Kaletra

Generic Name: lopinavir and ritonavir
Dosage Form: Oral solution

Kaletra Description

Kaletra (lopinavir/ritonavir) is a co-formulation of lopinavir and ritonavir. Lopinavir is an inhibitor of the HIV protease. As co-formulated in Kaletra, ritonavir inhibits the CYP3A-mediated metabolism of lopinavir, thereby providing increased plasma levels of lopinavir.

Lopinavir 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 628.80. 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 720.95. Ritonavir has the following structural formula:

Lopinavir is a white to light tan powder. It is freely soluble in methanol and ethanol, soluble in isopropanol and practically insoluble in water.

Kaletra capsules are available for oral administration in a strength of 133.3 mg lopinavir and 33.3 mg ritonavir with the following inactive ingredients: FD&C Yellow No. 6, gelatin, glycerin, oleic acid, polyoxyl 35 castor oil, propylene glycol, sorbitol special, titanium dioxide, and water.

Kaletra oral solution is available for oral administration as 80 mg lopinavir and 20 mg ritonavir per milliliter with the following inactive ingredients: Acesulfame potassium, alcohol, artificial cotton candy flavor, citric acid, glycerin, high fructose corn syrup, Magnasweet-110 flavor, menthol, natural& artificial vanilla flavor, peppermint oil, polyoxyl 40 hydrogenated castor oil, povidone, propylene glycol, saccharin sodium, sodium chloride, sodium citrate, and water.

Kaletra oral solution contains 42.4% alcohol (v/v).

Kaletra - Clinical Pharmacology

Microbiology

Mechanism of Action

Lopinavir, an inhibitor of the HIV protease, prevents cleavage of the Gag-Pol polyprotein, resulting in the production of immature, non-infectious viral particles.

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-1 laboratory strains ranged from 10-27 nM (0.006-0.017 µg/mL, 1 µg/mL = 1.6 µM) and ranged from 4-11 nM (0.003-0.007 µg/mL) against several HIV-1 clinical isolates (n = 6). In the presence of 50% human serum, the mean EC50 of lopinavir against these five laboratory strains ranged from 65-289 nM (0.04-0.18 µg/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 Kaletra 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 > 400 copies/mL at Week 24, 32, 40 and/or 48 were analyzed. No evidence of resistance to Kaletra was observed in 37 evaluable Kaletra-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 Kaletra in antiretroviral treatment naive pediatric patients (Study 940) appears to be consistent with that seen in adult patients (Study 863).

Resistance to Kaletra has been noted to emerge in patients treated with other protease inhibitors prior to Kaletra therapy. In Phase II studies of 227 antiretroviral treatment naive and protease inhibitor experienced patients, isolates from 4 of 23 patients with quantifiable (> 400 copies/mL) viral RNA following treatment with Kaletra 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 4 mutations associated with protease inhibitor resistance immediately prior to Kaletra 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 Kaletra therapy. The assessment of these mutational patterns is under study.

Cross-resistance – Preclinical Studies

Varying degrees of cross-resistance have been observed among HIV protease inhibitors. Little information is available on the cross-resistance of viruses that developed decreased susceptibility to lopinavir during Kaletra therapy.

The in vitro activity of lopinavir against clinical isolates from patients previously treated with a single protease inhibitor was determined. Isolates that displayed > 4-fold reduced susceptibility to nelfinavir (n = 13) and saquinavir (n = 4), displayed < 4-fold reduced susceptibility to lopinavir. Isolates with > 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 described in the following paragraph.

Clinical Studies – Antiviral Activity of Kaletra in Patients with Previous Protease Inhibitor Therapies

The clinical relevance of reduced in vitro susceptibility to lopinavir has been examined by assessing the virologic response to Kaletra therapy, with respect to baseline viral genotype and phenotype, in 56 NNRTI-naive patients with HIV RNA > 1000 copies/mL despite previous therapy with at least two protease inhibitors selected from nelfinavir, indinavir, saquinavir and ritonavir (Study 957). In this study, patients were initially randomized to receive one of two doses of Kaletra 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 wild-type EC50. Fifty-five percent (31/56) of these baseline isolates displayed a > 4-fold reduced susceptibility to lopinavir. These 31 isolates had a mean reduction in lopinavir susceptibility of 27.9-fold. Table 1 shows the 48 week virologic response (HIV RNA < 400 and < 50 copies) according to susceptibility and number of genotypic mutations at baseline in 50 evaluable patients enrolled in the study (957) described above. Because this was a select patient population and the sample size was small, the data depicted in Table 1 do not constitute definitive clinical susceptibility breakpoints. Additional data are needed to determine clinically significant breakpoints for Kaletra.

