NDC 0074-3008-60

Kaletra**®**

(Lopinavir and Ritonavir)

Tablets

100 mg / 25mg

60 Tablets

ALERT: Find out about medicines that should NOT be taken with Kaletra®

Attention Pharmacist: Do not cover ALERT box with pharmacy label.

Dispense the accompanying Medication Guide to each patient

Rx only abbvie


5 WARNINGS AND PRECAUTIONS

5.1 Risk of Serious Adverse Reactions Due to Drug Interactions

Initiation of KALETRA, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving KALETRA, may increase plasma concentrations of medications metabolized by CYP3A. Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of KALETRA, respectively. These interactions may lead to:

• Clinically significant adverse reactions, potentially leading to severe, life-threatening, or fatal events from greater exposures of concomitant medications.

• Clinically significant adverse reactions from greater exposures of KALETRA.

• Loss of therapeutic effect of KALETRA and possible development of resistance.

See Table 12 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations [see Drug Interactions (7)]. Consider the potential for drug interactions prior to and during KALETRA therapy; review concomitant medications during KALETRA therapy, and monitor for the adverse reactions associated with the concomitant medications [see Contraindications (4) and Drug Interactions (7)].

5.2 Toxicity in Preterm Neonates

KALETRA oral solution contains the excipients ethanol, approximately 42% (v/v) and propylene glycol, approximately 15% (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 ethanol 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 [see Dosage and Administration (2.4) and Overdosage (10)].

5.3 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 [see Warnings and Precautions (5.9)]. 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.

5.4 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 [see Use in Specific Populations (8.6)].

5.5 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 [see Clinical Pharmacology (12.3)].

5.6 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 [see Clinical Pharmacology (12.3)].

5.7 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. Consider monitoring for hyperglycemia, new onset diabetes mellitus or an exacerbation of diabetes mellitus in patients treated with KALETRA.

5.8 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.

Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain- Barré syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment.

5.9 Lipid Elevations

Treatment with KALETRA has resulted in large increases in the concentration of total cholesterol and triglycerides [see Adverse Reactions (6.1)]. 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 [see Contraindications (4) and Drug Interactions (7.3)].

5.10 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.

5.11 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.

5.12 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 [see Microbiology (12.4)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to KALETRA during pregnancy. Physicians are encouraged to register patients by calling the Antiretroviral Pregnancy Registry at 1-800-258-4263.

Risk Summary

Available data from the Antiretroviral Pregnancy Registry show no difference in the risk of overall major birth defects compared to the background rate for major birth defects of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) (see Data). The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15-20%. The background risk for major birth defects and miscarriage for the indicated population is unknown. Methodological limitations of the APR include the use of MACDP as the external comparator group. The MACDP population is not disease-specific, evaluates women and infants from a limited geographic area, and does not include outcomes for births that occurred at <20 weeks gestation (see Data). No treatment-related malformations were observed when lopinavir in combination with ritonavir was administered to pregnant rats or rabbits; however embryonic and fetal developmental toxicities occurred in rats administered maternally toxic doses.

Clinical Considerations

Dose Adjustments During Pregnancy and the Postpartum Period

Administer 400/100 mg of KALETRA twice daily in pregnant patients with no documented lopinavir-associated resistance substitutions [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)]. There are insufficient data to recommend KALETRA dosing for pregnant patients with any documented lopinavir-associated resistance substitutions. No dose adjustment of KALETRA is required for patients during the postpartum period.

Once daily KALETRA dosing is not recommended in pregnancy.

Avoid use of KALETRA oral solution during pregnancy due to the ethanol content. KALETRA oral solution contains the excipients ethanol, approximately 42% (v/v and propylene glycol, approximately 15%.

Data

Human Data

KALETRA was evaluated in 12 HIV-infected pregnant women in an open-label pharmacokinetic trial [see Clinical Pharmacology (12.3)]. No new trends in the safety profile were identified in pregnant women dosed with KALETRA compared to the safety described in non-pregnant adults, based on the review of these limited data.

