Human experience of acute overdosage with KALETRA is limited. Treatment of overdose with KALETRA should consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. There is no specific antidote for overdose with KALETRA. If indicated, elimination of unabsorbed drug should be achieved by emesis or gastric lavage. Administration of activated charcoal may also be used to aid in removal of unabsorbed drug. Since KALETRA is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the drug.
Table 1: Drugs That are Contraindicated with KALETRA
| Drug Class | Drugs within Class That are Contraindicated with KALETRA | Clinical Comments |
| Alpha 1- Adrenoreceptor Antagonist | Alfuzosin | Potentially increased alfuzosin concentrations can result in hypotension. |
| Antimycobacterial | Rifampin | May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents. |
| Antipsychotics | Lurasidone Pimozide |
Potential for serious and/or life-threatening reactions. Potential for cardiac arrhythmias. |
| Ergot Derivatives | Dihydroergotamine, ergotamine, methylergonovine | Potential for acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues. |
| GI Motility Agent | Cisapride | Potential for cardiac arrhythmias. |
| Herbal Products | St. John's Wort (hypericum perforatum) | May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors. |
| HMG-CoA Reductase Inhibitors | Lovastatin, simvastatin | Potential for myopathy including rhabdomyolysis. |
| PDE5 Enzyme Inhibitor | Sildenafila (Revatio®) when used for the treatment of pulmonary arterial hypertension | A safe and effective dose has not been established when used with KALETRA. There is an increased potential for sildenafil-associated adverse events, including visual abnormalities, hypotension, prolonged erection, and syncope. |
| Sedative/Hypnotics | Triazolam; orally administered midazolamb | Prolonged or increased sedation or respiratory depression. |
| a see DRUG INTERACTIONS, Table 6 for
co-administration of sildenafil in patients with erectile dysfunction. b see DRUG INTERACTIONS, Table 6 for parenterally administered midazolam. |
The following adverse reactions are discussed in greater detail in other sections of the labeling.
Because clinical trials are conducted under widely varying conditions, adverse reaction 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 AdultsThe safety of KALETRA has been investigated in about 2,600 patients in Phase II-IV clinical trials, of which about 700 have received a dose of 800/200 mg (6 capsules or 4 tablets) once daily. Along with nucleoside reverse transcriptase inhibitors (NRTIs), in some studies, KALETRA was used in combination with efavirenz or nevirapine.
In clinical studies the incidence of diarrhea in patients treated with either KALETRA capsules or tablets was greater in those patients treated once daily than in those patients treated twice daily. Any grade of diarrhea was reported by at least half of patients taking once daily Kaletra capsules or tablets. At the time of treatment discontinuation, 4.2-6.3% of patients taking once daily Kaletra and 1.8-3.7% of those taking twice daily Kaletra reported ongoing diarrhea.
Commonly reported adverse reactions to KALETRA included diarrhea, nausea, vomiting, hypertriglyceridemia and hypercholesterolemia. Diarrhea, nausea and vomiting may occur at the beginning of the treatment while hypertriglyceridemia and hypercholesterolemia may occur later. The following have been identified as adverse reactions of moderate or severe intensity (Table 2):
Table 2: Treatment-Emergent Adverse Reactions of
Moderate or Severe Intensity Occurring in at Least 0.1% of Adult Patients
Receiving KALETRA 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 |
| lymphadenop athy * | 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 | 0.81 |
| 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 | ||
| hypercholesterol emia* | 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 | 1.71 |
| menstrual disorders - amenorrhea, menorrhagia* | 10 | 1.72 |
| 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) |
||
The percentages of adult patients treated with combination therapy with Grade 3-4 laboratory abnormalities are presented in Table 3 (treatment-naïve patients) and Table 4 (treatmentexperienced patients).