Table 1. HIV RNA Response at Week 48 by Baseline Kaletra Susceptibility and by Number of Protease Inhibitor-associated Mutations1

Lopinavir susceptibility2 at baseline	HIV RNA < 400 copies/mL (%)	HIV RNA < 50 copies/mL (%)
1 Lopinavir susceptibility was determined by recombinant phenotypic technology performed by Virologic; genotype also performed by Virologic. 2 Fold change in susceptibility from wild type. 3 Thirteen of the 23 patient isolates contained PI mutations at positions 82, 84, and/or 90.
< 10 fold	25/27 (93%)	22/27 (81%)
> 10 and < 40 fold	11/15 (73%)	9/15 (60%)
≥ 40 fold	2/8 (25%)	2/8 (25%)
Number of protease inhibitor mutations at baseline
Up to 5	21/23 (91%)3	19/23 (83%)
> 5	17/27 (63%)	14/27 (52%)

There are insufficient data at this time to identify lopinavir-associated mutational patterns in isolates from patients on Kaletra 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, thereby increasing the plasma levels of lopinavir. Across studies, administration of Kaletra 400/100 mg twice-daily 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 twice-daily. 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 1 displays the mean steady-state plasma concentrations of lopinavir and ritonavir after Kaletra 400/100 mg twice-daily with food for 3 weeks from a pharmacokinetic study in HIV-infected adult subjects (n = 19).

Figure 1. Mean Steady-state Plasma Concentrations with 95% Confidence Intervals (CI) for HIV-Infected Adult Subjects (N = 19)

Absorption

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

Effects of Food on Oral Absorption

Administration of a single 400/100 mg dose of Kaletra capsules with a moderate fat meal (500-682 kcal, 23 to 25% calories from fat) was associated with a mean increase of 48 and 23% in lopinavir AUC and Cmax, respectively, relative to fasting. For Kaletra oral solution, the corresponding increases in lopinavir AUC and Cmax were 80 and 54%, respectively. Relative to fasting, administration of Kaletra with a high fat meal (872 kcal, 56% from fat) increased lopinavir AUC and Cmax by 97 and 43%, respectively, for capsules, and 130 and 56%, respectively, for oral solution. To enhance bioavailability and minimize pharmacokinetic variability Kaletra should be taken with food.

Distribution

At steady state, lopinavir is approximately 98-99% bound to plasma proteins. Lopinavir binds to both alpha-1-acid glycoprotein (AAG) and albumin; however, it has a higher affinity for AAG. At steady state, lopinavir protein binding remains constant over the range of observed concentrations after 400/100 mg Kaletra twice-daily, and is similar between healthy volunteers and HIV-positive 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 a potent CYP3A inhibitor which inhibits the metabolism of lopinavir, and therefore increases plasma levels of lopinavir. A 14C-lopinavir study in humans showed that 89% of the plasma radioactivity after a single 400/100 mg Kaletra 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 8 days. Unchanged lopinavir accounted for approximately 2.2 and 19.8% of the administered dose in urine and feces, respectively. After multiple dosing, less than 3% of the lopinavir dose is excreted unchanged in the urine. The apparent oral clearance (CL/F) of lopinavir is 5.98 ± 5.75 L/hr (mean ± SD, n = 19).

Once Daily Dosing

The pharmacokinetics of once daily Kaletra have been evaluated in HIV-infected subjects naïve to antiretroviral treatment. Kaletra 800/200 mg was administered in combination with emtricitabine 200 mg and tenofovir DF 300 mg as part of a once daily regimen. Multiple dosing of 800/200 mg Kaletra 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, occurring approximately 6 hours after administration. The mean steady-state 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 154.1 ± 61.4 µg•h/mL.

