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Kaletra (Lopinavir / Ritonavir) - Warnings and Precautions

 
 



WARNINGS

ALERT: Find out about medicines that should NOT be taken with KALETRA. This statement is included on the product's bottle label.

Drug Interactions

KALETRA is an inhibitor of the P450 isoform CYP3A. Co-administration of KALETRA and drugs primarily metabolized by CYP3A may result in increased plasma concentrations of the other drug that could increase or prolong its therapeutic and adverse effects (see Pharmacokinetics– Drug-drug Interactions , CONTRAINDICATIONS –Table 9: Drugs That Are Contraindicated With KALETRA, PRECAUTIONS – Table 10: Drugs That Should Not Be Co-administered With KALETRA and Table 11: Established and Other Potentially Significant Drug Interactions).

Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs is expected to substantially increase their concentrations and may result in an increase in associated adverse events including hypotension, syncope, visual changes and prolonged erection (see PRECAUTIONS– Drug Interactions and the complete prescribing information for sildenafil, tadalafil, and vardenafil.)

Concomitant use of KALETRA with lovastatin or simvastatin is not recommended. Caution should be exercised if HIV protease inhibitors, including KALETRA, are used concurrently with other HMG-CoA reductase inhibitors that are also metabolized by the CYP3A4 pathway (e.g., atorvastatin). The risk of myopathy, including rhabdomyolysis may be increased when HIV protease inhibitors, including KALETRA, are used in combination with these drugs.

Concomitant use of KALETRA and St. John's wort (hypericum perforatum), or products containing St. John's wort, is not recommended. Co-administration of protease inhibitors, including KALETRA, with St. John's wort is expected to substantially decrease protease inhibitor concentrations and may result in sub-optimal levels of lopinavir and lead to loss of virologic response and possible resistance to lopinavir or to the class of protease inhibitors.

A drug interaction study in healthy subjects has shown that ritonavir significantly increases plasma fluticasone propionate exposures, resulting in significantly decreased serum cortisol concentrations. Concomitant use of KALETRA and fluticasone propionate is expected to produce the same effects. Systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression have been reported during postmarketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Therefore, coadministration of fluticasone propionate and KALETRA is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects (see PRECAUTIONS– Drug Interactions).

Pancreatitis

Pancreatitis has been observed in patients receiving KALETRA therapy, including those who developed marked triglyceride elevations. In some cases, fatalities have been observed. Although a causal relationship to KALETRA has not been established, marked triglyceride elevations is a risk factor for development of pancreatitis (see PRECAUTIONS– Lipid Elevations). Patients with advanced HIV 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 should occur. Patients who exhibit these signs or symptoms should be evaluated and KALETRA and/or other antiretroviral therapy should be suspended as clinically appropriate.

Diabetes Mellitus/Hyperglycemia

New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in HIV-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.

PRECAUTIONS

Hepatic Impairment and Toxicity

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 CLINICAL PHARMACOLOGY – Hepatic Impairment). Patients with underlying hepatitis B or C or marked elevations in transaminases prior to treatment may be at increased risk for developing further transaminase elevations or hepatic decompensation. There have been postmarketing reports of hepatic dysfunction, including some fatalities. These have generally occurred in patients with advanced HIV disease taking multiple concomitant medications in the setting of underlying chronic hepatitis or cirrhosis. A causal relationship with KALETRA therapy has not been established. Increased AST/ALT monitoring should be considered in these patients, especially during the first several months of KALETRA treatment.

Resistance/Cross-resistance

Various degrees of cross-resistance among protease inhibitors have been observed. The effect of KALETRA therapy on the efficacy of subsequently administered protease inhibitors is under investigation (see Microbiology).

Hemophilia

There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis, 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.

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.

Lipid Elevations

Treatment with KALETRA has resulted in large increases in the concentration of total cholesterol and triglycerides (see ADVERSE REACTIONS – Table 16). 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. See  PRECAUTIONS– Table 11: Established and Other Potentially Significant Drug Interactions for additional information on potential drug interactions with KALETRA and HMG-CoA reductase inhibitors.

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 carinii pneumonia, or tuberculosis) which may necessitate further evaluation and treatment.

Information for Patients

A statement to patients and health care providers is included on the product's bottle label: "ALERT: Find out about medicines that should NOT be taken with KALETRA. " A Patient Package Insert (PPI) for KALETRA is available for patient information.

Patients should be told that sustained decreases in plasma HIV 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.

Patients should be informed that KALETRA is not a cure for HIV infection and that they may continue to develop opportunistic infections and other complications associated with HIV disease. The long-term effects of KALETRA are unknown at this time. Patients should be told that there are currently no data demonstrating that therapy with KALETRA can reduce the risk of transmitting HIV to others through sexual contact.