Antiretroviral Pregnancy Registry Data: Based on prospective reports from the Antiretroviral Pregnancy Registry (APR) of over 3,000 exposures to lopinavir containing regimens (including over 1,000 exposed in the first trimester), there was no difference between lopinavir and overall birth defects compared with the background birth defect rate of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program. The prevalence of birth defects in live births was 2.1% (95% CI: 1.4%-3.0%) following first- trimester exposure to lopinavir-containing regimens and 3.0% (95% CI: 2.4%-3.8%) following second and third trimester exposure to lopinavir- containing regimens. Based on prospective reports from the APR of over 5,000 exposures to ritonavir containing regimens (including over 2,000 exposures in the first trimester) there was no difference between ritonavir and overall birth defects compared with the U.S. background rate (MACDP). The prevalence of birth defects in live births was 2.2% (95% CI: 1.7%-2.8%) following first- trimester exposure to ritonavir-containing regimens and 2.9% (95% CI: 2.4%-3.6%) following second and third trimester exposure to ritonavir- containing regimens. For both lopinavir and ritonavir, sufficient numbers of first trimester exposures have been monitored to detect at least a 1.5 fold increase in risk of overall birth defects and a 2 fold increase in risk of birth defects in the cardiovascular and genitourinary systems.

Animal Data

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 administered lopinavir in combination with ritonavir (on gestation days 6-17) at a maternally toxic dosage. Based on AUC measurements, the drug exposures in rats at the toxic doses were approximately 0.7 times (for lopinavir) and 1.8 times (for ritonavir) the exposures in humans at the recommended therapeutic dose (400/100 mg twice daily). In a pre- and post-natal 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 administered lopinavir in combination with ritonavir (on gestation days 6-18) at a maternally toxic dosage. Based on AUC measurements, the drug exposures in rabbits at the toxic doses were approximately 0.6 times (for lopinavir) and similar to (for ritonavir) the exposures in humans at the recommended therapeutic dose (400/100 mg twice daily).

8.2 Lactation

Risk Summary

The Centers for Disease Control and Prevention recommend that HIV-1 infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1. Because of the potential for: 1) HIV transmission (in HIV-negative infants), 2) developing viral resistance (in HIV- positive infants), and 3) adverse reactions in the breastfed infant, instruct mothers not to breastfeed if they are receiving KALETRA.

8.3 Females and Males of Reproductive Potential

Contraception

Use of KALETRA may reduce the efficacy of combined hormonal contraceptives. Advise patients using combined hormonal contraceptives to use an effective alternative contraceptive method or an additional barrier method of contraception [see Drug Interactions (7.3)].

8.4 Pediatric Use

The safety, efficacy, and pharmacokinetic profiles of KALETRA in pediatric patients below the age of 14 days have not been established. KALETRA should not be administered once daily 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 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 HIV-1 RNA <400 copies/mL at Week 24 [see Adverse Reactions (6.2), Clinical Pharmacology (12.3), Clinical Studies (14.4)].

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) [see Adverse Reactions (6.2), Clinical Pharmacology (12.3), Clinical Studies (14.4)].

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 26 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 [see Adverse Reactions (6.2), Clinical Pharmacology (12.3)].

A prospective multicenter, randomized, open-label study evaluated the efficacy and safety of twice-daily versus once-daily dosing of KALETRA tablets dosed by weight as part of combination antiretroviral therapy (cART) in virologically suppressed HIV-1 infected children (n=173). Children were eligible when they were aged < 18 years, ≥ 15 kg in weight, receiving cART that included KALETRA, HIV-1 ribonucleic acid (RNA) < 50 copies/mL for at least 24 weeks and able to swallow tablets. At week 24, efficacy (defined as the proportion of subjects with plasma HIV-1 RNA less than 50 copies per mL) was significantly higher in subjects receiving twice daily dosing compared to subjects receiving once daily dosing. The safety profile was similar between the two treatment arms although there was a greater incidence of diarrhea in the once daily treated subjects.