Special Populations

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 Kaletra 300/75 mg/m2 twice-daily and 230/57.5 mg/m2 twice-daily have been studied in a total of 53 pediatric patients, ranging in age from 6 months to 12 years. The 230/57.5 mg/m2 twice-daily regimen without nevirapine and the 300/75 mg/m2 twice-daily regimen with nevirapine provided lopinavir plasma concentrations similar to those obtained in adult patients receiving the 400/100 mg twice-daily regimen (without nevirapine). Kaletra once-daily has not been evaluated in pediatric patients.

The mean steady-state lopinavir AUC, Cmax, and Cmin were 72.6 ± 31.1 µg•h/mL, 8.2 ± 2.9 and 3.4± 2.1 µg/mL, respectively after Kaletra 230/57.5 mg/m2 twice-daily without nevirapine (n = 12), and were 85.8 ± 36.9 µg•h/mL, 10.0 ± 3.3 and 3.6 ± 3.5 µg/mL, respectively, after 300/75 mg/m2 twice-daily with nevirapine (n = 12). The nevirapine regimen was 7 mg/kg twice-daily (6 months to 8 years) or 4 mg/kg twice-daily (> 8 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 Kaletra 400/100 mg twice-daily to HIV and HCV co-infected patients with mild to moderate hepatic impairment (n = 12) resulted in a 30% increase in lopinavir AUC and 20% increase in Cmax compared to HIV-infected subjects with normal hepatic function (n = 12). Additionally, the plasma protein binding of lopinavir was statistically significantly lower in both mild and moderate hepatic impairment compared to controls (99.09 vs. 99.31%, respectively). Caution should be exercised when administering Kaletra to subjects with hepatic impairment. Kaletra has not been studied in patients with severe hepatic impairment (see PRECAUTIONS).

Drug-drug Interactions

See also CONTRAINDICATIONS, WARNINGS and PRECAUTIONS– Drug Interactions.

Kaletra is an inhibitor of the P450 isoform CYP3A in vitro. Co-administration of Kaletra 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).

Kaletra does not inhibit CYP2D6, CYP2C9, CYP2C19, CYP2E1, CYP2B6 or CYP1A2 at clinically relevant concentrations.

Kaletra 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.

Kaletra 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, co-administration of Kaletra and other drugs that inhibit CYP3A may increase lopinavir plasma concentrations.

Drug interaction studies were performed with Kaletra and other drugs likely to be co-administered and some drugs commonly used as probes for pharmacokinetic interactions. The effects of co-administration of Kaletra on the AUC, Cmax and Cmin are summarized in Table 2 (effect of other drugs on lopinavir) and Table 3 (effect of Kaletra on other drugs). The effects 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 Table 10 in PRECAUTIONS.

Table 2. Drug Interactions: Pharmacokinetic Parameters for Lopinavir in the Presence of the Co-administered Drug (See PRECAUTIONS – Table 10 for Recommended Alterations in Dose or Regimen)

