الجرعة وطريقة الإعطاء
2 DOSAGE AND ADMINISTRATION Tablets: May be taken with or without food, swallowed whole and not chewed, broken, or crushed. ( 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 ) 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. 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 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 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 Ritonavir 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 2.4 Dosage Recommendations in Pediatric Patients Lopinavir and ritonavir tablets are not recommended for once daily dosing in pediatric patients younger than 18 years of age. Lopinavir and ritonavir 100/25 mg tablets should be considered only in children who have reliably demonstrated the ability to swallow the intact tablet. Pediatric Dosage Calculations Calculate the appropriate dose of lopinavir and ritonavir 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 lopinavir and ritonavir 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 (m 2 ) × Prescribed lopinavir dose (mg/m 2 ) = Administered lopinavir dose (mg) 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 lopinavir and ritonavir tablets. Table 5. Lopinavir And Ritonavir 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 Concomitant Therapy: Efavirenz, Nevirapine, or Nelfinavir 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 lopinavir and ritonavir tablets when given in combination with efavirenz, nevirapine, or nelfinavir. Table 7. Lopinavir And Ritonavir 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 )] † Please refer to the individual product labels for appropriate dosing in children. 288 2.5 Dosage Recommendations in Pregnancy Administer 400/100 mg of lopinavir and ritonavir twice daily in pregnant patients with no documented lopinavir-associated resistance substitutions. Once daily lopinavir and ritonavir 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 lopinavir and ritonavir is required for patients during the postpartum period.
Side Effects Overview
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 Macleods Pharma USA, Inc. at 1-888-943-3210 1-855-926-3384 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-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, 4.2-6.3% of patients taking once daily lopinavir and ritonavir and 1.8-3.7% 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 2.0 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. 1.0 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 furuncle* 86 3.3 METABOLISM AND NUTRITION DISORDERS hypercholesterolemia* 192 7.4 hypertriglyceridemia* 161 6.2 weight decreased* 61 2.3 decreased appetite 52 2.0 blood glucose disorders including diabetes mellitus* 30 1.1 weight increased* 20 0.8 lactic acidosis* 11 0.4 increased appetite 5 0.2 MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS musculoskeletal pain including arthralgia and back pain* 166 6.4 myalgia* 46 1.8 muscle disorders such as weakness and spasms* 34 1.3 rhabdomyolysis* 18 0.7 osteonecrosis 3 0.1 NERVOUS SYSTEM DISORDERS headache including migraine* 165 6.3 insomnia* 99 3.8 neuropathy and peripheral neuropathy* 51 2.0 dizziness* 45 1.7 ageusia* 19 0.7 convulsion* 9 0.3 tremor* 9 0.3 cerebral vascular event* 6 0.2 PSYCHIATRIC DISORDERS anxiety* 101 3.9 abnormal dreams* 19 0.7 libido decreased 19 0.7 RENAL AND URINARY DISORDERS renal failure* 31 1.2 hematuria* 20 0.8 nephritis* 3 0.1 REPRODUCTIVE SYSTEM AND BREAST DISORDERS erectile dysfunction* 34 1.7 1 menstrual disorders - amenorrhea, menorrhagia* 10 1.7 2 SKIN AND SUBCUTANEOUS TISSUE DISORDERS rash including maculopapular rash* 99 3.8 lipodystrophy acquired