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The US Food and Drug Administration (FDA) has approved a fixed-dose combination of the antiretroviral drug darunavir (800 mg) and the pharmacokinetic enhancer cobicistat (150 mg) for HIV"...
Risk Of Serious Adverse Reactions Due To Drug Interactions
Initiation of KALETRA, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving KALETRA, may increase plasma concentrations of medications metabolized by CYP3A. Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of KALETRA, respectively. These interactions may lead to:
- Clinically significant adverse reactions, potentially leading to severe, life-threatening, or fatal events from greater exposures of concomitant medications.
- Clinically significant adverse reactions from greater exposures of KALETRA.
- Loss of therapeutic effect of KALETRA and possible development of resistance.
See Table 6 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations [see DRUG INTERACTIONS]. Consider the potential for drug interactions prior to and during KALETRA therapy; review concomitant medications during KALETRA therapy, and monitor for the adverse reactions associated with the concomitant medications [see CONTRAINDICATIONS and DRUG INTERACTIONS].
Pancreatitis has been observed in patients receiving KALETRA therapy, including those who developed marked triglyceride elevations. In some cases, fatalities have been observed. Although a causal relationship to KALETRA has not been established, marked triglyceride elevations are a risk factor for development of pancreatitis [see Lipid Elevations]. 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.
Patients with underlying hepatitis B or C or marked elevations in transaminase prior to treatment may be at increased risk for developing or worsening of transaminase elevations or hepatic decompensation with use of KALETRA.
There have been postmarketing reports of hepatic dysfunction, including some fatalities. These have generally occurred in patients with advanced HIV-1 disease taking multiple concomitant medications in the setting of underlying chronic hepatitis or cirrhosis. A causal relationship with KALETRA therapy has not been established.
Elevated transaminases with or without elevated bilirubin levels have been reported in HIV-1 mono-infected and uninfected patients as early as 7 days after the initiation of KALETRA in conjunction with other antiretroviral agents. In some cases, the hepatic dysfunction was serious; however, a definitive causal relationship with KALETRA therapy has not been established.
Appropriate laboratory testing should be conducted prior to initiating therapy with KALETRA and patients should be monitored closely during treatment. Increased AST/ALT monitoring should be considered in the patients with underlying chronic hepatitis or cirrhosis, especially during the first several months of KALETRA treatment [see Use In Specific Populations].
QT Interval Prolongation
Postmarketing cases of QT interval prolongation and torsade de pointes have been reported although causality of KALETRA could not be established. Avoid use in patients with congenital long QT syndrome, those with hypokalemia, and with other drugs that prolong the QT interval [see CLINICAL PHARMACOLOGY].
PR Interval Prolongation
Lopinavir/ritonavir prolongs the PR interval in some patients. Cases of second or third degree atrioventricular block have been reported. KALETRA should be used with caution in patients with underlying structural heart disease, pre-existing conduction system abnormalities, ischemic heart disease or cardiomyopathies, as these patients may be at increased risk for developing cardiac conduction abnormalities.
The impact on the PR interval of co-administration of KALETRA with other drugs that prolong the PR interval (including calcium channel blockers, beta-adrenergic blockers, digoxin and atazanavir) has not been evaluated. As a result, co-administration of KALETRA with these drugs should be undertaken with caution, particularly with those drugs metabolized by CYP3A. Clinical monitoring is recommended [see DRUG INTERACTIONS, and CLINICAL PHARMACOLOGY].
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.
Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including KALETRA. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis) which may necessitate further evaluation and treatment.
Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment.
Treatment with KALETRA has resulted in large increases in the concentration of total cholesterol and triglycerides [see ADVERSE REACTIONS]. Triglyceride and cholesterol testing should be performed prior to initiating KALETRA therapy and at periodic intervals during therapy. Lipid disorders should be managed as clinically appropriate, taking into account any potential drug-drug interactions with KALETRA and HMG-CoA reductase inhibitors [see CONTRAINDICATIONS, DRUG INTERACTIONS, and CLINICAL PHARMACOLOGY].