Co-administered Drug	Dose of Co-administered Drug (mg)	Dose of Kaletra (mg)	n	Ratio (in combination with Co-administered drug-/alone) of Lopinavir Pharmacokinetic Parameters (90% CI); No Effect = 1.00
				Cmax	AUC		Cmin
All interaction studies conducted in healthy, HIV-negative subjects unless otherwise indicated. 1   The pharmacokinetics of ritonavir are unaffected by concurrent efavirenz. 2   Data extracted from the fosamprenavir package insert. 3  Study conducted in HIV-positive adult subjects. 4   Study conducted in HIV-positive pediatric subjects ranging in age from 6 months to 12 years. 5   Titrated to 800/200 BID 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. 6   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. 7  Data extracted from the tenofovir package insert. *   Parallel group design; n for Kaletra + co-administered drug, n for Kaletra alone. †   NC = No change.
Amprenavir	750 BID, 10 d	400/100 BID, 21 d	12	0.72 (0.65, 0.79)	0.62 (0.56, 0.70)		0.43 (0.34, 0.56)
Atorvastatin	20 QD, 4 d	400/100 BID, 14 d	12	0.90 (0.78, 1.06)	0.90 (0.79, 1.02)		0.92 (0.78, 1.10)
Efavirenz1	600 QHS, 9 d	400/100 BID, 9 d	11, 7*	0.97 (0.78, 1.22)	0.81 (0.64, 1.03)		0.61 (0.38, 0.97)
Fosamprenavir2	700 BID plus ritonavir 100 BID, 14 d	400/100 BID, 14 d	18	1.30 (0.85, 1.47)	1.37 (0.80, 1.55)		1.52 (0.72, 1.82)
Ketoconazole	200 single dose	400/100 BID, 16 d	12	0.89 (0.80, 0.99)	0.87 (0.75, 1.00)		0.75 (0.55, 1.00)
Nelfinavir	1000 BID, 10 d	400/100 BID, 21 d	13	0.79 (0.70, 0.89)	0.73 (0.63, 0.85)		0.62 (0.49, 0.78)
Nevirapine	200 BID, steady-state (> 1 yr)3	400/100 BID, steady-state	22, 19*	0.81 (0.62, 1.05)	0.73 (0.53, 0.98)		0.49 (0.28, 0.74)
	7 mg/kg or 4 mg/kg QD, 2 wk; BID 1 wk4	(> 1 yr) 300/75 mg/m2 BID, 3 wk	12, 15*	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 tablet BID, 10 d	12	1.08 (0.99, 1.17)	1.07 (0.99, 1.15)		1.03 (0.90, 1.18)
	40 QD, 5 d	800/200 tablet QD, 10 d	12	0.94 (0.88, 1.00)	0.92 (0.86, 0.99)		0.71 (0.57, 0.89)
Pravastatin	20 QD, 4 d	400/100 BID, 14 d	12	0.98 (0.89, 1.08)	0.95 (0.85, 1.05)		0.88 (0.77, 1.02)
Rifabutin	150 QD, 10 d	400/100 BID, 20 d	14	1.08 (0.97, 1.19)	1.17 (1.04, 1.31)		1.20 (0.96, 1.65)
Ranitidine	150 single dose	400/100 tablet BID, 10 d	12	0.99 (0.95, 1.03)	0.97 (0.93, 1.01)		0.90 (0.85, 0.95)
	150 single dose	800/200 tablet QD, 10 d	10	0.97 (0.95, 1.00)	0.95 (0.91, 0.99)		0.82 (0.74, 0.91)
Rifampin	600 QD, 10 d	400/100 BID, 20 d	22	0.45 (0.40, 0.51)	0.25 (0.21, 0.29)		0.01 (0.01, 0.02)
	600 QD, 14 d	800/200 BID, 9 d5	10	1.02 (0.85, 1.23)	0.84 (0.64, 1.10)		0.43 (0.19, 0.96)
	600 QD, 14 d	400/400 BID, 9 d6	9	0.93 (0.81, 1.07)	0.98 (0.81, 1.17)		1.03 (0.68, 1.56)
					Co-administration of Kaletra and rifampin is not recommended. (See PRECAUTIONS– Table 9 and Table 10)
Ritonavir3	100 BID, 3-4 wk	400/100 BID, 3-4 wk	8, 21*	1.28 (0.94, 1.76)	1.46 (1.04, 2.06)	2.16 (1.29, 3.62)
Tenofovir7	300 mg QD, 14 d	400/100 BID, 14 d	24	NC†	NC†	NC†

Table 3. Drug Interactions: Pharmacokinetic Parameters for Co-administered Drug in the Presence of Kaletra (See PRECAUTIONS – Table 10 for Recommended Alterations in Dose or Regimen)

