Drug Description

KALETRA (lopinavir/ritonavir) is a co-formulation of lopinavir and ritonavir. Lopinavir is an inhibitor of the HIV-1 protease. As co-formulated in KALETRA, ritonavir inhibits the CYP3A-mediated metabolism of lopinavir, thereby providing increased plasma levels of lopinavir.

KALETRA film-coated tablets are available for oral administration in two strengths:

• Yellow tablets containing 200 mg of lopinavir and 50 mg of ritonavir
• Pale yellow tablets containing 100 mg of lopinavir and 25 mg of ritonavir.

The yellow, 200 mg lopinavir/50 mg ritonavir, tablets contain the following inactive ingredients: copovidone, sorbitan monolaurate, colloidal silicon dioxide, and sodium stearyl fumarate. The following are the ingredients in the film coating: hypromellose, titanium dioxide, polyethylene glycol 400, hydroxypropyl cellulose, talc, colloidal silicon dioxide, polyethylene glycol 3350, yellow ferric oxide E172, and polysorbate 80.

The pale yellow, 100 mg lopinavir/25 mg ritonavir, tablets contain the following inactive ingredients: copovidone, sorbitan monolaurate, colloidal silicon dioxide, and sodium stearyl fumarate. The following are the ingredients in the film coating: polyvinyl alcohol, titanium dioxide, talc, polyethylene glycol 3350, and yellow ferric oxide E172.

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).

[For information about KALETRA capsules 133.3 mg lopinavir/33.3 mg ritonavir, consult the KALETRA capsules full prescribing information].

HIV/AIDS-Related Uses

KALETRA is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection.

The following points should be considered when initiating therapy with KALETRA:

• The use of other active agents with KALETRA is associated with a greater likelihood of treatment response.

• Genotypic or phenotypic testing and/or treatment history should guide the use of KALETRA. The number of baseline lopinavir resistance-associated substitutions affects the virologic response to KALETRA.

• Once daily administration of KALETRA is not recommended for any pediatric patients.

Dosing Information

Mode of Delivery

Oral.

Dosage Form

• KALETRA Tablets (film-coated), 200 mg lopinavir/50 mg ritonavir.

• KALETRA Tablets (film-coated), 100 mg lopinavir/25 mg ritonavir.

• KALETRA Oral Solution containing 400 mg lopinavir/100 mg ritonavir per 5 mL (80 mg lopinavir/20 mg ritonavir per mL).

[For information about KALETRA capsules 133.3 mg lopinavir/33.3 mg ritonavir, consult the KALETRA capsules full prescribing information].

DOSAGE AND ADMINISTRATION

KALETRA tablets may be taken with or without food. The tablets should be swallowed whole and not chewed, broken, or crushed.

KALETRA oral solution must be taken with food.

Adult Patients

• KALETRA tablets 400/100 mg (given as two 200/50 mg tablets) twice daily.
   
• KALETRA oral solution 400/100 mg (5 mL) twice daily.
   
• KALETRA tablets 800/200 mg (given as four 200/50 mg tablets) once daily in patients with less than three lopinavir resistance-associated substitutions.
   
• KALETRA oral solution 800/200 mg (10 mL) once daily in patients with less than three lopinavir resistance-associated substitutions.

Once daily administration of KALETRA is not recommended for adult patients with three or more of the following lopinavir resistance-associated substitutions: L10F/I/R/V, K20M/N/R, L24I, L33F, M36I, I47V, G48V, I54L/T/V, V82A/C/F/S/T, and I84V.

KALETRA should not be administered once daily in combination with carbamazepine, phenobarbital, or phenytoin.

Concomitant Therapy: Efavirenz, Nevirapine, Amprenavir or Nelfinavir

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

• A dose increase is recommended for all patients who use KALETRA tablets. The recommended dose of KALETRA tablets is 500/125 mg (such as two 200/50 tablets and one 100/25 mg tablet) twice daily in combination with efavirenz, nevirapine, amprenavir or nelfinavir.
   
• A dose increase is recommended for all patients who use KALETRA oral solution. The recommended dose of KALETRA oral solution is 533/133 mg (6.5 mL) twice daily when used in combination with efavirenz, nevirapine, amprenavir or nelfinavir.

Pediatric Patients

KALETRA tablets and oral solution should not be administered once daily in pediatric patients < 18 years of age.

KALETRA oral solution should not be administered to neonates before a postmenstrual age (first day of the mother’s last menstrual period to birth plus the time elapsed after birth) of 42 weeks and a postnatal age of at least 14 days has been attained.

KALETRA oral solution contains 42.4% (v/v) alcohol and 15.3% (w/v) propylene glycol. Special attention should be given to accurate calculation of the dose of KALETRA, transcription of the medication order, dispensing information and dosing instructions to minimize the risk for medication errors, and overdose. This is especially important for infants and young children. Total amounts of alcohol and propylene glycol from all medicines that are to be given to pediatric patients 14 days to 6 months of age should be taken into account in order to avoid toxicity from these excipients.

Prescribers should calculate the appropriate dose of KALETRA for each individual child based on body weight (kg) or body surface area (BSA) to avoid underdosing or exceeding the recommended adult dose.

Body surface area (BSA) can be calculated as follows:

BSA (m2) = sq rt [Ht(cm) x Wt(kg)/3600]

The KALETRA dose can be calculated based on weight or BSA:

Based on Weight:
Patient Weight (kg) × Prescribed lopinavir dose (mg/kg) = Administered lopinavir dose (mg)

Based on BSA:
Patient BSA (m²) × Prescribed lopinavir dose (mg/m²) = Administered lopinavir dose (mg)

If KALETRA oral solution is used, the volume (mL) of KALETRA solution can be determined as follows:

Volume of KALETRA solution (mL) = Administered lopinavir dose (mg) ÷ 80 (mg/mL)

The dose of the oral solution should be administered using a calibrated dosing syringe.

Before prescribing KALETRA 100/25 mg tablets, children should be assessed for the ability to swallow intact tablets. If a child is unable to reliably swallow a KALETRA tablet, the KALETRA oral solution formulation should be prescribed.

