Document
DailyMed Label: Kaletra
Title
DailyMed Label: Kaletra
Date
2023
Document type
DailyMed Prescription
Name
Kaletra
Generic name
Lopinavir and Ritonavir
Manufacturer
NuCare Pharmaceuticals,Inc.
Product information
NDC: 68071-2348
Product information
NDC: 68071-2348
Product information
NDC: 68071-2348
Description
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
S -[1
R *,(
R *), 3
R *, 4
R *]]-
N -[4-[[(2,6-dimethylphenoxy)acetyl]amino]-3-hydroxy-5-phenyl-1-(phenylmethyl)pentyl]tetrahydro-alpha-(1-methylethyl)-2-oxo-1(2
H )-pyrimidineacetamide. Its molecular formula is C
37 H
48 N
4 O
5 , 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:
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
S -(5
R *,8
R *,10
R *,11
R *)]. Its molecular formula is C
37 H
48 N
6 O
5 S
2 , 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:
KALETRA tablets are available for oral administration in two strengths:
Yellow or red tablets containing 200 mg of lopinavir and 50 mg of ritonavir
Pale yellow or pink 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: colloidal silicon dioxide, copovidone, sodium stearyl fumarate and sorbitan monolaurate. The following are the ingredients in the film coating: colloidal silicon dioxide, hydroxypropyl cellulose, hypromellose, polyethylene glycol 400, polyethylene glycol 3350, polysorbate 80, talc, titanium dioxide, and yellow ferric oxide E172.
The red, 200 mg lopinavir and 50 mg ritonavir, tablets contain the following inactive ingredients: colloidal silicon dioxide, copovidone, sodium stearyl fumarate and sorbitan monolaurate. The following are the ingredients in the film coating: colloidal silicon dioxide, hydroxypropyl cellulose, hypromellose, polyethylene glycol 400, polyethylene glycol 3350, polysorbate 80, talc, titanium dioxide, and red ferric oxide E172.
The pale yellow, 100 mg lopinavir and 25 mg ritonavir, tablets contain the following inactive ingredients: colloidal silicon dioxide, copovidone, sodium stearyl fumarate, and sorbitan monolaurate. The following are the ingredients in the film coating: polyethylene glycol 3350, polyvinyl alcohol, talc, titanium dioxide, and yellow ferric oxide E172.
The pink, 100 mg lopinavir and 25 mg ritonavir, tablets contain the following inactive ingredients: colloidal silicon dioxide, copovidone, sodium stearyl fumarate, and sorbitan monolaurate. The following are the ingredients in the film coating: polyethylene glycol 3350, polyvinyl alcohol, talc, titanium dioxide, and red 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, artificial cotton candy flavor, citric acid, ethanol, 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 approximately 42% (v/v) ethanol and approximately 15% (w/v) propylene glycol.
lopinavir-chem-structure
ritonavir-chem-structure
Indications
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.
Limitations of Use:
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 )]
.
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 )
Dosage
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 )
KALETRA oral solution is not recommended for use with polyurethane feeding tubes due to potential incompatibility. Feeding tubes composed of silicone or polyvinyl chloride (PVC) can be used.
(2.2)
Adults (
2.3 ):
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. (
2.5 ,
8.1 ,
12.3 )
Pediatric Patients (14 days and older) (
2.4 ):
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. (
2.3 ,
2.4 ,
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 (
2.4 ,
5.2 )
Pregnancy (
2.5 ):
400/100 mg twice daily in pregnant patients with no documented lopinavir-associated resistance substitutions.
There are insufficient data to recommend a 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.
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.
Because KALETRA oral solution contains ethanol and propylene glycol, it is not recommended for use with polyurethane feeding tubes due to potential incompatibility. Feeding tubes that are compatible with ethanol and propylene glycol, such as silicone and polyvinyl chloride (PVC) feeding tubes, can be used for administration of KALETRA oral solution. Follow instructions for use of the feeding tube to administer the medicine.
KALETRA can be given in once daily or twice daily dosing regimen at dosages noted in Tables 1 and 2. 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
[see Microbiology (
12.4 )]
.
In combination with carbamazepine, phenobarbital, or phenytoin
[see Drug Interactions (
7.3 )]
.
In combination with efavirenz, nevirapine, or nelfinavir
[see Drug Interactions (
7.3 ) and Clinical Pharmacology (
12.3 )]
.
In pediatric patients younger than 18 years of age
[see Dosage and Administration (
2.4 )]
.
In pregnant women
[see Dosage and Administration (
2.5 ), Use in Specific Populations (
8.1 ) and Clinical Pharmacology (
12.3 )]
.
Table 1. Recommended Dosage in Adults - 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
The dose of KALETRA must be increased when administered in combination with efavirenz, nevirapine or nelfinavir. Table 3 outlines the dosage recommendations for twice daily dosing when KALETRA is taken in combination with these agents.
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
KALETRA tablets and oral solution are not recommended for once daily dosing in pediatric patients younger than 18 years of age. The dose of the oral solution should be administered using the calibrated cup (supplied) or oral dosing syringe. KALETRA 100/25 mg tablets should be considered only in children who have reliably demonstrated the ability to swallow the intact tablet.
KALETRA oral solution is not recommended in 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 approximately 42% (v/v) ethanol and approximately 15% (w/v) propylene glycol. Total amounts of ethanol 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
[see Warnings and Precautions (
5.2 )
and
Overdosage (
10 )].
Pediatric Dosage Calculations
Calculate the appropriate dose of KALETRA for each individual pediatric patient based on body weight (kg) or body surface area (BSA) to avoid underdosing or exceeding the recommended adult dose.
Body surface area (BSA) can be calculated as follows:
The 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
2 ) × Prescribed lopinavir dose (mg/m
2 ) = Administered lopinavir dose (mg)
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)
Oral Solution Dosage Recommendation in Pediatric Patients 14 Days to Less Than 18 Years:
Table 4 summarizes the recommended daily dosing regimen for pediatric patients 14 days to less than 18 years of age using the oral solution.
