Kaletra 200 MG / 50 MG Oral Tablet
DRUG INTERACTIONS
7 See also Contraindications ( ), Warnings and Precautions ( ), Clinical Pharmacology ( ) 4 5.1 12.3 Co-administration of KALETRA can alter the plasma concentrations of other drugs and other drugs may alter the plasma concentrations of lopinavir.
The potential for drug-drug interactions must be considered prior to and during therapy.
( , , , ) 4 5.1 7 12.3 7.1 Potential for KALETRA to Affect Other Drugs Lopinavir/ritonavir is an inhibitor of CYP3A and may increase plasma concentrations of agents that are primarily metabolized by CYP3A.
Agents that are extensively metabolized by CYP3A and have high first pass metabolism appear to be the most susceptible to large increases in AUC (> 3-fold) when co-administered with KALETRA.
Thus, co-administration of KALETRA with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated.
Co-administration with other CYP3A substrates may require a dose adjustment or additional monitoring as shown in Table 13.
Additionally, KALETRA induces glucuronidation.
7.2 Potential for Other Drugs to Affect Lopinavir Lopinavir/ritonavir is a CYP3A substrate; therefore, drugs that induce CYP3A may decrease lopinavir plasma concentrations and reduce KALETRA’s therapeutic effect.
Although not observed in the KALETRA/ketoconazole drug interaction study, co-administration of KALETRA and other drugs that inhibit CYP3A may increase lopinavir plasma concentrations.
7.3 Established and Other Potentially Significant Drug Interactions Table 13 provides a listing of established or potentially clinically significant drug interactions.
Alteration in dose or regimen may be recommended based on drug interaction studies or predicted interaction .
[see Clinical Pharmacology ( ) for magnitude of interaction] 12.3 Table 13.
Established and Other Potentially Significant Drug Interactions Concomitant Drug Class: Drug Name Effect on Concentration of Lopinavir or Concomitant Drug Clinical Comments HIV-1 Antiviral Agents HIV-1 Protease Inhibitor: fosamprenavir/ritonavir ↓ amprenavir ↓ lopinavir An increased rate of adverse reactions has been observed with co-administration of these medications.
Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor: indinavir* ↑ indinavir Decrease indinavir dose to 600 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily .
KALETRA once daily has not been studied in combination with indinavir.
[see Clinical Pharmacology ( )] 12.3 HIV-1 Protease Inhibitor: nelfinavir* ↑ nelfinavir ↑ M8 metabolite of nelfinavir ↓ lopinavir KALETRA should not be administered once daily in combination with nelfinavir and .
[see Dosage and Administration ( ) 2 Clinical Pharmacology ( )] 12.3 HIV-1 Protease Inhibitor: ritonavir* ↑ lopinavir Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor: saquinavir* ↑ saquinavir The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily.
KALETRA once daily has not been studied in combination with saquinavir.
HIV-1 Protease Inhibitor: tipranavir ↓ lopinavir AUC and C min KALETRA should not be administered with tipranavir (500 mg twice daily) co-administered with ritonavir (200 mg twice daily).
HIV CCR5 – Antagonist: maraviroc ↑ maraviroc Concurrent administration of maraviroc with KALETRA will increase plasma levels of maraviroc.
When co-administered, patients should receive 150 mg twice daily of maraviroc.
For further details see complete prescribing information for Selzentry (maraviroc).
® Non-nucleoside Reverse Transcriptase Inhibitor: etravirine ↓ etravirine Because the reduction in the mean systemic exposures of etravirine in the presence of lopinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, no dose adjustment is required.
Non-nucleoside Reverse Transcriptase Inhibitors: efavirenz*, nevirapine* ↓ lopinavir KALETRA dose increase is recommended in all patients and .
Increasing the dose of KALETRA tablets to 500/125 mg (given as two 200/50 mg tablets and one 100/25 mg tablet) twice daily co-administered with efavirenz resulted in similar lopinavir concentrations compared to KALETRA tablets 400/100 mg (given as two 200/50 mg tablets) twice daily without efavirenz.
Increasing the dose of KALETRA tablets to 600/150 mg (given as three 200/50 mg tablets) twice daily co-administered with efavirenz resulted in significantly higher lopinavir plasma concentrations compared to KALETRA tablets 400/100 mg twice daily without efavirenz.
KALETRA should not be administered once daily in combination with efavirenz or nevirapine and .
[see Dosage and Administration ( ) 2 Clinical Pharmacology ( )] 12.3 [see Dosage and Administration ( ) 2 Clinical Pharmacology ( )] 12.3 Non-nucleoside Reverse Transcriptase Inhibitor: delavirdine ↑ lopinavir Appropriate doses of the combination with respect to safety and efficacy have not been established.
Non-nucleoside Reverse Transcriptase Inhibitor: rilpivirine ↑ rilpivirine No dose adjustment is required.
Nucleoside Reverse Transcriptase Inhibitor: didanosine KALETRA tablets can be administered simultaneously with didanosine without food.
For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food).
Nucleoside Reverse Transcriptase Inhibitor: tenofovir ↑ tenofovir KALETRA increases tenofovir concentrations.
The mechanism of this interaction is unknown.
Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir.
Nucleoside Reverse Transcriptase Inhibitors: abacavir zidovudine ↓ abacavir ↓ zidovudine KALETRA induces glucuronidation; therefore, KALETRA has the potential to reduce zidovudine and abacavir plasma concentrations.
The clinical significance of this potential interaction is unknown.
Other Agents Antiarrhythmics e.g.: amiodarone, bepridil, lidocaine (systemic), quinidine ↑ antiarrhythmics Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA.
Anticancer Agents: vincristine, vinblastine, dasatinib, nilotinib ↑ anticancer agents Concentrations of these drugs may be increased when co-administered with KALETRA resulting in the potential for increased adverse events usually associated with these anticancer agents.
For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when KALETRA is administered concurrently with vincristine or vinblastine.
If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor.
A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as KALETRA.
Please refer to the nilotinib and dasatinib prescribing information for dosing instructions.
Anticoagulants: warfarin, rivaroxaban ↑ rivaroxaban Concentrations of warfarin may be affected.
It is recommended that INR (international normalized ratio) be monitored.
Avoid concomitant use of rivaroxaban and KALETRA.
Co-administration of KALETRA and rivaroxaban is expected to result in increased exposure of rivaroxaban which may lead to risk of increased bleeding.
Anticonvulsants: carbamazepine, phenobarbital, phenytoin ↓ lopinavir ↓ phenytoin KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution.
KALETRA should not be administered once daily in combination with carbamazepine, phenobarbital, or phenytoin.
In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations.
Phenytoin levels should be monitored when co-administering with KALETRA.
Anticonvulsants: lamotrigine, valproate ↓ lamotrigine ↓ or ↔ valproate Co-administration of KALETRA and lamotrigine or valproate may decrease the exposure of lamotrigine or valproate.
A dose increase of lamotrigine or valproate may be needed when co-administered with KALETRA and therapeutic concentration monitoring for lamotrigine may be indicated; particularly during dosage adjustments.
Antidepressant: bupropion ↓ bupropion ↓ active metabolite, hydroxybupropion Concurrent administration of bupropion with KALETRA may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion).
Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion.
Antidepressant: trazodone ↑ trazodone Concomitant use of trazodone and KALETRA may increase concentrations of trazodone.
Adverse reactions 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 ↑ clarithromycin For patients with renal impairment, the following dosage adjustments should be considered: No dose adjustment for patients with normal renal function is necessary.
For patients with CL 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%.
CR For patients with CL < 30 mL/min the dose of clarithromycin should be decreased by 75%.
