Kaletra

1. Kaletra

Lopinavir and ritonavir combination is used in the treatment of the infection caused by the human immunodeficiency virus (HIV). HIV is the virus responsible for acquired immune deficiency syndrome (AIDS). It is used to slow the progression of disease in patients infected with HIV who have advanced symptoms, early symptoms, or no symptoms at all.

Lopinavir and ritonavir combination will not cure or prevent HIV infection or AIDS. It helps keep HIV from reproducing and appears to slow down the destruction of the immune system. This may help delay the development of problems usually related to AIDS or HIV disease. Lopinavir and ritonavir combination will not keep you from spreading HIV to other people. People who receive this medicine may continue to have other problems usually related to AIDS or HIV disease.

This medicine is available only with your doctor's prescription.

This product is available in the following dosage forms:

• Tablet
• Capsule, Liquid Filled
• Solution

GENERIC AVAILABLE: No

Medicines can interact with certain foods. In some cases, this may be harmful and your doctor may advise you to avoid certain foods. In the case of Kaletra there are no specific foods that you must exclude from your diet when receiving Kaletra.

Appropriate studies have not been performed on the relationship of age to the effects of lopinavir and ritonavir combination in infants younger than 14 days of age. Safety and efficacy have not been established. Kaletra® should not be used once a day in children. Kaletra® oral liquid should not be given to premature infants.

Absorption

Bioavailability

Lopinavir administered as a fixed combination containing lopinavir and ritonavir (lopinavir/ritonavir).1 Ritonavir decreases metabolism of lopinavir, resulting in increased lopinavir plasma concentrations.1

Absolute bioavailability of lopinavir co-formulated with ritonavir has not been established.1

Following multiple dosing for 3 weeks (400 mg of lopinavir/100 mg of ritonavir twice daily with food), peak plasma lopinavir concentrations attained approximately 4 hours after a dose.1

When a once-daily regimen is given for 4 weeks (800 mg of lopinavir/200 mg of ritonavir once daily with food), peak plasma lopinavir concentrations are attained approximately 6 hours after a dose.1

Plasma concentrations of lopinavir and ritonavir following administration as tablets similar to those following administration as capsules (no longer commercially available in the US) under nonfasting conditions.1 Tablet formulation associated with less pharmacokinetic variability than capsule formulation.1

Bioavailability of lopinavir and ritonavir following oral administration of crushed tablets is reduced compared with administration of an intact tablet.32

Food

Tablets: Administration with moderate- or high-fat meal does not have clinically important effect on lopinavir AUC or peak plasma concentration.1

Oral solution: Compared with administration in the fasting state, administration with a moderate-fat meal (500–682 kcal, 23–25% calories from fat) increases lopinavir AUC and peak plasma concentrations 80 and 54%, respectively.1 Administration with a high-fat meal (872 kcal, 56% from fat) increases lopinavir AUC and peak concentration 130 and 56%, respectively.1

Special Populations

Pediatric patients (<18 years of age weighing ≥15 kg): Increased lopinavir peak plasma concentrations and decreased lopinavir AUC observed with once-daily lopinavir/ritonavir regimens compared with twice-daily lopinavir/ritonavir regimens.45 Once-daily lopinavir/ritonavir regimens not bioequivalent to twice-daily regimens in pediatric patients.45

HIV-infected pregnant women: Lopinavir plasma concentrations decreased in second and third trimesters compared with concentrations observed at 8 weeks postpartum.1 Although total clearance of lopinavir increased during pregnancy, unbound lopinavir concentrations in pregnant women are similar to nonpregnant46 and postpartum women.47

Distribution

Extent

Lopinavir and, to a lesser extent, ritonavir cross the human placenta.202

Lopinavir and ritonavir distributed into milk in rats;1 lopinavir concentrations in human milk are very low or undetectable.202

Plasma Protein Binding

Approximately 98–99%.1 Lopinavir binds to both α1-acid glycoprotein (AAG) and albumin, but has a higher affinity for AAG.1

Elimination

Metabolism

Lopinavir extensively metabolized by CYP enzyme system, almost exclusively by CYP3A.1 Ritonavir, a potent inhibitor of CYP3A, is included in the fixed-combination preparation to inhibit metabolism of and increase plasma concentrations of lopinavir.1

Elimination Route

Both lopinavir and ritonavir principally eliminated by the liver.1

Approximately 10 and 83% of a lopinavir dose excreted in urine and feces, respectively, within 8 days.1 After multiple doses, <3% of a lopinavir dose excreted unchanged in urine.1