14 Days to 6 Months:

In pediatric patients 14 days to 6 months of age, the recommended dosage of lopinavir/ritonavir using KALETRA oral solution is 16/4 mg/kg or 300/75 mg/m² twice daily. Prescribers should calculate the appropriate dose based on body weight or body surface area.

Because no data exists for dosage when administered with efavirenz, nevirapine, amprenavir, or nelfinavir, it is recommended that KALETRA not be administered in combination with these drugs in patients < 6 months of age.

6 Months to 18 Years:

Without Concomitant Efavirenz, Nevirapine, Amprenavir or Nelfinavir

Dosing recommendations using oral solution
In children 6 months to 18 years of age, the recommended dosage of lopinavir/ritonavir using KALETRA oral solution without concomitant efavirenz, nevirapine, amprenavir, or nelfinavir is 230/57.5 mg/m² given twice daily, not to exceed the recommended adult dose (400/100 mg [5 mL] twice daily). If weight-based dosing is preferred, the recommended dosage of lopinavir/ritonavir for patients < 15 kg is 12/3 mg/kg given twice daily and the dosage for patients ≥ 15 kg to 40 kg is 10/2.5 mg/kg given twice daily.

Dosing recommendations using tablets
The dosing recommendations for pediatric patients 6 months to 18 years of age based on body weight or body surface area for KALETRA tablets are provided below.

Pediatric Dosing Recommendations for Patients 6 Months to 18 Years of Age Based on Body Weight or Body Surface Area for KALETRA Tablets Without Concomitant Efavirenz, Nevirapine, Amprenavir, or Nelfinavir

Body Weight (kg); Body Surface Area (m²) ^*: Recommended number of 100/25 mg Tablets Twice Daily

• 15 to 25 kg; ≥0.6 to < 0.9 m²: Recommended number of 100/25 mg Tablets Twice Daily = 2
• >25 to 35 kg; ≥0.9 to < 1.4 m²: Recommended number of 100/25 mg Tablets Twice Daily = 3
• >35 kg; ≥1.4 m²: Recommended number of 100/25 mg Tablets Twice Daily = 4 (or two 200/50 mg tablets)

^* KALETRA oral solution is available for children with a BSA less than 0.6 m² or those who are unable to reliably swallow a tablet.

Concomitant Therapy: Efavirenz, Nevirapine, Amprenavir, or Nelfinavir

Dosing recommendations using oral solution
A dose increase of KALETRA to 300/75 mg/m² using KALETRA oral solution is needed when coadministered with efavirenz, nevirapine, amprenavir, or nelfinavir in children (both treatment-naïve and treatment-experienced) 6 months to 18 years of age, not to exceed the recommended adult dose (533/133 mg [6.5 mL] twice daily). If weight-based dosing is preferred, the recommended dosage for patients <15 kg is 13/3.25 mg/kg given twice daily and the dosage for patients >15 kg to 45 kg is 11/2.75 mg/kg given twice daily.

Dosing recommendations using tablets
The dosing recommendations for pediatric patients 6 months to 18 years of age based on body weight or body surface area for KALETRA tablets when given in combination with efavirenz, nevirapine, amprenavir, or nelfinavir are provided below.

Pediatric Dosing Recommendations for Patients 6 Months to 18 Years of Age Based on Body Weight or Body Surface Area for KALETRA Tablets With Concomitant Efavirenz^†, Nevirapine, Amprenavir^† or Nelfinavir^†

Body Weight (kg); Body Surface Area (m2)^*: Recommended number of 100/25 mg Tablets Twice Daily

• 15 to 20 kg; ≥0.6 to < 0.8 m²: Recommended number of 100/25 mg Tablets Twice Daily = 2
• >20 to 30; ≥0.8 to < 1.2 m²: Recommended number of 100/25 mg Tablets Twice Daily = 3
• >30 to 45; ≥1.2 to <1.7m²: Recommended number of 100/25 mg Tablets Twice Daily = 4 (or two 200/50 mg tablets)
• >45 kg; ≥1.7 m²: Recommended number of 100/25 mg Tablets Twice Daily = 5 [see Dosage and Administration, Adult Patients]

^* KALETRA oral solution is available for children with a BSA less than 0.6 m2 or those who are unable to reliably swallow a tablet.
^† Please refer to the individual product labels for appropriate dosing in children.

[For information about KALETRA capsules, consult the KALETRA capsules full prescribing information].

Storage

Store KALETRA film-coated tablets at 20°-25°C (68°-77°F); excursions permitted to 15°-30°C (59° to 86°F)[see USP controlled room temperature]. Dispense in original container or USP equivalent tight container (250 mL or less). For patient use: exposure of this product to high humidity outside the original container or USP equivalent tight container (250 mL or less) for longer than 2 weeks is not recommended.

Store KALETRA oral solution at 2°-8°C (36°-46°F) 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 25°C (77°F), oral solution should be used within 2 months.

[For information about KALETRA capsules, consult the KALETRA capsules full prescribing information].

Pharmacology

Mechanism of Action
Lopinavir is an antiviral drug.

Pharmacokinetics
The pharmacokinetic properties of lopinavir co-administered with ritonavir have been evaluated in healthy adult volunteers and in HIV-1 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-1 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-1 infected adult subjects (n = 19). [Please consult the KALETRA full prescribing information to view Figure 1].

Absorption
In a pharmacokinetic study in HIV-1 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 (C_max) 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 oral solution. When administered under fasting conditions, both the mean AUC and C_max of lopinavir were 22% lower for the KALETRA oral solution relative to the capsule formulation.

Plasma concentrations of lopinavir and ritonavir after administration of two 200/50 mg KALETRA tablets are similar to three 133.3/33.3 mg KALETRA capsules under fed conditions with less pharmacokinetic variability.

Effects of Food on Oral Absorption
KALETRA Tablets
No clinically significant changes in C_max and AUC were observed following administration of KALETRA tablets under fed conditions compared to fasted conditions. Relative to fasting, administration of KALETRA tablets with a moderate fat meal (500 - 682 Kcal, 23 to 25% calories from fat) increased lopinavir AUC and C_max by 26.9% and 17.6%, respectively. Relative to fasting, administration of KALETRA tablets with a high fat meal (872 Kcal, 56% from fat) increased lopinavir AUC by 18.9% but not C_max. Therefore, KALETRA tablets may be taken with or without food.