Table 3: Grade 3-4 Laboratory Abnormalities Reported
in greater than or equal to 2% of Adult Antiretroviral-Naïve Patients
| Variable | Limit1 | Study 863 (48 Weeks) | Study 720 (360 Weeks) | Study 418 (48 weeks) | Study 730 (48 Weeks) | |||
| KALETRA 400/100 mg Twice Daily + d4T +3TC (N = 326) |
Nelfinavir 750 mg Three Times Daily + d4T + 3TC (N = 327) |
KALETRA Twice Daily + d4T + 3TC (N = 100) |
KALETRA 800/200 mg Once Daily + TDF + FTC (N=115) |
KALETRA 400/100 mg Twice Daily + TDF + FTC (N=75) |
KALETRA Once Daily + TDF +FTC (N=333) |
KALETRA Twice Daily + TDF +FTC (N=331) |
||
| Chemistry | High | |||||||
| Glucose | > 250 mg/dL | 2% | 2% | 4% | 3% | 1% | 0% | < 1% |
| Uric Acid | > 12 mg/dL | 2% | 2% | 5% | 0% | 3% | < 1% | 1% |
| SGOT/ AST2 | > 180 U/L | 2% | 4% | 10% | 5% | 3% | 1% | 2% |
| SGPT/ ALT2 | > 215U/L | 4% | 4% | 11% | 4% | 3% | 1% | 1% |
| GGT | > 300 U/L | N/A | N/A | 10% | N/A | N/A | N/A | N/A |
| Total Cholesterol | > 300 mg/dL | 9% | 5% | 27% | 3% | 3% | 4% | 3% |
| Triglycerid es | > 750 mg/dL | 9% | 1% | 29% | 5% | 4% | 3% | 6% |
| Amylase | > 2 x ULN | 3% | 2% | 4% | 7% | 5% | N/A | N/A |
| Lipase | > 2 x ULN | N/A | N/A | N/A | N/A | N/A | 3% | 5% |
| Chemistry | Low | |||||||
| Calculated Creatinine Clearance | < 50 mL/min | N/A | N/A | N/A | N/A | N/A | 2% | 2% |
| Hematology | Low | |||||||
| Neutrophils | < 0.75 x 109/L | 1% | 3% | 5% | 5% | 1% | 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 4: Grade 3-4 Laboratory Abnormalities Reported
in greater than or equal to 2% of Adult Protease Inhibitor-Experienced Patients
| Variable | Limit1 | Study 888 (48 Weeks) | Study 9572 and Study 7653 (84-144 Weeks) | Study 802 (48 Weeks) | ||
| KALETRA 400/100 mg Twice Daily + NVP + NRTIs (N = 148) |
Investigator-Selected Protease Inhibitor(s) + NVP + NRTIs (N = 140) |
KALETRA Twice Daily + NNRTI + NRTIs (N = 127) |
KALETRA 800/200 mg Once Daily +NRTIs (N=300) |
KALETRA 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/AST4 | > 180 U/L | 5% | 11% | 8% | 3% | 2% |
| SGPT/ALT4 | > 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 109/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 KALETRA 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 KALETRA in combination with NRTIs and nevirapine. 4 Criterion for Study 802 was > 5x ULN (AST/ALT). |
KALETRA oral solution dosed up to 300/75 mg per m² has been studied in 100 pediatric patients 6 months to 12 years of age. The adverse reaction profile seen during Study 940 was similar to that for adult patients.
Dysgeusia (22%), vomiting (21%), and diarrhea (12%) were the most common adverse reactions of any severity reported in pediatric patients treated with combination therapy for up to 48 weeks in Study 940. A total of 8 patients experienced adverse reactions of moderate to severe intensity. The adverse reactions meeting these criteria and reported for the 8 subjects include: hypersensitivity (characterized by fever, rash and jaundice), pyrexia, viral infection, constipation, hepatomegaly, pancreatitis, vomiting, alanine aminotransferase increased, dry skin, rash, and dysgeusia. Rash was the only event of those listed that occurred in 2 or more subjects (N = 3).
KALETRA oral solution and soft gelatin capsules dosed at higher than recommended doses including 400/100 mg per m² (without concomitant NNRTI) and 480/120 mg per 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 PatientsThe percentages of pediatric patients treated with combination therapy including KALETRA with Grade 3-4 laboratory abnormalities are presented in Table 5.
Table 5: Grade 3-4 Laboratory Abnormalities Reported
in greater than or equal to 2% Pediatric Patients in Study 940
| Variable | Limit1 | KALETRA Twice Daily + RTIs (N = 100) |
| Chemistry | High | |
| Sodium | > 149 mEq/L | 3% |
| Total Bilirubin | ≥ 3.0 x ULN | 3% |
| SGOT/AST | > 180U/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. |
The following adverse reactions have been reported during postmarketing use of KALETRA. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to KALETRA exposure.
Body as a WholeRedistribution/accumulation of body fat has been reported .
CardiovascularBradyarrhythmias. First-degree AV block, second-degree AV block, third-degree AV block, QTc interval prolongation, torsades (torsade) de pointes.
Skin and AppendagesToxic epidermal necrolysis (TEN), Stevens-Johnson syndrome and erythema multiforme.
KALETRA is indicated in combination with other antiretroviral agents for the treatment of HIV1 infection in adults and pediatric patients (14 days and older).
The following points should be considered when initiating therapy with KALETRA:
The pharmacokinetic properties of lopinavir co-administered with ritonavir have been evaluated in healthy adult volunteers and in HIV-1 infected patients; no substantial differences were observed between the two groups. Lopinavir is essentially completely metabolized by CYP3A. Ritonavir inhibits the metabolism of lopinavir, thereby increasing the plasma levels of lopinavir. Across studies, administration of KALETRA 400/100 mg twice daily yields mean steady-state lopinavir plasma concentrations 15-to 20-fold higher than those of ritonavir in HIV-1 infected patients. The plasma levels of ritonavir are less than 7% of those obtained after the ritonavir dose of 600 mg twice daily. The in vitro antiviral EC50 of lopinavir is approximately 10-fold lower than that of ritonavir. Therefore, the antiviral activity of KALETRA is due to lopinavir.