KALETRA administered in combination with efavirenz, nevirapine, or nelfinavir in patients younger than 6 months of age is not recommended. Total dose of KALETRA oral solution in pediatric patients should not exceed the recommended adult daily dose of 400/100 mg (5mL) twice daily.
Table 4. KALETRA Oral Solution Daily Dosage Recommendations in Pediatric Patients 14 days to Less Than 18 Years Without Concomitant Efavirenz, Nevirapine, or Nelfinavir
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
Older than 6 months to less than 18 years
Less than15 kg
12/3
230/57.5
Given twice
daily
15 kg to 40 kg
10/2.5
Tablet Dosage Recommendation in Pediatric Patients Older than 6 Months to Less than 18 Years:
Table 5 provides the dosing recommendations for pediatric patients older than 6 months to less than 18 years of age based on body weight or body surface area for KALETRA tablets.
Table 5. KALETRA Tablet Daily Dosage Recommendations in Pediatric Patients > 6 Months to < 18 Years of Age Without Concomitant Efavirenz, Nevirapine, or Nelfinavir
Body Weight (kg)
Body Surface Area (m
2 )
*
Recommended number
of 100/25 mg Tablets
Twice Daily
≥15 to 25
≥0.6 to < 0.9
2
>25 to 35
≥0.9 to < 1.4
3
>35
≥1.4
4
* KALETRA oral solution is available for children with a BSA less than 0.6 m
2 or those who are unable to reliably swallow a tablet.
Concomitant Therapy: Efavirenz, Nevirapine, or Nelfinavir
Dosing recommendations using oral solution
Table 6 provides the dosing recommendations for pediatric patients older than 6 months to less than 18 years of age based on body weight or body surface area for KALETRA Oral Solution when given in combination with efavirenz, nevirapine, or nelfinavir:
Table 6. KALETRA Oral Solution Daily Dosage Recommendations for Pediatric Patients > 6 Months to < 18 Years of Age With Concomitant Efavirenz, Nevirapine, or Nelfinavir
Patient Age
Based on Weight
(mg/kg)
Based on BSA
(mg/m
2 )
Frequency
> 6 months to
< 18 years
<15 kg
13/3.25
300/75
Given twice
daily
≥15 kg to 45 kg
11/2.75
Dosing recommendations using tablets
Table 7 provides the dosing recommendations for pediatric patients older than 6 months to less than 18 years of age based on body weight or body surface area for KALETRA tablets when given in combination with efavirenz, nevirapine, or nelfinavir.
Table 7. KALETRA Tablet Daily Dosage Recommendations for Pediatric Patients > 6 Months to < 18 Years of Age With Concomitant Efavirenz
† , Nevirapine, or Nelfinavir
†
Body Weight (kg)
Body Surface Area (m
2 )
*
Recommended number of
100/25 mg Tablets Twice Daily
≥15 to 20
≥0.6 to < 0.8
2
>20 to 30
≥0.8 to < 1.2
3
>30 to 45
≥1.2 to <1.7
4
>45
≥1.7
5
[see Dosage and Administration (
2.4 )]
* KALETRA oral solution is available for children with a BSA less than 0.6 m
2 or those who are unable to reliably swallow a tablet.
† Please refer to the individual product labels for appropriate dosing in children.
Body surface area equation.
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 (
8.1 ) and Clinical Pharmacology (
12.3 )]
.
There are insufficient data to recommend dosing in pregnant women with any documented lopinavir-associated resistance substitutions.
No dosage adjustment of 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 )]
.
Dosage forms
Tablets:
200 mg lopinavir, 50 mg ritonavir: Yellow, film-coated, ovaloid, debossed with the “a” logo and the code KA containing 200 mg lopinavir and 50 mg ritonavir.
100 mg lopinavir, 25 mg ritonavir: Pale yellow, film-coated, ovaloid, debossed with the “a” logo and the code KC containing 100 mg lopinavir and 25 mg ritonavir.
200 mg lopinavir, 50 mg ritonavir: Red, film-coated, ovaloid, debossed with the “a” logo and the code AL containing 200 mg lopinavir and 50 mg ritonavir.
100 mg lopinavir, 25 mg ritonavir: Pink, film-coated, ovaloid, debossed with the “a” logo and the code AC containing 100 mg lopinavir and 25 mg ritonavir.
Oral Solution:
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).
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 )
Contraindications
KALETRA is contraindicated in patients with previously demonstrated clinically significant hypersensitivity (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, urticaria, angioedema) to any of its ingredients, including ritonavir.
KALETRA is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening reactions
[see Drug Interactions (
7.1 ) and Clinical Pharmacology (
12.3 )]
.
Alpha 1- Adrenoreceptor Antagonist: alfuzosin
Antianginal: ranolazine
Antiarrhythmic: dronedarone
Anti-gout: colchicine
Antipsychotics: lurasidone, pimozide
Ergot Derivatives: dihydroergotamine, ergotamine, methylergonovine
GI Motility Agent: cisapride
Hepatitis C direct acting antiviral: elbasvir/grazoprevir
HMG-CoA Reductase Inhibitors: lovastatin, simvastatin
Microsomal triglyceride transfer protein (MTTP) Inhibitor: lomitapideMicrosomal triglyceride transfer protein (MTTP) Inhibitor: lomitapide
PDE5 Inhibitor: sildenafil (Revatio
® ) when used for the treatment of pulmonary arterial hypertension
Sedative/Hypnotics: triazolam, orally administered midazolam
KALETRA is contraindicated with drugs that are potent CYP3A inducers where significantly reduced lopinavir plasma concentrations may be associated with the potential for loss of virologic response and possible resistance and cross-resistance
[see Drug Interactions (
7.2 ) and Clinical Pharmacology (
12.3 )]
.