CR Antifungals: ketoconazole*, itraconazole, voriconazole ↑ ketoconazole ↑ itraconazole ↓ voriconazole High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended.
Co-administration of voriconazole with KALETRA has not been studied.
However, a study has been shown that administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%; therefore, co-administration of KALETRA and voriconazole may result in decreased voriconazole concentrations and the potential for decreased voriconazole effectiveness and should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole.
Otherwise, alternative antifungal therapies should be considered in these patients.
Anti-gout: colchicine ↑ colchicine Patients with renal or hepatic impairment should not be given colchicine with KALETRA.
0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later.
Dose to be repeated no earlier than 3 days.
If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.
If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.
Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Treatment of gout flares-co-administration of colchicine in patients on KALETRA: Prophylaxis of gout flares-co-administration of colchicine in patients on KALETRA: Treatment of familial Mediterranean fever (FMF)-co-administration of colchicine in patients on KALETRA: Antimycobacterial: bedaquiline ↑ bedaquiline Bedaquiline should only be used with KALETRA if the benefit of co-administration outweighs the risk .
[see Pharmacokinetics ( )] 12.3 Antimycobacterial: rifabutin* ↑ rifabutin and rifabutin metabolite Dosage 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 reactions is warranted in patients receiving the combination.
Further dosage reduction of rifabutin may be necessary.
Antimycobacterial: rifampin ↓ lopinavir 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.
A study evaluated combination of rifampin 600 mg once daily, with KALETRA 800/200 mg twice daily or KALETRA 400/100 mg + ritonavir 300 mg twice daily.
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 for magnitude of interaction .
[see Clinical Pharmacology ( ) 12.3 ] Antiparasitic: atovaquone ↓ atovaquone Clinical significance is unknown; however, increase in atovaquone doses may be needed.
Antipsychotics: quetiapine ↑ quetiapine Consider alternative antiretroviral therapy to avoid increases in quetiapine exposures.
If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions.
Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring.
Initiation of KALETRA in patients taking quetiapine: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.
Initiation of quetiapine in patients taking KALETRA: Benzodiazepines: parenterally administered midazolam ↑ midazolam Midazolam is extensively metabolized by CYP3A4.
Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration.
Therefore, KALETRA should not be given with orally administered midazolam .
If KALETRA is co-administered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered.
[see Contraindications ( )] 4 Contraceptive: ethinyl estradiol* ↓ ethinyl estradiol Because 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.
Corticosteroids (systemic): e.g.
budesonide, dexamethasone, prednisone ↓ lopinavir ↑ glucocorticoids Use with caution.
KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly.
Concomitant use may result in increased steroid concentrations and reduced serum cortisol concentrations.
Concomitant use of glucocorticoids that are metabolized by CYP3A, particularly for long-term use, should consider the potential benefit of treatment versus the risk of systemic corticosteroid effects.
Concomitant use may increase the risk for development of systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression.
Dihydropyridine Calcium Channel Blockers: e.g.
felodipine, nifedipine, nicardipine ↑ dihydropyridine calcium channel blockers Caution is warranted and clinical monitoring of patients is recommended.
Disulfiram/metronidazole KALETRA 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).
Endothelin Receptor Antagonists: bosentan ↑ bosentan In patients who have been receiving KALETRA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Discontinue use of bosentan at least 36 hours prior to initiation of KALETRA.
After at least 10 days following the initiation of KALETRA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Co-administration of bosentan in patients on KALETRA: Co-administration of KALETRA in patients on bosentan: HCV-Protease Inhibitor: boceprevir ↓ lopinavir ↓ boceprevir ↓ ritonavir It is not recommended to co-administer KALETRA and boceprevir.
Concomitant administration of KALETRA and boceprevir reduced boceprevir, lopinavir and ritonavir steady-state exposures .
[see Clinical Pharmacology ( )] 12.3 HCV-Protease Inhibitor: simeprevir ↑ simeprevir It is not recommended to co-administer KALETRA and simeprevir.
HMG-CoA Reductase Inhibitors: atorvastatin rosuvastatin ↑ atorvastatin ↑ rosuvastatin Use atorvastatin with caution and at the lowest necessary dose.
Titrate rosuvastatin dose carefully and use the lowest necessary dose; do not exceed rosuvastatin 10 mg/day.
See Drugs with No Observed or Predicted Interactions with KALETRA and Clinical Pharmacology for drug interaction data with other HMG-CoA reductase inhibitors.
( ) 7.4 ( ) 12.3 Immunosuppressants: e.g.
cyclosporine, tacrolimus, sirolimus ↑ immunosuppressants Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA.
Inhaled or Intranasal Steroids e.g.: fluticasone, budesonide ↑ glucocorticoids Concomitant use of KALETRA and fluticasone or other glucocorticoids that are metabolized by CYP3A is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects.
Concomitant use may result in increased steroid concentrations and reduce serum cortisol concentrations.
Systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression have been reported during postmarketing use in patients when certain ritonavir-containing products have been co-administered with fluticasone propionate or budesonide.
Long-acting beta-adrenoceptor Agonist: salmeterol ↑ salmeterol Concurrent administration of salmeterol and KALETRA is not recommended.
The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.
Narcotic Analgesics: methadone,* fentanyl ↓ methadone ↑ fentanyl Dosage of methadone may need to be increased when co-administered with KALETRA.
Concentrations of fentanyl are expected to increase.
Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with KALETRA.
PDE5 inhibitors: avanafil, sildenafil, tadalafil, vardenafil ↑ avanafil ↑ sildenafil ↑ tadalafil ↑ vardenafil Do not use KALETRA with avanafil because a safe and effective avanafil dosage regimen has not been established.
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 PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection.
Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Sildenafil (Revatio ) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) because a safe and effective dose has not been established when used with KALETRA .
The following dose adjustments are recommended for use of tadalafil (Adcirca ) with KALETRA: In patients receiving KALETRA for at least one week, start ADCIRCA at 20 mg once daily.
Increase to 40 mg once daily based upon individual tolerability.
Avoid use of ADCIRCA during the initiation of KALETRA.
Stop ADCIRCA at least 24 hours prior to starting KALETRA.
After at least one week following the initiation of KALETRA, resume ADCIRCA at 20 mg once daily.
Increase to 40 mg once daily based upon individual tolerability.
Use of PDE5 inhibitors for erectile dysfunction: It is recommended not to exceed the following doses: • Sildenafil: 25 mg every 48 hours • Tadalafil: 10 mg every 72 hours • Vardenafil: 2.5 mg every 72 hours Use with increased monitoring for adverse events.
® [see Contraindications ( )] 4 ® Co-administration of ADCIRCA in patients on KALETRA: Co-administration of KALETRA in patients on ADCIRCA: * for magnitude of interaction.
see Clinical Pharmacology ( ) 12.3 7.4 Drugs with No Observed or Predicted Interactions with KALETRA Drug interaction or clinical studies reveal no clinically significant interaction between KALETRA and desipramine (CYP2D6 probe), pitavastatin, pravastatin, stavudine, lamivudine, omeprazole, raltegravir, or ranitidine.
Based on known metabolic profiles, clinically significant drug interactions are not expected between KALETRA and dapsone, trimethoprim/sulfamethoxazole, azithromycin, erythromycin, or fluconazole.
OVERDOSAGE
10 Overdoses with KALETRA oral solution have been reported.
One of these reports described fatal cardiogenic shock in a 2.1 kg infant who received a single dose of 6.5 mL of KALETRA oral solution (520 mg lopinavir, approximately 10-fold above the recommended lopinavir dose) nine days prior.
The following events have been reported in association with unintended overdoses in preterm neonates: complete AV block, cardiomyopathy, lactic acidosis, and acute renal failure .