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.
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.
Because the potential for HIV-1 cross-resistance among protease inhibitors has not been fully explored in treatment-na´ve patients, it is unknown what effect therapy with KALETRA will have on the activity of subsequently administered protease inhibitors [see Microbiology].
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide)
Patients or parents of patients should be informed that:
- They should pay special attention to accurate administration of their dose to minimize the risk of accidental overdose or underdose of KALETRA.
- They should inform their healthcare provider if their children's weight changes in order to make sure that the child's KALETRA dose is the correct one.
- They should take the prescribed dose of KALETRA as directed and to set up a daily routine in order to do so.
- KALETRA capsules should be taken with food to enhance absorption.
- Sustained decreases in plasma HIV-1 RNA have been associated with a reduced risk of progression to AIDS and death. Patients should remain under the care of a physician while using KALETRA. Patients should be advised to take KALETRA and other concomitant antiretroviral therapy every day as prescribed. KALETRA must always be used in combination with other antiretroviral drugs. Patients should not alter the dose or discontinue therapy without consulting with their doctor. If a dose of KALETRA is missed patients should take the dose as soon as possible and then return to their normal schedule. However, if a dose is skipped the patient should not double the next dose. The amount of HIV-1 virus in their blood may increase if the medicine is stopped for even a short time. The virus may become resistant to KALETRA and become harder to treat.
- KALETRA is not a cure for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients should remain under the care of a physician when using KALETRA.
Patients should be advised to avoid doing things that can spread HIV-1 infection to others.
- Do not share needles or other injection equipment.
- Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
- Do not have any kind of sex without protection. Always practice safe sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.
- Do not breastfeed. We do not know if KALETRA can be passed to the baby through breast milk and whether it could harm the baby. Also, mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk.
- KALETRA may interact with some drugs; therefore, patients should be advised to report to their doctor the use of any other prescription, non-prescription medication or herbal products, particularly St. John's Wort.
- Patients taking didanosine should take didanosine one hour before or two hours after KALETRA capsules.
- If they are receiving avanafil, sildenafil, tadalafil, or vardenafil for the treatment of erectile dysfunction, there may be an increased risk of associated adverse reactions including hypotension, visual changes, and sustained erection, and should promptly report any symptoms to their doctor. If they are currently using or planning to use avanafil or tadalafil (for the treatment of pulmonary arterial hypertension) they should ask their doctor about potential adverse reactions these medications may cause when taken with KALETRA. The doctor may choose not to keep them on avanafil, or may adjust the dose of tadalafil while initiating treatment with KALETRA.
- If they are receiving estrogen-based hormonal contraceptives, additional or alternate contraceptive measures should be used during therapy with KALETRA.
- If they are taking or before they begin using Serevent® (salmeterol) and KALETRA, they should talk to their doctor about problems these two medications may cause when taken together. The doctor may choose not to keep someone on Serevent® (salmeterol).
- If they are taking or before they begin taking Advair® (salmeterol in combination with fluticasone propionate) and KALETRA, they should talk to their doctor about problems these two medications may cause when taken together. The doctor may choose not to keep someone on Advair® (salmeterol in combination with fluticasone propionate).
Potential Adverse Effects
- Skin rashes ranging in severity from mild to toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, erythema multiforme, urticaria, and angioedema have been reported in patients receiving KALETRA or its components lopinavir and/or ritonavir. Patients should be advised to contact their healthcare provider if they develop a rash while taking KALETRA. The healthcare provider will determine if treatment should be continued or an alternative antiretroviral regimen used.
- Patients should be advised that appropriate liver function testing will be conducted prior to initiating and during therapy with KALETRA. Pre-existing liver disease including Hepatitis B or C can worsen with use of KALETRA. This can be seen as worsening of transaminase elevations or hepatic decompensation. Patients should be advised that their liver function tests will need to be monitored closely especially during the first several months of KALETRA treatment and that they should notify their healthcare provider if they develop the signs and symptoms of worsening liver disease including loss of appetite, abdominal pain, jaundice, and itchy skin.