including facial wasting* 58 2.2 dermatitis/rash including eczema and seborrheic dermatitis* 50 1.9 night sweats* 42 1.6 pruritus* 29 1.1 alopecia 10 0.4 capillaritis and vasculitis* 3 0.1 VASCULAR DISORDERS hypertension* 47 1.8 deep vein thrombosis* 17 0.7 *Represents a medical concept including several similar MedDRA PTs 1. Percentage of male population (N=2,038) 2. Percentage of female population (N=574) Laboratory Abnormalities in Adults The percentages of adult patients treated with combination therapy with Grade 3-4 laboratory abnormalities are presented in Table 9 (treatment-naïve patients) and Table 10 (treatment-experienced patients). Table 9. Grade 3-4 Laboratory Abnormalities Reported in ≥ 2% of Adult Antiretroviral-Naïve Patients Study 863 (48 Weeks) Study 720 (360 Weeks) Study 730 (48 Weeks) Variable Limit 1 Lopinavir And Ritonavir 400/100 mg Twice Daily + d4T +3TC (N = 326) Nelfinavir 750 mg Three Times Daily + d4T + 3TC (N = 327) Lopinavir And Ritonavir Twice Daily + d4T + 3TC (N = 100) Lopinavir And Ritonavir Once Daily + TDF +FTC (N=333) Lopinavir And Ritonavir Twice Daily + TDF +FTC (N=331) Chemistry High Glucose > 250 mg/dL 2% 2% 4% 0% <1% Uric Acid >12 mg/dL 2% 2% 5% <1% 1% SGOT/ AST 2 > 180 U/L 2% 4% 10% 1% 2% SGPT/ ALT 2 >215 U/L 4% 4% 11% 1% 1% GGT >300 U/L N/A N/A 10% N/A N/A Total Cholesterol >300 mg/dL 9% 5% 27% 4% 3% Triglycerides >750 mg/dL 9% 1% 29% 3% 6% Amylase >2 x ULN 3% 2% 4% N/A N/A Lipase >2 x ULN N/A N/A N/A 3% 5% Chemistry Low Calculated Creatinine Clearance <50 mL/min N/A N/A N/A 2% 2% Hematology Low Neutrophils <0.75 x 10 9 /L 1% 3% 5% 2% 1% 1 ULN = upper limit of the normal range; N/A = Not Applicable. 2 Criterion for Study 730 was >5x ULN (AST/ALT). Table 10. Grade 3-4 Laboratory Abnormalities Reported in ≥ 2% of Adult Protease Inhibitor-Experienced Patients Study 888 (48 Weeks) Study 957 2 and Study 765 3 (84-144 Weeks) Study 802 (48 Weeks) Variable Limit 1 Lopinavir And Ritonavir 400/100 mg Twice Daily + NVP + NRTIs (N = 148) Investigator-Selected Protease Inhibitor(s) + NVP + NRTIs (N = 140) Lopinavir And Ritonavir Twice Daily + NNRTI + NRTIs (N = 127) Lopinavir And Ritonavir 800/200 mg Once Daily +NRTIs (N=300) Lopinavir And Ritonavir 400/100 mg Twice Daily +NRTIs (N=299) Chemistry High Glucose >250 mg/dL 1% 2% 5% 2% 2% Total Bilirubin >3.48 mg/dL 1% 3% 1% 1% 1% SGOT/AST 4 >180 U/L 5% 11% 8% 3% 2% SGPT/ALT 4 >215 U/L 6% 13% 10% 2% 2% GGT >300 U/L N/A N/A 29% N/A N/A Total Cholesterol >300 mg/dL 20% 21% 39% 6% 7% Triglycerides >750 mg/dL 25% 21% 36% 5% 6% Amylase >2 x ULN 4% 8% 8% 4% 4% Lipase >2 x ULN N/A N/A N/A 4% 1% Creatine Phosphokinase >4 x ULN N/A N/A N/A 4% 5% Chemistry Low Calculated Creatinine Clearance <50 mL/min N/A N/A N/A 3% 3% Inorganic Phosphorus <1.5 mg/dL 1% 0% 2% 1% <1% Hematology Low Neutrophils <0.75 x 10 9 /L 1% 2% 4% 3% 4% Hemoglobin <80 g/L 1% 1% 1% 1% 2% 1 ULN = upper limit of the normal range; N/A = Not Applicable. 2 Includes clinical laboratory data from patients receiving 400/100 mg twice daily (n = 29) or 533/133 mg twice daily (n = 28) for 84 weeks. Patients received lopinavir and ritonavir in combination with NRTIs and efavirenz. 3 Includes clinical laboratory data from patients receiving 400/100 mg twice daily (n = 36) or 400/200 mg twice daily (n = 34) for 144 weeks. Patients received lopinavir and ritonavir in combination with NRTIs and nevirapine. 