Anticancer Agents: apalutamide
Antimycobacterial: rifampin
Herbal Products: St. John's Wort (hypericum perforatum)
Hypersensitivity to KALETRA (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, urticaria, angioedema) or any of its ingredients, including ritonavir. (
4 )
Co-administration with drugs highly dependent on CYP3A for clearance and for which elevated plasma levels may result in serious and/or life-threatening events. (
4 )
Co-administration with potent CYP3A inducers where significantly reduced lopinavir plasma concentrations may be associated with the potential for loss of virologic response and possible resistance and cross resistance. (
4 )
Warnings
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. (
2.4 ,
5.2 )
Pancreatitis: Fatalities have occurred; suspend therapy as clinically appropriate. (
5.3 )
Hepatotoxicity: Fatalities have occurred. Monitor liver function before and during therapy, especially in patients with underlying hepatic disease, including hepatitis B and hepatitis C, or marked transaminase elevations. (
5.4 ,
8.6 )
QT interval prolongation and isolated cases of torsade de pointes have been reported although causality could not be established. Avoid use in patients with congenital long QT syndrome, those with hypokalemia, and with other drugs that prolong the QT interval. (
5.1 ,
5.5 ,
12.3 )
PR interval prolongation may occur in some patients. Cases of second and third degree heart block have been reported. Use with caution in patients with pre-existing conduction system disease, ischemic heart disease, cardiomyopathy, underlying structural heart disease or when administering with other drugs that may prolong the PR interval. (
5.1 ,
5.6 ,
12.3 )
Patients may develop new onset or exacerbations of diabetes mellitus, hyperglycemia (
5.7 ), immune reconstitution syndrome. (
5.8 ), redistribution/accumulation of body fat. (
5.10 )
Total cholesterol and triglycerides elevations. Monitor prior to therapy and periodically thereafter. (
5.9 )
Hemophilia: Spontaneous bleeding may occur, and additional factor VIII may be required. (
5.11 )
Initiation of KALETRA, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving KALETRA, may increase plasma concentrations of medications metabolized by CYP3A. Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of KALETRA, respectively. These interactions may lead to:
Clinically significant adverse reactions, potentially leading to severe, life-threatening, or fatal events from greater exposures of concomitant medications.
Clinically significant adverse reactions from greater exposures of KALETRA.
Loss of therapeutic effect of KALETRA and possible development of resistance.
See Table 12 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations
[see Drug Interactions (
7 )]
. Consider the potential for drug interactions prior to and during KALETRA therapy; review concomitant medications during KALETRA therapy, and monitor for the adverse reactions associated with the concomitant medications
[see Contraindications (
4 )
and
Drug Interactions (
7 )]
.
KALETRA oral solution contains the excipients ethanol, approximately 42% (v/v) and propylene glycol, approximately 15% (w/v). When administered concomitantly with propylene glycol, ethanol competitively inhibits the metabolism of propylene glycol, which may lead to elevated concentrations. Preterm neonates may be at increased risk of propylene glycol-associated adverse events due to diminished ability to metabolize propylene glycol, thereby leading to accumulation and potential adverse events. Postmarketing life-threatening cases of cardiac toxicity (including complete AV block, bradycardia, and cardiomyopathy), lactic acidosis, acute renal failure, CNS depression and respiratory complications leading to death have been reported, predominantly in preterm neonates receiving 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 ethanol and propylene glycol from all medicines that are to be given to infants should be taken into account in order to avoid toxicity from these excipients
[see Dosage and Administration (
2.4 )
and
Overdosage (
10 )]
.
Pancreatitis has been observed in patients receiving KALETRA therapy, including those who developed marked triglyceride elevations. In some cases, fatalities have been observed. Although a causal relationship to KALETRA has not been established, marked triglyceride elevations are a risk factor for development of pancreatitis
[see Warnings and Precautions (
5.9 )]
. Patients with advanced HIV-1 disease may be at increased risk of elevated triglycerides and pancreatitis, and patients with a history of pancreatitis may be at increased risk for recurrence during KALETRA therapy.
Pancreatitis should be considered if clinical symptoms (nausea, vomiting, abdominal pain) or abnormalities in laboratory values (such as increased serum lipase or amylase values) suggestive of pancreatitis occur. Patients who exhibit these signs or symptoms should be evaluated and KALETRA and/or other antiretroviral therapy should be suspended as clinically appropriate.
Patients with underlying hepatitis B or C or marked elevations in transaminase prior to treatment may be at increased risk for developing or worsening of transaminase elevations or hepatic decompensation with use of KALETRA.
There have been postmarketing reports of hepatic dysfunction, including some fatalities. These have generally occurred in patients with advanced HIV-1 disease taking multiple concomitant medications in the setting of underlying chronic hepatitis or cirrhosis. A causal relationship with KALETRA therapy has not been established.
Elevated transaminases with or without elevated bilirubin levels have been reported in HIV-1 mono-infected and uninfected patients as early as 7 days after the initiation of KALETRA in conjunction with other antiretroviral agents. In some cases, the hepatic dysfunction was serious; however, a definitive causal relationship with KALETRA therapy has not been established.
Appropriate laboratory testing should be conducted prior to initiating therapy with KALETRA and patients should be monitored closely during treatment. Increased AST/ALT monitoring should be considered in the patients with underlying chronic hepatitis or cirrhosis, especially during the first several months of KALETRA treatment
[see Use in Specific Populations (
8.6 )].
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 )]
.
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 )]
.
New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during post-marketing surveillance in HIV-1 infected patients receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease inhibitor therapy and these events has not been established. Consider monitoring for hyperglycemia, new onset diabetes mellitus or an exacerbation of diabetes mellitus in patients treated with KALETRA.
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including KALETRA. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as
Mycobacterium avium infection, cytomegalovirus,
Pneumocystis jirovecii pneumonia [PCP], or tuberculosis) which may necessitate further evaluation and treatment.
Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment.
Treatment with KALETRA has resulted in large increases in the concentration of total cholesterol and triglycerides
[see Adverse Reactions (
6.1 )]
. Triglyceride and cholesterol testing should be performed prior to initiating KALETRA therapy and at periodic intervals during therapy. Lipid disorders should be managed as clinically appropriate, taking into account any potential drug-drug interactions with KALETRA and HMG-CoA reductase inhibitors
[see Contraindications (
4 )
and
Drug Interactions (
7.3 )]
.
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.