KALETRA Oral Solution
Relative to fasting, administration of KALETRA oral solution with a moderate fat meal (500 - 682 Kcal, 23 to 25% calories from fat) increased lopinavir AUC and C_max by 80 and 54%, respectively. Relative to fasting, administration of KALETRA oral solution with a high fat meal (872 Kcal, 56% from fat) increased lopinavir AUC and C_max by 130% and 56%, respectively. To enhance bioavailability and minimize pharmacokinetic variability KALETRA oral solution should be taken with food.

Distribution
At steady state, lopinavir is approximately 98-99% bound to plasma proteins. Lopinavir binds to both alpha-1acid 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-1 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-1 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 (C_max) of 11.8 ± 3.7 μg/mL, occurring approximately 6 hours after administration. The mean steady-state lopinavir trough concentration prior to the morning dose was 3.2 ± 2.1 μg/mL and minimum concentration within a dosing interval was 1.7 ± 1.6 μg/mL. Lopinavir AUC over a 24 hour dosing interval averaged 154.1 ± 61.4 μg• h/mL.

The pharmacokinetics of once daily KALETRA has also been evaluated in treatment experienced HIV-1 infected subjects. Lopinavir exposure (C_max, AUC_[0-24h], C_trough) with once daily KALETRA administration in treatment experienced subjects is comparable to the once daily lopinavir exposure in treatment naïve subjects.

Effects on Electrocardiogram
QTcF interval was evaluated in a randomized, placebo and active (moxifloxacin 400 mg once daily) controlled crossover study in 39 healthy adults, with 10 measurements over 12 hours on Day 3. The maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline-correction were 5.3 (8.1) and 15.2 (18.0) mseconds (msec) for 400/100 mg twice daily and supratherapeutic 800/200 mg twice daily KALETRA, respectively. KALETRA 800/200 mg twice daily resulted in a Day 3 mean C_max approximately 2-fold higher than the mean C_max observed with the approved once daily and twice daily KALETRA doses at steady state.

PR interval prolongation was also noted in subjects receiving KALETRA in the same study on Day 3. The maximum mean (95% upper confidence bound) difference from placebo in the PR interval after baseline-correction were 24.9 (21.5, 28.3) and 31.9 (28.5, 35.3) msec for 400/100 mg twice daily and supratherapeutic 800/200 mg twice daily KALETRA, respectively.

Special Populations

Gender, Race and Age
No gender related pharmacokinetic differences have been observed in adult patients. No clinically important pharmacokinetic differences due to race have been identified. Lopinavir pharmacokinetics have not been studied in elderly patients.

Pediatric Patients
The pharmacokinetics of KALETRA oral solution 300/75 mg/m² twice daily and 230/57.5 mg/m² twice daily have been studied in a total of 53 pediatric patients in Study 940, 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).

The mean steady-state lopinavir AUC, C_max, and C_min were 72.6 ± 31.1 μg•h/mL, 8.2 ± 2.9 and 3.4 ± 2.1 μg/mL, respectively after KALETRA oral solution 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).

The pharmacokinetics of KALETRA oral solution at approximately 300/75 mg/m² twice daily have also been evaluated in infants at approximately 6 weeks of age (n = 9) and between 6 weeks and 6 months of age (n = 18) in Study 1030. The mean steady-state lopinavir AUC₁₂, C_max, and C₁₂ were 43.4 ± 14.8 μg• h/mL, 5.2 ± 1.8 μg/mL and 1.9 ± 1.1 μg/mL, respectively, in infants at approximately 6 weeks of age, and 74.5 ± 37.9 μg• h/mL, 9.4 ± 4.9 and 3.1 ± 1.8 μg/mL, respectively, in infants between 6 weeks and 6 months of age after KALETRA oral solution was administered at approximately 300/75 mg/m² twice daily without concomitant NNRTI therapy.

The pharmacokinetics of KALETRA soft gelatin capsule and oral solution (Group 1: 400/100 mg/m² twice daily + 2 NRTIs; Group 2: 480/120 mg/m² twice daily + ≥ 1 NRTI + 1 NNRTI) have been evaluated in children and adolescents age ≥ 2 years to < 18 years of age who had failed prior therapy (n=26) in Study 1038. KALETRA doses of 400/100 and 480/120 mg/m² resulted in high lopinavir exposure, as almost all subjects had lopinavir AUC₁₂ above 100 μg•h/mL. Both groups of subjects also achieved relatively high average minimum lopinavir concentrations.

KALETRA once daily has not been evaluated in pediatric patients.

Renal Impairment
Lopinavir pharmacokinetics have not been studied in patients with renal impairment; however, since the renal clearance of lopinavir is negligible, a decrease in total body clearance is not expected in patients with renal impairment.

Hepatic Impairment
Lopinavir is principally metabolized and eliminated by the liver. Multiple dosing of KALETRA 400/100 mg twice daily to HIV-1 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 C_max compared to HIV-1 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.

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 and Drug Interactions].

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, C_max and C_min are summarized in Table 10 (effect of other drugs on lopinavir) and Table 11 (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 Drug Interactions. [Please consult the KALETRA full prescribing information to view Table 10 and Table 11].

Microbiology

Mechanism of Action
Lopinavir, an inhibitor of the HIV-1 protease, prevents cleavage of the Gag-Pol polyprotein, resulting in the production of immature, non-infectious viral particles.

Antiviral Activity
The antiviral activity of lopinavir against laboratory HIV strains and clinical HIV-1 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) values of lopinavir against five different HIV-1 subtype B 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 subtype B clinical isolates (n = 6). In the presence of 50% human serum, the mean EC₅₀ values of lopinavir against these five HIV-1 laboratory strains ranged from 65-289 nM (0.04-0.18 μg/mL), representing a 7 to 11-fold attenuation. Combination antiviral drug activity studies with lopinavir in cell cultures demonstrated additive to antagonistic activity with nelfinavir and additive to synergistic activity with amprenavir, atazanavir, indinavir, saquinavir and tipranavir. The EC₅₀ values of lopinavir against three different HIV-2 strains ranged from 12-180 nM (0.008-113 μg/mL).