Healthcare professionals should be aware that KALETRA oral solution is highly concentrated and therefore, should pay special attention to accurate calculation of the dose of KALETRA, transcription of the medication order, dispensing information and dosing instructions to minimize the risk for medication errors and overdose.
This is especially important for infants and young children.
[see Warnings and Precautions ( )] 5.2 KALETRA oral solution contains 42.4% alcohol (v/v) and 15.3% propylene glycol (w/v).
Ingestion of the product over the recommended dose by an infant or a young child could result in significant toxicity and could potentially be lethal.
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 gastric lavage.
Administration of activated charcoal may also be used to aid in removal of unabsorbed drug.
Since lopinavir is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the drug.
However, dialysis can remove both alcohol and propylene glycol in the case of overdose with KALETRA oral solution.
DESCRIPTION
11 KALETRA is a co-formulation of lopinavir and ritonavir.
Lopinavir is an inhibitor of the HIV-1 protease.
As co-formulated in KALETRA, ritonavir inhibits the CYP3A-mediated metabolism of lopinavir, thereby providing increased plasma levels of lopinavir.
Lopinavir is chemically designated as [1 -[1 *,( *), 3 *, 4 *]]- -[4-[[(2,6-dimethylphenoxy)acetyl]amino]-3-hydroxy-5-phenyl-1-(phenylmethyl)pentyl]tetrahydro-alpha-(1-methylethyl)-2-oxo-1(2 )-pyrimidineacetamide.
Its molecular formula is C H N O , and its molecular weight is 628.80.
Lopinavir is a white to light tan powder.
It is freely soluble in methanol and ethanol, soluble in isopropanol and practically insoluble in water.
Lopinavir has the following structural formula: S R R R R N H 37 48 4 5 Ritonavir is chemically designated as 10-hydroxy-2-methyl-5-(1-methylethyl)-1- [2-(1-methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-bis(phenylmethyl)-2,4,7,12-tetraazatridecan-13-oic acid, 5-thiazolylmethyl ester, [5 -(5 *,8 *,10 *,11 *)].
Its molecular formula is C H N O S , and its molecular weight is 720.95.
Ritonavir is a white to light tan powder.
It is freely soluble in methanol and ethanol, soluble in isopropanol and practically insoluble in water.
Ritonavir has the following structural formula: S R R R R 37 48 6 5 2 KALETRA tablets are available for oral administration in two strengths: Yellow tablets containing 200 mg of lopinavir and 50 mg of ritonavir Pale yellow tablets containing 100 mg of lopinavir and 25 mg of ritonavir.
The yellow, 200 mg lopinavir and 50 mg ritonavir, tablets contain the following inactive ingredients: copovidone, sorbitan monolaurate, colloidal silicon dioxide, and sodium stearyl fumarate.
The following are the ingredients in the film coating: hypromellose, titanium dioxide, polyethylene glycol 400, hydroxypropyl cellulose, talc, colloidal silicon dioxide, polyethylene glycol 3350, yellow ferric oxide E172, and polysorbate 80.
The pale yellow, 100 mg lopinavir and 25 mg ritonavir, tablets contain the following inactive ingredients: copovidone, sorbitan monolaurate, colloidal silicon dioxide, and sodium stearyl fumarate.
The following are the ingredients in the film coating: polyvinyl alcohol, titanium dioxide, talc, polyethylene glycol 3350, and yellow ferric oxide E172.
KALETRA oral solution is available for oral administration as 80 mg lopinavir and 20 mg ritonavir per milliliter with the following inactive ingredients: acesulfame potassium, alcohol, artificial cotton candy flavor, citric acid, glycerin, high fructose corn syrup, Magnasweet-110 flavor, menthol, natural & artificial vanilla flavor, peppermint oil, polyoxyl 40 hydrogenated castor oil, povidone, propylene glycol, saccharin sodium, sodium chloride, sodium citrate, and water.
KALETRA oral solution contains 42.4% alcohol (v/v).
Chemical structure for lopinavir.
Chemical structure for ritonavir.
CLINICAL STUDIES
14 14.1 Adult Patients without Prior Antiretroviral Therapy Study 863: KALETRA Capsules twice daily + stavudine + lamivudine compared to nelfinavir three times daily + stavudine + lamivudine Study 863 was a randomized, double-blind, multicenter trial comparing treatment with KALETRA capsules (400/100 mg twice daily) plus stavudine and lamivudine versus nelfinavir (750 mg three times daily) plus stavudine and lamivudine in 653 antiretroviral treatment naïve patients.
Patients had a mean age of 38 years (range: 19 to 84), 57% were Caucasian, and 80% were male.
Mean baseline CD4+ cell count was 259 cells/mm (range: 2 to 949 cells/mm ) and mean baseline plasma HIV-1 RNA was 4.9 log copies/mL (range: 2.6 to 6.8 log copies/mL).
3 3 10 10 Treatment response and outcomes of randomized treatment are presented in Table 18.
Table 18.
Outcomes of Randomized Treatment Through Week 48 (Study 863) Outcome KALETRA+d4T+3TC (N = 326) Nelfinavir+d4T+3TC (N = 327) Responder 1 75% 62% Virologic failure Rebound Never suppressed through Week 48 2 9% 7% 2% 25% 15% 9% Death 2% 1% Discontinued due to adverse events 4% 4% Discontinued for other reasons 3 10% 8% 1 Patients achieved and maintained confirmed HIV-1 RNA < 400 copies/mL through Week 48.
2 Includes confirmed viral rebound and failure to achieve confirmed < 400 copies/mL through Week 48.
3 Includes lost to follow-up, patient’s withdrawal, non-compliance, protocol violation and other reasons.
Overall discontinuation through Week 48, including patients who discontinued subsequent to virologic failure, was 17% in the KALETRA arm and 24% in the nelfinavir arm.
Through 48 weeks of therapy, there was a statistically significantly higher proportion of patients in the KALETRA arm compared to the nelfinavir arm with HIV-1 RNA < 400 copies/mL (75% vs.
62%, respectively) and HIV-1 RNA < 50 copies/mL (67% vs.
52%, respectively).
Treatment response by baseline HIV-1 RNA level subgroups is presented in Table 19.
Table 19.
Proportion of Responders Through Week 48 by Baseline Viral Load (Study 863) Baseline Viral Load (HIV-1 RNA copies/mL) KALETRA +d4T+3TC Nelfinavir +d4T+3TC <400 copies/mL 1 <50 copies/mL 2 n <400 copies/mL 1 <50 copies/mL 2 n < 30,000 74% 71% 82 79% 72% 87 ≥ 30,000 to < 100,000 81% 73% 79 67% 54% 79 ≥ 100,000 to < 250,000 75% 64% 83 60% 47% 72 ≥ 250,000 72% 60% 82 44% 33% 89 1 Patients achieved and maintained confirmed HIV-1 RNA < 400 copies/mL through Week 48.
2 Patients achieved HIV-1 RNA < 50 copies/mL at Week 48.
Through 48 weeks of therapy, the mean increase from baseline in CD4+ cell count was 207 cells/mm for the KALETRA arm and 195 cells/mm for the nelfinavir arm.
3 3 Study 730: KALETRA Tablets once daily + tenofovir DF + emtricitabine compared to KALETRA Tablets twice daily + tenofovir DF + emtricitabine Study 730 was a randomized, open-label, multicenter trial comparing treatment with KALETRA 800/200 mg once daily plus tenofovir DF and emtricitabine versus KALETRA 400/100 mg twice daily plus tenofovir DF and emtricitabine in 664 antiretroviral treatment-naïve patients.
Patients were randomized in a 1:1 ratio to receive either KALETRA 800/200 mg once daily (n = 333) or KALETRA 400/100 mg twice daily (n = 331).