Increased bleeding, including spontaneous skin hematomas and hemarthrosis have been reported in patients with hemophilia type A and B treated with protease inhibitors. In some patients additional factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced. A causal relationship between protease inhibitor therapy and these events has not been established.
Because the potential for HIV 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 )].
Adverse reactions
The following adverse reactions are discussed in greater detail in other sections of the labeling.
Drug interactions
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 )
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 12.
Additionally, KALETRA induces glucuronidation.
Published data suggest that lopinavir is an inhibitor of OATP1B1.
These examples are a guide and not considered a comprehensive list of all possible drugs that may interact with lopinavir/ritonavir. The healthcare provider should consult appropriate references for comprehensive information.
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.
Table 12 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 Contraindications (
4 ), Warnings and Precautions (
5.1 ), Clinical Pharmacology (
12.3 )]
for magnitude of interaction.
Table 12. 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.
HIV-1 Protease Inhibitor:
nelfinavir*
↑ nelfinavir
↑ M8 metabolite of nelfinavir
↓ lopinavir
KALETRA once daily in combination with nelfinavir is not recommended
[see Dosage and Administration (
2 )]
.
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
Co-administration with tipranavir (500 mg twice daily) and ritonavir (200 mg twice daily) is not recommended.
HIV CCR5 – Antagonist:
maraviroc*
↑ maraviroc
When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for maraviroc.
Non-nucleoside Reverse
Transcriptase Inhibitors:
efavirenz*,
nevirapine*
↓ lopinavir
Increase the dose of KALETRA tablets to 500/125 mg when KALETRA tablet is co-administered with efavirenz or nevirapine. KALETRA once daily in combination with efavirenz or nevirapine is not recommended
[see Dosage and Administration (
2 )]
.
Non-nucleoside Reverse
Transcriptase Inhibitor:
delavirdine
↑ lopinavir
Appropriate doses of the combination with respect to safety and efficacy have not been established.
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 disoproxil fumarate*
↑ tenofovir
Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir.
Nucleoside Reverse
Transcriptase Inhibitors:
abacavir
zidovudine
↓ abacavir
↓ zidovudine
The clinical significance of this potential interaction is unknown.
Other Agents
Alpha 1- Adrenoreceptor
Antagonist:
alfuzosin
↑ alfuzosin
Contraindicated due to potential hypotension
[see Contraindications (
4 )]
.
Antianginal:
ranolazine
↑ ranolazine
Contraindicated due to potential for serious and/or life-threatening reactions
[see Contraindications (
4 )]
.
Antiarrhythmics:
dronedarone
↑ dronedarone
Contraindicated due to potential for cardiac arrhythmias
[see Contraindications (
4 )]
.
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:
abemaciclib,
apalutamide,
encorafenib,
ibrutinib,
ivosidenib,
dasatinib,
neratinib,
nilotinib,
venetoclax,
vinblastine,
vincristine
↑ anticancer agents
↓lopinavir/ritonavir
#
Apalutamide is contraindicated due to potential for loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors
[see Contraindications (
4 )]
.
Avoid co-administration of encorafenib or ivosidenib with KALETRA due to potential risk of serious adverse events such as QT interval prolongation. If co-administration of encorafenib with KALETRA cannot be avoided, modify dose as recommended in encorafenib USPI. If co-administration of ivosidenib with KALETRA cannot be avoided, reduce ivosidenib dose to 250 mg once daily.
Avoid use of neratinib, venetoclax or ibrutinib with KALETRA.
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
↑↓ warfarin
↑ rivaroxaban
Concentrations of warfarin may be affected. Initial frequent monitoring of the INR during KALETRA and warfarin co-administration is recommended.
Avoid concomitant use of rivaroxaban and KALETRA. Co-administration of KALETRA and rivaroxaban may lead to increased risk of 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 once daily in combination with carbamazepine, phenobarbital, or phenytoin is not recommended.
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
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
Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion.
Antidepressant:
trazodone
↑ trazodone
Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. A lower dose of trazodone should be considered.
Anti-infective:
clarithromycin
↑ clarithromycin
For patients with renal impairment, adjust clarithromycin dose as follows:
For patients on KALETRA with CL
CR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%.
For patients on KALETRA with CL
CR < 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
isavuconazonium sulfate*
↑ ketoconazole
↑ itraconazole
↓ voriconazole
↑ isavuconazonium
High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended.
The coadministration of voriconazole and KALETRA should be avoided unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Isavuconazonium and Kaletra should be coadministered with caution. Alternative antifungal therapies should be considered in these patients.
Anti-gout:
colchicine
↑ colchicine
Contraindicated due to potential for serious and/or life-threatening reactions in patients with renal and/or hepatic impairment
[see Contraindications (
4 )]
.
For patients with normal renal or hepatic function:
Treatment of gout flares-co-administration of colchicine in patients on 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.
Prophylaxis of gout flares-co-administration of colchicine in patients on KALETRA:
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.
Treatment of familial Mediterranean fever (FMF)-co-administration of colchicine in patients on KALETRA:
Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Antimycobacterial:
rifampin
↓ lopinavir
Contraindicated due to potential loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents
[see Contraindications (
4 )]
.
Antimycobacterial:
bedaquiline
↑ bedaquiline
Bedaquiline should only be used with KALETRA if the benefit of co-administration outweighs the risk.
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.
Antiparasitic:
atovaquone
↓ atovaquone
Clinical significance is unknown; however, increase in atovaquone doses may be needed.
Antipsychotics:
lurasidone
pimozide
↑ lurasidone
↑ pimozide
Contraindicated due to potential for serious and/or life-threatening reactions
[see Contraindications (
4 )]
.
Contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias
[see Contraindications (
4 )]
.
Antipsychotics:
quetiapine
↑ quetiapine
Initiation of KALETRA in patients taking 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 quetiapine in patients taking KALETRA:
Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.
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.
Dihydropyridine Calcium
Channel Blockers: e.g.
felodipine,
nifedipine,
nicardipine
↑ dihydropyridine calcium channel blockers
Clinical monitoring of patients is recommended and a dose reduction of the dihydropyridine calcium channel blocker may be considered.