Half-life

Adults: Mean lopinavir half-life is 4.1–5.8 hours following multiple doses of lopinavir/ritonavir (twice-daily dosing).34

Special Populations

Peak plasma concentrations and AUC of lopinavir increased 20 and 30%, respectively, in patients with mild to moderate hepatic impairment.1 Plasma protein binding decreased in these patients compared with other individuals (99.09 versus 99.31%).1 Pharmacokinetics not studied in patients with severe hepatic impairment.1

Pharmacokinetics not studied in renal impairment; alterations not expected since renal clearance of lopinavir is negligible.1

Take this medicine exactly as directed by your doctor. Do not change the dose or stop using this medicine without checking first with your doctor. When your supply of this medicine is running low, contact your doctor or pharmacist ahead of time. Do not allow yourself to run out of this medicine.

This medicine comes with a Medication Guide. Read and follow the instructions carefully before starting treatment and each time you refill your prescription. Ask your doctor or pharmacist if you have any questions.

This medicine works best when there is a constant amount in the blood. To help keep the amount constant, do not miss any doses. If you need help in planning the best times to take your medicine, check with your doctor.

Lopinavir and ritonavir combination must be taken with other medicines that are used to treat HIV. Take all of the medicines your doctor has prescribed at the right time of day and in correct order. Do not stop using your medicine unless your doctor tells you to.

It is important that lopinavir and ritonavir oral liquid be taken with food. Use a calibrated dosing syringe or medicine cup to measure the dose for the oral liquid. Do not use a polyurethane feeding tube to give this medicine.

Lopinavir and ritonavir tablets may be taken with or without food. Swallow the tablets whole. Do not crush, break, or chew them.

If you are also using didanosine (Videx®), take it 1 hour before or 2 hours after taking Kaletra® oral liquid. Didanosine can be taken (without food) at the same time as Kaletra® tablets.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For treatment of HIV infection:
  • For oral dosage form (solution):
    • Adults—400 milligrams (mg) of lopinavir and 100 mg of ritonavir (5 milliliters [mL]) two times a day with food or 800 mg of lopinavir and 200 mg of ritonavir (10 mL) once a day with food. Your doctor may adjust your dose as needed.
    • Children 6 months and older—Dose is based on body weight or body size and must be determined by your child's doctor. The recommended dose is 10 to 12 milligrams per kilogram (mg/kg) of body weight or 230 milligrams per square meter (mg/m[2]) of body size for lopinavir and 2.5 to 3 mg/kg or 57.5 (mg/m[2]) for ritonavir two times a day with food. Your doctor may adjust your dose as needed.
    • Children 14 days to 6 months of age—Dose is based on body weight or body size and must be determined by your child's doctor. The recommended dose is 16 milligrams per kilogram (mg/kg) of body weight or 300 milligrams per square meter (mg/m[2]) of body size for lopinavir and 4 mg/kg or 75 (mg/m[2]) for ritonavir two times a day with food.
    • Children younger than 14 days of age—Use is not recommended, unless your doctor determines it is safe to be given.
  • For oral dosage form (tablets):
    • Adults—400 milligrams (mg) of lopinavir and 100 mg of ritonavir (2 tablets) two times a day or 800 mg of lopinavir and 200 mg of ritonavir (4 tablets) once a day. Your doctor may adjust your dose as needed.
    • Children 6 months and older—The child must be able to swallow a tablet whole. Dose is based on body weight and must be determined by your child's doctor. The recommended dose is 200 to 400 milligrams (mg) of lopinavir and 50 to 100 mg of ritonavir (2 to 4 tablets) two times a day. Your doctor may adjust your dose as needed.
    • Children 14 days to 6 months of age—This dosage form is usually not used for infants. Please refer to the oral solution dosage form.
    • Infants younger than 14 days of age—Use is not recommended, unless your doctor determines it is safe to be given.

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

It is best to store the Kaletra® oral liquid in a closed container in the refrigerator. Do not freeze. If you must store the liquid at room temperature, use the medicine within 2 months and keep it away from excessive heat.

The Kaletra® tablets should be stored in a closed container at room temperature, away from heat, moisture, and direct light. Do not store this medicine out of the original container and in places with high humidity for more than 2 weeks.

It is very important that your doctor check the progress of you or your child at regular visits to make sure this medicine is working properly. Blood and urine tests may be needed to check for unwanted effects.