Co-administered Drug	Dose of Co-administered Drug (mg)	Dose of Kaletra (mg)	n	Ratio (in combination with Kaletra/alone) of Co-administered Drug Pharmacokinetic Parameters (90% CI); No Effect = 1.00
				Cmax	AUC	Cmin
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   Data extracted from the fosamprenavir package insert. 4  Effect on the dose-normalized sum of rifabutin parent and 25-O-desacetyl rifabutin active metabolite. 5   Data extracted from the tenofovir package insert. *   Parallel group design; n for Kaletra + co-administered drug, n for co-administered drug alone. N/A = Not available. †   NC = No change.
Amprenavir1	750 BID, 10 d combo vs. 1200 BID, 14 d alone	400/100 BID, 21 d	11	1.12 (0.91, 1.39)	1.72 (1.41, 2.09)	4.57 (3.51, 5.95)
Atorvastatin	20 QD, 4 d	400/100 BID, 14 d	12	4.67 (3.35, 6.51)	5.88 (4.69, 7.37)	2.28 (1.91, 2.71)
Desipramine2	100 single dose	400/100 BID, 10 d	15	0.91 (0.84, 0.97)	1.05 (0.96, 1.16)	N/A
Efavirenz	600 QHS, 9 d	400/100 BID, 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 µg QD, 21 d (Ortho Novum®)	400/100 BID, 14 d	12	0.59 (0.52, 0.66)	0.58 (0.54, 0.62)	0.42 (0.36, 0.49)
Fosamprenavir3	700 BID plus ritonavir 100 BID, 14 d	400/100 BID, 14 d	18	0.42 (0.30, 0.58)	0.37 (0.28, 0.49)	0.35 (0.27, 0.46)
Indinavir1	600 BID, 10 d combo nonfasting vs. 800 TID, 5 d alone fasting	400/100 BID, 15 d	13	0.71 (0.63, 0.81)	0.91 (0.75, 1.10)	3.47 (2.60, 4.64)
Ketoconazole	200 single dose	400/100 BID, 16 d	12	1.13 (0.91, 1.40)	3.04 (2.44, 3.79)	N/A
Methadone	5 single dose	400/100 BID, 10 d	11	0.55 (0.48, 0.64)	0.47 (0.42, 0.53)	N/A
Nelfinavir1	1000 BID, 10 d combo vs. 1250 BID, 14 d alone	400/100 BID, 21 d	13	0.93 (0.82, 1.05)	1.07 (0.95, 1.19)	1.86 (1.57, 2.22)
M8 metabolite				2.36 (1.91, 2.91)	3.46 (2.78, 4.31)	7.49 (5.85, 9.58)
Nevirapine	200 QD, 14 d; BID, 6 d	400/100 BID, 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®)	400/100 BID, 14 d	12	0.84 (0.75, 0.94)	0.83 (0.73, 0.94)	0.68 (0.54, 0.85)
Pravastatin	20 QD, 4 d	400/100 BID, 14 d	12	1.26 (0.87, 1.83)	1.33 (0.91, 1.94)	N/A
Rifabutin	150 QD, 10 d; combo vs. 300 QD, 10 d; alone	400/100 BID, 10 d	12	2.12 (1.89, 2.38)	3.03 (2.79, 3.30)	4.90 (3.18, 5.76)
25-O-desacetyl rifabutin				23.6 (13.7, 25.3)	47.5 (29.3, 51.8)	94.9 (74.0, 122)
Rifabutin + 25-O-desacetyl rifabutin4				3.46 (3.07, 3.91)	5.73 (5.08, 6.46)	9.53 (7.56, 12.01)
Saquinavir1	800 BID, 10 d combo vs. 1200 TID, 5 d alone,	400/100 BID, 15 d	14	6.34 (5.32, 7.55)	9.62 (8.05, 11.49)	16.74 (13.73, 20.42)
	1200 BID, 5 d combo vs. 1200 TID, 5 d alone	400/100 BID, 20 d	10	6.44 (5.59, 7.41)	9.91 (8.28, 11.86)	16.54 (10.91, 25.08)
Tenofovir5	300 mg QD, 14 d	400/100 BID, 14 d	24	NC†	1.32 (1.26, 1.38)	1.51 (1.32, 1.66)

Indications and Usage for Kaletra

Kaletra is indicated in combination with other antiretroviral agents for the treatment of HIV-infection. This indication is based on analyses of plasma HIV RNA levels and CD4 cell counts in controlled studies of Kaletra of 48 weeks duration and in smaller uncontrolled dose-ranging studies of Kaletra of 144-204 weeks duration.

Once-daily administration of Kaletra is not recommended in therapy-experienced patients.

When initiating treatment with Kaletra in therapy-naïve patients, it should be noted that the incidence of diarrhea was greater for Kaletra once-daily compared to Kaletra 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 or possibly related to drug) (see CLINICAL PHARMACOLOGY, ADVERSE REACTIONS, and DOSAGE AND ADMINISTRATION).

Description of Clinical Studies

Patients Without Prior Antiretroviral Therapy

Study 863: Kaletra twice-daily + stavudine + lamivudine compared to nelfinavir three-times-daily + stavudine + lamivudine

Study 863 is an ongoing, randomized, double-blind, multicenter trial comparing treatment with Kaletra (400/100 mg twice-daily) plus stavudine and lamivudine versus nelfinavir (750 mg three-times-daily) plus stavudine and lamivudine in 653 antiretroviral treatment naïve 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 Table 4.