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.

Patients receiving sildenafil, tadalafil, or vardenafil should be advised that they may be at an increased risk of associated adverse events including hypotension, visual changes, and sustained erection, and should promptly report any symptoms to their doctor.

Patients receiving estrogen-based hormonal contraceptives should be instructed that additional or alternate contraceptive measures should be used during therapy with KALETRA.

KALETRA should be taken with food to enhance absorption.

Patients should be informed that 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.

Drug Interactions

KALETRA is an inhibitor of CYP3A (cytochrome P450 3A) both in vitro and in vivo. Co-administration of KALETRA and drugs primarily metabolized by CYP3A (e.g., dihydropyridine calcium channel blockers, HMG-CoA reductase inhibitors, immunosuppressants and PDE5 inhibitors) may result in increased plasma concentrations of the other drugs that could increase or prolong their therapeutic and adverse effects (see  Table 11. Established and Other Potentially Significant Drug Interactions). Agents that are extensively metabolized by CYP3A and have high first pass metabolism appear to be the most susceptible to large increases in AUC (> 3-fold) when co-administered with KALETRA.

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. Co-administration of KALETRA and drugs that induce CYP3A may decrease lopinavir plasma concentrations and reduce its therapeutic effect (see Table 11. Established and Other Potentially Significant Drug Interactions). Although not noted with concurrent ketoconazole, co-administration of KALETRA and other drugs that inhibit CYP3A may increase lopinavir plasma concentrations.

Drugs that are contraindicated and not recommended for co-administration with KALETRA are included in Table 10. Drugs That Should Not Be Co-administered With KALETRA. These recommendations are based on either drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for serious events or loss of efficacy.

Table 10. Drugs That Should Not Be Co-administered With KALETRA
Drug Class: Drug Name Clinical Comment
Antihistamines:
astemizole, terfenadine
CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
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. (See Table 10 for further details).
Ergot Derivatives:
dihydroergotamine, ergonovine, ergotamine, methylergonovine
CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
GI Motility Agent:
cisapride
CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as 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 serious reactions such as risk of myopathy including rhabdomyolysis.
Neuroleptic:
pimozide
CONTRAINDICATED due to the potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Sedative/Hypnotics:
midazolam, triazolam
CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression.
Table 11. Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction See CLINICAL PHARMACOLOGY for Magnitude of Interaction – Table 3 and Table 4
Concomitant Drug Class:
Drug Name
Effect on Concentration of lopinavir or Concomitant Drug Clinical Comment

*  See CLINICALPHARMACOLOGY for Magnitude of Interaction – Table 3 and Table 4.

