Lopinavir and Ritonavir

1 INDICATIONS AND USAGE Lopinavir and ritonavir is indicated in combination with other antiretroviral agents for the treatment of HIV- 1 infection in adults and pediatric patients 14 days and older. Limitations of Use: Genotypic or phenotypic testing and/or treatment history should guide the use of lopinavir and ritonavir. The number of baseline lopinavir resistance-associated substitutions affects the virologic response to lopinavir and ritonavir [ see Microbiology (12.4) ] . Lopinavir and ritonavir is an HIV-1 protease inhibitor indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients (14 days and older). ( 1 )

2 DOSAGE AND ADMINISTRATION Tablets: May be taken with or without food, swallowed whole and not chewed, broken, or crushed. ( 2.1 ) Oral solution: must be taken with food. ( 2.1 ) Adults ( 2.3 ): Total recommended daily dosage is 800/200 mg given once or twice daily. Lopinavir and ritonavir can be given as once daily or twice daily regimen. See Full Prescribing Information for details. Lopinavir and ritonavir 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. ( 12.4 ) In combination with carbamazepine, phenobarbital, or phenytoin. ( 7.3 ) In combination with efavirenz, nevirapine, or nelfinavir. ( 12.3 ) In pregnant women. ( 2.5 , 8.1 , 12.3 ) Pediatric Patients (14 days and older) ( 2.4 ): Lopinavir and ritonavir once daily dosing regimen is not recommended in pediatric patients. Twice daily dose is based on body weight or body surface area. Concomitant Therapy in Adults and Pediatric Patients: Dose adjustments of lopinavir and ritonavir may be needed when co-administering with efavirenz, nevirapine, or nelfinavir. ( 2.3 , 2.4 , 7.3 ) Lopinavir and ritonavir 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 ( 2.4 , 5.2 ) Pregnancy ( 2.5 ): 400/100 mg twice daily in pregnant patients with no documented lopinavir-associated resistance substitutions. There are insufficient data to recommend a lopinavir and ritonavir dose for pregnant patients with any documented lopinavir and ritonavir-associated resistance substitutions. No dose adjustment of lopinavir and ritonavir is required for patients during the postpartum period. 2.1 General Administration Recommendations Lopinavir and ritonavir tablets may be taken with or without food. The tablets should be swallowed whole and not chewed, broken, or crushed. Lopinavir and ritonavir oral solution must be taken with food. 2.3 Dosage Recommendations in Adults Lopinavir and ritonavir can be given in once daily or twice daily dosing regimen at dosages noted in Tables 1 and 2. Lopinavir and ritonavir 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 - Lopinavir and Ritonavir Once Daily Regimen Lopinavir and Ritonavir 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 - Lopinavir and Ritonavir Twice Daily Regimen Lopinavir and Ritonavir 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 lopinavir and ritonavir must be increased when administered in combination with efavirenz, nevirapine or nelfinavir. Table 3 outlines the dosage recommendations for twice daily dosing when lopinavir and ritonavir is taken in combination with these agents. Table 3. Recommended Dosage in Adults - Lopinavir and Ritonavir Twice Daily Regimen in Combination with Efavirenz, Nevirapine, or Nelfinavir Lopinavir and R…

5 WARNINGS AND PRECAUTIONS The following have been observed in patients receiving lopinavir and ritonavir: The concomitant use of lopinavir and ritonavir and certain other drugs may result in known or potentially significant drug interactions. Consult the full prescribing information prior to and during treatment for potential drug interactions. ( 5.1 , 7.3 ) Toxicity in preterm neonates: Lopinavir and ritonavir oral solution should not be used in preterm neonates in the immediate postnatal period because of possible toxicities. A safe and effective dose of lopinavir and ritonavir oral solution in this patient population has not been established. ( 2.4 , 5.2 ) Pancreatitis: Fatalities have occurred; suspend therapy as clinically appropriate. ( 5.3 ) Hepatotoxicity: Fatalities have occurred. Monitor liver function before and during therapy, especially in patients with underlying hepatic disease, including hepatitis B and hepatitis C, or marked transaminase elevations. ( 5.4 , 8.6 ) QT interval prolongation and isolated cases of torsade de pointes have been reported although causality 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. ( 5.1 , 5.5 , 12.3 ) PR interval prolongation may occur in some patients. Cases of second and third degree heart block have been reported. Use with caution in patients with pre-existing conduction system disease, ischemic heart disease, cardiomyopathy, underlying structural heart disease or when administering with other drugs that may prolong the PR interval. ( 5.1 , 5.6 , 12.3 ) Patients may develop new onset or exacerbations of diabetes mellitus, hyperglycemia ( 5.7 ), immune reconstitution syndrome ( 5.8 ), redistribution/accumulation of body fat. ( 5.10 ) Total cholesterol and triglycerides elevations. Monitor prior to therapy and periodically thereafter. ( 5.9 ) Hemophilia: Spontaneous bleeding may occur, and additional factor VIII may be required. ( 5.11 ) 5.1 Risk of Serious Adverse Reactions Due to Drug Interactions Initiation of lopinavir and ritonavir, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving lopinavir and ritonavir, may increase plasma concentrations of medications metabolized by CYP3A. Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of lopinavir and ritonavir, 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 lopinavir and ritonavir. Loss of therapeutic effect of lopinavir and ritonavir 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 lopinavir and ritonavir therapy; review concomitant medications during lopinavir and ritonavir 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 Lopinavir and ritonavir 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 bl…