Do not use this medicine if you or your child are also using alfuzosin (Uroxatral®), cisapride (Propulsid®), colchicine (Colcrys®), dronedarone (Multaq®), elbasvir/grazoprevir (Zepatier®), ergot medicines (eg, dihydroergotamine, ergotamine, methylergonovine, Cafergot®, Ergomar®, Methergine®, or Migranal®), lovastatin (Advicor®, Altoprev®, Mevacor®), lurasidone (Latuda®), oral midazolam (Versed®), pimozide (Orap®), ranolazine (Ranexa®), rifampin (Rifadin®), sildenafil (Revatio®), simvastatin (Simcor®, Vytorin®, Zocor®), or triazolam (Halcion®).

Do not take other medicines unless they have been discussed with your doctor. This includes prescription and nonprescription (over-the-counter [OTC]) medicines, and herbal (eg, St. John's wort) or vitamin supplements.

Pancreatitis may occur while you are using this medicine. Check with your doctor right away if you or your child have sudden and severe stomach pain, chills, constipation, nausea, vomiting, fever, or lightheadedness.

Check with your doctor right away if you or your child have pain or tenderness in the upper stomach, pale stools, dark urine, loss of appetite, nausea, unusual tiredness or weakness, or yellow eyes or skin. These could be symptoms of a serious liver problem.

This medicine may increase blood sugar levels. Check with your doctor if you or your child notice a change in the results of your blood or urine sugar tests.

This medicine may cause heart rhythm problems, including PR or QT prolongation. It may change the way your heart beats and cause fainting or serious side effects in some patients. Contact your doctor right away if you or your child have any symptoms of heart rhythm problems, such as fast, pounding, or irregular heartbeats.

This medicine may increase the amount of cholesterol and fats in your blood. If this condition occurs, your doctor may give you some medicines that can lower the amount of cholesterol and fats in the blood. Talk to your doctor if you or your child have concerns.

If you or your child develop a skin rash, hives, or any allergic reaction to this medicine, check with your doctor as soon as possible.

If you are taking the oral liquid, you should limit the amount of alcohol you drink. The Kaletra® oral liquid contains 42% alcohol. Talk to your doctor if you or your child are taking, or plan to take, metronidazole (Flagyl®) or disulfiram (Antabuse®).

Birth control pills that contain estrogen may not work as well while you are using this medicine. To keep from getting pregnant, use an additional form of birth control along with your pills. Other forms of birth control include condoms, a diaphragm, or contraceptive foam or jelly.

Your immune system may get stronger when you start taking HIV medicines. Tell your doctor right away if you notice any changes in your health. Sometimes the immune system will start to fight infections that were hidden in your body, such as pneumonia or tuberculosis, or may result in a flare-up of a hidden autoimmune disorder such as Graves disease, polymyositis, or Guillain-Barré syndrome.

This medicine may cause you to have excess body fat. Tell your doctor if you or your child notice changes in your body shape, such as an increased amount of fat in the upper back and neck, or around the chest and stomach area. You might also lose fat from the legs, arms, and face.

This medicine may increase the risk of bleeding in patients with hemophilia (a bleeding disorder). Talk with your doctor about this risk.

This medicine will not keep you from giving HIV to your partner during sex. Make sure you understand this and practice safe sex, even if your partner also has HIV, by using a latex condom or other barrier method. This medicine will also not keep you from giving HIV to other people if they are exposed to your blood. Do not re-use or share needles with anyone.

General Administration Recommendations

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.

Because Kaletra oral solution contains ethanol, it is not recommended for use with polyurethane feeding tubes due to potential incompatibility.

Dosage Recommendations in Adults

Considerations in Determining Kaletra Once Daily vs. Twice Daily Dosing Regimen:

• Kaletra can be given as once daily or twice daily dosing regimen in patients with less than three lopinavir resistance-associated substitutions.
• Kaletra must be given as twice daily dosing regimen in patients with three or more resistance-associated substitutions.
• Table 1 includes the recommended once daily dosing regimen and Tables 2 and 3 include the recommended twice daily dosing regimen.

Kaletra once daily dosing regimen is not recommended in:

• 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 [see Microbiology (12.4)].
• In combination with carbamazepine, phenobarbital, or phenytoin [see Drug Interactions (7.3)].
• In combination with efavirenz, nevirapine, or nelfinavir [see Drug Interactions (7.3) and Clinical Pharmacology (12.3)].
• In pregnant women [see Dosage and Administration (2.4), Use in Specific Populations (8.1) and Clinical Pharmacology (12.3)].

The dose of Kaletra must be increased when administered in combination with efavirenz, nevirapine or nelfinavir.