8.5 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.

8.6 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 [see Warnings and Precautions (5.4) and Clinical Pharmacology (12.3)].

13 NONCLINICAL TOXICOLOGY

13.1 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).

16 HOW SUPPLIED/STORAGE AND HANDLING

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

Formulation**** and strength	Available Presentations	Bottle size**** and NDC codes
Tablets: 200 mg lopinavir/**** 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)
	Red film-coated ovaloid tablets debossed with the code AL	Bottles of 120 tablets (NDC0074-4014-12)
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)
	Pink film-coated ovaloid tablets debossed with the code AC	Bottles of 60 tablets (NDC 0074-3008-60)
Oral Solution: 80 mg lopinavir and**** 20 mg ritonavir per mL	Light yellow to orange colored liquid supplied in amber-colored multiple-dose bottles containing 400 mg lopinavir and 100 mg ritonavir per 5 mL packaged with a marked dosing cup	160 mL bottle (NDC 0074-3956-46)

Recommended Storage:

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

MEDICATION GUIDE
KALETRA**®**** (kuh-LEE-tra)** (lopinavir and ritonavir)**** tablets	KALETRA**®**** (kuh-LEE-tra)** (lopinavir and ritonavir)**** oral solution
What is the most important information I should know about KALETRA? KALETRA may cause serious side effects, including:
*Interactions with other medicines. It is important to know the medicines that should not be taken with KALETRA. For more information, see "Who should not take KALETRA?” ***Side Effects in babies taking KALETRA oral solution.**KALETRA oral solution contains alcohol (ethanol) and propylene glycol. Call your healthcare provider right away if your baby appears too sleepy or their breathing changes. ***Inflammation of your pancreas (pancreatitis).**KALETRA can cause pancreatitis which may be serious and may lead to death. People who have high levels of a certain fat (triglycerides) have a risk for developing pancreatitis. If you have advanced HIV-1 disease, you may have an increased risk of high triglyceride levels in your blood, and pancreatitis. If you have a history of pancreatitis, you may have an increased risk of it coming back again during treatment with KALETRA. Tell your healthcare provider if you have any signs or symptoms of pancreatitis including:
° nausea ° vomiting ° stomach-area (abdominal) pain
*Liver problems. Liver problems, including death, can happen in people who take KALETRA. Your healthcare provider should do blood tests before and during your treatment with KALETRA to check your liver function. If you have Hepatitis B or Hepatitis C, or other liver problems, you may have an increased risk for developing new or worsening of liver problems during treatment with KALETRA. Tell your healthcare provider right away if you have any signs and symptoms of liver problems including:
○ loss of appetite ○ yellow skin and whites of eyes (jaundice) ○ dark-colored urine	○ pale colored stools ○ itchy skin ○ stomach area (abdominal) pain
*Changes in your heart rhythm and the electrical activity of your heart. These changes may be seen on an EKG (electrocardiogram) and can lead to serious heart problems. Your risk for these problems may be higher if you: ○ have a history of abnormal heart rhythm or certain types of heart problems. ○ take other medicines that can affect your heart rhythm during treatment with KALETRA. Tell your healthcare provider right away if you have any of these symptoms:
○ dizziness ○ lightheadedness	○ fainting ○ sensation of abnormal heartbeats
**See “What are the possible side effects of KALETRA?”**for more information about serious side effects.
What is KALETRA? KALETRA is a prescription medicine that is used with other antiretroviral medicines to treat Human Immunodeficiency Virus-1 (HIV-1) infection in adults and children 14 days of age and older. HIV is the virus that causes AIDS (Acquired Immune Deficiency Syndrome). It is not known if KALETRA is safe and effective in children under 14 days old.
Who should not take KALETRA? Do not take KALETRA if you: are allergic to lopinavir, ritonavir, or any of the ingredients in KALETRA. See the end of this Medication Guide for a complete list of ingredients in KALETRA. if you take any of the following medicines: ○ alfuzosin ○ apalutamide ○ ranolazine ○ dronedarone ○ colchicine, if you have kidney or liver problems. ○ rifampin ○ lurasidone ○ pimozide ○ ergot containing medicines including: ▪ dihydroergotamine mesylate ▪ ergotamine tartrate ▪ methylergonovine ○ cisapride ○ elbasvir/grazoprevir ○ lovastatin ○ simvastatin ○ lomitapide ○ sildenafil (Revatio®), when used for the treatment of pulmonary arterial hypertension ○ triazolam ○ midazolam when taken by mouth ○ St. John’s Wort (Hypericum perforatum®) Serious problems can happen if you or your child takes any of the medicines listed above with KALETRA.