Disulfiram/metronidazole
KALETRA oral solution contains ethanol, 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
Co-administration of bosentan in patients on KALETRA:
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.
Co-administration of KALETRA in patients on bosentan:
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.
Ergot Derivatives:
dihydroergotamine,
ergotamine,
methylergonovine
↑ ergot derivatives
Contraindicated due to potential for acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues
[see Contraindications (
4 )]
.
GI Motility Agent:
cisapride
↑ cisapride
Contraindicated due to potential for cardiac arrhythmias
[see Contraindications (
4 )]
.
GnRH Receptor Antagonists:
elagolix
↑ elagolix
↓ lopinavir/ritonavir
Concomitant use of elagolix 200 mg twice daily and KALETRA for more than 1 month is not recommended due to potential risk of adverse events such as bone loss and hepatic transaminase elevations. Limit concomitant use of elagolix 150 mg once daily and KALETRA to 6 months.
Hepatitis C direct acting
antiviral:
elbasvir/grazoprevir
↑ elbasvir/grazoprevir
Contraindicated due to increased risk of alanine transaminase (ALT) elevations
[see Contraindications (
4 )]
.
Hepatitis C direct acting antivirals:
boceprevir*
glecaprevir/pibrentasvir
simeprevir
sofosbuvir/velpatasvir/voxilaprevir
ombitasvir/paritaprevir/
ritonavir and dasabuvir*
↓ lopinavir
↓ boceprevir
↓ ritonavir
↑glecaprevir
↑ pibrentasvir
↑ simeprevir
↑ sofosbuvir
↑ velpatasvir
↑ voxilaprevir
↑ ombitasvir
↑ paritaprevir
↑ ritonavir
↔ dasabuvir
It is not recommended to co-administer KALETRA and boceprevir, glecaprevir/pibrentasvir,
simeprevir, sofosbuvir/velpatasvir/voxilaprevir, or ombitasvir/paritaprevir/ritonavir and dasabuvir.
Herbal Products:
St. John's Wort
(hypericum perforatum)
↓ lopinavir
Contraindicated due to potential for loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors
[see Contraindications (
4 )]
.
Lipid-modifying agents
HMG-CoA Reductase
Inhibitors:
lovastatin
simvastatin
atorvastatin
rosuvastatin
Microsomal triglyceride transfer protein (MTTP) Inhibitor: lomitapide
↑ lovastatin
↑ simvastatin
↑ atorvastatin
↑ rosuvastatin
↑ lomitapide
Contraindicated due to potential for myopathy including rhabdomyolysis
[see Contraindications (
4 )]
.
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.
Lomitapide is a sensitive substrate for CYP3A4 metabolism. CYP3A4 inhibitors increase the exposure of lomitapide, with strong inhibitors increasing exposure approximately 27-fold. Concomitant use of moderate or strong CYP3A4 inhibitors with lomitapide is contraindicated due to potential for hepatotoxicity
[see Contraindications (
4 )]
.
Immunosuppressants: e.g.
cyclosporine,
tacrolimus,
sirolimus
↑ immunosuppressants
Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA.
Kinase Inhibitors:
fostamatinib
(also see anticancer
agents above)
↑ fostamatinib
metabolite R406
Monitor for toxicities of R406 such as hepatotoxicity and neutropenia. Fostamatinib dose reduction may be required.
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.
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
Sildenafil when used for the treatment of pulmonary arterial hypertension (Revatio
® ) is contraindicated due to the potential for sildenafil-associated adverse events, including visual abnormalities, hypotension, prolonged erection, and syncope
[see Contraindications (
4 )]
.
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 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
[see Contraindications (
4 )]
.
The following dose adjustments are recommended for use of tadalafil (Adcirca
® ) with KALETRA:
Co-administration of ADCIRCA in patients on 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.
Co-administration of KALETRA in patients on ADCIRCA:
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.
Sedative/Hypnotics:
triazolam,
orally administered midazolam
↑ triazolam
↑ midazolam
Contraindicated due to potential for prolonged or increased sedation or respiratory depression
[see Contraindications (
4 )]
.
Sedative/Hypnotics:
parenterally administered midazolam
↑ 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.
Systemic/Inhaled/
Nasal/Ophthalmic
Corticosteroids: e.g.,
betamethasone
budesonide
ciclesonide
dexamethasone
fluticasone
methylprednisolone
mometasone
prednisone
triamcinolone
↓ lopinavir
↑ glucocorticoids
Coadministration with oral dexamethasone or other systemic corticosteroids that induce CYP3A may result in loss of therapeutic effect and development of resistance to lopinavir. Consider alternative corticosteroids.
Coadministration with corticosteroids whose exposures are significantly increased by strong CYP3A inhibitors can increase the risk for Cushing’s syndrome and adrenal suppression.
Alternative corticosteroids including beclomethasone and prednisolone (whose PK and/or PD are less affected by strong CYP3A inhibitors relative to other studied steroids) should be considered, particularly for long-term use.
*
see Clinical Pharmacology (
12.3 )
for magnitude of interaction.
# refers to interaction with apalutamide.
Drug interaction or clinical studies reveal no clinically significant interaction between KALETRA and desipramine (CYP2D6 probe), etravirine, pitavastatin, pravastatin, stavudine, lamivudine, omeprazole, raltegravir, ranitidine, or rilpivirine.
Based on known metabolic profiles, clinically significant drug interactions are not expected between KALETRA and dapsone, trimethoprim/sulfamethoxazole, azithromycin, erythromycin, or fluconazole.
Use in_specific_populations
Lactation: Breastfeeding not recommended. (
8.2 )
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)
(see Data) . The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15-20%. The background risk for major birth defects and miscarriage for the indicated population is unknown. Methodological limitations of the APR include the use of MACDP as the external comparator group. The MACDP population is not disease-specific, evaluates women and infants from a limited geographic area, and does not include outcomes for births that occurred at <20 weeks gestation
(see Data) . 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
[see Dosage and Administration (
2.5 ) and Clinical Pharmacology (
12.3 )]
. 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.