4 Criterion for Study 802 was >5x ULN (AST/ALT). Adverse Reactions in Pediatric Patients Lopinavir and ritonavir 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). Lopinavir and ritonavir 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). Lopinavir and ritonavir 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 lopinavir and ritonavir with Grade 3-4 laboratory abnormalities are presented in Table 11. Table 11. Grade 3-4 Laboratory Abnormalities Reported in ≥ 2% Pediatric Patients in Study 940 Variable Limit 1 Lopinavir and Ritonavir Twice Daily + RTIs (N = 100) Chemistry High Sodium > 149 mEq/L 3% Total Bilirubin ≥ 3.0 x ULN 3% SGOT/AST > 180 U/L 8% SGPT/ALT > 215 U/L 7% Total Cholesterol > 300 mg/dL 3% Amylase > 2.5 x ULN 7%2 Chemistry Low Sodium < 130 mEq/L 3% Hematology Low Platelet Count < 50 x 109/L 4% Neutrophils < 0.40 x 109/L 2% 1 ULN = upper limit of the normal range. 2 Subjects with Grade 3-4 amylase confirmed by elevations in pancreatic amylase. 6.2 Postmarketing Experience The following adverse reactions have been reported during postmarketing use of lopinavir and ritonavir. 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 lopinavir and ritonavir 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 )]. Renal and Urinary Disorders Nephrolithiasis Skin and Appendages Toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome and erythema multiforme.
التحذيرات والاحتياطات
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 ritonaviroral 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 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 lopinavir and ritonavir oral solution. 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. However, if the benefit of using Lopinavir and ritonavir 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 Lopinavir and ritonavir 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 lopinavir and ritonavir therapy, including those who developed marked triglyceride elevations. In some cases, fatalities have been observed. Although a causal relationship to lopinavir and ritonavir have 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 lopinavir and ritonavir 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 lopinavir and ritonavir 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 lopinavir and ritonavir. 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 lopinavir and ritonavir 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 lopinavir and ritonavir in conjunction with other antiretroviral agents. In some cases, the hepatic dysfunction was serious; however, a definitive causal relationship with lopinavir and ritonavir therapy has not been established. Appropriate laboratory testing should be conducted prior to initiating therapy with lopinavir and ritonavir 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 lopinavir and ritonavir 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 lopinavir and ritonavir 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. Lopinavir and ritonavir 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 lopinavir and ritonavir 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 lopinavir and ritonavir 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 lopinavir and ritonavir. 5.8 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including lopinavir and ritonavir. 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 lopinavir and ritonavir 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 lopinavir and ritonavir therapy and at periodic intervals during therapy. Lipid disorders should be managed as clinically appropriate, taking into account any potential drug-drug interactions with lopinavir and ritonavir 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 lopinavir and ritonavir -treated patients, it is unknown what effect therapy with lopinavir and ritonavir will have on the activity of subsequently administered protease inhibitors [see Microbiology ( 12.4 )].