Before taking KALETRA, tell your healthcare provider about all of your medical conditions, including if you: have ever had a serious skin rash or an allergic reaction to medicines that contain lopinavir or ritonavir. have or had pancreas problems. have liver problems, including Hepatitis B or Hepatitis C. have any heart problems, including if you have a condition called Congenital Long QT Syndrome. have low potassium in your blood. have diabetes. have high cholesterol in your blood. have hemophilia. KALETRA may cause increased bleeding. are pregnant or plan to become pregnant. It is not known if KALETRA will harm your unborn baby. ○ KALETRA oral solution contains alcohol (ethanol) and propylene glycol. You should not take KALETRA oral solution during pregnancy because there is no safe level of alcohol exposure during pregnancy. Tell your healthcare provider if you become pregnant during treatment with KALETRA. ○ KALETRA may reduce how well hormonal birth control works. Females who may become pregnant should use another effective form of birth control or an additional barrier method of birth control during treatment with KALETRA. **○**Pregnancy Registry: There is a pregnancy registry for women who take antiretroviral medicines during pregnancy. The purpose of the pregnancy registry is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this registry. are breastfeeding or plan to breastfeed.Do not breastfeed if you take KALETRA. ○ You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby. ○ Talk to your healthcare provider about the best way to feed your baby. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.** Many medicines interact with KALETRA.** Keep a list of your medicines to show your healthcare provider and pharmacist. You can ask your healthcare provider or pharmacist for a list of medicines that interact with KALETRA. Do not start taking a new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take KALETRA with other medicines. Your healthcare provider may need to change the dose of other medicines during treatment with KALETRA.
How should I take KALETRA? Take KALETRA every day exactly as prescribed by your healthcare provider. Stay under the care of your healthcare provider during treatment with KALETRA. It is important to set up a dosing schedule and follow it every day. Do not change your treatment or stop treatment without first talking with your healthcare provider. Swallow KALETRA tablets whole. Do not chew, break, or crush KALETRA tablets. KALETRA tablets can be taken with or without food. KALETRA oral solution must be taken with food. If you are taking both didanosine and KALETRA: ○ Didanosine can be taken at the same time as KALETRA tablets, without food. ○ Take didanosine either 1 hour before or 2 hours after taking KALETRA oral solution. If you are pregnant: ○ Youshould not take KALETRA tablets on a 1 time each day dose schedule. ○ Avoid use ofKALETRA oral solution. If your child is prescribed KALETRA: ○ Tell your healthcare provider if your child’s weight changes. KALETRAshould not be given to children on a 1 time each day dose schedule. When giving KALETRA to your child, give KALETRA exactly as prescribed. ○ Use the dosing cup (supplied) or an oral syringe with mL (milliliter) markings to give the prescribed dose of KALETRA oral solution to your child. Your pharmacist should provide an oral syringe to you. ○ KALETRA oral solution contains propylene glycol and a large amount of alcohol (ethanol). KALETRA oral solutionshould not be given to babies younger than 14 days of age unless your healthcare provider thinks it is right for your baby. Talk with your healthcare provider if you plan to take or give KALETRA oral solution through a feeding tube. KALETRA oral solution contains propylene glycol and alcohol (ethanol), and should not be used with certain feeding tubes. You may have a greater chance of getting diarrhea if you take KALETRA 1 time each day than if you take it 2 times each day. *Do not miss a dose of KALETRA. This could make the virus harder to treat. If you forget to take KALETRA, take the missed dose right away. If it is almost time for your next dose,do not take the missed dose. Instead, follow your regular dosing schedule by taking your next dose at its regular time.Do not take more than one dose of KALETRA at one time. *If you or your child take more than the prescribed dose of KALETRA, call your healthcare provider or go to the nearest emergency room right away.
What are the possible side effects of KALETRA? KALETRA can cause serious side effects, including: See**“What is the most important information I should know about KALETRA?”**
*Diabetes and high blood sugar (hyperglycemia). You may develop new or worsening diabetes or high blood sugar during treatment with KALETRA. Tell your healthcare provider if you get any of the following signs or symptoms:
○ urinate more often than usual ○ increased hunger or thirst	○ unusual weight loss ○ increase in your blood sugar levels