4 CONTRAINDICATIONS Lopinavir and ritonavir is contraindicated in patients with previously demonstrated clinically significant hypersensitivity (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, urticaria, angioedema) to any of its ingredients, including ritonavir. Lopinavir and ritonavir 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 [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ] . ○ Alpha 1- Adrenoreceptor Antagonist : alfuzosin ○ Antianginal: ranolazine ○ Antiarrhythmic: dronedarone ○ Anti-gout: colchicine ○ Antipsychotics: lurasidone, pimozide ○ Ergot Derivatives: dihydroergotamine, ergotamine, methylergonovine ○ GI Motility Agent: cisapride ○ Hepatitis C direct acting antiviral: elbasvir/grazoprevir ○ HMG-CoA Reductase Inhibitors: lovastatin, simvastatin ○ Microsomal triglyceride transfer protein (MTTP) Inhibitor: lomitapide ○ PDE5 Inhibitor: sildenafil (Revatio ® ) when used for the treatment of pulmonary arterial hypertension ○ Sedative/Hypnotics: triazolam, orally administered midazolam Lopinavir and ritonavir is contraindicated with drugs that are 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 [see Drug Interactions (7.2) and Clinical Pharmacology (12.3) ]. ○ Anticancer Agents: apalutamide ○ Antimycobacterial: rifampin ○ Herbal Products: St. John's Wort (hypericum perforatum) Hypersensitivity to lopinavir and ritonavir (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, urticaria, angioedema) or any of its ingredients, including ritonavir. ( 4 ) Co-administration with drugs highly dependent on CYP3A for clearance and for which elevated plasma levels may result in serious and/or life-threatening events. ( 4 ) Co-administration 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. ( 4 )

7 DRUG INTERACTIONS Co-administration of lopinavir and ritonavir can alter the plasma concentrations of other drugs and other drugs may alter the plasma concentrations of lopinavir. The potential for drug-drug interactions must be considered prior to and during therapy. ( 4 , 5.1 , 7 , 12.3 ) 7.1 Potential for Lopinavir and Ritonavir 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 lopinavir and ritonavir. Thus, co-administration of lopinavir and ritonavir 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 in Table 12. Additionally, lopinavir and ritonavir induces glucuronidation. Published data suggest that lopinavir is an inhibitor of OATP1B1. These examples are a guide and not considered a comprehensive list of all possible drugs that may interact with lopinavir/ritonavir. The healthcare provider should consult appropriate references for comprehensive information. 7.2 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 lopinavir and ritonavir’s therapeutic effect. Although not observed in the lopinavir and ritonavir/ketoconazole drug interaction study, co-administration of lopinavir and ritonavir and other drugs that inhibit CYP3A may increase lopinavir plasma concentrations. 7.3 Established and Other Potentially Significant Drug Interactions Table 12 provides a listing of established or potentially clinically significant drug interactions. Alteration in dose or regimen may be recommended based on drug interaction studies or predicted interaction [see Contraindications (4) , Warnings and Precautions (5.1) , Clinical Pharmacology (12.3) ] for magnitude of interaction. Table 12. Established and Other Potentially Significant Drug Interactions Concomitant Drug Class: Drug Name Effect on Concentration of Lopinavir or Concomitant Drug Clinical Comments HIV-1 Antiviral Agents HIV-1 Protease Inhibitor: fosamprenavir/ritonavir ↓ amprenavir ↓ lopinavir An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established. HIV-1 Protease Inhibitor: indinavir* ↑ indinavir Decrease indinavir dose to 600 mg twice daily, when co-administered with lopinavir and ritonavir 400/100 mg twice daily. Lopinavir and ritonavir once daily has not been studied in combination with indinavir. HIV-1 Protease Inhibitor: nelfinavir* ↑ nelfinavir ↑ M8 metabolite of nelfinavir ↓ lopinavir Lopinavir and ritonavir once daily in combination with nelfinavir is not recommended [see Dosage and Administration (2) ] . HIV-1 Protease Inhibitor: ritonavir* ↑ lopinavir Appropriate doses of additional ritonavir in combination with lopinavir and ritonavir with respect to safety and efficacy have not been established. HIV-1 Protease Inhibitor: saquinavir ↑ saquinavir The saquinavir dose is 1,000 mg twice daily, when co-administered with lopinavir and ritonavir 400/100 mg twice daily. Lopinavir and ritonavir once daily has not been studied in combination with saquinavir. HIV-1 Protease Inhibitor: tipranavir* ↓ lopinavir Co-administration with tipranavir (500 mg twice daily) and ritonavir (200 mg twice daily) is not recommended. HIV CCR5 – Antagonist: maraviroc* ↑ maraviroc When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing informatio…