الحرائك الدوائية
12.3 Pharmacokinetics The pharmacokinetic properties of lopinavir are summarized in Table 13. The steady-state pharmacokinetic parameters of lopinavir are summarized in Table 14. Under fed conditions, lopinavir concentrations were similar following administration of lopinavir and ritonavir tablets to capsules with less pharmacokinetic variability.Under fed conditions (500 kcal, 25% from fat), lopinavir concentrations were similar following administration of lopinavir and ritonavir capsules and oral solution. Table 13. Pharmacokinetic Properties of Lopinavir Absorption Tmax (hr)a 4.4 ± 0.8 Effect of meal (relative to fasting) Tablet Oral Solution ↑ 19%b Distribution % Bound to human plasma proteins > 98 Vd/Fa (L) 16.9 Metabolism Metabolism CYP3A Elimination Major route of elimination hepatic t1/2 (h)a 6.9 ± 2.2 % of dose excreted in urine 10.4 ± 2.3 % of dose excreted in feces 82.6 ± 2.5 a.Lopinavir and ritonavir tablet b. Changes in AUC values Table 14. Steady-State Pharmacokinetic Parameters of Lopinavir, Mean ± SD Pharmacokinetic Parameter Twice Daily a Once Daily b Cmax (µg/mL) 9.8 ± 3.7 11.8 ± 3.7 Cmin (µg/mL) 5.5 ± 2.7 1.7 ± 1.6 AUCtau (µg•h/mL) 92.6 ± 36.7 154.1 ± 61.4 a. 19 HIV-1 subjects, Lopinavir and ritonavir 400/100 mg twice daily b. 24 HIV-1 subjects, Lopinavir and ritonavir 800/200 mg + emtricitabine 200 mg + tenofovir DF 300 mg Specific Populations Gender, Race and Age No gender or race related pharmacokinetic differences have been observed in adult patients. Lopinavir pharmacokinetics have not been studied in elderly patients. Pediatric Patients The 230/57.5 mg/m2 twice daily regimen without nevirapine and the 300/75 mg/m2 twice daily regimen with nevirapine provided lopinavir plasma concentrations similar to those obtained in adult patients receiving the 400/100 mg twice daily regimen without nevirapine. Table 15. Lopinavir Pharmacokinetic Data from Pediatric Clinical Trials, Mean ± SD Cmax (μg/mL) Cmin (μg/mL) AUC12 (μg•hr/m ) Age ≥ 14 Days to < 6 Weeks Cohort (N = 9): 5.17 ± 1.84a 1.40 ± 0.48a 43.39 ± 14.80a Age ≥ 6 Weeks to < 6 Months Cohort (N = 18): 9.39 ± 4.91a 1.95 ± 1.80a 74.50 ± 37.87a Age ≥ 6 Months to ≤ 12 years Cohort (N = 24): 8.2 ± 2.9b 3.4 ± 2.1b 72.6 ± 31.1b 10.0 ± 3.3c 3.6 ± 3.5c 85.8 ± 36.9c Lopinavir and ritonavir oral solution300/75 mg/m2 twice daily without concomitant NNRTI therapy Lopinavir and ritonavir oral solution 230/57.5 mg/m2 twice daily without nevirapine (n=12) Lopinavir and ritonavir oral solution 300/75 mg/m2 twice daily with nevirapine (n=12) Pregnancy The C12h values of lopinavir were lower during the second and third trimester by approximately 40% as compared to post-partum in 12 HIV-infected pregnant women received lopinavir and ritonavir 400 mg/100 mg twice daily. Yet this decrease is not considered clinically relevant in patients with no documented lopinavir