Your healthcare provider may need to start you on medicine to treat high blood sugar or change your diabetes medicines. *Changes in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Call your healthcare provider right away if you start having new symptoms after starting your HIV-1 medicine. *Increases in certain fat (triglycerides and cholesterol) levels in your blood. Large increases of triglycerides and cholesterol can be seen in blood test results of some people who take KALETRA. Your healthcare provider should do blood tests to check your cholesterol and triglyceride levels before you start taking KALETRA and during your treatment. *Changes in body fat can happen in some people who take antiretroviral therapy. These changes may include increased amount of fat in the upper back and neck ("buffalo hump"), breast, and around the middle of your body (trunk). Loss of fat from the legs, arms and face may also happen. The exact cause and long-term health effects of these conditions are not known at this time. *Increased bleeding in people with hemophilia. Some people with hemophilia have increased bleeding with KALETRA or similar medicines. ***Skin rash, which can be severe,**can happen in people who take KALETRA. Tell your healthcare provider if you have a history of skin rash with other medicine used to treat your HIV-1 infection or if you get any skin rash during treatment with KALETRA. *Kidney stones Common side effects of KALETRA include:
• diarrhea • nausea	• vomiting • increased fats in blood (triglycerides or cholesterol)
These are not all of the possible side effects of KALETRA. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store KALETRA? KALETRA tablets: Store KALETRA tablets at room temperature, between 68°F to 77°F (20°C to 25°C). Store KALETRA tablets in the original container. Do not keep KALETRA tablets out of the container it comes in for longer than 2 weeks, especially in areas where there is a lot of humidity. Keep the container closed tightly. KALETRA oral solution: Store KALETRA oral solution in a refrigerator, between 36°F to 46°F (2°C to 8°C). KALETRA oral solution that is kept refrigerated may be used until the expiration date printed on the label. KALETRA oral solution that is stored at room temperature (less than 77°F or 25°C) should be used within 2 months. Keep KALETRA oral solution away from high heat. Throw away any medicine that is out of date or that you no longer need. Keep KALETRA and all medicines out of the reach of children.
General information about the safe and effective use of KALETRA. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use KALETRA for a condition for which it was not prescribed. Do not give KALETRA to other people, even if they have the same condition you have. It may harm them. You can ask your pharmacist or healthcare provider for information about KALETRA that is written for health professionals.
What are the ingredients in KALETRA? Active ingredients: lopinavir and ritonavir Inactive ingredients: KALETRA 200 mg lopinavir and 50 mg ritonavir yellow tablets: colloidal silicon dioxide, copovidone, sodium stearyl fumarate, and sorbitan monolaurate. The film coating contains: colloidal silicone dioxide, hydroxypropyl cellulose, hypromellose, polyethylene glycol 400, polyethylene glycol 3350, polysorbate 80, talc, titanium dioxide, and yellow ferric oxide E172. KALETRA 200 mg lopinavir and 50 mg ritonavir red tablets: colloidal silicon dioxide, copovidone, sodium stearyl fumarate, and sorbitan monolaurate. The film coating contains: colloidal silicone dioxide, hydroxypropyl cellulose, hypromellose, polyethylene glycol 400, polyethylene glycol 3350, polysorbate 80, talc, titanium dioxide, and red ferric oxide E172. KALETRA 100 mg lopinavir and 25 mg ritonavir pale yellow tablets: colloidal silicon dioxide, copovidone, sodium stearyl fumarate, and sorbitan monolaurate. The film coating contains: polyethylene glycol 3350, polyvinyl alcohol, talc, titanium dioxide, and yellow ferric oxide E172. KALETRA 100 mg lopinavir and 25 mg ritonavir pink tablets: colloidal silicon dioxide, copovidone, sodium stearyl fumarate, and sorbitan monolaurate. The film coating contains: polyethylene glycol 3350, polyvinyl alcohol, talc, titanium dioxide, and red ferric oxide E172. KALETRA oral solution: acesulfame potassium, artificial cotton candy flavor, citric acid, ethanol (a type of alcohol), glycerin, high fructose corn syrup, Magnasweet-110 flavor, menthol, natural and 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 approximately 42% ethanol (a type of alcohol) and approximately 15% propylene glycol.“See How should I take KALETRA?” For more information about KALETRA call 1-800-633-9110 or go to www.KALETRA.com Manufactured by AbbVie Inc., North Chicago, IL 60064 USA KALETRA is a trademark of AbbVie Inc. © 2023 AbbVie Inc. All rights reserved. The brands listed are trademarks of their respective owners and are not trademarks of AbbVie Inc. The makers of these brands are not affiliated with and do not endorse AbbVie Inc. or its products. 20077914