Further stratification within each group was 1:1 (tablet vs.
capsule).
Patients administered the capsule were switched to the tablet formulation at Week 8 and maintained on their randomized dosing schedule.
Patients were administered emtricitabine 200 mg once daily and tenofovir DF 300 mg once daily.
Mean age of patients enrolled was 39 years (range: 19 to 71); 75% were Caucasian, and 78% were male.
Mean baseline CD4+ cell count was 216 cells/mm (range: 20 to 775 cells/mm ) and mean baseline plasma HIV-1 RNA was 5.0 log copies/mL (range: 1.7 to 7.0 log copies/mL).
3 3 10 10 Treatment response and outcomes of randomized treatment through Week 48 are presented in Table 20.
Table 20.
Outcomes of Randomized Treatment Through Week 48 (Study 730) Outcome KALETRA Once Daily + TDF + FTC (n = 333) KALETRA Twice Daily + TDF + FTC (n = 331) Responder 1 78% 77% Virologic failure Rebound Never suppressed through Week 48 2 10% 5% 5% 8% 5% 3% Death 1% <1% Discontinued due to adverse events 4% 3% Discontinued for other reasons 3 8% 11% 1 Patients achieved and maintained confirmed HIV-1 RNA < 50 copies/mL through Week 48.
2 Includes confirmed viral rebound and failure to achieve confirmed < 50 copies/mL through Week 48.
3 Includes lost to follow-up, patient’s withdrawal, non-compliance, protocol violation and other reasons.
Through 48 weeks of therapy, 78% in the KALETRA once daily arm and 77% in the KALETRA twice daily arm achieved and maintained HIV-1 RNA < 50 copies/mL (95% confidence interval for the difference, -5.9% to 6.8%).
Mean CD4+ cell count increases at Week 48 were 186 cells/mm for the KALETRA once daily arm and 198 cells/mm for the KALETRA twice daily arm.
3 3 14.2 Adult Patients with Prior Antiretroviral Therapy Study 888: KALETRA Capsules twice daily + nevirapine + NRTIs compared to investigator-selected protease inhibitor(s) + nevirapine + NRTIs Study 888 was a randomized, open-label, multicenter trial comparing treatment with KALETRA capsules (400/100 mg twice daily) plus nevirapine and nucleoside reverse transcriptase inhibitors versus investigator-selected protease inhibitor(s) plus nevirapine and nucleoside reverse transcriptase inhibitors in 288 single protease inhibitor-experienced, non-nucleoside reverse transcriptase inhibitor (NNRTI)-naïve patients.
Patients had a mean age of 40 years (range: 18 to 74), 68% were Caucasian, and 86% were male.
Mean baseline CD4+ cell count was 322 cells/mm (range: 10 to 1059 cells/mm ) and mean baseline plasma HIV-1 RNA was 4.1 log copies/mL (range: 2.6 to 6.0 log copies/mL).
3 3 10 10 Treatment response and outcomes of randomized treatment through Week 48 are presented in Table 21.
Table 21.
Outcomes of Randomized Treatment Through Week 48 (Study 888) Outcome KALETRA + nevirapine + NRTIs (n = 148) Investigator-Selected Protease Inhibitor(s) + nevirapine + NRTIs (n = 140) Responder 1 57% 33% Virologic failure Rebound Never suppressed through Week 48 2 24% 11% 13% 41% 19% 23% Death 1% 2% Discontinued due to adverse events 5% 11% Discontinued for other reasons 3 14% 13% 1 Patients achieved and maintained confirmed HIV-1 RNA < 400 copies/mL through Week 48.
2 Includes confirmed viral rebound and failure to achieve confirmed < 400 copies/mL through Week 48.
3 Includes lost to follow-up, patient’s withdrawal, non-compliance, protocol violation and other reasons.
Through 48 weeks of therapy, there was a statistically significantly higher proportion of patients in the KALETRA arm compared to the investigator-selected protease inhibitor(s) arm with HIV-1 RNA < 400 copies/mL (57% vs.
33%, respectively).
Through 48 weeks of therapy, the mean increase from baseline in CD4+ cell count was 111 cells/mm for the KALETRA arm and 112 cells/mm for the investigator-selected protease inhibitor(s) arm.
3 3 Study 802: KALETRA Tablets 800/200 mg Once Daily Versus 400/100 mg Twice Daily when Co-administered with Nucleoside/Nucleotide Reverse Transcriptase Inhibitors in Antiretroviral-Experienced, HIV-1 Infected Subjects M06-802 was a randomized open-label study comparing the safety, tolerability, and antiviral activity of once daily and twice daily dosing of KALETRA tablets in 599 subjects with detectable viral loads while receiving their current antiviral therapy.
Of the enrolled subjects, 55% on both treatment arms had not been previously treated with a protease inhibitor and 81 – 88% had received prior NNRTIs as part of their anti-HIV treatment regimen.
Patients were randomized in a 1:1 ratio to receive either KALETRA 800/200 mg once daily (n = 300) or KALETRA 400/100 mg twice daily (n = 299).
Patients were administered at least two nucleoside/nucleotide reverse transcriptase inhibitors selected by the investigator.
Mean age of patients enrolled was 41 years (range: 21 to 73); 51% were Caucasian, and 66% were male.
Mean baseline CD4+ cell count was 254 cells/mm (range: 4 to 952 cells/mm ) and mean baseline plasma HIV-1 RNA was 4.3 log copies/mL (range: 1.7 to 6.6 log copies/mL).
3 3 10 10 Treatment response and outcomes of randomized treatment through Week 48 are presented in Table 22.
Table 22.
Outcomes of Randomized Treatment Through Week 48 (Study 802) Outcome KALETRA Once Daily + NRTIs (n = 300) KALETRA Twice Daily + NRTIs (n = 299) Virologic Success (HIV-1 RNA <50 copies/mL) 57% 54% Virologic failure 1 22% 24% No virologic data in Week 48 window Discontinued study due to adverse event or death 2 5% 7% Discontinued study for other reasons 3 13% 12% Missing data during window but on study 3% 3% 1 Includes patients who discontinued prior to Week 48 for lack or loss of efficacy and patients with HIV-1 RNA ≥ 50 copies/mL at Week 48.
2 Includes patients who discontinued due to adverse events or death at any time from Day 1 through Week 48 if this resulted in no virologic data on treatment at Week 48.
3 Includes withdrawal of consent, loss to follow-up, non-compliance, protocol violation and other reasons.
Through 48 weeks of treatment, the mean change from baseline for CD4 + cell count was 135 cells/mm for the once daily group and 122 cells/mm for the twice daily group.
3 3 14.3 Other Studies Supporting Approval in Adult Patients Study 720: KALETRA twice daily + stavudine + lamivudine Study 765: KALETRA twice daily + nevirapine + NRTIs Study 720 (patients prior antiretroviral therapy) and study 765 (patients prior protease inhibitor therapy) were randomized, blinded, multi-center trials evaluating treatment with KALETRA at up to three dose levels (200/100 mg twice daily [720 only], 400/100 mg twice daily, and 400/200 mg twice daily).
In Study 720, all patients switched to 400/100 mg twice daily between Weeks 48-72.
Patients in study 720 had a mean age of 35 years, 70% were Caucasian, and 96% were male, while patients in study 765 had a mean age of 40 years, 73% were Caucasian, and 90% were male.
Mean (range) baseline CD4+ cell counts for patients in study 720 and study 765 were 338 (3-918) and 372 (72-807) cells/mm , respectively.