Table 3 outlines the dosage recommendations for twice daily dosing when Kaletra is taken in combination with efavirenz, nevirapine or nelfinavir.

Dosage Recommendations in Pediatric Patients

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

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 [see Warnings and Precautions (5.2)].

Kaletra oral solution contains approximately 42% (v/v) ethanol and approximately 15% (w/v) propylene glycol. Special attention should be given to accurate calculation of the dosage 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 ethanol 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 [see Warnings and Precautions (5.2) and Overdosage (10)].

Pediatric Dosage Calculations

Calculate the appropriate dose of Kaletra for each individual pediatric patient 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:

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)

Dosage Recommendation in Pediatric Patients 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. Table 4 summarizes the recommended daily dosing regimen for pediatric patients 14 days to 6 months.

It is recommended that Kaletra not be administered in combination with efavirenz, nevirapine, or nelfinavir in patients < 6 months of age.

Dosage Recommendation in Pediatric Patients > 6 Months to < 18 Years:

Without Concomitant Efavirenz, Nevirapine, 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, 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. Table 5 summarizes the recommended daily dosing regimen for pediatric patients > 6 months to < 18 years.

Dosing recommendations using tablets

Table 6 provides the dosing recommendations for pediatric patients > 6 months to < 18 years of age based on body weight or body surface area for Kaletra tablets.

Concomitant Therapy: Efavirenz, Nevirapine, or Nelfinavir

Dosing recommendations using oral solution

A dose increase of Kaletra to 300/75 mg/m2 using Kaletra oral solution is needed when co-administered with efavirenz, nevirapine, 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

Table 7 provides 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, or nelfinavir.

Dosage Recommendations in Pregnancy

Administer 400/100 mg of Kaletra twice daily in pregnant patients with no documented lopinavir-associated resistance substitutions. Once daily Kaletra dosing is not recommended in pregnancy [see Use in Specific Populations (8.1) and Clinical Pharmacology (12.3)].

• There are insufficient data to recommend dosing in pregnant women with any documented lopinavir-associated resistance substitutions.
• No dosage adjustment of Kaletra is required for patients during the postpartum period.
• Avoid use of Kaletra oral solution in pregnant women [see Use in Specific Populations (8.1)].

The following adverse reactions are discussed in greater detail in other sections of the labeling.

• QT Interval Prolongation, PR Interval Prolongation [see Warnings and Precautions (5.5, 5.6)]
• Drug Interactions [see Warnings and Precautions (5.1)]
• Pancreatitis [see Warnings and Precautions (5.3)]
• Hepatotoxicity [see Warnings and Precautions (5.4)]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Adverse Reactions in Adults

The safety of Kaletra has been investigated in about 2,600 patients in Phase II-IV clinical trials, of which about 700 have received a dose of 800/200 mg (6 capsules or 4 tablets) once daily. Along with nucleoside reverse transcriptase inhibitors (NRTIs), in some studies, Kaletra was used in combination with efavirenz or nevirapine.

In clinical studies the incidence of diarrhea in patients treated with either Kaletra capsules or tablets was greater in those patients treated once daily than in those patients treated twice daily. Any grade of diarrhea was reported by at least half of patients taking once daily Kaletra capsules or tablets. At the time of treatment discontinuation, 4.2-6.3% of patients taking once daily Kaletra and 1.8-3.7% of those taking twice daily Kaletra reported ongoing diarrhea.

Commonly reported adverse reactions to Kaletra included diarrhea, nausea, vomiting, hypertriglyceridemia and hypercholesterolemia. Diarrhea, nausea and vomiting may occur at the beginning of the treatment while hypertriglyceridemia and hypercholesterolemia may occur later. The following have been identified as adverse reactions of moderate or severe intensity (Table 9):

Laboratory Abnormalities in Adults

The percentages of adult patients treated with combination therapy with Grade 3-4 laboratory abnormalities are presented in Table 10 (treatment-naïve patients) and Table 11 (treatment-experienced patients).

Adverse Reactions in Pediatric Patients

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).

Kaletra oral solution and soft gelatin capsules dosed at higher than recommended doses including 400/100 mg/m2 (without concomitant NNRTI) and 480/120 mg/m2 (with concomitant NNRTI) have been studied in 26 pediatric patients 7 to 18 years of age in Study 1038. Patients also had saquinavir mesylate added to their regimen at Week 4. Rash (12%), blood cholesterol abnormal (12%) and blood triglycerides abnormal (12%) were the only adverse reactions reported in greater than 10% of subjects. Adverse drug reactions of moderate to severe intensity occurring in 2 or more subjects included rash (N=3), blood triglycerides abnormal (N=3), and electrocardiogram QT prolonged (N=2). Both subjects with QT prolongation had additional predisposing conditions such as electrolyte abnormalities, concomitant medications, or pre-existing cardiac abnormalities.