Figure 1 displays the mean steady-state plasma concentrations of lopinavir and ritonavir after KALETRA 400/100 mg twice daily with food for 3 weeks from a pharmacokinetic study in HIV-1 infected adult subjects (n = 19).
Figure 1: Mean Steady-State Plasma Concentrations with
95% Confidence Intervals (CI) for HIV-1 Infected Adult Subjects (N = 19)
In a pharmacokinetic study in HIV-1 positive subjects (n = 19), multiple dosing with 400/100 mg KALETRA twice daily with food for 3 weeks produced a mean ± SD lopinavir peak plasma concentration (Cmax ) of 9.8 ± 3.7 μg per mL, occurring approximately 4 hours after administration. The mean steady-state trough concentration prior to the morning dose was 7.1 ± 2.9 μg per mL and minimum concentration within a dosing interval was 5.5 ± 2.7 μg per mL. Lopinavir AUC over a 12 hour dosing interval averaged 92.6 ± 36.7 μg•h per mL. The absolute bioavailability of lopinavir co-formulated with ritonavir in humans has not been established. Under nonfasting conditions (500 kcal, 25% from fat), lopinavir concentrations were similar following administration of KALETRA co-formulated capsules and oral solution. When administered under fasting conditions, both the mean AUC and Cmax of lopinavir were 22% lower for the KALETRA oral solution relative to the capsule formulation.
Effects of Food on Oral Absorption
Administration of a single 400/100 mg dose of KALETRA capsules with a moderate fat meal (500-682 kcal, 23 to 25% calories from fat) was associated with a mean increase of 48 and 23% in lopinavir AUC and Cmax , respectively, relative to fasting. Relative to fasting, administration of KALETRA capsules with a high fat meal (872 kcal, 56% from fat) increased lopinavir AUC and Cmax by 97 and 43%, respectively. To enhance bioavailability and minimize pharmacokinetic variability KALETRA capsules should be taken with food.
DistributionAt steady state, lopinavir is approximately 98-99% bound to plasma proteins. Lopinavir binds to both alpha-1-acid glycoprotein (AAG) and albumin; however, it has a higher affinity for AAG. At steady state, lopinavir protein binding remains constant over the range of observed concentrations after 400/100 mg KALETRA twice daily, and is similar between healthy volunteers and HIV-1 positive patients.
MetabolismIn vitro experiments with human hepatic microsomes indicate that lopinavir primarily undergoes oxidative metabolism. Lopinavir is extensively metabolized by the hepatic cytochrome P450 system, almost exclusively by the CYP3A isozyme. Ritonavir is a potent CYP3A inhibitor which inhibits the metabolism of lopinavir, and therefore increases plasma levels of lopinavir. A 14Clopinavir study in humans showed that 89% of the plasma radioactivity after a single 400/100 mg KALETRA dose was due to parent drug. At least 13 lopinavir oxidative metabolites have been identified in man. Ritonavir has been shown to induce metabolic enzymes, resulting in the induction of its own metabolism. Pre-dose lopinavir concentrations decline with time during multiple dosing, stabilizing after approximately 10 to 16 days.
EliminationFollowing a 400/100 mg 14C-lopinavir/ritonavir dose, approximately 10.4 ± 2.3% and 82.6 ± 2.5% of an administered dose of 14C-lopinavir can be accounted for in urine and feces, respectively, after 8 days. Unchanged lopinavir accounted for approximately 2.2 and 19.8% of the administered dose in urine and feces, respectively. After multiple dosing, less than 3% of the lopinavir dose is excreted unchanged in the urine. The apparent oral clearance (CL/F) of lopinavir is 5.98 ± 5.75 L per hr (mean ± SD, n = 19).
Once Daily DosingThe pharmacokinetics of once daily KALETRA have been evaluated in HIV-1 infected subjects naïve to antiretroviral treatment. KALETRA 800/200 mg was administered in combination with emtricitabine 200 mg and tenofovir DF 300 mg as part of a once daily regimen. Multiple dosing of 800/200 mg KALETRA once daily for 4 weeks with food (n = 24) produced a mean ± SD lopinavir peak plasma concentration (Cmax ) of 11.8 ± 3.7 μg per mL, occurring approximately 6 hours after administration. The mean steady-state lopinavir trough concentration prior to the morning dose was 3.2 ± 2.1 μg per mL and minimum concentration within a dosing interval was 1.7 ± 1.6 μg per mL. Lopinavir AUC over a 24 hour dosing interval averaged 154.1 ± 61.4 μg•h per mL.