Table 4. Outcomes of Randomized Treatment Through Week 48 (Study 863)

Outcome	Kaletra+d4T+3TC (N = 326)	Nelfinavir+d4T+3TC (N = 327)
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. Overall discontinuation through Week 48, including patients who discontinued subsequent to virologic failure, was 17% in the Kaletra arm and 24% in the nelfinavir arm.
Responder1	75%	62%
Virologic failure2    Rebound    Never suppressed through Week 48	9% 7% 2%	25% 15% 9%
Death	2%	1%
Discontinued due to adverse event	4%	4%
Discontinued for other reasons3	10%	8%

Through 48 weeks of therapy, there was a statistically significantly higher proportion of patients in the Kaletra arm compared to the nelfinavir arm with HIV RNA < 400 copies/mL (75% vs. 62%, respectively) and HIV RNA < 50 copies/mL (67% vs. 52%, respectively). Treatment response by baseline HIV RNA level subgroups is presented in Table 5.

Table 5. Proportion of Responders Through Week 48 by Baseline Viral Load (Study 863)

Baseline Viral Load (HIV-1 RNA copies/mL)	Kaletra +d4T+3TC			Nelfinavir +d4T+3TC
	< 400 copies/mL1	< 50 copies/mL2	n	< 400 copies/mL1	< 50 copies/mL2	n
1   Patients achieved and maintained confirmed HIV RNA < 400 copies/mL through Week 48. 2   Patients achieved HIV RNA < 50 copies/mL at Week 48.
< 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%	89

Through 48 weeks of therapy, the mean increase from baseline in CD4 cell count was 207 cells/mm3 for the Kaletra arm and 195 cells/mm3 for the nelfinavir arm.

Study 418: Kaletra once-daily + tenofovir DF + emtricitabine compared to Kaletra twice-daily + tenofovir DF + emtricitabine

Study 418 is an ongoing, randomized, open-label, multicenter trial comparing treatment with Kaletra 800/200 mg once-daily plus tenofovir DF and emtricitabine versus Kaletra 400/100 mg twice-daily plus tenofovir DF and emtricitabine in 190 antiretroviral treatment naïve 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 6.

Table 6. Outcomes of Randomized Treatment Through Week 48 (Study 418)

Outcome	Kaletra QD + TDF + FTC (n = 115)	Kaletra BID + TDF + FTC (n = 75)
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 Week 48. 3   Includes lost to follow-up, patient’s withdrawal, non-compliance, protocol violation and other reasons.
Responder1	71%	65%
Virologic failure2 Rebound Never suppressed through Week 48	10% 6% 3%	9% 5% 4%
Death	0%	1%
Discontinued due to an adverse event	12%	7%
Discontinued for other reasons3	7%	17%

Through 48 weeks of therapy, 71% in the Kaletra once-daily arm and 65% in the Kaletra 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 Kaletra once-daily arm and 196 cells/mm3 for the Kaletra twice-daily arm.

Patients with Prior Antiretroviral Therapy

Study 888: Kaletra twice-daily + nevirapine + NRTIs compared to investigator-selected protease inhibitor(s) + nevirapine + NRTIs

Study 888 is a randomized, open-label, multicenter trial comparing treatment with Kaletra (400/100 mg twice-daily) 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)-naïve 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 baseline plasma 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 in Table 7.

Table 7. Outcomes of Randomized Treatment Through Week 48 (Study 888)

Outcome	Kaletra + nevirapine + NRTIs (n = 148)	Investigator-Selected Protease Inhibitor(s) + nevirapine + NRTIs (n = 140)
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.
Responder1	57%	33%
Virologic Failure2	24%	41%
Rebound      Never suppressed through Week 48	11% 13%	19% 23%
Death	1%	2%
Discontinued due to adverse events	5%	11%
Discontinued for other reasons3	14%	13%

Through 48 weeks of therapy, there was a statistically significantly higher proportion of patients in the Kaletra arm compared to the investigator-selected protease inhibitor(s) arm with HIV RNA < 400 copies/mL (57% vs. 33%, respectively).

Through 48 weeks of therapy, the mean increase from baseline in CD4 cell count was 111 cells/mm3 for the Kaletra arm and 112 cells/mm3 for the investigator-selected protease inhibitor(s) arm.