Mean (range) baseline plasma HIV-1 RNA levels for patients in study 720 and study 765 were 4.9 (3.3 to 6.3) and 4.0 (2.9 to 5.8) log copies/mL, respectively.
without with 3 10 Through 360 weeks of treatment in study 720, the proportion of patients with HIV-1 RNA < 400 (< 50) copies/mL was 61% (59%) [n = 100].
Among patients completing 360 weeks of treatment with CD4+ cell count measurements [n=60], the mean (median) increase in CD4+ cell count was 501 (457) cells/mm .
Thirty-nine patients (39%) discontinued the study, including 13 (13%) discontinuations due to adverse reactions and 1 (1%) death.
3 Through 144 weeks of treatment in study 765, the proportion of patients with HIV-1 RNA < 400 (< 50) copies/mL was 54% (50%) [n = 70], and the corresponding mean increase in CD4+ cell count was 212 cells/mm .
Twenty-seven patients (39%) discontinued the study, including 5 (7%) discontinuations secondary to adverse reactions and 2 (3%) deaths.
3 14.4 Pediatric Studies Study 1030 was an open-label, multicenter, dose-finding trial evaluating the pharmacokinetic profile, tolerability, safety and efficacy of KALETRA oral solution containing lopinavir 80 mg/mL and ritonavir 20 mg/mL at a dose of 300/75 mg/m twice daily plus 2 NRTIs in HIV-1 infected infants ≥14 days and <6 months of age.
2 Ten infants, ≥14 days and <6 wks of age, were enrolled at a median (range) age of 5.7 (3.6-6.0) weeks and all completed 24 weeks.
At entry, median (range) HIV-1 RNA was 6.0 (4.7-7.2) log copies/mL.
Seven of 10 infants had HIV-1 RNA <400 copies/mL at Week 24.
At entry, median (range) CD4+ percentage was 41 (16-59) with a median decrease of 1% (95% CI: -10, 18) from baseline to week 24 in 6 infants with available data.
10 Twenty-one infants, between 6 weeks and 6 months of age, were enrolled at a median (range) age of 14.7 (6.9-25.7) weeks and 19 of 21 infants completed 24 weeks.
At entry, median (range) HIV RNA level was 5.8 (3.7-6.9) log copies/mL.
Ten of 21 infants had HIV RNA <400 copies/mL at Week 24.
At entry, the median (range) CD4+ percentage was 32 (11-54) with a median increase of 4% (95% CI: -1, 9) from baseline to week 24 in 19 infants with available data.
10 .
See Clinical Pharmacology ( ) for pharmacokinetic results 12.3 Study 940 was an 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 naïve (44%) and experienced (56%) pediatric patients.
All patients were non-nucleoside reverse transcriptase inhibitor naïve.
Patients were randomized to either 230 mg lopinavir/57.5 mg ritonavir per m or 300 mg lopinavir/75 mg ritonavir per m .
Naïve patients also received lamivudine and stavudine.
Experienced patients received nevirapine plus up to two nucleoside reverse transcriptase inhibitors.
2 2 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 m 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/mm and mean baseline plasma HIV-1 RNA was 4.7 log copies/mL.
2 3 10 Through 48 weeks of therapy, the proportion of patients who achieved and sustained an HIV-1 RNA < 400 copies/mL was 80% for antiretroviral naïve patients and 71% for antiretroviral experienced patients.
The mean increase from baseline in CD4+ cell count was 404 cells/mm for antiretroviral naïve and 284 cells/mm for antiretroviral experienced patients treated through 48 weeks.
At 48 weeks, two patients (2%) had prematurely discontinued the study.
One antiretroviral naïve patient prematurely discontinued secondary to an adverse reaction, while one antiretroviral experienced patient prematurely discontinued secondary to an HIV-1 related event.
3 3 Dose selection in pediatric patients was based on the following: Among patients 14 days to 6 months of age receiving 300/75 mg/m twice daily without nevirapine, plasma concentrations were lower than those observed in adults or in older children.
This dose resulted in HIV-1 RNA < 400 copies/mL in 55% of patients (70% in those initiating treatment at <6 weeks of age).
2 Among patients 6 months to 12 years of age, the 230/57.5 mg/m oral solution twice daily regimen without nevirapine and the 300/75 mg/m 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).
These doses resulted in treatment benefit (proportion of patients with HIV-1 RNA < 400 copies/mL) similar to that seen in the adult clinical trials.
2 2 Among patients 12 to 18 years of age receiving 400/100 mg/m or 480/120 mg/m (with efavirenz) twice daily, plasma concentrations were 60-100% higher than among 6 to 12 year old patients receiving 230/57.5 mg/m .
Mean apparent clearance was similar to that observed in adult patients receiving standard dose and in patients 6 to 12 years of age.
Although changes in HIV-1 RNA in patients with prior treatment failure were less than anticipated, the pharmacokinetic data supports use of similar dosing as in patients 6 to 12 years of age, not to exceed the recommended adult dose.
2 2 2 For all age groups, the body surface area dosing was converted to body weight dosing using the patient’s prescribed lopinavir dose.
HOW SUPPLIED
16 /STORAGE AND HANDLING NDC:54569-5752-0 in a BOTTLE of 120 TABLET, FILM COATEDS 16.1 KALETRA Tablets, 200 mg lopinavir and 50 mg ritonavir Yellow film-coated ovaloid tablets debossed with the “a” logo and the code KA: Bottles of 120 tablets ….…………… (NDC 0074-6799-22) Recommended Storage Store KALETRA tablets at 20°-25°C (68°-77°F); excursions permitted to 15°-30°C (59° to 86°F) [see USP controlled room temperature].
Dispense in original container or USP equivalent tight container (250 mL or less).
For patient use: exposure of this product to high humidity outside the original container or USP equivalent tight container (250 mL or less) for longer than 2 weeks is not recommended.
16.2 KALETRA Tablets, 100 mg lopinavir and 25 mg ritonavir Pale yellow film-coated ovaloid tablets debossed with the “a” logo and the code KC: Bottles of 60 tablets ….…………… (NDC 0074-0522-60) Recommended Storage Store KALETRA tablets at 20°-25°C (68°-77°F); excursions permitted to 15°-30°C (59° to 86°F)[see USP controlled room temperature].
Dispense in original container or USP equivalent tight container (100 mL or less).
For patient use: exposure of this product to high humidity outside the original container or USP equivalent tight container (100 mL or less) for longer than 2 weeks is not recommended.
16.3 KALETRA Oral Solution KALETRA (lopinavir and ritonavir) oral solution is a light yellow to orange colored liquid supplied in amber-colored multiple-dose bottles containing 400 mg lopinavir and 100 mg ritonavir per 5 mL (80 mg lopinavir and 20 mg ritonavir per mL) packaged with a marked dosing cup in the following size: 160 mL bottle……………………………….(NDC 0074-3956-46) Recommended Storage Store KALETRA oral solution at 2°-8°C (36°-46°F) until dispensed.
Avoid exposure to excessive heat.
For patient use, refrigerated KALETRA oral solution remains stable until the expiration date printed on the label.
If stored at room temperature up to 25°C (77°F), oral solution should be used within 2 months.
RECENT MAJOR CHANGES
Dosage and Administration General Administration Recommendations ( ) 2.1 01/2015 Dosage Recommendations in Adults ( ) 2.2 01/2015 Dosage Recommendations in Pediatric Patients ( ) 2.3 01/2015 Dosage Recommendations in Pregnancy ( ) 2.4 01/2015 Warnings and Precautions Risk of Serious Adverse Reactions Due to Drug Interactions ( ) 5.1 03/2015
GERIATRIC USE
8.5 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.
DOSAGE FORMS AND STRENGTHS
3 : Yellow, film-coated, ovaloid, debossed with the “a” logo and the code KA providing 200 mg lopinavir and 50 mg ritonavir.