The pharmacokinetics of once daily KALETRA has also been evaluated in treatment experienced HIV-1 infected subjects. Lopinavir exposure (Cmax , AUC [0-24h] , Ctrough ) with once daily KALETRA administration in treatment experienced subjects is comparable to the once daily lopinavir exposure in treatment naïve subjects.
Effects On ElectrocardiogramQTcF interval was evaluated in a randomized, placebo and active (moxifloxacin 400 mg once daily) controlled crossover study in 39 healthy adults, with 10 measurements over 12 hours on Day 3. The maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline-correction were 5.3 (8.1) and 15.2 (18.0) mseconds (msec) for 400/100 mg twice daily and supratherapeutic 800/200 mg twice daily KALETRA, respectively. KALETRA 800/200 mg twice daily resulted in a Day 3 mean Cmax approximately 2-fold higher than the mean Cmax observed with the approved once daily and twice daily KALETRA doses at steady state.
PR interval prolongation was also noted in subjects receiving KALETRA in the same study on Day 3. The maximum mean (95% upper confidence bound) difference from placebo in the PR interval after baseline-correction were 24.9 (21.5, 28.3) and 31.9 (28.5, 35.3) msec for 400/100 mg twice daily and supratherapeutic 800/200 mg twice daily KALETRA, respectively.
Antiretroviral Pregnancy Registry
To monitor maternal-fetal outcomes of pregnant women exposed to KALETRA, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.
Human Data
There are no adequate and well-controlled studies in pregnant women. KALETRA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Antiretroviral Pregnancy Registry: As of January 2011, the Antiretroviral Pregnancy Registry (APR) has received prospective reports of 2458 exposures to lopinavir containing regimens (738 exposed in the first trimester and 1720 exposed in the second and third trimester). Birth defects occurred in 16 of the 738 (2.2%) live births (first trimester exposure) and 41 of the 1720 (2.4%) live births (second/third trimester exposure). Among pregnant women in the U.S. reference population, the background rate of birth defects is 2.7%. There was no association between lopinavir and overall birth defects observed in the APR.
Animal Data
No treatment-related malformations were observed when lopinavir in combination with ritonavir was administered to pregnant rats or rabbits. Embryonic and fetal developmental toxicities (early resorption, decreased fetal viability, decreased fetal body weight, increased incidence of skeletal variations and skeletal ossification delays) occurred in rats at a maternally toxic dosage. Based on AUC measurements, the drug exposures in rats at the toxic doses were approximately 0.7-fold for lopinavir and 1.8-fold for ritonavir for males and females that of the exposures in humans at the recommended therapeutic dose (400/100 mg twice daily). In a peri-and postnatal study in rats, a developmental toxicity (a decrease in survival in pups between birth and postnatal Day 21) occurred.
No embryonic and fetal developmental toxicities were observed in rabbits at a maternally toxic dosage. Based on AUC measurements, the drug exposures in rabbits at the toxic doses were approximately 0.6-fold for lopinavir and 1.0-fold for ritonavir that of the exposures in humans at the recommended therapeutic dose (400/100 mg twice daily).
KALETRA (lopinavir/ritonavir) capsules are orange soft gelatin capsules imprinted with the “a” logo and the code PK. KALETRA is available as 133.3 mg lopinavir/33.3 mg ritonavir capsules.
Storage And HandlingKALETRA (lopinavir/ritonavir) capsules are orange soft gelatin capsules imprinted with the “a” logo and the code PK. KALETRA is available as 133.3 mg lopinavir/33.3 mg ritonavir capsules in the following package sizes:
Bottles of 180 capsules each....................(NDC 0074-3959-77)
Recommended storage: Store KALETRA soft gelatin capsules at 36 -46°F (2 -8°C) until dispensed. Avoid exposure to excessive heat. For patient use, refrigerated KALETRA capsules remain stable until the expiration date printed on the label. If stored at room temperature up to 77°F (25°C), capsules should be used within 2 months.
AbbVie Inc., North Chicago, IL 60064 USA. Revised: Sep 2016
Included as part of the PRECAUTIONS section.
PRECAUTIONS Risk Of Serious Adverse Reactions Due To Drug InteractionsInitiation 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:
See Table 6 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. 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.
PancreatitisPancreatitis has been observed in patients receiving KALETRA therapy, including those who developed marked triglyceride elevations. In some cases, fatalities have been observed. Although a causal relationship to KALETRA has not been established, marked triglyceride elevations are a risk factor for development of pancreatitis. Patients with advanced HIV-1 disease may be at increased risk of elevated triglycerides and pancreatitis, and patients with a history of pancreatitis may be at increased risk for recurrence during KALETRA therapy.
Pancreatitis should be considered if clinical symptoms (nausea, vomiting, abdominal pain) or abnormalities in laboratory values (such as increased serum lipase or amylase values) suggestive of pancreatitis occur. Patients who exhibit these signs or symptoms should be evaluated and KALETRA and/or other antiretroviral therapy should be suspended as clinically appropriate.