and ritonavir -associated resistance substitutions receiving 400 mg/100 mg twice daily [see Use in Specific Populations ( 8.1 )]. Renal Impairment Lopinavir pharmacokinetics have not been studied in patients with renal impairment; however, since the renal clearance of lopinavir is negligible, a decrease in total body clearance is not expected in patients with renal impairment. Hepatic Impairment Multiple dosing of lopinavir and ritonavir 400/100 mg twice daily to HIV-1 and HCV co-infected patients with mild to moderate hepatic impairment (n = 12) resulted in a 30% increase in lopinavir AUC and 20% increase in Cmax compared to HIV-1 infected subjects with normal hepatic function (n = 12). Additionally, the plasma protein binding of lopinavir was statistically significantly lower in both mild and moderate hepatic impairment compared to controls (99.09 vs. 99.31%, respectively). Lopinavir and ritonavir has not been studied in patients with severe hepatic impairment [see Warnings and Precautions ( 5.4 ) and Use in Specific Populations ( 8.6) ]. Drug Interactions Lopinavir and ritonavir is an inhibitor of the P450 isoform CYP3A in vitro. Lopinavir and ritonavir does not inhibit CYP2D6, CYP2C9, CYP2C19, CYP2E1, CYP2B6 or CYP1A2 at clinically relevant concentrations. Lopinavir and ritonavir has been shown in vivo to induce its own metabolism and to increase the biotransformation of some drugs metabolized by cytochrome P450 enzymes and by glucuronidation. The effects of co-administration of lopinavir and ritonavir on the AUC, Cmax and Cmin are summarized in Table 16 (effect of other drugs on lopinavir) and Table 17 (effect of lopinavir and ritonavir on other drugs). For information regarding clinical recommendations, see Table 12 in Drug Interactions ( 7 ). Table 16. Drug Interactions: Pharmacokinetic Parameters for Lopinavir in the Presence of the Co-administered Drug for Recommended Alterations in Dose or Regimen Co- administered Drug Dose of Co- administered Drug (mg) Dose of Lopinavir and Ritonavir (mg) n Ratio (in combination with Co-administered drug/alone) of Lopinavir Pharmacokinetic Parameters (90% CI); No Effect = 1.00 Cmax AUC Cmin Efavirenz1 600 at bedtime 400/100 capsule twice daily 11, 73 0.97 (0.78, 1.22) 0.81 (0.64, 1.03) 0.61 (0.38, 0.97) 600 at bedtime 500/125 tablet twice daily 19 1.12 (1.02, 1.23) 1.06 (0.96, 1.17) 0.90 (0.78, 1.04) 600 at bedtime 600/150 tablet twice daily 23 1.36 (1.28, 1.44) 1.36 (1.28, 1.44) 1.32 (1.21, 1.44) Etravirine 200 twice daily 400/100 mg twice day (tablets) 16 0.89 (0.82-0.96) 0.87 (0.83-0.92) 0.80 (0.73-0.88) Fosamprenavir2 700 twice daily plus ritonavir 100 twice daily 400/100 capsule twice daily 18 1.30 (0.85, 1.47) 1.37 (0.80, 1.55) 1.52 (0.72, 1.82) Ketoconazole 200 single dose 400/100 capsule twice daily 12 0.89 (0.80, 0.99) 0.87 (0.75, 1.00) 0.75 (0.55, 1.00) Nelfinavir 1000 twice