Once daily KALETRA dosing is not recommended in pregnancy.
Avoid use of KALETRA oral solution during pregnancy due to the ethanol content. KALETRA oral solution contains the excipients ethanol, approximately 42% (v/v and propylene glycol, approximately 15%.
Data
Human Data
KALETRA was evaluated in 12 HIV-infected pregnant women in an open-label pharmacokinetic trial
[see Clinical Pharmacology (
12.3 )]
. 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.
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. The prevalence of birth defects in live births was 2.1% (95% CI: 1.4%-3.0%) following first-trimester exposure to lopinavir-containing regimens and 3.0% (95% CI: 2.4%-3.8%) following second and third trimester exposure to lopinavir-containing regimens. 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). The prevalence of birth defects in live births was 2.2% (95% CI: 1.7%-2.8%) following first-trimester exposure to ritonavir-containing regimens and 2.9% (95% CI: 2.4%-3.6%) following second and third trimester exposure to ritonavir-containing regimens. 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 administered lopinavir in combination with ritonavir (on gestation days 6-17) at a maternally toxic dosage. Based on AUC measurements, the drug exposures in rats at the toxic doses were approximately 0.7 times (for lopinavir) and 1.8 times (for ritonavir) the exposures in humans at the recommended therapeutic dose (400/100 mg twice daily). In a pre- and post-natal 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 administered lopinavir in combination with ritonavir (on gestation days 6-18) at a maternally toxic dosage. Based on AUC measurements, the drug exposures in rabbits at the toxic doses were approximately 0.6 times (for lopinavir) and similar to (for ritonavir) the exposures in humans at the recommended therapeutic dose (400/100 mg twice daily).
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: 1) HIV transmission (in HIV-negative infants), 2) developing viral resistance (in HIV- positive infants), and 3) adverse reactions in the breastfed infant, instruct mothers not to breastfeed if they are receiving KALETRA.
Contraception
Use of KALETRA may reduce the efficacy of combined hormonal contraceptives. Advise patients using combined hormonal contraceptives to use an effective alternative contraceptive method or an additional barrier method of contraception
[see Drug Interactions (
7.3 )]
.
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
2 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
12 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
[see Adverse Reactions (
6.2 ), Clinical Pharmacology (
12.3 ), Clinical Studies (
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
2 oral solution twice daily regimen without nevirapine and the 300/75 mg/m
2 oral solution twice daily regimen with nevirapine provided lopinavir plasma concentrations similar to those obtained in adult patients receiving the 400/100 mg twice daily regimen (without nevirapine)
[see Adverse Reactions (
6.2 ), Clinical Pharmacology (
12.3 ), Clinical Studies (
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
2 twice daily + ≥ 2 NRTIs; Group 2: 480/120 mg/m
2 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
[see Adverse Reactions (
6.2 ), Clinical Pharmacology (
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.
Clinical studies of KALETRA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, appropriate caution should be exercised in the administration and monitoring of KALETRA in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
KALETRA is principally metabolized by the liver; therefore, caution should be exercised when administering this drug to patients with hepatic impairment, because lopinavir concentrations may be increased
[see Warnings and Precautions (
5.4 )
and
Clinical Pharmacology (
12.3 )]
.
How supplied
KALETRA
® (lopinavir and ritonavir) tablets and oral solution are available in the following strengths and package sizes:
200 mg lopinavir/50 mg ritonavir
Yellow film-coated ovaloid tablets debossed
with the a logo and the code KA
Store KALETRA tablets at 20°- 25°C (68°- 77°F); excursions permitted to 15°- 30°C (59°- 86°F) [see USP controlled room temperature]. Dispense in original container or USP equivalent tight container.
For patient use: exposure of this product to high humidity outside the original container or USP equivalent tight container for longer than 2 weeks is not recommended.
Recommended Storage:
Clinical pharmacology
KALETRA is a fixed-dose combination of HIV-1 antiviral drugs lopinavir
[see Microbiology (
12.4 )]
and ritonavir. As co-formulated in KALETRA, ritonavir inhibits the CYP3A-mediated metabolism of lopinavir, thereby providing increased plasma levels of lopinavir.
Cardiac Electrophysiology
The effect of KALETRA on QTcF interval was evaluated in a placebo and active (moxifloxacin 400 mg once daily) controlled crossover study in 39 healthy adults. The maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline-correction were 5.3 (8.1) and 15.2 (18.0) mseconds (msec) for 400/100 mg twice daily and supratherapeutic 800/200 mg twice daily KALETRA, respectively. KALETRA 800/200 mg twice daily resulted in a Day 3 mean C
max approximately 2-fold higher than the mean C
max observed with the approved once daily and twice daily KALETRA doses at steady state. The maximum mean (95% upper confidence bound) difference from placebo in the PR interval after baseline-correction were 24.9 (21.5, 28.3) and 31.9 (28.5, 35.3) msec for 400/100 mg twice daily and supratherapeutic 800/200 mg twice daily KALETRA, respectively
[see Warnings and Precautions (
5.5 ,
5.6 )]
.
The pharmacokinetic properties of lopinavir are summarized in Table 13. The steady-state pharmacokinetic parameters of lopinavir are summarized in Table 14. Under fed conditions, lopinavir concentrations were similar following administration of KALETRA tablets to capsules with less pharmacokinetic variability. Under fed conditions (500 kcal, 25% from fat), lopinavir concentrations were similar following administration of KALETRA capsules and oral solution.