Resistance
HIV-1 isolates with reduced susceptibility to lopinavir have been selected in cell culture. The presence of ritonavir does not appear to influence the selection of lopinavir-resistant viruses in cell culture.

The selection of resistance to KALETRA in antiretroviral treatment naïve patients has not yet been characterized. In a study of 653 antiretroviral treatment naïve patients (Study 863), plasma viral isolates from each patient on treatment with plasma HIV-1 RNA > 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 substitution in HIV-1 protease, was observed in 25/76 (33%) of evaluable nelfinavir-treated patients. The selection of resistance to KALETRA in antiretroviral treatment naïve 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 studies of 227 antiretroviral treatment naïve 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 (indinavir, nelfinavir, or saquinavir) and one patient had received treatment with multiple protease inhibitors (indinavir, ritonavir, and saquinavir). All four of these patients had at least 4 substitutions associated with protease inhibitor resistance immediately prior to KALETRA therapy. Following viral rebound, isolates from these patients all contained additional substitutions, some of which are recognized to be associated with protease inhibitor resistance. However, there are insufficient data at this time to identify patterns of lopinavir resistance-associated substitutions in isolates from patients on KALETRA therapy. The assessment of these patterns is under study.

Cross-resistance - Preclinical Studies
Varying degrees of cross-resistance have been observed among HIV-1 protease inhibitors. Little information is available on the cross-resistance of viruses that developed decreased susceptibility to lopinavir during KALETRA therapy.

The antiviral activity in cell culture 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 susceptibility in cell culture to lopinavir has been examined by assessing the virologic response to KALETRA therapy in treatment-experienced patients, with respect to baseline viral genotype in three studies and baseline viral phenotype in one study. Virologic response to KALETRA has been shown to be affected by the presence of three or more of the following amino acid substitutions in protease at baseline: L10F/I/R/V, K20M/N/R, L24I, L33F, M36I, I47V, G48V, I54L/T/V, V82A/C/F/S/T, and I84V. Table 12 shows the 48-week virologic response (HIV-1 RNA <400 copies/mL) according to the number of the above protease inhibitor resistance-associated substitutions at baseline in studies 888 and 765 [see Clinical Studies (14.2) and (14.3)] and study 957 (see below). Once daily administration of KALETRA for adult patients with three or more of the above substitutions is not recommended. [Please consult the KALETRA full prescribing information to view Table 12].

Virologic response to KALETRA therapy with respect to phenotypic susceptibility to lopinavir at baseline was examined in Study 957. In this study 56 NNRTI-naïve patients with HIV-1 RNA >1,000 copies/mL despite previous therapy with at least two protease inhibitors selected from indinavir, nelfinavir, ritonavir, and saquinavir were randomized to receive one of two doses of KALETRA in combination with efavirenz and nucleoside reverse transcriptase inhibitors (NRTIs). The EC₅₀ values of lopinavir against the 56 baseline viral isolates ranged from 0.5- to 96-fold the wild-type EC₅₀ value. Fifty-five percent (31/56) of these baseline isolates displayed >4-fold reduced susceptibility to lopinavir. These 31 isolates had a median reduction in lopinavir susceptibility of 18-fold. Response to therapy by baseline lopinavir susceptibility is shown in Table 13. [Please consult the KALETRA full prescribing information to view Table 13].

USE IN SPECIFIC POPULATIONS

Pregnancy
Pregnancy Category C.

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

No embryonic and fetal developmental toxicities were observed in rabbits at a maternally toxic dosage. Based on AUC measurements, the drug exposures in rabbits at the toxic doses were approximately 0.6-fold for lopinavir and 1.0-fold for ritonavir that of the exposures in humans at the recommended therapeutic dose (400/100 mg twice daily). There are, however, no adequate and well-controlled studies in pregnant women. KALETRA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to KALETRA, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.

Nursing Mothers
The Centers for Disease Control and Prevention recommend that HIV-1 infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV-1. Studies in rats have demonstrated that lopinavir is secreted in milk. It is not known whether lopinavir is secreted in human milk. Because of both the potential for HIV-1 transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving KALETRA.

Pediatric Use
The safety, efficacy, and pharmacokinetic profiles of KALETRA in pediatric patients below the age of 14 days have not been established. KALETRA once daily has not been evaluated in pediatric patients.

An open-label, multi-center, dose-finding trial was performed to evaluate the pharmacokinetic profile, tolerability, safety and efficacy of KALETRA oral solution containing lopinavir 80 mg/mL and ritonavir 20 mg/mL at a dose of with 300/75 mg/m² twice daily plus two NRTIs in HIV-infected infants ≥14 days and < 6 months of age. Results revealed that infants younger than 6 months of age generally had lower lopinavir AUC₁₂ than older children (6 months to 12 years of age), however, despite the lower lopinavir drug exposure observed, antiviral activity was demonstrated as reflected in the proportion of subjects who achieved HIVRNA <400 copies/mL at Week 24.

Safety and efficacy in pediatric patients > 6 months of age was demonstrated in a clinical trial in 100 patients. The clinical trial was an open-label, multicenter trial evaluating the pharmacokinetic profile, tolerability, safety, and efficacy of KALETRA oral solution containing lopinavir 80 mg/mL and ritonavir 20 mg/mL in 100 antiretroviral naïve and experienced pediatric patients ages 6 months to 12 years. Dose selection for patients 6 months to 12 years of age was based on the following results. The 230/57.5 mg/m² oral solution twice daily regimen without nevirapine and the 300/75 mg/m² oral solution 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).

A prospective multicenter, open-label trial evaluated the pharmacokinetic profile, tolerability, safety and efficacy of high-dose KALETRA with or without concurrent NNRTI therapy (Group 1: 400/100 mg/m² twice daily + ≥ 2 NRTIs; Group 2: 480/120 mg/m² twice daily + ≥ 1 NRTI + 1 NNRTI) in children and adolescents ≥ 2 years to < 18 years of age who had failed prior therapy. Patients also had saquinavir mesylate added to their regimen. This strategy was intended to assess whether higher than approved doses of KALETRA could overcome protease inhibitor cross-resistance. High doses of KALETRA exhibited a safety profile similar to those observed in previous trials; changes in HIV-1 RNA were less than anticipated; three patients had HIV-1 RNA <400 copies/mL at Week 48. CD4+ cell count increases were noted in the eight patients who remained on treatment for 48 weeks.