Tablets, 200 mg lopinavir, 50 mg ritonavir : Pale yellow, film-coated, ovaloid, debossed with the “a” logo and the code KC providing 100 mg lopinavir and 25 mg ritonavir.
Tablets, 100 mg lopinavir, 25 mg ritonavir : Light yellow to orange colored liquid containing 400 mg lopinavir and 100 mg ritonavir per 5 mL (80 mg lopinavir and 20 mg ritonavir per mL).
Oral Solution Tablets: 200 mg lopinavir and 50 mg ritonavir ( ) 3 Tablets: 100 mg lopinavir and 25 mg ritonavir ( ) 3 Oral solution: 80 mg lopinavir and 20 mg ritonavir per milliliter ( ) 3
MECHANISM OF ACTION
12.1 Mechanism of Action Lopinavir is an antiviral drug .
As co-formulated in KALETRA, ritonavir inhibits the CYP3A-mediated metabolism of lopinavir, thereby providing increased plasma levels of lopinavir.
[see Microbiology ( )] 12.4
INDICATIONS AND USAGE
1 KALETRA is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients (14 days and older).
The following points should be considered when initiating therapy with KALETRA: The use of other active agents with KALETRA is associated with a greater likelihood of treatment response and .
[see Microbiology ( ) 12.4 Clinical Studies ( )] 14 Genotypic or phenotypic testing and/or treatment history should guide the use of KALETRA .
The number of baseline lopinavir resistance-associated substitutions affects the virologic response to KALETRA .
[see Microbiology ( )] 12.4 [see Microbiology ( )] 12.4 KALETRA is an HIV-1 protease inhibitor indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients (14 days and older).
( ) 1
PEDIATRIC USE
8.4 Pediatric Use 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.
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/mL and ritonavir 20 mg/mL at a dose of 300/75 mg/m twice daily plus two NRTIs in HIV-infected infants ≥14 days and < 6 months of age.
Results revealed that infants younger than 6 months of age generally had lower lopinavir AUC 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 HIV-1 RNA <400 copies/mL at Week 24 .
2 12 [see Adverse Reactions ( ), Clinical Pharmacology ( ), Clinical Studies ( )] 6.2 12.3 14.4 Safety and efficacy in pediatric patients > 6 months of age 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/mL and ritonavir 20 mg/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/m oral solution twice daily regimen without nevirapine and the 300/75 mg/m 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) .
2 2 [see Adverse Reactions ( ), Clinical Pharmacology ( ), Clinical Studies ( )] 6.2 12.3 14.4 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/m twice daily + ≥ 2 NRTIs; Group 2: 480/120 mg/m twice daily + ≥ 1 NRTI + 1 NNRTI) in 26 children and adolescents ≥ 2 years to < 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 <400 copies/mL at Week 48.
CD4+ cell count increases were noted in the eight patients who remained on treatment for 48 weeks .
2 2 [see Adverse Reactions ( ), Clinical Pharmacology ( )] 6.2 12.3 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.
PREGNANCY
8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to KALETRA during pregnancy.
Physicians are encouraged to register patients by calling the Antiretroviral Pregnancy Registry at 1-800-258-4263.
Risk Summary Available data from the Antiretroviral Pregnancy Registry show no difference in the risk of overall major birth defects compared to the background rate for major birth defects of 2.7% in the U.S.
reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP).
No treatment-related malformations were observed when lopinavir in combination with ritonavir was administered to pregnant rats or rabbits; however embryonic and fetal developmental toxicities occurred in rats administered maternally toxic doses.
Clinical Considerations Dose Adjustments During Pregnancy and the Postpartum Period Administer 400/100 mg of KALETRA twice daily in pregnant patients with no documented lopinavir-associated resistance substitutions .
There are insufficient data to recommend KALETRA dosing for pregnant patients with any documented lopinavir-associated resistance substitutions.
No dose adjustment of KALETRA is required for patients during the postpartum period.
[see Dosage and Administration ( ) and Clinical Pharmacology ( )] 2.4 12.3 Once daily KALETRA dosing is not recommended in pregnancy.
Avoid use of KALETRA oral solution during pregnancy due to the alcohol content.
KALETRA oral solution contains the excipients alcohol (42.4% v/v) and propylene glycol (15.3% w/v).
Data Human Data KALETRA was evaluated in 12 HIV-infected pregnant women in an open-label pharmacokinetic trial .
No new trends in the safety profile were identified in pregnant women dosed with KALETRA compared to the safety described in non-pregnant adults, based on the review of these limited data.
[see Clinical Pharmacology ( )] 12.3 Antiretroviral Pregnancy Registry Data: Based on prospective reports from the Antiretroviral Pregnancy Registry (APR) of over 3,000 exposures to lopinavir containing regimens (including over 1,000 exposed in the first trimester), there was no difference between lopinavir and overall birth defects compared with the background birth defect rate of 2.7% in the U.S.
reference population of the Metropolitan Atlanta Congenital Defects Program.
Based on prospective reports from the APR of over 5,000 exposures to ritonavir containing regimens (including over 2,000 exposures in the first trimester) there was no difference between ritonavir and overall birth defects compared with the U.S.
background rate (MACDP).
For both lopinavir and ritonavir, sufficient numbers of first trimester exposures have been monitored to detect at least a 1.5 fold increase in risk of overall birth defects and a 2 fold increase in risk of birth defects in the cardiovascular and genitourinary systems.
Animal Data 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).
NUSRING MOTHERS
8.2 Lactation Risk Summary 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.
Because of the potential for HIV-1 transmission in breastfed infants, advise women not to breastfeed.
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS The following have been observed in patients receiving KALETRA: The concomitant use of KALETRA and certain other drugs may result in known or potentially significant drug interactions.
Consult the full prescribing information prior to and during treatment for potential drug interactions.
( , ) 5.1 7.3 Toxicity in preterm neonates: KALETRA oral solution should not be used in preterm neonates in the immediate postnatal period because of possible toxicities.
A safe and effective dose of KALETRA oral solution in this patient population has not been established.
( , ).
2.3 5.2 Pancreatitis: Fatalities have occurred; suspend therapy as clinically appropriate.
( ) 5.3 Hepatotoxicity: Fatalities have occurred.
Monitor liver function before and during therapy, especially in patients with underlying hepatic disease, including hepatitis B and hepatitis C, or marked transaminase elevations.
( , ) 5.4 8.6 QT interval prolongation and isolated cases of torsade de pointes have been reported although causality could not be established.
Avoid use in patients with congenital long QT syndrome, those with hypokalemia, and with other drugs that prolong the QT interval.
( , , ) 5.1 5.5 12.3 PR interval prolongation may occur in some patients.
Cases of second and third degree heart block have been reported.
Use with caution in patients with pre-existing conduction system disease, ischemic heart disease, cardiomyopathy, underlying structural heart disease or when administering with other drugs that may prolong the PR interval.
( , , ) 5.1 5.6 12.3 Patients may develop new onset or exacerbations of diabetes mellitus, hyperglycemia ( ), immune reconstitution syndrome.
( ), redistribution/accumulation of body fat.
( ) 5.7 5.8 5.10 Total cholesterol and triglycerides elevations.
Monitor prior to therapy and periodically thereafter.
( ) 5.9 Hemophilia: Spontaneous bleeding may occur, and additional factor VIII may be required.
( ) 5.11 5.2 Toxicity in Preterm Neonates KALETRA oral solution contains the excipients alcohol (42.4% v/v) and propylene glycol (15.3% w/v).
When administered concomitantly with propylene glycol, ethanol competitively inhibits the metabolism of propylene glycol, which may lead to elevated concentrations.