HIV-Antiviral Agents
Non-nucleoside Reverse Transcriptase Inhibitors:
efavirenz*,
nevirapine*
↓ LopinavirA dose increase of KALETRA to 533/133 mg (4 capsules or 6.5 mL) twice daily taken with food is recommended when used in combination with efavirenz or nevirapine (see  DOSAGE AND ADMINISTRATION). KALETRA should not be administered once-daily in combination with efavirenz or nevirapine.
NOTE:  Efavirenz and nevirapine induce the activity of CYP3A and thus have the potential to decrease plasma concentrations of other protease inhibitors when used in combination with KALETRA.
Non-nucleoside Reverse Transcriptase Inhibitor:
delavirdine
↑ LopinavirAppropriate doses of the combination with respect to safety and efficacy have not been established.
Nucleoside Reverse Transcriptase Inhibitor:
didanosine
It is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA (given with food).
Nucleoside Reverse Transcriptase Inhibitor:
tenofovir
↑ TenofovirKALETRA increases tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving KALETRA and tenofovir should be monitored for tenofovir-associated adverse events.
HIV-Protease Inhibitor:
amprenavir*
↑ Amprenavir (amprenavir 750 mg BID + KALETRA produces ↑ AUC, similar Cmax, ↑ Cmin, relative to amprenavir 1200 mg BID
↓ Lopinavir
Increase KALETRA dose to 533/133 mg and decrease amprenavir dose to amprenavir 750 mg BID, when co-administered. (see  DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY – Table 3 and Table 4). KALETRA should not be administered once-daily in combination with amprenavir. Appropriate doses of the combination of fosamprenavir and KALETRA have not been established.
HIV-Protease Inhibitor:
fosamprenavir
↓ Amprenavir
↓ Lopinavir
An increased rate of adverse events has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV-Protease Inhibitor:
indinavir*
↑ Indinavir (indinavir 600 mg BID + KALETRA produces similar AUC, ↓ Cmax, ↑ Cmin relative to indinavir 800 mg TIDDecrease indinavir dose to 600 mg BID, when co-administered with KALETRA 400/100 mg BID (see  CLINICAL PHARMACOLOGY – Table 4). KALETRA once-daily has not been studied in combination with indinavir.
HIV-Protease Inhibitor:
nelfinavir*
↑ Nelfinavir (nelfinavir 1000 mg BID + KALETRA produces similar AUC, similar Cmax, ↑ Cmin relative to nelfinavir 1250 mg BID)
↑ M8 metabolite of nelfinavir
↓ Lopinavir
Increase KALETRA dose to 533/133 mg and decrease nelfinavir dose to 1000 mg BID, when co-administered (see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY – Table 3 and Table 4). KALETRA should not be administered once-daily in combination with nelfinavir.
HIV-Protease Inhibitor:
saquinavir*
↑ Saquinavir (saquinavir 800 mg BID + KALETRA produces ↑ AUC,↑ Cmax, ↑ Cmin relative to saquinavir 1200 mg TID)Decrease saquinavir dose to 800 mg BID, when co-administered with KALETRA 400/100 mg BID (see  CLINICAL PHARMACOLOGY – Table 4). KALETRA once-daily has not been studied in combination with saquinavir.
HIV-Protease Inhibitor:
tipranavir
↓ Lopinavir AUC and CminKALETRA should not be administered with tipranavir (500 mg twice-daily) co-administered with ritonavir (200 mg twice-daily).
HIV-Protease Inhibitor:
ritonavir*
↑ LopinavirAppropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established.
Other Agents
Antiarrhythmics:
amiodarone,
bepridil,
lidocaine (systemic), and
quinidine
↑ AntiarrhythmicsCaution is warranted and therapeutic concentration monitoring is recommended for antiarrhythmics when co-administered with KALETRA, if available.
Anticoagulant:
warfarin
Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
Anticonvulsants:
carbamazepine,
phenobarbital,
phenytoin
↓ LopinavirUse with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly. KALETRA should not be administered once-daily in combination with carbamazepine, phenobarbital, or phenytoin.
Antidepressant:
trazodone
↑ TrazodoneConcomitant use of trazodone and KALETRA may increase concentrations of trazodone. Adverse events of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered.
Anti-infective:
clarithromycin
↑ ClarithromycinFor patients with renal impairment, the following dosage adjustments should be considered:
  • For patients with CLCR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%.
  • For patients with CLCR < 30 mL/min the dose of clarithromycin should be decreased by 75%.


No dose adjustment for patients with normal renal function is necessary.
Antifungals:
ketoconazole*,
itraconazole,
voriconazole
↑ Ketoconazole
↑ Itraconazole
Voriconazole effect is unknown.
High doses of ketoconazole or itraconazole (> 200 mg/day) are not recommended. Co-administration of voriconazole with KALETRA has not been studied. However, administration of voriconazole with ritonavir 400 mg every 12 hours decreased voriconazole steady-state AUC by an average of 82%. The effect of lower ritonavir doses on voriconazole is not known at this time. Until data are available, voriconazole should not be administered to patients receiving KALETRA.
Antimycobacterial:
rifabutin*
↑ Rifabutin and rifabutin metaboliteDosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse events is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary.
Antimycobacterial:
Rifampin
↓ LopinavirMay lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents. A study evaluated combination of rifampin 600 mg QD, with KALETRA 800/200 mg BID or KALETRA 400/100 mg + ritonavir 300 mg BID. Pharmacokinetic and safety results from this study do not allow for a dose recommendation. Nine subjects (28%) experienced a ≥ grade 2 increase in ALT/AST, of which seven (21%) prematurely discontinued study per protocol. Based on the study design, it is not possible to determine whether the frequency or magnitude of the ALT/AST elevations observed is higher than what would be seen with rifampin alone. (See CLINICAL PHARMACOLOGY for Magnitude of Interaction – Table 3).
Antiparasitic:
atovaquone
↓ AtovaquoneClinical significance is unknown; however, increase in atovaquone doses may be needed.
Calcium Channel Blockers, Dihydropyridine:
e.g., felodipine,
nifedipine,
nicardipine
↑ Dihydropyridine calcium channel blockersCaution is warranted and clinical monitoring of patients is recommended.
Corticosteroid:
Dexamethasone
↓ LopinavirUse with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly.
Disulfiram/metronidazoleKALETRA oral solution contains alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole).
PDE5 inhibitors:
sildenafil,
tadalafil,
vardenafil
↑ Sildenafil
↑ Tadalafil
↑ Vardenafil
Use sildenafil with caution at reduced doses of 25 mg every 48 hours with increased monitoring for adverse events.
Use tadalafil with caution at reduced doses of 10 mg every 72 hours with increased monitoring for adverse events.
Use vardenafil with caution at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring for adverse events.
HMG-CoA Reductase Inhibitors:
atorvastatin*
rosuvastatin
↑ atorvastatin
↑ rosuvastatin
Use lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin or fluvastatin in combination with KALETRA.
Immunosuppressants:
cyclosporine,
tacrolimus,
rapamycin
↑ ImmunosuppressantsTherapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA.
Inhaled Steroid:
fluticasone
↑ FluticasoneConcomitant use of fluticasone propionate and KALETRA may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Co-administration of fluticasone propionate and KALETRA is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effect (see WARNINGS)
Narcotic Analgesic:
Methadone*
↓ MethadoneDosage of methadone may need to be increased when co-administered with KALETRA.
Oral Contraceptive:
ethinyl estradiol*
↓ Ethinyl estradiolBecause contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended.