Geriatric Use
Clinical studies of KALETRA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, appropriate caution should be exercised in the administration and monitoring of KALETRA in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Hepatic Impairment
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.

Adverse Events/Toxicity

WARNINGS AND PRECAUTIONS

Drug Interactions - CYP3A Enzyme Inhibition
KALETRA is a CYP3A inhibitor. Initiating treatment with KALETRA in patients receiving medications metabolized by CYP3A or initiating medications metabolized by CYP3A in patients already maintained on KALETRA may result in increased plasma concentrations of concomitant medications. Higher plasma concentrations of concomitant medications can result in increased or prolonged therapeutic or adverse effects, potentially leading to severe, life-threatening or fatal events. The potential for drug-drug interactions must be considered prior to and during therapy with KALETRA. Review of other medications taken by patients and monitoring of patients for adverse effects is recommended during therapy with KALETRA.

See Contraindications and Drug Interactions for listing of drugs that are contraindicated for use with KALETRA due to potentially life-threatening adverse events, significant drug interactions, or loss of virologic activity.

Toxicity in Preterm Neonates
KALETRA oral solution contains the excipients alcohol (42.4% v/v) and propylene glycol (15.3% w/v). When administered concomitantly with propylene glycol, ethanol competitively inhibits the metabolism of propylene glycol, which may lead to elevated concentrations. Preterm neonates may be at increased risk of propylene glycol-associated adverse events due to diminished ability to metabolize propylene glycol, thereby leading to accumulation and potential adverse events. Postmarketing life-threatening cases of cardiac toxicity (including complete AV block, bradycardia, and cardiomyopathy), lactic acidosis, acute renal failure, CNS depression and respiratory complications leading to death have been reported, predominantly in preterm neonates receiving KALETRA oral solution.

KALETRA oral solution should not be used in preterm neonates in the immediate postnatal period because of possible toxicities. A safe and effective dose of KALETRA oral solution in this patient population has not been established. However, if the benefit of using KALETRA oral solution to treat HIV infection in infants immediately after birth outweighs the potential risks, infants should be monitored closely for increases in serum osmolality and serum creatinine, and for toxicity related to KALETRA oral solution including: hyperosmolality, with or without lactic acidosis, renal toxicity, CNS depression (including stupor, coma, and apnea), seizures, hypotonia, cardiac arrhythmias and ECG changes, and hemolysis. Total amounts of alcohol and propylene glycol from all medicines that are to be given to infants should be taken into account in order to avoid toxicity from these excipients.

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 are a risk factor for development of pancreatitis. Patients with advanced HIV-1 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 occur. Patients who exhibit these signs or symptoms should be evaluated and KALETRA and/or other antiretroviral therapy should be suspended as clinically appropriate.

Hepatotoxicity
Patients with underlying hepatitis B or C or marked elevations in transaminase prior to treatment may be at increased risk for developing or worsening of transaminase elevations or hepatic decompensation with use of KALETRA.

There have been postmarketing reports of hepatic dysfunction, including some fatalities. These have generally occurred in patients with advanced HIV-1 disease taking multiple concomitant medications in the setting of underlying chronic hepatitis or cirrhosis. A causal relationship with KALETRA therapy has not been established.

Elevated transaminases with or without elevated bilirubin levels have been reported in HIV-1 mono-infected and uninfected patients as early as 7 days after the initiation of KALETRA in conjunction with other antiretroviral agents. In some cases, the hepatic dysfunction was serious; however, a definitive causal relationship with KALETRA therapy has not been established.

Appropriate laboratory testing should be conducted prior to initiating therapy with KALETRA and patients should be monitored closely during treatment. Increased AST/ALT monitoring should be considered in the patients with underlying chronic hepatitis or cirrhosis, especially during the first several months of KALETRA treatment.

Diabetes Mellitus/Hyperglycemia
New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during post-marketing surveillance in HIV-1 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.

PR Interval Prolongation
Lopinavir/ritonavir prolongs the PR interval in some patients. Cases of second or third degree atrioventricular block have been reported. KALETRA should be used with caution in patients with underlying structural heart disease, pre-existing conduction system abnormalities, ischemic heart disease or cardiomyopathies, as these patients may be at increased risk for developing cardiac conduction abnormalities.

The impact on the PR interval of co-administration of KALETRA with other drugs that prolong the PR interval (including calcium channel blockers, beta-adrenergic blockers, digoxin and atazanavir) has not been evaluated. As a result, co-administration of KALETRA with these drugs should be undertaken with caution, particularly with those drugs metabolized by CYP3A. Clinical monitoring is recommended.

QT Interval Prolongation
Postmarketing cases of QT interval prolongation and torsade de pointes have been reported although causality of KALETRA could not be established. Avoid use in patients with congenital long QT syndrome, those with hypokalemia, and with other drugs that prolong the QT interval.

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 jirovecii pneumonia [PCP], or tuberculosis) which may necessitate further evaluation and treatment.

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. 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, taking into account any potential drug-drug interactions with KALETRA and HMG-CoA reductase inhibitors.

Patients with Hemophilia
Increased bleeding, including spontaneous skin hematomas and hemarthrosis have been reported 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.

Resistance/Cross-resistance
Because the potential for HIV cross-resistance among protease inhibitors has not been fully explored in KALETRA-treated patients, it is unknown what effect therapy with KALETRA will have on the activity of subsequently administered protease inhibitors.

Clinical Trials Experience
The most common adverse reactions (> 5%) occurring in adult patients were diarrhea, nausea, abdominal pain, asthenia, vomiting, headache, and dyspepsia.

KALETRA oral solution dosed up to 300/75 mg/m² has been studied in 100 pediatric patients 6 months to 12 years of age. The adverse reaction profile seen during Study 940 was similar to that for adult patients.