Laboratory Abnormalities in Pediatric Patients

The percentages of pediatric patients treated with combination therapy including Kaletra with Grade 3-4 laboratory abnormalities are presented in Table 12.

Postmarketing Experience

The following adverse reactions have been reported during postmarketing use of Kaletra. Because these reactions are reported voluntarily from a population of unknown size, it is not possible to reliably estimate their frequency or establish a causal relationship to Kaletra exposure.

Body as a Whole
Redistribution/accumulation of body fat has been reported [see Warnings and Precautions (5.10)].

Cardiovascular
Bradyarrhythmias. First-degree AV block, second-degree AV block, third-degree AV block, QTc interval prolongation, torsades (torsade) de pointes [see Warnings and Precautions (5.5, 5.6)].

Skin and Appendages
Toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome and erythema multiforme.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Lopinavir/ritonavir combination was evaluated for carcinogenic potential by oral gavage administration to mice and rats for up to 104 weeks. Results showed an increase in the incidence of benign hepatocellular adenomas and an increase in the combined incidence of hepatocellular adenomas plus carcinoma in both males and females in mice and males in rats at doses that produced approximately 1.6-2.2 times (mice) and 0.5 times (rats) the human exposure (based on AUC0-24hr measurement) at the recommended dose of 400/100 mg Kaletra twice daily. Administration of lopinavir/ritonavir did not cause a statistically significant increase in the incidence of any other benign or malignant neoplasm in mice or rats.

Carcinogenicity studies in mice and rats have been carried out on ritonavir. In male mice, there was a dose dependent increase in the incidence of both adenomas and combined adenomas and carcinomas in the liver. Based on AUC measurements, the exposure at the high dose was approximately 4-fold for males that of the exposure in humans with the recommended therapeutic dose (400/100 mg Kaletra twice daily). There were no carcinogenic effects seen in females at the dosages tested. The exposure at the high dose was approximately 9-fold for the females that of the exposure in humans. There were no carcinogenic effects in rats. In this study, the exposure at the high dose was approximately 0.7-fold that of the exposure in humans with the 400/100 mg Kaletra twice daily regimen. Based on the exposures achieved in the animal studies, the significance of the observed effects is not known.

Mutagenesis

Neither lopinavir nor ritonavir was found to be mutagenic or clastogenic in a battery of in vitro and in vivo assays including the Ames bacterial reverse mutation assay using S. typhimurium and E. coli, the mouse lymphoma assay, the mouse micronucleus test and chromosomal aberration assays in human lymphocytes.

Impairment of Fertility

Lopinavir in combination with ritonavir at a 2:1 ratio produced no effects on fertility in male and female rats at levels of 10/5, 30/15 or 100/50 mg/kg/day. Based on AUC measurements, the exposures in rats at the high doses were approximately 0.7-fold for lopinavir and 1.8-fold for ritonavir of the exposures in humans at the recommended therapeutic dose (400/100 mg twice daily).

Kaletra® (lopinavir and ritonavir) tablets and oral solution are available in the following strengths and package sizes:

Kaletra Tablets, 200 mg lopinavir and 50 mg ritonavir

Yellow film-coated ovaloid tablets debossed with the “a” logo and the code KA:

Bottles of 120 tablets ….…………… (NDC 0074-6799-22)

Recommended Storage

Store Kaletra 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.

Kaletra Tablets, 100 mg lopinavir and 25 mg ritonavir

Pale yellow film-coated ovaloid tablets debossed with the “a” logo and the code KC:

Bottles of 60 tablets ….…………… (NDC 0074-0522-60)

Recommended Storage

Store Kaletra 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 (100 mL or less). For patient use: exposure of this product to high humidity outside the original container or USP equivalent tight container (100 mL or less) for longer than 2 weeks is not recommended.

Kaletra Oral Solution

Kaletra (lopinavir and ritonavir) oral solution is a light yellow to orange colored liquid supplied in amber-colored multiple-dose bottles containing 400 mg lopinavir and 100 mg ritonavir per 5 mL (80 mg lopinavir and 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 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.

Kaletra can cause a serious heart problem, especially if you use certain other medicines at the same time. Tell your doctor about all your current medicines and any medicine you start or stop using.

Call your doctor at once if you have a headache with chest pain, fast or pounding heartbeats, and severe dizziness.