Table 13. Pharmacokinetic Properties of Lopinavir
Absorption
T
max (hr)
a
4.4 ± 0.8
Effect of meal
(relative to fasting)
Tablet
Oral solution
↑ 19%
b
↑ 130%
b
Distribution
% Bound to human plasma proteins
> 98
V
d /F
a (L)
16.9
Metabolism
Metabolism
CYP3A
Elimination
Major route of elimination
hepatic
t
1/2 (h)
a
6.9 ± 2.2
% of dose excreted in urine
10.4 ± 2.3
% of dose excreted in feces
82.6 ± 2.5
a. Kaletra tablet
b. Changes in AUC values
Table 14. Steady-State Pharmacokinetic Parameters of Lopinavir, Mean ± SD
Pharmacokinetic Parameter
Twice Daily
a
Once Daily
b
C
max (µg/mL)
9.8 ± 3.7
11.8 ± 3.7
C
min (µg/mL)
5.5 ± 2.7
1.7 ± 1.6
AUC
tau (µg•h/mL)
92.6 ± 36.7
154.1 ± 61.4
19 HIV-1 subjects, Kaletra 400/100 mg twice daily
24 HIV-1 subjects, Kaletra 800/200 mg + emtricitabine 200 mg + tenofovir DF 300 mg
Specific Populations
Gender, Race and Age
No gender or race related pharmacokinetic differences have been observed in adult patients. Lopinavir pharmacokinetics have not been studied in elderly patients.
Pediatric Patients
The 230/57.5 mg/m
2 twice daily regimen without nevirapine and the 300/75 mg/m
2 twice daily regimen with nevirapine provided lopinavir plasma concentrations similar to those obtained in adult patients receiving the 400/100 mg twice daily regimen without nevirapine.
Table 15. Lopinavir Pharmacokinetic Data from Pediatric Clinical Trials, Mean ± SD
C
max (μg/mL)
C
min (μg/mL)
AUC
12 (μg•hr/m
)
Age ≥ 14 Days to < 6 Weeks Cohort (N = 9):
5.17 ± 1.84
a
1.40 ± 0.48
a
43.39 ± 14.80
a
Age ≥ 6 Weeks to < 6 Months Cohort (N = 18):
9.39 ± 4.91
a
1.95 ± 1.80
a
74.50 ± 37.87
a
Age ≥ 6 Months to ≤ 12 years Cohort (N = 24):
8.2 ± 2.9
b
3.4 ± 2.1
b
72.6 ± 31.1
b
10.0 ± 3.3
c
3.6 ± 3.5
c
85.8 ± 36.9
c
KALETRA oral solution300/75 mg/m
2 twice daily without concomitant NNRTI therapy
KALETRA oral solution 230/57.5 mg/m
2 twice daily without nevirapine (n=12)
KALETRA oral solution 300/75 mg/m
2 twice daily with nevirapine (n=12)
Pregnancy
The C
12h values of lopinavir were lower during the second and third trimester by approximately 40% as compared to post-partum in 12 HIV-infected pregnant women received KALETRA 400 mg/100 mg twice daily. Yet this decrease is not considered clinically relevant in patients with no documented KALETRA-associated resistance substitutions receiving 400 mg/100 mg twice daily
[see Use in Specific Populations (
8.1 )]
.
Renal Impairment
Lopinavir pharmacokinetics have not been studied in patients with renal impairment; however, since the renal clearance of lopinavir is negligible, a decrease in total body clearance is not expected in patients with renal impairment.
Hepatic Impairment
Multiple dosing of KALETRA 400/100 mg twice daily to HIV-1 and HCV co-infected patients with mild to moderate hepatic impairment (n = 12) resulted in a 30% increase in lopinavir AUC and 20% increase in C
max compared to HIV-1 infected subjects with normal hepatic function (n = 12). Additionally, the plasma protein binding of lopinavir was statistically significantly lower in both mild and moderate hepatic impairment compared to controls (99.09 vs. 99.31%, respectively). KALETRA has not been studied in patients with severe hepatic impairment
[see Warnings and Precautions (
5.4 )
and
Use in Specific Populations (
8.6 )]
.
Drug Interactions
KALETRA is an inhibitor of the P450 isoform CYP3A
in vitro . 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.
The effects of co-administration of KALETRA on the AUC, C
max and C
min are summarized in Table 16 (effect of other drugs on lopinavir) and Table 17 (effect of KALETRA on other drugs). For information regarding clinical recommendations, see Table 12 in
Drug Interactions (
7 )
.
Table 16. Drug Interactions: Pharmacokinetic Parameters for Lopinavir in the Presence of the Co-administered Drug for Recommended Alterations in Dose or Regimen
Co-
administered
Drug
Dose of Co-
administered
Drug
(mg)
Dose of
KALETRA
(mg)
n
Ratio (in combination with
Co-administered drug/alone) of
Lopinavir Pharmacokinetic
Parameters (90% CI);
No Effect = 1.00
C
max
AUC
C
min
Efavirenz
1
600 at
bedtime
400/100 capsule
twice daily
11,
7
3
0.97
(0.78, 1.22)
0.81
(0.64, 1.03)
0.61
(0.38, 0.97)
600 at
bedtime
500/125 tablet
twice daily
19
1.12
(1.02, 1.23)
1.06
(0.96, 1.17)
0.90
(0.78, 1.04)
600 at
bedtime
600/150 tablet
twice daily
23
1.36
(1.28, 1.44)
1.36
(1.28, 1.44)
1.32
(1.21, 1.44)
Etravirine
200 twice
daily
400/100 mg
twice day
(tablets)