Dysgeusia (22%), vomiting (21%), and diarrhea (12%) were the most common adverse reactions of any severity reported in pediatric patients treated with combination therapy for up to 48 weeks in Study 940. A total of 8 patients experienced adverse reactions of moderate to severe intensity. The adverse reactions meeting these criteria and reported for the 8 subjects include: hypersensitivity (characterized by fever, rash and jaundice), pyrexia, viral infection, constipation, hepatomegaly, pancreatitis, vomiting, alanine aminotransferase increased, dry skin, rash, and dysgeusia. Rash was the only event of those listed that occurred in 2 or more subjects (N = 3).

KALETRA oral solution dosed at 300/75 mg/m² has been studied in 31 pediatric patients 14 days to 6 months of age. The adverse reaction profile in Study 1030 was similar to that observed in older children and adults. No adverse reaction was reported in greater than 10% of subjects. Adverse drug reactions of moderate to severe intensity occurring in 2 or more subjects included decreased neutrophil count (N=3), anemia (N=2), high potassium (N=2), and low sodium (N=2).

Drug and Food Interactions

• 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 reactions.
   
• Co-administration of KALETRA is contraindicated with potent CYP3A inducers where significantly reduced lopinavir plasma concentrations may be associated with the potential for loss of virologic response and possible resistance and cross-resistance. These drugs are listed in below.

See Contraindications for a listing of drugs that are contraindicated with KALETRA.

Drug Interactions - CYP3A Enzyme Inhibition
KALETRA is a CYP3A inhibitor. Initiating treatment with KALETRA in patients receiving medications metabolized by CYP3A or initiating medications metabolized by CYP3A in patients already maintained on KALETRA may result in increased plasma concentrations of concomitant medications. Higher plasma concentrations of concomitant medications can result in increased or prolonged therapeutic or adverse effects, potentially leading to severe, life-threatening or fatal events. The potential for drug-drug interactions must be considered prior to and during therapy with KALETRA. Review of other medications taken by patients and monitoring of patients for adverse effects is recommended during therapy with KALETRA.

Potential for KALETRA to Affect Other Drugs
Lopinavir/ritonavir is an inhibitor of CYP3A and may increase plasma concentrations of agents that are primarily metabolized by CYP3A. Agents that are extensively metabolized by CYP3A and have high first pass metabolism appear to be the most susceptible to large increases in AUC (> 3-fold) when co-administered with KALETRA. Thus, co-administration of KALETRA with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated. Co-administration with other CYP3A substrates may require a dose adjustment or additional monitoring as shown below.

Additionally, KALETRA induces glucuronidation.

Potential For Other Drugs To Affect Lopinavir
Lopinavir/ritonavir is a CYP3A substrate; therefore, drugs that induce CYP3A may decrease lopinavir plasma concentrations and reduce KALETRA’s therapeutic effect. Although not observed in the KALETRA/ketoconazole drug interaction study, co-administration of KALETRA and other drugs that inhibit CYP3A may increase lopinavir plasma concentrations.

Established and Other Potentially Significant Drug Interactions

HIV-1 Antiviral Agents
• Non-nucleoside Reverse Transcriptase Inhibitors: efavirenz, nevirapine. KALETRA dose increase is recommended in all patients.

Increasing the dose of KALETRA tablets to 500/125 mg (given as two 200/50 mg tablets and one 100/25 mg tablet) twice daily coadministered with efavirenz resulted in similar lopinavir concentrations compared to KALETRA tablets 400/100 mg (given as two 200/50 mg tablets) twice daily without efavirenz. Increasing the dose of KALETRA tablets to 600/150 mg (given as three 200/50 mg tablets) twice daily co-administered with efavirenz resulted in significantly higher lopinavir plasma concentrations compared to KALETRA tablets 400/100 mg twice daily without efavirenz.

KALETRA should not be administered once daily in combination with efavirenz or nevirapine.

• Non-nucleoside Reverse Transcriptase Inhibitor: delavirdine. Appropriate doses of the combination with respect to safety and efficacy have not been established.

• Nucleoside Reverse Transcriptase Inhibitor: didanosine. KALETRA tablets can be administered simultaneously with didanosine without food.

For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food).

• Nucleoside Reverse Transcriptase Inhibitor: tenofovir. KALETRA increases tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir.

• Nucleoside Reverse Transcriptase Inhibitor: abacavir, zidovudine. KALETRA induces glucuronidation; therefore, KALETRA has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown.

• HIV-1 Protease Inhibitor: amprenavir. KALETRA should not be administered once daily in combination with amprenavir.

• HIV-1 Protease Inhibitor: fosamprenavir/ritonavir. An increased rate of adverse reactions has been observed with coadministration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established.

• HIV-1 Protease Inhibitor: indinavir. Decrease indinavir dose to 600 mg twice daily, when co administered with KALETRA 400/100 mg twice daily. KALETRA once daily has not been studied in combination with indinavir.

• HIV-1 Protease Inhibitor: nelfinavir. KALETRA should not be administered once daily in combination with nelfinavir.

• HIV-1 Protease Inhibitor: ritonavir. Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established.
 
• HIV-1 Protease Inhibitor: saquinavir. The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily. KALETRA once daily has not been studied in combination with saquinavir.

• HIV-1 Protease Inhibitor: tipranavir. KALETRA should not be administered with tipranavir (500 mg twice daily) co-administered with ritonavir (200 mg twice daily).

• HIV CCR5 – antagonist: maraviroc. Concurrent administration of maraviroc with KALETRA will increase plasma levels of maraviroc. When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for Selzentry® (maraviroc).

Other Agents
• Antiarrhythmics: amiodarone, bepridil, lidocaine (systemic), and quinidine. Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when coadministered with KALETRA.
 
• Anticancer Agents: vincristine, vinblastine, dasatinib, nilotinib. Concentrations of these drugs may be increased when coadministered with KALETRA resulting in the potential for increased adverse events usually associated with these anticancer agents.
For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when KALETRA is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor. A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring coadministration with strong CYP3A inhibitors such as KALETRA. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions.

• Anticoagulant: warfarin. Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
 
• Anticonvulsants: carbamazepine, phenobarbital, phenytoin. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution.
KALETRA should not be administered once daily in combination with carbamazepine, phenobarbital, or phenytoin.
 