HepatotoxicityPatients 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.
QT Interval ProlongationPostmarketing 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.
PR Interval ProlongationLopinavir/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.
Diabetes Mellitus/HyperglycemiaNew 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.
Immune Reconstitution SyndromeImmune 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.
Lipid ElevationsTreatment with KALETRA has resulted in large increases in the concentration of total cholesterol and triglycerides. Triglyceride and cholesterol testing should be performed prior to initiating KALETRA therapy and at periodic intervals during therapy. Lipid disorders should be managed as clinically appropriate, taking into account any potential drug-drug interactions with KALETRA and HMG-CoA reductase inhibitors.
Fat RedistributionRedistribution/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.
Patients With HemophiliaIncreased bleeding, including spontaneous skin hematomas and hemarthrosis have been reported in patients with hemophilia type A and B treated with protease inhibitors. In some patients additional factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced. A causal relationship between protease inhibitor therapy and these events has not been established.
Resistance/Cross-resistanceBecause the potential for HIV-1 cross-resistance among protease inhibitors has not been fully explored in treatment-naïve patients, it is unknown what effect therapy with KALETRA will have on the activity of subsequently administered protease inhibitors.
Patient Counseling InformationAdvise the patient to read the FDA-approved patient labeling (Medication Guide)
Patients or parents of patients should be informed that:
General InformationLopinavir/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.
MutagenesisNeither 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 FertilityLopinavir 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 per kg per 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).
Use In Specific Populations Pregnancy Pregnancy Category CAntiretroviral Pregnancy Registry
To monitor maternal-fetal outcomes of pregnant women exposed to KALETRA, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.
Human Data
There are no adequate and well-controlled studies in pregnant women. KALETRA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Antiretroviral Pregnancy Registry: As of January 2011, the Antiretroviral Pregnancy Registry (APR) has received prospective reports of 2458 exposures to lopinavir containing regimens (738 exposed in the first trimester and 1720 exposed in the second and third trimester). Birth defects occurred in 16 of the 738 (2.2%) live births (first trimester exposure) and 41 of the 1720 (2.4%) live births (second/third trimester exposure). Among pregnant women in the U.S. reference population, the background rate of birth defects is 2.7%. There was no association between lopinavir and overall birth defects observed in the APR.
Animal Data
No treatment-related malformations were observed when lopinavir in combination with ritonavir was administered to pregnant rats or rabbits. Embryonic and fetal developmental toxicities (early resorption, decreased fetal viability, decreased fetal body weight, increased incidence of skeletal variations and skeletal ossification delays) occurred in rats at a maternally toxic dosage. Based on AUC measurements, the drug exposures in rats at the toxic doses were approximately 0.7-fold for lopinavir and 1.8-fold for ritonavir for males and females that of the exposures in humans at the recommended therapeutic dose (400/100 mg twice daily). In a peri-and postnatal study in rats, a developmental toxicity (a decrease in survival in pups between birth and postnatal Day 21) occurred.
No embryonic and fetal developmental toxicities were observed in rabbits at a maternally toxic dosage. Based on AUC measurements, the drug exposures in rabbits at the toxic doses were approximately 0.6-fold for lopinavir and 1.0-fold for ritonavir that of the exposures in humans at the recommended therapeutic dose (400/100 mg twice daily).
Nursing MothersThe Centers for Disease Control and Prevention recommend that HIV-1 infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1. Studies in rats have demonstrated that lopinavir is secreted in milk. It is not known whether lopinavir is secreted in human milk. Because of both the potential for HIV-1 transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving KALETRA.
Pediatric UseThe 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. The KALETRA Oral Solution full prescribing information should be consulted for information for young children who cannot swallow KALETRA Capsules.
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 per mL and ritonavir 20 mg per mL at a dose of 300/75 mg per m² twice daily plus two NRTIs in HIV-infected infants at least 14 days and less than 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 HIV1 RNA less than 400 copies per mL at Week 24.
Safety and efficacy in pediatric patients 6 months of age and older 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 per mL and ritonavir 20 mg per 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 per m² oral solution twice daily regimen without nevirapine and the 300/75 mg per m² oral solution twice daily regimen with nevirapine provided lopinavir plasma concentrations similar to those obtained in adult patients receiving the 400/100 mg twice daily regimen (without nevirapine).
A prospective multicenter, open-label trial evaluated the pharmacokinetic profile, tolerability, safety and efficacy of high-dose KALETRA with or without concurrent NNRTI therapy (Group 1: 400/100 mg per m² twice daily plus 2 or more NRTIs; Group 2: 480/120 mg per m² twice daily plus 1 or more NRTIs plus 1 NNRTI) in 26 children and adolescents at least 2 years to less than 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 less than 400 copies per mL at Week 48. CD4+ cell count increases were noted in the eight patients who remained on treatment for 48 weeks.