Preterm neonates may be at increased risk of propylene glycol-associated adverse events due to diminished ability to metabolize propylene glycol, thereby leading to accumulation and potential adverse events.
Postmarketing life-threatening cases of cardiac toxicity (including complete AV block, bradycardia, and cardiomyopathy), lactic acidosis, acute renal failure, CNS depression and respiratory complications leading to death have been reported, predominantly in preterm neonates receiving KALETRA oral solution.
KALETRA oral solution should not be used in preterm neonates in the immediate postnatal period because of possible toxicities.
A safe and effective dose of KALETRA oral solution in this patient population has not been established.
However, if the benefit of using KALETRA oral solution to treat HIV infection in infants immediately after birth outweighs the potential risks, infants should be monitored closely for increases in serum osmolality and serum creatinine, and for toxicity related to KALETRA oral solution including: hyperosmolality, with or without lactic acidosis, renal toxicity, CNS depression (including stupor, coma, and apnea), seizures, hypotonia, cardiac arrhythmias and ECG changes, and hemolysis.
Total amounts of alcohol and propylene glycol from all medicines that are to be given to infants should be taken into account in order to avoid toxicity from these excipients and .
[see Dosage and Administration ( ) 2.3 Overdosage ( )] 10 5.3 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 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.
[see Warnings and Precautions ( )] 5.9 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.
5.4 Hepatotoxicity Patients with underlying hepatitis B or C or marked elevations in transaminase prior to treatment may be at increased risk for developing or worsening of transaminase elevations or hepatic decompensation with use of 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 ( )].
8.6 5.5 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 ( )] 12.3 5.6 PR Interval Prolongation Lopinavir/ritonavir prolongs the PR interval in some patients.
Cases of second or third degree atrioventricular block have been reported.
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 Clinical Pharmacology ( )] 12.3 5.7 Diabetes Mellitus/Hyperglycemia New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during post-marketing surveillance in HIV-1 infected patients receiving protease inhibitor therapy.
Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events.
In some cases, diabetic ketoacidosis has occurred.
In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases.
Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease inhibitor therapy and these events has not been established.
5.8 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 infection, cytomegalovirus, pneumonia [PCP], or tuberculosis) which may necessitate further evaluation and treatment.
Mycobacterium avium Pneumocystis jirovecii Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment.
5.9 Lipid Elevations Treatment with 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 and [see Adverse Reactions ( )] 6.1 [see Contraindications ( ) 4 Drug Interactions ( )].
7.3 5.10 Fat Redistribution Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy.
The mechanism and long-term consequences of these events are currently unknown.
A causal relationship has not been established.
5.11 Patients with Hemophilia Increased bleeding, including spontaneous skin hematomas and hemarthrosis have been reported in patients with hemophilia type A and B treated with protease inhibitors.
In some patients additional factor VIII was given.
In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced.
A causal relationship between protease inhibitor therapy and these events has not been established.
5.12 Resistance/Cross-resistance Because the potential for HIV cross-resistance among protease inhibitors has not been fully explored in KALETRA-treated patients, it is unknown what effect therapy with KALETRA will have on the activity of subsequently administered protease inhibitors [see Microbiology ( )].
12.4
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide) Patients or parents of patients should be informed that: General Information 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 tablets may be taken with or without food.
KALETRA oral solution 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.
.
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 have any kind of sex without protection .
Mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk.
Do not breastfeed Drug Interactions 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.
KALETRA tablets can be taken at the same time as didanosine without food.
Patients taking didanosine should take didanosine one hour before or two hours after KALETRA oral solution.
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.
KALETRA Tablets, 200 mg lopinavir and 50 mg ritonavir Manufactured by AbbVie LTD, Barceloneta, PR 00617 for AbbVie Inc., North Chicago, IL 60064 USA KALETRA Tablets, 100 mg lopinavir and 25 mg ritonavir and KALETRA Oral Solution AbbVie Inc., North Chicago, IL 60064 USA The brands listed are trademarks of their respective owners and are not trademarks of AbbVie Inc.
The makers of these brands are not affiliated with and do not endorse AbbVie Inc.
or its products.
© 2015 AbbVie Inc.
All rights reserved.
DOSAGE AND ADMINISTRATION
2 Tablets: May be taken with or without food, swallowed whole and not chewed, broken, or crushed.
( ) 2.1 Oral solution: must be taken with food.
( ) 2.1 ( ): Adults 2.2 Total recommended daily dosage is 800/200 mg given once or twice daily.
KALETRA can be given as once daily or twice daily regimen.
See Full Prescribing Information for details.
KALETRA once daily dosing regimen is not recommended in: Adult patients with three or more of the following lopinavir resistance-associated substitutions: L10F/I/R/V, K20M/N/R, L24I, L33F, M36I, I47V, G48V, I54L/T/V, V82A/C/F/S/T, and I84V.
( ) 12.4 In combination with carbamazepine, phenobarbital, or phenytoin.
( ) 7.3 In combination with efavirenz, nevirapine, or nelfinavir.
( ) 12.3 In pregnant women.
( , , ) 2.4 8.1 12.3 ( ): Pediatric Patients (14 days and older) 2.3 KALETRA once daily dosing regimen is not recommended in pediatric patients.
Twice daily dose is based on body weight or body surface area.
Concomitant Therapy in Adults and Pediatric Patients: Dose adjustments of KALETRA may be needed when co-administering with efavirenz, nevirapine, or nelfinavir.
( , , ) 2.2 2.3 7.3 KALETRA oral solution should not be administered to neonates before a postmenstrual age (first day of the mother’s last menstrual period to birth plus the time elapsed after birth) of 42 weeks and a postnatal age of at least 14 days has been attained ( , ) 2.3 5.2 ( ): Pregnancy 2.4 400/100 mg twice daily in pregnant patients with no documented lopinavir-associated resistance substitutions.
There are insufficient data to recommend a KALETRA dose for pregnant patients with any documented KALETRA-associated resistance substitutions.
No dose adjustment of KALETRA is required for patients during the postpartum period.
2.1 General Administration Recommendations KALETRA tablets may be taken with or without food.
The tablets should be swallowed whole and not chewed, broken, or crushed.
KALETRA oral solution must be taken with food.
2.2 Dosage Recommendations in Adults Considerations in Determining KALETRA Once Daily vs.
Twice Daily Dosing Regimen: KALETRA can be given as once daily or twice daily dosing regimen in patients with less than three lopinavir resistance-associated substitutions.
KALETRA must be given as twice daily dosing regimen in patients with three or more resistance-associated substitutions.
Table 1 includes the recommended once daily dosing regimen and Tables 2 and 3 include the recommended twice daily dosing regimen.
KALETRA once daily dosing regimen is not recommended in: 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 .
Adult [see Microbiology ( )] 12.4 In combination with carbamazepine, phenobarbital, or phenytoin .
[see Drug Interactions ( )] 7.3 .
In combination with efavirenz, nevirapine, or nelfinavir [see Drug Interactions ( ) and Clinical Pharmacology ( )] 7.3 12.3 In pregnant women .
[see Dosage and Administration ( ), Use in Specific Populations ( ) and Clinical Pharmacology ( )] 2.4 8.1 12.3 administered in combination with efavirenz, nevirapine or nelfinavir.
The dose of KALETRA must be increased when for twice daily dosing when KALETRA is taken in combination with efavirenz, nevirapine or nelfinavir.
Table 3 outlines the dosage recommendations Table 1.
Recommended Dosage in Adults- KALETRA Once Daily Regimen KALETRA Dosage Form Recommended Dosage 200 mg/50 mg Tablets 800 mg/200 mg (4 tablets) once daily 80 mg/20 mg per mL Oral Solution 800 mg/200 mg (10 mL) once daily Table 2.