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to lopinavir and ritonavir 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 to 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 lopinavir and ritonavir 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 lopinavir and ritonavir dosing for pregnant patients with any documented lopinavir-associated resistance substitutions. No dose adjustment of lopinavir and ritonavir is required for patients during the postpartum period. Once daily lopinavir and ritonavir dosing is not recommended in pregnancy. Avoid use of lopinavir and ritonavir oral solution during pregnancy due to the ethanol content. lopinavir and ritonavir oral solution contains the excipients ethanol, approximately 42% (v/v and propylene glycol, approximately 15%. Data Human Data Lopinavir and ritonavir 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 lopinavir and ritonavir 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% to 3%) following first-trimester exposure to lopinavir-containing regimens and 3% (95% CI: 2.4% to 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% to 2.8%) following first-trimester exposure to ritonavir-containing regimens and 2.9% (95% CI: 2.4% to 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 bi…

8.3 Females and Males of Reproductive Potential Contraception Use of lopinavir and ritonavir 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) ] .

6 ADVERSE REACTIONS 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) ] Commonly reported adverse reactions to lopinavir and ritonavir included diarrhea, nausea, vomiting, hypertriglyceridemia and hypercholesterolemia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Laurus Generics Inc. at 1-833-3-LAURUS (1-833-352-8787) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 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 lopinavir and ritonavir has been investigated in about 2,600 patients in Phase II to 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, lopinavir and ritonavir was used in combination with efavirenz or nevirapine. In clinical studies the incidence of diarrhea in patients treated with either lopinavir and ritonavir 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 lopinavir and ritonavir capsules or tablets. At the time of treatment discontinuation, 4.2 to 6.3% of patients taking once daily lopinavir and ritonavir and 1.8 to 3.7% of those taking twice daily lopinavir and ritonavir reported ongoing diarrhea. Commonly reported adverse reactions to lopinavir and ritonavir 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 8): Table 8. Adverse Reactions of Moderate or Severe Intensity Occurring in at Least 0.1% of Adult Patients Receiving Lopinavir and Ritonavir in Combined Phase II/IV Studies (N=2,612) System Organ Class (SOC) and Adverse Reaction n % BLOOD AND LYMPHATIC SYSTEM DISORDERS anemia* 54 2.1 leukopenia and neutropenia* 44 1.7 lymphadenopathy* 35 1.3 CARDIAC DISORDERS atherosclerosis such as myocardial infarction* 10 0.4 atrioventricular block* 3 0.1 tricuspid valve incompetence* 3 0.1 EAR AND LABYRINTH DISORDERS vertigo* 7 0.3 tinnitus 6 0.2 ENDOCRINE DISORDERS hypogonadism* 16 0.8 1 EYE DISORDERS visual impairment* 8 0.3 GASTROINTESTINAL DISORDERS diarrhea* 510 19.5 nausea 269 10.3 vomiting* 177 6.8 abdominal pain (upper and lower)* 160 6.1 gastroenteritis and colitis* 66 2.5 dyspepsia 53 2 pancreatitis* 45 1.7 Gastroesophageal Reflux Disease (GERD)* 40 1.5 hemorrhoids 39 1.5 flatulence 36 1.4 abdominal distension 34 1.3 constipation* 26 1 stomatitis and oral ulcers* 24 0.9 duodenitis and gastritis* 20 0.8 gastrointestinal hemorrhage including rectal hemorrhage* 13 0.5 dry mouth 9 0.3 gastrointestinal ulcer* 6 0.2 fecal incontinence 5 0.2 GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS fatigue including asthenia* 198 7.6 HEPATOBILIARY DISORDERS hepatitis including AST, ALT, and GGT increases* 91 3.5 hepatomegaly 5 0.2 cholangitis 3 0.1 hepatic steatosis 3 0.1 IMMUNE SYSTEM DISORDERS hypersensitivity including urticaria and angioedema* 70 2.7 immune reconstitution syndrome 3 0.1 INFECTIONS AND INFESTATIONS upper respiratory tract infection* 363 13.9 lower respiratory tract infection* 202 7.7 skin infections including cellulitis, folliculitis, and furuncl…