daily 400/100 capsule twice daily 13 0.79 (0.70, 0.89) 0.73 (0.63, 0.85) 0.62 (0.49, 0.78) Nevirapine 200 twice daily steady-state 400/100 capsule twice daily 22, 193 0.81 (0.62, 1.05) 0.73 (0.53, 0.98) 0.49 (0.28, 0.74) 7 mg/kg or 4 mg/kg once daily; twice daily 1 wk5 (> 1 yr) 300/ 75 mg/m2 oral solution twice daily 12, 153 0.86 (0.64, 1.16) 0.78 (0.56, 1.09) 0.45 (0.25, 0.81) Ombitasvir/ paritaprevir/ ritonavir+ dasabuvir2 25/150/100 + dasabuvir 400 400/100 tablet twice daily 6 0.87 (0.76, 0.99) 0.94 (0.81, 1.10) 1.15 (0.93, 1.42) Omeprazole 40 once daily, 5 d 400/100 tablet twice daily, 10 d 12 1.08 (0.99, 1.17) 1.07 (0.99, 1.15) 1.03 (0.90, 1.18) 40 once daily, 5 d 800/200 tablet once daily, 10 d 12 0.94 (0.88, 1.00) 0.92 (0.86, 0.99) 0.71 (0.57, 0.89) Pravastatin 20 once daily, 4 d 400/100 capsule twice daily, 14 d 12 0.98 (0.89, 1.08) 0.95 (0.85, 1.05) 0.88 (0.77, 1.02) Ranitidine 150 single dose 400/100 tablet twice daily, 10 d 12 0.99 (0.95, 1.03) 0.97 (0.93, 1.01) 0.90 (0.85, 0.95) 150 single dose 800/200 tablet once daily, 10 d 10 0.97 (0.95, 1.00) 0.95 (0.91, 0.99) 0.82 (0.74, 0.91) Rifabutin 150 once daily 400/100 capsule twice daily 14 1.08 (0.97, 1.19) 1.17 (1.04, 1.31) 1.20 (0.96, 1.65) Rifampin 600 once daily 400/100 capsule twice daily 22 0.45 (0.40, 0.51) 0.25 (0.21, 0.29) 0.01 (0.01, 0.02) 600 once daily 800/200 capsule twice daily 10 1.02 (0.85, 1.23) 0.84 (0.64, 1.10) 0.43 (0.19, 0.96) 600 once daily 400/400 capsule twice daily 9 0.93 (0.81, 1.07) 0.98 (0.81, 1.17) 1.03 (0.68, 1.56) Rilpivirine 150 once daily 400/100 twice daily (capsules) 15 0.96 (0.88-1.05) 0.99 (0.89-1.10) 0.89 (0.73-1.08) Ritonavir 100 twice daily 400/100 capsule twice daily 8, 213 1.28 (0.94, 1.76) 1.46 (1.04, 2.06) 2.16 (1.29, 3.62) Tipranavir/ ritonavir 500/200 twice daily 400/100 capsule twice daily 21 693 0.53 (0.40, 0.69) 0.45 (0.32, 0.63) 0.30 (0.17, 0.51) 0.484 (0.40, 0.58) 1 Reference for comparison is lopinavir/ritonavir 400/100 mg twice daily without efavirenz. 2 Data extracted from the U.S. prescribing information of co-administered drugs. 3 Parallel group design 4 Drug levels obtained at 8-16 hours post dose N/A = Not available. Table 17. Drug Interactions: Pharmacokinetic Parameters for Co-administered Drug in the Presence of Lopinavir And Ritonavir for Recommended Alterations in Dose or Regimen Co- administered Drug Dose of Co- administered Drug (mg) Dose of Lopinavir and Ritonavir (mg) n Ratio (in combination with Lpinavir and Ritonavir /alone) of Co- administered Drug Pharmacokinetic Parameters (90% CI); No Effect = 1.00 Cmax AUC Cmin Bedaquiline1 400 single dose 400/100 twice daily N/A N/A 1.22 (1.11, 1.34) N/A Efavirenz 600 at bedtime 400/100 capsule twice daily 11, 123 0.91 (0.72, 1.15) 0.84 (0.62, 1.15) 0.84 (0.58, 1.20) Elbasvir/ grazoprevir1 50 once daily 400/100 twice daily 10 2.87 (2.29, 3.58) 3.71 (3.05, 4.53) 4.58 (3.72, 5.64) 200 once daily 13 7.31 (5.65, 9.45) 12.86 (10.25, 16.13) 21.70 (12.99, 36.25) Ethinyl Estradiol 35 µg once daily (Ortho Novum®) 400/100 capsule twice daily 12 0.59 (0.52, 0.66) 0.58 (0.54, 0.62) 0.42 (0.36, 0.49) Etravirine 200 twice daily 400/100 tablet twice day 16 0.70 (0.64-0.78) 0.65 (0.59-0.71) 0.55 (0.49-0.62) Fosamprenavir1 700 twice daily plus ritonavir 100 twice daily 400/100 capsule twice daily 18 0.42 (0.30, 0.58) 0.37 (0.28, 0.49) 0.35 (0.27, 0.46) Indinavir 600 twice daily combo nonfasting vs. 800 three times daily alone fasting 400/100 capsule twice daily 13 0.71 (0.63, 0.81) 0.91 (0.75, 1.10) 3.47 (2.60, 4.64) Ketoconazole 200 single dose 400/100 capsule twice daily 12 1.13 (0.91, 1.40) 3.04 (2.44, 3.79) N/A Maraviroc1 300 twice daily 400/100 twice daily 11 1.97 (1.66, 2.34) 3.95 (3.43, 4.56) 9.24 (7.98, 10.7) Methadone 5 single dose 400/100 capsule twice daily 11 0.55 (0.48, 0.64) 0.47 (0.42, 0.53) N/A Nelfinavir 1000 twice daily combo vs. 1250 twice daily alone 400/100 capsule twice daily 13 0.93 (0.82, 1.05) 1.07 (0.95, 1.19) 1.86 (1.57, 2.22) M8 metabolite 2.36 (1.91, 2.91) 3.46 (2.78, 4.31) 7.49 (5.85, 9.58) Nevirapine 200 once daily twice daily 400/100 capsule twice daily 5, 63 1.05 (0.72, 1.52) 1.08 (0.72, 1.64) 1.15 (0.71, 1.86) Norethindrone 1 once daily (Ortho Novum®) 400/100 capsule twice daily 12 0.84 (0.75, 0.94) 0.83 (0.73, 0.94) 0.68 (0.54, 0.85) Ombitasvir/ paritaprevir/ ritonavir+ dasabuvir1 25/150/100 + dasabuvir 400 400/100 tablet twice daily 6 1.14 (1.01, 1.28) 1.17 (1.07, 1.28) 1.24 (1.14, 1.34) 2.04 (1.30, 3.20) 2.17 (1.63, 2.89) 2.36 (1.00, 5.55) 1.55 (1.16, 2.09) 2.05 (1.49, 2.81) 5.25 (3.33, 8.28) 0.99 (0.75, 1.31) 0.93 (0.75, 1.15) 0.68 (0.57, 0.80) Pitavastatin1 4 once daily 400/100 tablet twice daily 23 0.96 (0.84-1.10) 0.80 (0.73-0.87) N/A Pravastatin 20 once daily 400/100 capsule twice daily 12 1.26 (0.87, 1.83) 1.33 (0.91, 1.94) N/A Rifabutin 150 once daily combo vs. 300 once daily alone 400/100 capsule twice daily 12 2.12 (1.89, 2.38) 3.03 (2.79, 3.30) 4.90 (3.18, 5.76) 25- O -desacetyl rifabutin 23.6 (13.7, 25.3) 47.5 (29.3, 51.8) 94.9 (74.0, 122) Rifabutin + 25- O -desacetyl rifabutin 3.46 (3.07, 3.91) 5.73 (5.08, 6.46) 9.53 (7.56, 12.01) Rilpivirine 150 once daily 400/100 capsules twice daily 15 1.29 (1.18-1.40) 1.52 (1.36-1.70) 1.74 (1.46-2.08) Rosuvastatin2 20 once daily 400/100 tablet twice daily 15 4.66 (3.4, 6.4) 2.08 (1.66, 2.6) 1.04 (0.9, 1.2) Tenofovir alafenamide1 10 once daily 800/200 tablet once daily 10 2.19 (1.72, 2.79) 1.47 (1.17, 1.85) N/A Tenofovir disoproxil fumarate1 300 once daily 400/100 capsule twice daily 24 No Change 1.32 (1.26, 1.38) 1.51 (1.32, 1.66) 1 Data extracted from the U.S. prescribing information of co-administered drugs. 2 Kiser, et al. J Acquir Immune Defic Syndr. 2008 Apr 15; 47(5):570-8. 3 Parallel group design N/A = Not available.