Recommended Dosage in Adults – KALETRA Twice Daily Regimen KALETRA Dosage Form Recommended Dosage 200 mg/50 mg Tablets 400 mg/100 mg (2 tablets) twice daily 80 mg/20 mg per mL Oral Solution 400 mg/100 mg (5 mL) twice daily Table 3.
Recommended Dosage in Adults – KALETRA Twice Daily Regimen in Combination with Efavirenz, Nevirapine, or Nelfinavir KALETRA Dosage Form Recommended Dosage 200 mg/50 mg Tablets and 100 mg/25 mg Tablets 500 mg/125 mg (2 tablets of 200 mg/50 mg + 1 tablet of 100 mg/25 mg) twice daily 80 mg/20 mg per mL Oral Solution 520 mg/130 mg (6.5 mL) twice daily 2.3 Dosage Recommendations in Pediatric Patients KALETRA tablets and oral solution should not be administered once daily in pediatric patients < 18 years of age.
The dose of the oral solution should be administered using a calibrated dosing syringe.
Before prescribing KALETRA 100/25 mg tablets, children should be assessed for the ability to swallow intact tablets.
If a child is unable to reliably swallow a KALETRA tablet, the KALETRA oral solution formulation should be prescribed.
KALETRA oral solution should not be administered to neonates before a postmenstrual age (first day of the mother’s last menstrual period to birth plus the time elapsed after birth) of 42 weeks and a postnatal age of at least 14 days has been attained .
[see Warnings and Precautions ( )] 5.2 KALETRA oral solution contains 42.4% (v/v) alcohol and 15.3% (w/v) propylene glycol.
Special attention should be given to accurate calculation of the dosage of KALETRA, transcription of the medication order, dispensing information and dosing instructions to minimize the risk for medication errors, and overdose.
This is especially important for infants and young children.
Total amounts of alcohol and propylene glycol from all medicines that are to be given to pediatric patients 14 days to 6 months of age should be taken into account in order to avoid toxicity from these excipients and [see Warnings and Precautions ( ) 5.2 Overdosage ( )].
10 Pediatric Dosage Calculations Calculate the appropriate dose of KALETRA for each individual based on body weight (kg) or body surface area (BSA) to avoid underdosing or exceeding the recommended adult dose.
pediatric patient Body surface area (BSA) can be calculated as follows: The KALETRA dose can be calculated based on weight or BSA: Based on Weight: Patient Weight (kg) × Prescribed lopinavir dose (mg/kg) = Administered lopinavir dose (mg) Based on BSA: Patient BSA (m ) × Prescribed lopinavir dose (mg/m ) = Administered lopinavir dose (mg) 2 2 If KALETRA oral solution is used, the volume (mL) of KALETRA solution can be determined as follows: Volume of KALETRA solution (mL) = Administered lopinavir dose (mg) ÷ 80 (mg/mL) Dosage Recommendation in Pediatric Patients 14 Days to 6 Months: In pediatric patients 14 days to 6 months of age, the recommended dosage of lopinavir/ritonavir using KALETRA oral solution is 16/4 mg/kg or 300/75 mg/m twice daily.
Prescribers should calculate the appropriate dose based on body weight or body surface area.
Table 4 summarizes the recommended daily dosing regimen for pediatric patients 14 days to 6 months.
2 It is recommended that KALETRA not be administered in combination in patients < 6 months of age.
with efavirenz, nevirapine, or nelfinavir Table 4.
Recommended KALETRA Oral Daily Dosage in Pediatric Patients 14 days to 6 months Patient Age Based on Weight (mg/kg) Based on BSA (mg/m ) 2 Frequency 14 days to 6 months 16/4 300/75 Given twice daily 6 Months to 18 Years: Dosage Recommendation in Pediatric Patients Without Concomitant Efavirenz, Nevirapine, or Nelfinavir Dosing recommendations using oral solution In children 6 months to 18 years of age, the recommended dosage of lopinavir/ritonavir using KALETRA oral solution without concomitant efavirenz, nevirapine, or nelfinavir is 230/57.5 mg/m given twice daily, not to exceed the recommended adult dose (400/100 mg [5 mL] twice daily).
If weight-based dosing is preferred, the recommended dosage of lopinavir/ritonavir for patients < 15 kg is 12/3 mg/kg given twice daily and the dosage for patients ≥ 15 kg to 40 kg is 10/2.5 mg/kg given twice daily.
Table 5 summarizes the recommended daily dosing regimen for pediatric patients 6 months to 18 years.
2 Table 5.
Recommended KALETRA Oral Daily Dosage in Pediatric Patients 6 months to 18 years Patient Age Based on Weight (mg/kg) Based on BSA (mg/m ) 2 Frequency 6 months to 18 years <15 kg 12/3 230/57.5 Given twice daily ≥15 kg to 40 kg 10/2.5 Dosing recommendations using tablets Table 6 provides the dosing recommendations for pediatric patients 6 months to 18 years of age based on body weight or body surface area for KALETRA tablets.
Table 6.
Pediatric Dosing Recommendations for Patients 6 Months to 18 Years of Age Based on Body Weight or Body Surface Area for KALETRA Tablets Without Concomitant Efavirenz, Nevirapine, or Nelfinavir Body Weight (kg) Body Surface Area (m ) 2 * Recommended number of 100/25 mg Tablets Twice Daily 15 to 25 ≥0.6 to 25 to 35 ≥0.9 to 35 ≥1.4 4 (or two 200/50 mg tablets) * KALETRA oral solution is available for children with a BSA less than 0.6 m or those who are unable to reliably swallow a tablet.
2 Concomitant Therapy: Efavirenz, Nevirapine, or Nelfinavir Dosing recommendations using oral solution A dose increase of KALETRA to 300/75 mg/m using KALETRA oral solution is needed when co-administered with efavirenz, nevirapine, or nelfinavir in children (both treatment-naïve and treatment-experienced) 6 months to 18 years of age, not to exceed the recommended adult dose (533/133 mg [6.5 mL] twice daily).
If weight-based dosing is preferred, the recommended dosage for patients 15 kg to 45 kg is 11/2.75 mg/kg given twice daily.
2 Dosing recommendations using tablets Table 7 provides the dosing recommendations for pediatric patients 6 months to 18 years of age based on body weight or body surface area for KALETRA tablets when given in combination with efavirenz, nevirapine, or nelfinavir.
Table 7.
Pediatric Dosing Recommendations for Patients 6 Months to 18 Years of Age Based on Body Weight or Body Surface Area for KALETRA Tablets With Concomitant Efavirenz , Nevirapine, or Nelfinavir † † Body Weight (kg) Body Surface Area (m ) 2 * Recommended number of 100/25 mg Tablets Twice Daily 15 to 20 ≥0.6 to 20 to 30 ≥0.8 to 30 to 45 ≥1.2 to 45 ≥1.7 5 [see Dosage and Administration ( )] 2.2 * KALETRA oral solution is available for children with a BSA less than 0.6 m or those who are unable to reliably swallow a tablet.
Please refer to the individual product labels for appropriate dosing in children.
2 † Body surface area equation.
2.4 Dosage Recommendations in Pregnancy Administer 400/100 mg of KALETRA twice daily in pregnant patients with no documented lopinavir-associated resistance substitutions.
Once daily KALETRA dosing is not recommended in pregnancy .
[see Use in Specific Populations ( ) and Clinical Pharmacology ( )] 8.1 12.3 There are insufficient data to recommend dosing in pregnant women with any documented lopinavir-associated resistance substitutions.
No dosage adjustment of KALETRA is required for patients during the postpartum period.
Avoid use of KALETRA oral solution in pregnant women .
[see Use in Specific Populations ( )] 8.1