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.
Geriatric UseClinical studies of KALETRA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, appropriate caution should be exercised in the administration and monitoring of KALETRA in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Hepatic ImpairmentKALETRA 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.
KALETRA capsules must be taken with food.
Adult PatientsOnce daily administration of KALETRA is not recommended for adult patients with three or more of the following lopinavir resistance-associated substitutions: L10F/I/R/V, K20M/N/R, L24I, L33F, M36I, I47V, G48V, I54L/T/V, V82A/C/F/S/T, and I84V.
KALETRA should not be administered once daily in combination with carbamazepine, phenobarbital, or phenytoin.
Concomitant Therapy: Efavirenz, Nevirapine, Or NelfinavirKALETRA capsules should not be administered as a once-daily regimen in combination with efavirenz, nevirapine, or nelfinavir.
KALETRA capsules should not be administered once daily in pediatric patients less than 18 years of age.
For children less than 12 years of age who weigh greater than 40 kg or for children greater than 12 years of age, the maximum dose of 400/100 mg twice daily (given as three 133/33 mg capsules twice daily taken with food) is recommended.
The use of KALETRA oral solution is recommended for children 14 days to 12 years of age who weigh less than 40 kg and in those children who cannot swallow capsules. Please refer to the KALETRA oral solution full prescribing information for pediatric dosage and administration and other important information for these children.
Concomitant Therapy: Efavirenz, Nevirapine, Or NelfinavirA dose increase is recommended for all pediatric patients who use KALETRA capsules. For children weighing more than 45 kg, the recommended dose of KALETRA capsules is 533/133 mg twice daily (given as four 133/33 mg capsules twice daily taken with food) when used in combination with efavirenz, nevirapine, or nelfinavir.
KALETRA is an inhibitor of the P450 isoform CYP3A in vitro. Co-administration of KALETRA and drugs primarily metabolized by CYP3A may result in increased plasma concentrations of the other drug, which could increase or prolong its therapeutic and adverse effects.
KALETRA does not inhibit CYP2D6, CYP2C9, CYP2C19, CYP2E1, CYP2B6 or CYP1A2 at clinically relevant concentrations.
KALETRA has been shown in vivo to induce its own metabolism and to increase the biotransformation of some drugs metabolized by cytochrome P450 enzymes and by glucuronidation.
KALETRA is metabolized by CYP3A. Drugs that induce CYP3A activity would be expected to increase the clearance of lopinavir, resulting in lowered plasma concentrations of lopinavir. Although not noted with concurrent ketoconazole, co-administration of KALETRA and other drugs that inhibit CYP3A may increase lopinavir plasma concentrations.
Drug interaction studies were performed with KALETRA and other drugs likely to be coadministered and some drugs commonly used as probes for pharmacokinetic interactions. The effects of co-administration of KALETRA on the AUC, Cmax and Cmin are summarized in Table 7 (effect of other drugs on lopinavir) and Table 8 (effect of KALETRA on other drugs). The effects of other drugs on ritonavir are not shown since they generally correlate with those observed with lopinavir (if lopinavir concentrations are decreased, ritonavir concentrations are decreased) unless otherwise indicated in the table footnotes. For information regarding clinical recommendations, see Table 6 in DRUG INTERACTIONS.
Table 7: 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 KALETRA (mg) | n | Ratio (in combination with co-administered drug/alone) of Lopinavir Pharmaco CI)kinetic Parameters (90% ; No Effect = 1.00 |
||
| Cmax | AUC | Cmin | ||||
| Boceprevir | 800 q8h, 6 d | 400/100 tablet twice daily, 22 d | 13 | 0.70 (0.65, 0.77) |
0.6612 (0.60, 0.72) |
0.57 (0.49, 0.65) |
| Efavirenz1,2 | 600 at bedtime, 9 d | 400/100 capsule twice daily, 9 d | 11, 7* | 0.97 (0.78, 1.22) |
0.81 (0.64, 1.03) |