Other Studies

Study 720: Kaletra twice-daily + stavudine + lamivudine

Study 765: Kaletra twice-daily + nevirapine + NRTIs

Study 720 (patients without prior antiretroviral therapy) and study 765 (patients with prior protease inhibitor therapy) are randomized, blinded, multi-center trials evaluating treatment with Kaletra at up to three dose levels (200/100 mg twice-daily [720 only], 400/100 mg twice-daily, and 400/200 mg twice-daily). In Study 720, all patients switched to 400/100 mg twice-daily between Weeks 48-72. Patients in study 720 had a mean age of 35 years, 70% were Caucasian, and 96% were male, while patients in study 765 had a mean age of 40 years, 73% were Caucasian, and 90% were male. Mean (range) baseline CD4 cell counts for patients in study 720 and study 765 were 338 (3-918) and 372 (72-807) cells/mm3, respectively. Mean (range) baseline plasma HIV-1 RNA levels for patients in study 720 and study 765 were 4.9 (3.3 to 6.3) and 4.0 (2.9 to 5.8) log10 copies/mL, respectively.

Through 204 weeks of treatment in study 720, the proportion of patients with HIV RNA < 400 (< 50) copies/mL was 71% (70%) [n = 100], and the corresponding mean increase in CD4 cell count was 440 cells/mm3. Twenty-eight patients (28%) discontinued the study, including 9 (9%) discontinuations due to adverse events and 1 (1%) death. Through 144 weeks of treatment in study 765, the proportion of patients with HIV RNA < 400 (< 50) copies/mL was 54% (50%) [n = 70], and the corresponding mean increase in CD4 cell count was 212 cells/mm3. Twenty-seven patients (39%) discontinued the study, including 9 (13%) discontinuations secondary to adverse events and 2 (3%) deaths.

CONTRAINDICATIONS

Kaletra is contraindicated in patients with known hypersensitivity to any of its ingredients, including ritonavir.

Co-administration of Kaletra is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events. These drugs are listed in Table 8.

Table 8. Drugs That Are Contraindicated With Kaletra

Drug Class	Drugs Within Class That Are Contraindicated With Kaletra
Antihistamines	Astemizole, Terfenadine
Ergot Derivatives	Dihydroergotamine, Ergonovine, Ergotamine, Methylergonovine
GI motility agent	Cisapride
Neuroleptic	Pimozide
Sedative/Hypnotics	Midazolam, Triazolam

Warnings

ALERT: Find out about medicines that should NOT be taken with Kaletra. This statement is included on the product"s bottle label.

Drug Interactions

Kaletra is an inhibitor of the P450 isoform CYP3A. Co-administration of Kaletra and drugs primarily metabolized by CYP3A may result in increased plasma concentrations of the other drug that could increase or prolong its therapeutic and adverse effects (see Pharmacokinetics–Drug-drug Interactions, CONTRAINDICATIONS –Table 8: Drugs That Are Contraindicated With Kaletra, PRECAUTIONS – Table 9: Drugs That Should Not Be Co-administered With Kaletra and Table 10: Established and Other Potentially Significant Drug Interactions).

Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving Kaletra. Co-administration of Kaletra with these drugs is expected to substantially increase their concentrations and may result in an increase in associated adverse events including hypotension, syncope, visual changes and prolonged erection (see PRECAUTIONS– Drug Interactions and the complete prescribing information for sildenafil, tadalafil, and vardenafil.)

Concomitant use of Kaletra with lovastatin or simvastatin is not recommended. Caution should be exercised if HIV protease inhibitors, including Kaletra, are used concurrently with other HMG-CoA reductase inhibitors that are also metabolized by the CYP3A4 pathway (e.g., atorvastatin). The risk of myopathy, including rhabdomyolysis may be increased when HIV protease inhibitors, including Kaletra, are used in combination with these drugs.

Concomitant use of Kaletra and St. John"s wort (hypericum perforatum), or products containing St. John"s wort, is not recommended. Co-administration of protease inhibitors, including Kaletra, with St. John"s wort is expected to substantially decrease protease inhibitor concentrations and may result in sub-optimal levels of lopinavir and lead to loss of virologic response and possible resistance to lopinavir or to the class of protease inhibitors.

