children enrolled.

Laboratory AbnormalitiesThe percentages of pediatric patients treated with combination therapy including lopinavir/ritonavirwith Grade 3 to 4 laboratory abnormalities are presentented in Table 12

Table 12Grade 3 to 4 Laboratory Abnormalities Reported in

Greater Than or Equal to 2% Pediatrics Patients

Variable Limit+Lopinavir/ritonavir

B.I.D. + RTIs(N = 100)

Chemistry High Sodium >149 mEq/L 3.0%

Total billirubin > 2.9 x ULN 3.0%

SGOT/AST > 180 U/L 8.0%

SGPT/ALT >215 U/L 7.0%

Total Cholesterol >300 mg/dL or >7.77 mmol/L 3.0%

Amylase > 2.5 x ULN 7.0%++

Chemistry Low Sodium < 130 mEq/L 3.0%

Hematology Low

Platelet Count < 50 x 109/L 4.0%

Neutrophils < 0.40 x 109/L 2.0%

+ ULN = upper limit of the normal range ++Subject with Grade 3 to 4 amylase confirmed by elevations in pancreatic amylase

Postmarketing Experience

Hepatitis has been reported in patients on lopinavir/ritonavir therapy. Stevens Johnson Syndromeand erythema multiforme have been reported. Bradyarrythmia has been reported.

Cases of osteonecrosis have been reported, particulary in patients with generallyacknowledged risk factors, advanced HIV disease of long-term exposure to combinationantiretroviral theraphy (CART). The frequency of this unknown.

OVERDOSAGE

Human experience of acute overdosage with lopinavir/ritonavir is limited. Treatment of overdosewith lopinavir/ritonavir ritonavir should consist of general supportive measures including monitoringof vital signs and observation of the clinical status of the patient. There is no specific antidote foroverdose with lopinavir/ritonavir. If indicated, elimination of unabsorbed drug should be achieved byemesis or gastric lavage. Administration of active charcoal may also be used to aid in removal ofunabsorbed drug. Since lopinavir/ritonavir is highly protein bound,dialysis is unlikely to beneficial insignificant removal of the drug.

DOSAGE AND ADMINISTRATION

Adults

Lopinavir/ritonavir tablets shuold be swallowed whole and not chewed, broken or crushed.

The recommended oral dose of lopinavir/ritonavir is as follows:Theraphy-Naive Patients

Lopinavir/ritonavir tablets 400/100 mg (2 tablets) twice -daily with or without food.Lopinavir/ritonavir tablets 800/200 mg (4 tablets) once -daily taken with or without food.

Therapy-Experienced Patients

Lopinavir/ritonavir tablets 400/100 mg (2 tablets) twice -daily taken with or without food.

Once daily administration of lopinavir/ritonavir has not been studied in therapy-experiencedpatients.

Concomitant Therapy

Omeprazole and Ranitidin

Lopinavir/ritonavir tablets can be used in combination with acid reducing agents (omeprazole andranitidine) with no dose adjustment (see Table 1).

Efavirenz, Nevirapine, Amprenavir, Fosamprenavir, or Nelfinavir

Lopinavir/ritonavir 400/100 mg tablets can be used twice daily in combination with these drugs withno dose adjustment (see PRECAUTIONS Drug Interactions).

Lopinavir/ritonavir should not be administered as a once-daily regimen in combination withefavirenz, nevirapine, amprenavir or nelfinavir.

Concomitant therapy: Efavirenz, nevirapine, amprenavir or nelfinavir.A dose increase of lovinavir/ritonavir to 533/133 mg twice-daily taken with food isrecommended when used in combination with efavirenz, nevirapine, amprenavir or nelfinafir.

Pedriatic PatientsThe adult dose of lopinavir/ritonavir tablets (400/100 mg BID) may be used in children 40 Kg orgreater or with a Body Surface Area (BSA)* greater than 1.3 m2. Lopinavir/ritonavir once daily hasnot been evaluated in pediatric patients.

*BSA (m2) = SQR RT [Height (cm) x Weight (kg)] / 3600

HARUS DENGAN RESEP DOKTER

STORAGEStore at or bellow 30º C. Shelf-life : 2 years.

HOW SUPPLIEDRed tablets:Aluvia (lopinavir/ritonavir) tablets are red, film coated tablets embossed with the Abott logo and theAbott-Code AL. Lopinavir/ritonavir is available as 200 mg lopinavir/50 mg ritonavir.

PRESENTATIONBox of Bottle of 120 film-coated tabletsReg. No : ............

Manufactured by:Abbott GmbH & Co KG, Imported by:Ludwigshafen, Germany 67061 P.T Abbot IndonesiaPacked by: Jl. Raya Jakarta Bogor Km. 37Abbot Laboratoties Ltd. Depok 16415, INDONESIAQueenborough, Kent, UKJl. Raya Jakarta-Bogor Km. 37,

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