In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA.

• Antidepressant: bupropion. Concurrent administration of bupropion with KALETRA may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion.

• Antidepressant: trazodone. Concomitant use of trazodone and KALETRA may increase concentrations of trazodone. Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered.

• Anti-infective: clarithromycin. For patients with renal impairment, the following dosage adjustments should be considered:

• For patients with CLCR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%.
• For patients with CLCR < 30 mL/min the dose of clarithromycin should be decreased by 75%. No dose adjustment for patients with normal renal function is necessary.

• Antifungals: ketoconazole, itraconazole, voriconazole. High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended.
Co-administration of voriconazole with KALETRA has not been studied. However, a study has been shown that administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%; therefore, coadministration of KALETRA and voriconazole may result in decreased voriconazole concentrations and the potential for decreased voriconazole effectiveness and should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Otherwise, alternative antifungal therapies should be considered in these patients.

• Anti-gout: colchicine. Patients with renal or hepatic impairment should not be given colchicine with KALETRA.
Treatment of gout flares-co-administration of colchicine in patients on KALETRA: 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days.
Prophylaxis of gout flares-co-administration of colchicine in patients on KALETRA: If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.
Treatment of familial Mediterranean fever (FMF)-co-administration of colchicine in patients on KALETRA: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).

• Antimycobacterial: rifabutin. Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary.

• Antimycobacterial: rifampin. May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other coadministered antiretroviral agents. A study evaluated combination of rifampin 600 mg once daily, with KALETRA 800/200 mg twice daily or KALETRA 400/100 mg + ritonavir 300 mg twice daily. Pharmacokinetic and safety results from this study do not allow for a dose recommendation. Nine subjects (28%) experienced a ≥ grade 2 increase in ALT/AST, of which seven (21%) prematurely discontinued study per protocol. Based on the study design, it is not possible to determine whether the frequency or magnitude of the ALT/AST elevations observed is higher than what would be seen with rifampin alone.

• Antiparasitic: atovaquone. Clinical significance is unknown; however, increase in atovaquone doses may be needed.

• Benzodiazepines: parenterally administered midazolam. Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, KALETRA should not be given with orally administered midazolam. If KALETRA is coadministered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered.

• Calcium Channel Blockers, dihydropyridine: e.g., felodipine, nifedipine, nicardipine. Caution is warranted and clinical monitoring of patients is recommended.

• Contraceptive: ethinyl estradiol. Because contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended.

• Corticosteroid: dexamethasone. Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly.

• Disulfiram/metronidazole. KALETRA oral solution contains alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).

• Endothelin receptor antagonists: bosentan. Co-administration of bosentan in patients on KALETRA: In patients who have been receiving KALETRA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Co-administration of KALETRA in patients on bosentan: Discontinue use of bosentan at least 36 hours prior to initiation of KALETRA.
After at least 10 days following the initiation of KALETRA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

• HMG-CoA Reductase Inhibitors: atorvastatin rosuvastatin. Use atorvastatin with caution and at the lowest necessary dose. Titrate rosuvastatin dose carefully and use the lowest necessary dose; do not exceed rosuvastatin 10 mg/day. See Drugs with No Observed or Predicted Interactions with KALETRA and Clinical Pharmacology for drug interaction data with other HMG-CoA reductase inhibitors.

• Immunosuppressants: cyclosporine, tacrolimus, rapamycin. Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA.

• Inhaled Steroid: fluticasone. Concomitant use of fluticasone propionate and KALETRA may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during post-marketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Co-administration of fluticasone propionate and KALETRA is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effect.

• Long-acting beta-adrenoceptor agonist: salmeterol. Concurrent administration of salmeterol and KALETRA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.

• Narcotic Analgesic: methadone, fentanyl. Dosage of methadone may need to be increased when co-administered with KALETRA.
Concentrations of fentanyl are expected to increase. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with KALETRA.

• PDE5 inhibitors: sildenafil, tadalafil, vardenafil. 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 PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection.

Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH):
Sildenafil (Revatio^®) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) because a safe and effective dose has not been established when used with KALETRA.

The following dose adjustments are recommended for use of tadalafil (Adcirca^®) with KALETRA:

Co-administration of ADCIRCA in patients on KALETRA: In patients receiving KALETRA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Co-administration of KALETRA in patients on ADCIRCA: Avoid use of ADCIRCA during the initiation of KALETRA. Stop ADCIRCA at least 24 hours prior to starting KALETRA. After at least one week following the initiation of KALETRA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Use of PDE5 inhibitors for erectile dysfunction:
It is recommended not to exceed the following doses:

• Sildenafil: 25 mg every 48 hours
• Tadalafil: 10 mg every 72 hours
• Vardenafil: 2.5 mg every 72 hours

Use with increased monitoring for adverse events.

Drugs with No Observed or Predicted Interactions with KALETRA
Drug interaction studies reveal no clinically significant interaction between KALETRA and desipramine (CYP2D6 probe), pitavastatin, pravastatin, stavudine, lamivudine, omeprazole, or ranitidine.

Based on known metabolic profiles, clinically significant drug interactions are not expected between KALETRA and dapsone, trimethoprim/sulfamethoxazole, azithromycin, erythromycin, or fluconazole.

[For information about KALETRA capsules, consult the KALETRA capsules full prescribing information].

Contraindications

• KALETRA is contraindicated in patients with previously demonstrated clinically significant hypersensitivity (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme) 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 reactions.

• Co-administration of KALETRA is contraindicated with potent CYP3A inducers where significantly reduced lopinavir plasma concentrations may be associated with the potential for loss of virologic response and possible resistance and cross-resistance. These drugs are listed below.

Drugs That Are Contraindicated With KALETRA

• Alpha 1-Adrenoreceptor antagonist: Alfuzosin. Potentially increased alfuzosin concentrations can result in hypotension.
   
• Antimycobacterial: Rifampin. May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents.
   
• Ergot Derivatives: Dihydroergotamine, ergonovine, ergotamine, methylergonovine. Potential for acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
   
• GI motility agent: Cisapride. Potential for cardiac arrhythmias.
   