0.61 (0.38, 0.97) |
| 600 at bedtime, 9 d | 500/125 tablet twice daily, 10 d | 19 | 1.12 (1.02, 1.23) |
1.06 (0.96, 1.17) |
0.90 (0.78, 1.04) |
|
| 600 at bedtime, 9 d | 600/150 tablet twice daily, 10 d | 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 twice day (tablets) | 16 | 0.89 (0.82-0.96) |
0.87 (0.83-0.92) |
0.80 (0.73-0.88) |
| Fosamprenavir3 | 700 twice daily plus ritonavir 100 twice daily, 14 d | 400/100 capsule twice daily, 14 d | 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, 16 d | 12 | 0.89 (0.80, 0.99) |
0.87 (0.75, 1.00) |
0.75 (0.55, 1.00) |
| Nelfinavir | 1000 twice daily, 10 d | 400/100 capsule twice daily, 21 d | 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 ( > 1 yr)4# | 400/100 capsule twice daily, steady-state | 22, 19* | 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, 2 wk; twice daily 1 wk5 | ( > 1 yr) 300/75 mg/m² oral solution twice daily, 3 wk | 12, 15* | 0.86 (0.64, 1.16) |
0.78 (0.56, 1.09) |
0.45 (0.25, 0.81) |
|
| 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) |
|
| Pitavastatin6 | 4 once daily, 5 d | 400/100 tablet twice daily, 16 d | 23 | 0.93 (0.88, 0.98) |
0.91 (0.86, 0.97) |
N/A |
| 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) |
| Rifabutin | 150 once daily, 10 d | 400/100 capsule twice daily, 20 d | 14 | 1.08 (0.97, 1.19) |
1.17 (1.04, 1.31) |
1.20 (0.96, 1.65) |
| 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) |
|
| Rifampin | 600 once daily, 10 d | 400/100 capsule twice daily, 20 d | 22 | 0.45 (0.40, 0.51) |
0.25 (0.21, 0.29) |
0.01 (0.01, 0.02) |
| 600 once daily, 14 d | 800/200 capsule twice daily, 9 d7 | 10 | 1.02 (0.85, 1.23) |
0.84 (0.64, 1.10) |
0.43 (0.19, 0.96) |
|
| 600 once daily, 14 d | 400/400 capsule twice daily, 9 d8 | 9 | 0.93 (0.81, 1.07) |
0.98 (0.81, 1.17) |
1.03 (0.68, 1.56) |
|
| Rilpivirine | 150 once daily13 | 400/100 twice daily (capsules) | 15 | 0.96 (0.88-1.05) |
0.99 (0.89-1.10) |
0.89 (0.73-1.08) |
| Ritonavir4 | 100 twice daily, 3-4 wk# | 400/100 capsule twice daily, 3-4 wk | 8, 21* | 1.28 (0.94, 1.76) |
1.46 (1.04, 2.06) |
2.16 (1.29, 3.62) |
| Tenofovir9 | 300 once daily, 14 d | 400/100 capsule twice daily, 14 d | 24 | NC† | NC† | NC† |
| Tipranavir/ritonavir4 | 500/200 twice daily (28 doses) # |
400/100 capsule twice daily (27 doses) | 21, 69 | 0.53 (0.40, 0.69)10 |
0.45 (0.32, 0.63)10 |
0.30 (0.17, 0.51)10 0.48 (0.40, 0.58)11 |
| All interaction studies conducted in healthy, HIV-1
negative subjects unless otherwise indicated. 1 The pharmacokinetics of ritonavir are unaffected by concurrent efavirenz. 2 Reference for comparison is lopinavir/ritonavir 400/100 mg twice daily without efavirenz. 3 Data extracted from the fosamprenavir package insert. 4 Study conducted in HIV-1 positive adult subjects. 5 Study conducted in HIV-1 positive pediatric subjects ranging in age from 6 months to 12 years. 6 Data extracted from the pitavastatin package insert and results presented at the 2011 International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (Morgan, et al, poster #MOPE170). 7 Titrated to 800/200 twice daily as 533/133 twice daily x 1 d, 667/167 twice daily x 1 d, then 800/200 twice daily x 7 d, compared to 400/100 twice daily x 10 days alone. 8 Titrated to 400/400 twice daily as 400/200 twice daily x 1 d, 400/300 twice daily x 1 d, then 400/400 twice daily x 7 d, compared to 400/100 twice daily x 10 days alone. 9 Data extracted from the tenofovir package insert. 10 Intensive PK analysis. 11 Drug levels obtained at 8-16 hrs post-dose. 12 AUC parameter is AUC (0-last) 13 This interaction study has been performed with a dose higher than the recommended dose for rilpivirine (25 mg once daily) assessing the maximal effect on the co-administered drug. * Parallel group design; n for KALETRA + co-administered drug, n for KALETRA alone. N/A = Not available. † NC = No change. # For the nevirapine 200 mg twice daily study, ritonavir, and tipranavir/ritonavir studies, KALETRA was administered with or without food. For all other studies, KALETRA was administered with food. |
Table 8: Drug Interactions: Pharmacokinetic Parameters