This Medication Guide has been approved by the U.S. Food and Drug Administration.
Revised: April 2023

2 DOSAGE AND ADMINISTRATION

2.1 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.

2.2 Administering Oral Solution by Feeding Tube

Because KALETRA oral solution contains ethanol and propylene glycol, it is not recommended for use with polyurethane feeding tubes due to potential incompatibility. Feeding tubes that are compatible with ethanol and propylene glycol, such as silicone and polyvinyl chloride (PVC) feeding tubes, can be used for administration of KALETRA oral solution. Follow instructions for use of the feeding tube to administer the medicine.

2.3 Dosage Recommendations in Adults

KALETRA can be given in once daily or twice daily dosing regimen at dosages noted in Tables 1 and 2. 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 pediatric patients younger than 18 years of age [see Dosage and Administration (2.4)].

• In pregnant women [see Dosage and Administration (2.5), Use in Specific Populations (8.1) and Clinical Pharmacology (12.3)].

Table 1. Recommended Dosage in Adults - KALETRA Once Daily Regimen

KALETRA Dosage Form	Recommended Dosage
200 mg/50 mg Tablets	800 mg/200 mg (4 tablets) once daily
80 mg/20 mg per mL Oral Solution	800 mg/200 mg (10 mL) once daily

Table 2. Recommended Dosage in Adults - KALETRA Twice Daily Regimen

KALETRA Dosage Form	Recommended Dosage
200 mg/50 mg Tablets	400 mg/100 mg (2 tablets) twice daily
80 mg/20 mg per mL Oral Solution	400 mg/100 mg (5 mL) twice daily

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 these agents.