Other Drugs

Drug interaction studies reveal no clinically significant interaction between KALETRA and desipramine (CYP2D6 probe), pravastatin, stavudine, lamivudine, omeprazole or ranitidine.

Based on known metabolic profiles, clinically significant drug interactions are not expected between KALETRA and fluvastatin, dapsone, trimethoprim/sulfamethoxazole, azithromycin, erythromycin, or fluconazole.

Zidovudine and Abacavir: KALETRA induces glucuronidation; therefore, KALETRA has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown.

Carcinogenesis, Mutagenesis and 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. However, 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.

Lopinavir in combination with ritonavir at a 2:1 ratio produced no effects on fertility in male and female rats at levels of 10/5, 30/15 or 100/50 mg/kg/day. Based on AUC measurements, the exposures in rats at the high doses were approximately 0.7-fold for lopinavir and 1.8-fold for ritonavir of the exposures in humans at the recommended therapeutic dose (400/100 mg twice-daily).

Pregnancy

Pregnancy Category C

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). There are, however, 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

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.

Nursing Mothers

The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV. 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 transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving KALETRA.

Geriatric Use

Clinical studies of KALETRA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, appropriate caution should be exercised in the administration and monitoring of KALETRA in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Pediatric Use

The safety and pharmacokinetic profiles of KALETRA in pediatric patients below the age of 6 months have not been established. In HIV-infected patients age 6 months to 12 years, the adverse event profile seen during a clinical trial was similar to that for adult patients. The evaluation of the antiviral activity of KALETRA in pediatric patients in clinical trials is ongoing.

Study 940 is an ongoing open-label, multicenter trial evaluating the pharmacokinetic profile, tolerability, safety and efficacy of KALETRA oral solution containing lopinavir 80 mg/mL and ritonavir 20 mg/mL in 100 antiretroviral naive (44%) and experienced (56%) pediatric patients. All patients were non-nucleoside reverse transcriptase inhibitor naive. Patients were randomized to either 230 mg lopinavir/57.5 mg ritonavir per m2 or 300 mg lopinavir/75 mg ritonavir per m2. Naive patients also received lamivudine and stavudine. Experienced patients received nevirapine plus up to two nucleoside reverse transcriptase inhibitors.

Safety, efficacy and pharmacokinetic profiles of the two dose regimens were assessed after three weeks of therapy in each patient. After analysis of these data, all patients were continued on the 300 mg lopinavir/75 mg ritonavir per m2 dose. Patients had a mean age of 5 years (range 6 months to 12 years) with 14% less than 2 years. Mean baseline CD4 cell count was 838 cells/mm3 and mean baseline plasma HIV-1 RNA was 4.7 log10 copies/mL.

Through 48 weeks of therapy, the proportion of patients who achieved and sustained an HIV RNA < 400 copies/mL was 80% for antiretroviral naive patients and 71% for antiretroviral experienced patients. The mean increase from baseline in CD4 cell count was 404 cells/mm3 for antiretroviral naive and 284 cells/mm3 for antiretroviral experienced patients treated through 48 weeks. At 48 weeks, two patients (2%) had prematurely discontinued the study. One antiretroviral naive patient prematurely discontinued secondary to an adverse event attributed to KALETRA, while one antiretroviral experienced patient prematurely discontinued secondary to an HIV-related event.

Dose selection for patients 6 months to 12 years of age was based on the following results. 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). KALETRA once-daily has not been evaluated in pediatric patients.

Page last updated: 2007-07-23

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