• Herbal Products: St. John's Wort (hypericum perforatum). May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors.
   
• HMG-CoA Reductase Inhibitors: Lovastatin, simvastatin. Potential for myopathy including rhabdomyolysis.
   
• PDE5 enzyme inhibitor: Sildenafil^a (Revatio^®) when used for the treatment of pulmonary arterial hypertension. A safe and effective dose has not been established when used with KALETRA. There is an increased potential for sildenafil-associated adverse events, including visual abnormalities, hypotension, prolonged erection, and syncope.
   
• Neuroleptic: Pimozide. Potential for cardiac arrhythmias.
   
• Sedative/Hypnotics: Triazolam; orally administered midazolam^b. Prolonged or increased sedation or respiratory depression.

^a see Drug Interactions for coadministration of sildenafil in patients with erectile dysfunction.
^b see Drug Interactions, for parenterally administered midazolam. [1] [2]

References

[1] FDA Kaletra Prescribing Information, February 2011. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021251s039,021906s032lbl.pdf. Accessed 10/14/2011.

[2] FDA Kaletra Prescribing Information, February 2012. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021251s042,021906s035lbl.pdf. Accessed 03/04/2012.

Clinical Trials

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Chemistry

CAS Name

Lopinavir/ritonavir: 2,4,7,12-Tetraazatridecan-13-oic acid, 10-hydroxy-2-methyl-5-(1-methylethyl)- 1-(2-(1-methylethyl)-4-thiazolyl)- 3,6-dioxo-8,11-bis(phenylmethyl)-, 5-thiazolylmethyl ester, (5S,8S,10S,11S)-, mixt. with (aS)-N-((1S,3S,4S)-4- (((2,6-dimethylphenoxy)acetyl)amino)- 3-hydroxy-5-phenyl-1- (phenylmethyl)pentyl)tetrahydro-a- (1-methylethyl) -2-oxo-1(2H)- pyrimidineacetamide [1]Lopinavir: (alphaS)-Tetrahydro- N-[(alphaS)-alpha-[(2S,3S)-2-hydroxy- 4-phenyl-3-[2-(2,6-xylyloxy)acetamido] butyl]phenethyl]-alpha-isopropyl-2-oxo- 1(2H)-pyrimidineacetamide [2] Ritonavir: 5-Thiazolylmethyl [(alphaS)- alpha-[(1S,3S)-1-hydroxy-3-[(2S)-2-[3-[(2- isopropyl-4-thiazolyl)methyl]-3-methylureido]- 3-methylbutyramido]-4-phenylbutyl]phenethyl] carbamate [3]

CAS Number

Lopinavir/ritonavir: 369372-47-4 [4]Lopinavir: 192725-17-0 [5] Ritonavir: 155213-67-5 [6]

Molecular Formula

C37-H48-N4-O5.C37-H48-N6-O5 [7]

Molecular Weight

Lopinavir: 628.80; Ritonavir: 720.95 [8]

Physical Description

Lopinavir: White to light tan powder. [9]

Ritonavir: White to light tan powder. [10]

Solubility

Lopinavir: Freely soluble in methanol and ethanol; soluble in isopropanol; practically insoluble in water. [11]

Ritonavir: Freely soluble in methanol and ethanol; soluble in isopropanol; practically insoluble in water. [12]

References

[1] ChemIDplus Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 10/14/2011.

[2] ChemIDplus Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 10/14/2011.

[3] ChemIDplus Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 10/14/2011.

[4] ChemIDplus Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 10/14/2011.

[5] ChemIDplus Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 10/14/2011.

[6] ChemIDplus Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 10/14/2011.

[7] ChemIDplus Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 10/14/2011.

[8] FDA Kaletra Prescribing Information, February 2011. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021251s039,021906s032lbl.pdf. Accessed 10/14/2011.

[9] FDA Kaletra Prescribing Information, February 2011. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021251s039,021906s032lbl.pdf. Accessed 10/14/2011.

[10] FDA Kaletra Prescribing Information, February 2011. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021251s039,021906s032lbl.pdf. Accessed 10/14/2011.

[11] FDA Kaletra Prescribing Information, February 2011. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021251s039,021906s032lbl.pdf. Accessed 10/14/2011.

[12] FDA Kaletra Prescribing Information, February 2011. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021251s039,021906s032lbl.pdf. Accessed 10/14/2011.

Further Reading

Kaletra Tablets and Oral Solution Prescribing Information from the FDA web site [PDF]. A more current version may be available on the manufacturer's web site.
Johnson MA, Gathe JC Jr, Podzamczer D, Molina JM, Naylor CT, Chiu YL, King MS, Podsadecki TJ, Hanna GJ, Brun SC. A Once-Daily Lopinavir/Ritonavir-Based Regimen Provides Noninferior Antiviral Activity Compared With a Twice-Daily Regimen. J Acquir Immune Defic Syndr. 2006 Aug 31; [Epub ahead of print].
Oldfield V, Plosker GL. Lopinavir/Ritonavir: a review of its use in the management of HIV infection. Drugs. 2006;66(9):1275-99.
Ribera E, Azuaje C, Lopez RM, Diaz M, Feijoo M, Pou L, Crespo M, Curran A, Ocana I, Pahissa A. Atazanavir and lopinavir/ritonavir: pharmacokinetics, safety and efficacy of a promising double-boosted protease inhibitor regimen. AIDS. 2006 May 12;20(8):1131-9.
Rosso R, Di Biagio A, Dentone C, Gattinara GC, Martino AM, Vigano A, Merlo M, Giaquinto C, Rampon O, Bassetti M, Gatti G, Viscoli C. Lopinavir/ritonavir exposure in treatment-naive HIV-infected children following twice or once daily administration. J Antimicrob Chemother. 2006 Jun;57(6):1168-71. Epub 2006 Apr 10.

Manufacturer Information

Kaletra

Abbott Laboratories
One Hundred Abbott Park Rd
Abbott Park, IL 60064-3500
Phone: 800-633-9110

Lopinavir/ritonavir

Abbott Laboratories
One Hundred Abbott Park Rd
Abbott Park, IL 60064-3500
Phone: 800-633-9110