Table 3. Recommended Dosage in Adults - KALETRA Twice Daily Regimen in Combination with Efavirenz, Nevirapine, or Nelfinavir

KALETRA Dosage Form	Recommended Dosage
200 mg/50 mg Tablets and 100 mg/25 mg Tablets	500 mg/125 mg (2 tablets of 200 mg/50 mg + 1 tablet of 100 mg/25 mg) twice daily
80 mg/20 mg per mL Oral Solution	520 mg/130 mg (6.5 mL) twice daily

2.4 Dosage Recommendations in Pediatric Patients

KALETRA tablets and oral solution are not recommended for once daily dosing in pediatric patients younger than 18 years of age. The dose of the oral solution should be administered using the calibrated cup (supplied) or oral dosing syringe. KALETRA 100/25 mg tablets should be considered only in children who have reliably demonstrated the ability to swallow the intact tablet.

KALETRA oral solution is not recommended in 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. 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)

Oral Solution Dosage Recommendation in Pediatric Patients 14 Days to Less Than 18 Years:

Table 4 summarizes the recommended daily dosing regimen for pediatric patients 14 days to less than 18 years of age using the oral solution.

KALETRA administered in combination with efavirenz, nevirapine, or nelfinavir in patients younger than 6 months of age is not recommended. Total dose of KALETRA oral solution in pediatric patients should not exceed the recommended adult daily dose of 400/100 mg (5mL) twice daily.

Table 4. KALETRA Oral Solution Daily Dosage Recommendations in Pediatric Patients 14 days to Less Than 18 Years Without Concomitant Efavirenz, Nevirapine, or Nelfinavir

Patient Age	Based on Weight**** (mg/kg)	Based on BSA**** (mg/m2)	Frequency
14 days to 6 months	16/4	300/75	Given twice daily
Older than 6 months to less than 18 years	Less than15 kg	12/3	230/57.5	Given twice daily
	15 kg to 40 kg	10/2.5

Tablet Dosage Recommendation in Pediatric Patients Older than 6 Months to Less than 18 Years:

Table 5 provides the dosing recommendations for pediatric patients older than 6 months to less than 18 years of age based on body weight or body surface area for KALETRA tablets.

Table 5. KALETRA Tablet Daily Dosage Recommendations in Pediatric Patients > 6 Months to < 18 Years of Age Without Concomitant Efavirenz, Nevirapine, or Nelfinavir

Body Weight (kg)	Body Surface Area (m2)*****	Recommended number**** of 100/25 mg Tablets**** Twice Daily
≥15 to 25	≥0.6 to < 0.9	2
25 to 35	≥0.9 to < 1.4	3
35	≥1.4	4
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, or Nelfinavir

Dosing recommendations using oral solution

Table 6 provides the dosing recommendations for pediatric patients older than 6 months to less than 18 years of age based on body weight or body surface area for KALETRA Oral Solution when given in combination with efavirenz, nevirapine, or nelfinavir:

Table 6. KALETRA Oral Solution Daily Dosage Recommendations for Pediatric Patients > 6 Months to < 18 Years of Age With Concomitant Efavirenz, Nevirapine, or Nelfinavir

Patient Age	Based on Weight**** (mg/kg)	Based on BSA**** (mg/m2)	Frequency
6 months to < 18 years	<15 kg	13/3.25	300/75	Given twice daily
	≥15 kg to 45 kg	11/2.75

Dosing recommendations using tablets

Table 7 provides the dosing recommendations for pediatric patients older than 6 months to less than 18 years of age based on body weight or body surface area for KALETRA tablets when given in combination with efavirenz, nevirapine, or nelfinavir.

**Table 7. KALETRA Tablet Daily Dosage Recommendations for Pediatric Patients

6 Months to < 18 Years of Age With Concomitant Efavirenz****†, Nevirapine, or Nelfinavir†**

Body Weight (kg)	Body Surface Area (m2)*****	Recommended number of 100/25 mg Tablets Twice Daily
≥15 to 20	≥0.6 to < 0.8	2
20 to 30	≥0.8 to < 1.2	3
30 to 45	≥1.2 to <1.7	4
45	≥1.7	5 [see Dosage and Administration (2.4)]
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.

2.5 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)].