- New onset of diabetes or exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during KALETRA use. Patients should be advised to notify their healthcare provider if they develop the signs and symptoms of diabetes mellitus including frequent urination, excessive thirst, extreme hunger or unusual weight loss and/or an increased blood sugar while on KALETRA as they may require a change in their diabetes treatment or new treatment.
- KALETRA might produce changes in the electrocardiogram (e.g., PR and/or QT prolongation). Patients should consult their physician if they experience symptoms such as dizziness, lightheadedness, abnormal heart rhythm or loss of consciousness.
- They should seek medical assistance immediately if they develop a sustained penile erection lasting more than 4 hours while taking KALETRA and a PDE 5 Inhibitor such as Viagra, Cialis or Levitra.
- Redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long term health effects of these conditions are not known at this time.
- Patients should be informed that there may be a greater chance of developing diarrhea with the once daily regimen as compared with the twice daily regimen.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Lopinavir/ritonavir combination was evaluated for carcinogenic potential by oral gavage administration to mice and rats for up to 104 weeks. Results showed an increase in the incidence of benign hepatocellular adenomas and an increase in the combined incidence of hepatocellular adenomas plus carcinoma in both males and females in mice and males in rats at doses that produced approximately 1.6-2.2 times (mice) and 0.5 times (rats) the human exposure (based on AUC0-24hr measurement) at the recommended dose of 400/100 mg KALETRA twice daily. Administration of lopinavir/ritonavir did not cause a statistically significant increase in the incidence of any other benign or malignant neoplasm in mice or rats.
Carcinogenicity studies in mice and rats have been carried out on ritonavir. In male mice, there was a dose dependent increase in the incidence of both adenomas and combined adenomas and carcinomas in the liver. Based on AUC measurements, the exposure at the high dose was approximately 4-fold for males that of the exposure in humans with the recommended therapeutic dose (400/100 mg KALETRA twice daily). There were no carcinogenic effects seen in females at the dosages tested. The exposure at the high dose was approximately 9-fold for the females that of the exposure in humans. There were no carcinogenic effects in rats. In this study, the exposure at the high dose was approximately 0.7-fold that of the exposure in humans with the 400/100 mg KALETRA twice daily regimen. Based on the exposures achieved in the animal studies, the significance of the observed effects is not known.
Neither lopinavir nor ritonavir was found to be mutagenic or clastogenic in a battery of in vitro and in vivo assays including the Ames bacterial reverse mutation assay using S. typhimurium and E. coli, the mouse lymphoma assay, the mouse micronucleus test and chromosomal aberration assays in human lymphocytes.
Impairment of Fertility
Lopinavir in combination with ritonavir at a 2:1 ratio produced no effects on fertility in male and female rats at levels of 10/5, 30/15 or 100/50 mg 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 Category C.
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.
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.
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).
The Centers for Disease Control and Prevention recommend that HIV-1 infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1. 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.
The safety, efficacy, and pharmacokinetic profiles of KALETRA in pediatric patients below the age of 14 days have not been established. KALETRA should not be administered once daily in pediatric patients. 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 [see ADVERSE REACTIONS, CLINICAL PHARMACOLOGY, and Clinical Studies].
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 na´ve 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) [see ADVERSE REACTIONS, CLINICAL PHARMACOLOGY, and Clinical Studies].
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 [see ADVERSE REACTIONS, and CLINICAL PHARMACOLOGY].
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.
Clinical studies of KALETRA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, appropriate caution should be exercised in the administration and monitoring of KALETRA in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
KALETRA is principally metabolized by the liver; therefore, caution should be exercised when administering this drug to patients with hepatic impairment, because lopinavir concentrations may be increased [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].
Last reviewed on RxList: 7/15/2015
This monograph has been modified to include the generic and brand name in many instances.
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