for Co-administered Drug in the Presence of KALETRA for Recommended Alterations
in Dose or Regimen
| Co- administered Drug | Dose of Coadministered Drug (mg) | Dose of KALETRA (mg) | n | Ratio (in combination with KALETRA/alone) of Co-administered Drug Pharmacokinetic Parameters (90% CI); No Effect = 1.00 | ||
| Cmax | AUC | Cmin | ||||
| Bedaquiline1 | 400 single dose | 400/100 twice daily, 24 d | N/A | N/A | 1.22 (1.11, 1.34) |
N/A |
| Boceprevir | 800 q8h, 6 d | 400/100 tablet twice daily, 22 d | 139 | 0.50 (0.45, 0.55) |
0.55 (0.49, 0.61) |
0.43 (0.36, 0.53) |
| Desipramine2 | 100 single dose | 400/100 capsule twice daily, 10 d | 15 | 0.91 (0.84, 0.97) |
1.05 (0.96, 1.16) |
N/A |
| Efavirenz | 600 at bedtime, 9 d | 400/100 capsule twice daily, 9 d | 11, 12* | 0.91 (0.72, 1.15) |
0.84 (0.62, 1.15) |
0.84 (0.58, 1.20) |
| Ethinyl Estradiol | 35 |ig once daily, 21 d (Ortho Novum®) | 400/100 capsule twice daily, 14 d | 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 twice day (tablets) | 16 | 0.70 (0.64-0.78) |
0.65 (0.59-0.71) |
0.55 (0.49-0.62) |
| Fosamprenavir3 | 700 twice daily plus ritonavir 100 twice daily, 14 d | 400/100 capsule twice daily, 14 d | 18 | 0.42 (0.30, 0.58) |
0.37 (0.28, 0.49) |
0.35 (0.27, 0.46) |
| Indinavir4 | 600 twice daily, 10 d combo nonfasting vs. 800 three times daily, 5 d alone fasting | 400/100 capsule twice daily, 15 d | 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, 16 d | 12 | 1.13 (0.91, 1.40) |
3.04 (2.44, 3.79) |
N/A |
| Methadone | 5 single dose | 400/100 capsule twice daily, 10 d | 11 | 0.55 (0.48, 0.64) |
0.47 (0.42, 0.53) |
N/A |
| Nelfinavir4 | 1000 twice daily, 10 d combo vs. 1250 twice daily 14 d alone | 400/100 capsule twice daily, 21 d | 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, 14 d; twice daily, 6 d | 400/100 capsule twice daily, 20 d | 5, 6* | 1.05 (0.72, 1.52) |
1.08 (0.72, 1.64) |
1.15 (0.71, 1.86) |
| Norethindrone | 1 once daily, 21 d (Ortho Novum®) | 400/100 capsule twice daily, 14 d | 12 | 0.84 (0.75, 0.94) |
0.83 (0.73, 0.94) |
0.68 (0.54, 0.85) |
| Pitavastatin5 | 4 once daily, 5 d | 400/100 tablet twice daily, 16 d | 23 | 0.96 (0.84, 1.10) |
0.80 (0.73, 0.87) |
N/A |
| Pravastatin | 20 once daily, 4 d | 400/100 capsule twice daily, 14 d | 12 | 1.26 (0.87, 1.83) |
1.33 (0.91, 1.94) |
N/A |
| Rifabutin | 150 once daily, 10 d; combo vs. 300 once daily, 10 d; alone | 400/100 capsule twice daily, 10 d | 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 rifabutin6 | 3.46 (3.07, 3.91) |
5.73 (5.08, 6.46) |
9.53 (7.56, 12.01) |
|||
| Rilpivirine | 150 once daily10 | 400/100 twice daily (capsules) | 15 | 1.29 (1.18-1.40) |
1.52 (1.36-1.70) |
1.74 (1.46-2.08) |
| Rosuvastatin7 | 20 once daily, 7 d | 400/100 tablet twice daily, 7 d | 15 | 4.66 (3.4, 6.4) |
2.08 (1.66, 2.6) |
1.04 (0.9, 1.2) |
| Tenofovir8 | 300 once daily, 14 d | 400/100 capsule twice daily, 14 d | 24 | NC† | 1.32 (1.26, 1.38) |
1.51 (1.32, 1.66) |
| All interaction studies conducted in healthy, HIV-1
negative subjects unless otherwise indicated. 1 Data extracted from the bedaquiline package insert. 2 Desipramine is a probe substrate for assessing effects on CYP2D6-mediated metabolism. 3 Data extracted from the fosamprenavir package insert. 4 Ratio of parameters for indinavir, and nelfinavir are not normalized for dose. 5 Data extracted from the pitavastatin package insert and results presented at the 2011 International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (Morgan, et al, poster #MOPE170). 6 Effect on the dose-normalized sum of rifabutin parent and 25-O-desacetyl rifabutin active metabolite. 7 Kiser, et al. J Acquir Immune Defic Syndr. 2008 Apr 15;47(5):570-8. 8 Data extracted from the tenofovir package insert. 9 N=12 for Cmin (test arm) 10 This interaction study has been performed with a dose higher than the recommended dose for rilpivirine (25 mg once daily) assessing the maximal effect on the co-administered drug. * Parallel group design; n for KALETRA + co-administered drug, n for co-administered drug alone. N/A = Not available. † NC = No change. |
