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Kaletra (Lopinavir / Ritonavir) - Indications and Dosage

 
 



INDICATIONS AND USAGE

KALETRA is indicated in combination with other antiretroviral agents for the treatment of HIV-infection.

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 5.

Table 5. 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.

Responder175%62%
Virologic failure2
    Rebound
   Never suppressed through Week 48
9%
7%
2%
25%
15%
9%
Death2%1%
Discontinued due to adverse event 4%4%
Discontinued for other reasons310%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 6.

Table 6. 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/mL 1 < 50 copies/mL 2 n < 400 copies/mL 1 < 50 copies/mL 2 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.

< 30,00074%71%8279%72%87
≥ 30,000 to < 100,00081%73%7967%54%79
≥ 100,000 to < 250,00075%64%8360%47%72
≥ 250,00072%60%8244%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 7.

Table 7. 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.

Responder171%65%
Virologic failure2
Rebound
Never suppressed through Week 48
10%
6%
3%
9%
5%
4%
Death0%1%
Discontinued due to an adverse event12%7%
Discontinued for other reasons37%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 8.

Table 8. 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.

Responder157%33%
Virologic Failure224%41%
     Rebound
     Never suppressed through Week 48
11%
13%
19%
23%
Death1%2%
Discontinued due to adverse events 5%11%
Discontinued for other reasons314%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 720had 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 360 weeks of treatment in study 720, the proportion of patients with HIV RNA < 400 (< 50) copies/mL was 61% (59%) [n = 100]. Among patients completing 360 weeks of treatment with CD4 cell count measurements [n=60], the mean (median) increase in CD4 cell count was 501 (457) cells/mm3. Thirty-nine patients (39%) discontinued the study, including 15 (15%) 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.

DOSAGE AND ADMINISTRATION

KALETRA capsules and oral solution must be taken with food.

The recommended oral dose of KALETRA is as follows: (Please also refer to INDICATIONS AND USAGE and ADVERSE REACTIONS)

Adults

Therapy-Naïve Patients

  • KALETRA 400/100 mg (3 capsules or 5.0 mL) twice-daily taken with food.
  • KALETRA 800/200 mg (6 capsules or 10 mL) once-daily taken with food.

Therapy-experienced Patients

  • KALETRA 400/100 mg (3 capsules or 5.0 mL) twice-daily taken with food.

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

Concomitant therapy: Efavirenz, nevirapine, amprenavir or nelfinavir

A dose increase of KALETRA to 533/133 mg (4 capsules or 6.5 mL) twice-daily taken with food is recommended when used in combination with efavirenz, nevirapine, amprenavir or nelfinavir (see CLINICAL PHARMACOLOGY– Drug-drug Interactions and/or PRECAUTIONS – Table 11).

KALETRA should not be administered as a once-daily regimen in combination with efavirenz, nevirapine, amprenavir or nelfinavir.

Pediatric Patients

In children 6 months to 12 years of age, the recommended dosage of KALETRA oral solution is 12/3 mg/kg for those 7 to < 15 kg and 10/2.5 mg/kg for those 15 to 40 kg (approximately equivalent to 230/57.5 mg/m2) twice-daily taken with food, up to a maximum dose of 400/100 mg in children > 40 kg (5.0 mL or 3 capsules) twice-daily. KALETRA once-daily has not been evaluated in pediatric patients. It is preferred that the prescriber calculate the appropriate milligram dose for each individual child ≤ 12 years old and determine the corresponding volume of solution or number of capsules. However, as an alternative, the following table contains dosing guidelines for KALETRA oral solution based on body weight. When possible, dose should be administered using a calibrated dosing syringe.

Weight
(kg)
Dose
(mg/kg)*
Volume of oral solution BID
(80 mg lopinavir/20 mg ritonavir per mL)

*   Dosing based on the lopinavir component of lopinavir/ritonavir solution (80 mg/20 mg per mL).

Without nevirapine, efavirenz or amprenavir
7 to < 15 kg12 mg/kg BID
     7 to 10 kg1.25 mL
     > 10 to < 15 kg1.75 mL
15 to 40 kg10 mg/kg BID
     15 to 20 kg2.25 mL
     > 20 to 25 kg2.75 mL
     > 25 to 30 kg3.5 mL
     > 30 to 35 kg4.0 mL
     > 35 to 40 kg4.75 mL
> 40 kgAdult dose5 mL (or 3 capsules)

Note: Use adult dosage recommendation for children > 12 years of age.

Concomitant Therapy: Efavirenz, nevirapine or amprenavir

A dose increase of KALETRA oral solution to 13/3.25 mg/kg for those 7 to < 15 kg and 11/2.75 mg/kg for those 15 to 45 kg (approximately equivalent to 300/75 mg/m2) twice-daily taken with food, up to a maximum dose of 533/133 mg in children > 45 kg twice-daily is recommended when used in combination with efavirenz, nevirapine or amprenavir in children 6 months to 12 years of age. The following table contains dosing guidelines for KALETRA oral solution based on body weight, when used in combination with efavirenz, nevirapine or amprenavir in children (see CLINICAL PHARMACOLOGY– Drug-drug Interactions and/or PRECAUTIONS – Table 11).

Weight
(kg)
Dose
(mg/kg)*
Volume of oral solution BID (80 mg lopinavir/20 mg ritonavir per mL)

*   Dosing based on the lopinavir component of lopinavir/ritonavir solution (80 mg/20 mg per mL).

With nevirapine, efavirenz or amprenavir
7 to < 15 kg13 mg/kg BID
     7 to 10 kg1.5 mL
     > 10 to < 15 kg2.0 mL
15 to 45 kg11 mg/kg BID
     15 to 20 kg2.5 mL
     > 20 to 25 kg3.25 mL
     > 25 to 30 kg4.0 mL
     > 30 to 35 kg4.5 mL
     > 35 to 40 kg5.0 mL (or 3 capsules)
     > 40 to 45 kg5.75 mL
> 45 kgAdult dose6.5 mL (or 4 capsules)

Note: Use adult dosage recommendation for children > 12 years of age.

HOW SUPPLIED

KALETRA (lopinavir/ritonavir) capsules are orange soft gelatin capsules imprinted with the corporate Abbott“A” logo and the Abbo-Code PK. KALETRA is available as 133.3 mg lopinavir/33.3 mg ritonavir capsules in the following package sizes:

Bottles of 180 capsules each….…………… (NDC 0074-3959-77)

Recommended storage: Store KALETRA soft gelatin capsules at 36°F - 46°F (2°C - 8°C) until dispensed. Avoid exposure to excessive heat. For patient use, refrigerated KALETRA capsules remain stable until the expiration date printed on the label. If stored at room temperature up to 77°F (25°C), capsules should be used within 2 months.

KALETRA (lopinavir/ritonavir) oral solution is a light yellow to orange colored liquid supplied in amber-colored multiple-dose bottles containing 400 mg lopinavir/100 mg ritonavir per 5 mL (80 mg lopinavir/20 mg ritonavir per mL) packaged with a marked dosing cup in the following size:

160 mL bottle……………………………….(NDC 0074-3956-46)

Recommended storage: Store KALETRA oral solution at 36°F - 46°F (2°C - 8°C) until dispensed. Avoid exposure to excessive heat. For patient use, refrigerated KALETRA oral solution remains stable until the expiration date printed on the label. If stored at room temperature up to 77°F (25°C), oral solution should be used within 2 months.

Abbott Laboratories

North Chicago, IL 60064, U.S.A.

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