A drug interaction study in healthy subjects has shown that ritonavir significantly increases plasma fluticasone propionate exposures, resulting in significantly decreased serum cortisol concentrations. Concomitant use of Kaletra and fluticasone propionate is expected to produce the same effects. Systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression have been reported during postmarketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Therefore, coadministration of fluticasone propionate and Kaletra is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects (see PRECAUTIONS– Drug Interactions ).

Pancreatitis

Pancreatitis has been observed in patients receiving Kaletra therapy, including those who developed marked triglyceride elevations. In some cases, fatalities have been observed. Although a causal relationship to Kaletra 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 Kaletra 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 Kaletra and/or other antiretroviral therapy should be suspended as clinically appropriate.

Diabetes Mellitus/Hyperglycemia

New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in HIV-infected patients receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease inhibitor therapy and these events has not been established.

Precautions

Hepatic Impairment and Toxicity

Kaletra is principally metabolized by the liver; therefore, caution should be exercised when administering this drug to patients with hepatic impairment, because lopinavir concentrations may be increased (see CLINICAL PHARMACOLOGY –Hepatic Impairment).Patients with underlying hepatitis B or C or marked elevations in transaminases prior to treatment may be at increased risk for developing further transaminase elevations or hepatic decompensation. 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 Kaletra therapy has not been established. Increased AST/ALT monitoring should be considered in these patients, especially during the first several months of Kaletra treatment.

Resistance/Cross-resistance

Various degrees of cross-resistance among protease inhibitors have been observed. The effect of Kaletra 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. A causal relationship between protease inhibitor therapy and these events has not been established.

Fat Redistribution

Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and" cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

Lipid Elevations

Treatment with Kaletra has resulted in large increases in the concentration of total cholesterol and triglycerides (see ADVERSE REACTIONS – Table15). Triglyceride and cholesterol testing should be performed prior to initiating Kaletra therapy and at periodic intervals during therapy. Lipid disorders should be managed as clinically appropriate. See PRECAUTIONS– Table 10: Established and Other Potentially Significant Drug Interactions for additional information on potential drug interactions with Kaletra and HMG-CoA reductase inhibitors.

Immune Reconstitution Syndrome

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

Information for Patients

A statement to patients and health care providers is included on the product"s bottle label: "ALERT: Find out about medicines that should NOT be taken with Kaletra." A Patient Package Insert (PPI) for Kaletra is available for patient information.

Patients should be told that sustained decreases in plasma HIV RNA have been associated with a reduced risk of progression to AIDS and death. Patients should remain under the care of a physician while using Kaletra. Patients should be advised to take Kaletra and other concomitant antiretroviral therapy every day as prescribed. Kaletra must always be used in combination with other antiretroviral drugs. Patients should not alter the dose or discontinue therapy without consulting with their doctor. If a dose of Kaletra is missed patients should take the dose as soon as possible and then return to their normal schedule. However, if a dose is skipped the patient should not double the next dose.

Patients should be informed that Kaletra is not a cure for HIV infection and that they may continue to develop opportunistic infections and other complications associated with HIV disease. The long-term effects of Kaletra are unknown at this time. Patients should be told that there are currently no data demonstrating that therapy with Kaletra can reduce the risk of transmitting HIV to others through sexual contact.

Kaletra may interact with some drugs; therefore, patients should be advised to report to their doctor the use of any other prescription, non-prescription medication or herbal products, particularly St. John"s wort.

Patients taking didanosine should take didanosine one hour before or two hours after Kaletra.

Patients receiving sildenafil, tadalafil, or vardenafil should be advised that they may be at an increased risk of associated adverse events including hypotension, visual changes, and sustained erection, and should promptly report any symptoms to their doctor.

Patients receiving estrogen-based hormonal contraceptives should be instructed that additional or alternate contraceptive measures should be used during therapy with Kaletra.

Kaletra should be taken with food to enhance absorption.

Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long term health effects of these conditions are not known at this time.

Drug Interactions

Kaletra is an inhibitor of CYP3A (cytochrome P450 3A) both in vitro and in vivo. Co-administration of Kaletra and drugs primarily metabolized by CYP3A (e.g., dihydropyridine calcium channel blockers, HMG-CoA reductase inhibitors, immunosuppressants and PDE5 inhibitors) may result in increased plasma concentrations of the other d



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