16
0.89
(0.82-0.96)
0.87
(0.83-0.92)
0.80
(0.73-0.88)
Fosamprenavir
2
700 twice daily
plus ritonavir
100 twice daily
400/100 capsule
twice daily
18
1.30
(0.85, 1.47)
1.37
(0.80, 1.55)
1.52
(0.72, 1.82)
Ketoconazole
200 single dose
400/100 capsule
twice daily
12
0.89
(0.80, 0.99)
0.87
(0.75, 1.00)
0.75
(0.55, 1.00)
Nelfinavir
1000 twice daily
400/100 capsule
twice daily
13
0.79
(0.70, 0.89)
0.73
(0.63, 0.85)
0.62
(0.49, 0.78)
Nevirapine
200 twice daily
steady-state
400/100 capsule
twice daily
22,
19
3
0.81
(0.62, 1.05)
0.73
(0.53, 0.98)
0.49
(0.28, 0.74)
7 mg/kg or
4 mg/kg once
daily;
twice daily
1 wk
5
(> 1 yr) 300/
75 mg/m
2
oral solution
twice daily
12,
15
3
0.86
(0.64, 1.16)
0.78
(0.56, 1.09)
0.45
(0.25, 0.81)
Ombitasvir/
paritaprevir/
ritonavir+
dasabuvir
2
25/150/100 +
dasabuvir 400
400/100 tablet
twice daily
6
0.87
(0.76, 0.99)
0.94
(0.81, 1.10)
1.15
(0.93, 1.42)
Omeprazole
40 once
daily,
5 d
400/100 tablet
twice daily,
10 d
12
1.08
(0.99, 1.17)
1.07
(0.99, 1.15)
1.03
(0.90, 1.18)
40 once
daily,
5 d
800/200 tablet
once daily,
10 d
12
0.94
(0.88, 1.00)
0.92
(0.86, 0.99)
0.71
(0.57, 0.89)
Pravastatin
20 once
daily,
4 d
400/100 capsule
twice daily,
14 d
12
0.98
(0.89, 1.08)
0.95
(0.85, 1.05)
0.88
(0.77, 1.02)
Ranitidine
150 single
dose
400/100 tablet
twice daily,
10 d
12
0.99
(0.95, 1.03)
0.97
(0.93, 1.01)
0.90
(0.85, 0.95)
150 single dose
800/200 tablet
once daily,
10 d
10
0.97
(0.95, 1.00)
0.95
(0.91, 0.99)
0.82
(0.74, 0.91)
Rifabutin
150 once daily
400/100 capsule
twice daily
14
1.08
(0.97, 1.19)
1.17
(1.04, 1.31)
1.20
(0.96, 1.65)
Rifampin
600 once daily
400/100 capsule
twice daily
22
0.45
(0.40, 0.51)
0.25
(0.21, 0.29)
0.01
(0.01, 0.02)
600 once daily
800/200 capsule
twice daily
10
1.02
(0.85, 1.23)
0.84
(0.64, 1.10)
0.43
(0.19, 0.96)
600 once daily
400/400 capsule
twice daily
9
0.93
(0.81, 1.07)
0.98
(0.81, 1.17)
1.03
(0.68, 1.56)
Rilpivirine
150 once
daily
400/100 twice
daily (capsules)
15
0.96
(0.88-1.05)
0.99
(0.89-1.10)
0.89
(0.73-1.08)
Ritonavir
100 twice daily
400/100 capsule
twice daily
8,
21
3
1.28
(0.94, 1.76)
1.46
(1.04, 2.06)
2.16
(1.29, 3.62)
Tipranavir/
ritonavir
500/200 twice
daily
400/100 capsule
twice daily
21
69
3
0.53
(0.40, 0.69)
0.45
(0.32, 0.63)
0.30
(0.17, 0.51)
0.48
4
(0.40, 0.58)
1 Reference for comparison is lopinavir/ritonavir 400/100 mg twice daily without efavirenz.
2 Data extracted from the U.S. prescribing information of co-administered drugs.
3 Parallel group design
4 Drug levels obtained at 8-16 hours post dose
N/A = Not available.
Table 17. Drug Interactions: Pharmacokinetic Parameters for Co-administered Drug in the Presence of KALETRA for Recommended Alterations in Dose or Regimen
Co-
administered
Drug
Dose of Co-
administered
Drug (mg)
Dose of
KALETRA
(mg)
n
Ratio (in combination with
KALETRA/alone) of Co-
administered Drug
Pharmacokinetic Parameters
(90% CI); No Effect = 1.00
C
max
AUC
C
min
Bedaquiline
1
400 single dose
400/100 twice
daily
N/A
N/A
1.22
(1.11, 1.34)
N/A
Efavirenz
600 at bedtime
400/100
capsule twice
daily
11,
12
3
0.91
(0.72, 1.15)
0.84
(0.62, 1.15)
0.84
(0.58, 1.20)
Elbasvir/
grazoprevir
1
50 once daily
400/100 twice
daily
10
2.87
(2.29, 3.58)
3.71
(3.05, 4.53)
4.58
(3.72, 5.64)
200 once daily
13
7.31
(5.65, 9.45)
12.86
(10.25, 16.13)
21.70
(12.99, 36.25)
Ethinyl
Estradiol
35 µg once
daily
(Ortho Novum
® )
400/100
capsule twice
daily
12
0.59
(0.52, 0.66)
0.58
(0.54, 0.62)
0.42
(0.36, 0.49)
Etravirine
200 twice daily
400/100 tablet
twice day
16
0.70
(0.64-0.78)
0.65
(0.59-0.71)
0.55
(0.49-0.62)
Fosamprenavir
1
700 twice daily
plus ritonavir
100 twice
daily
400/100
capsule twice
daily
18
0.42
(0.30, 0.58)
0.37
(0.28, 0.49)
0.35
(0.27, 0.46)
Indinavir
600 twice
daily combo
nonfasting vs.
800 three times
daily alone
fasting
400/100
capsule twice
daily
13
0.71
(0.63, 0.81)
0.91
(0.75, 1.10)
3.47
(2.60, 4.64)
Ketoconazole
200 single dose
400/100
capsule twice
daily
12
1.13
(0.91, 1.40)
3.04
(2.44, 3.79)
N/A
Maraviroc
1
300 twice daily
400/100
twice daily
11
1.97
(1.66, 2.34)
3.95
(3.43, 4.56)
9.24
(7.98, 10.7)
Methadone
5 single dose
400/100
capsule twice
daily
11
0.55
(0.48, 0.64)
0.47
(0.42, 0.53)
N/A
Nelfinavir
1000 twice
daily
combo vs.
1250 twice
daily alone
400/100
capsule twice
daily
13
0.93
(0.82, 1.05)
1.07
(0.95, 1.19)
1.86
(1.57, 2.22)
M8 metabolite
2.36
(1.91, 2.91)
3.46
(2.78, 4.31)
7.49
(5.85, 9.58)
Nevirapine
200 once daily
twice daily
400/100
capsule twice
daily
5,
6
3
1.05
(0.72, 1.52)
1.08
(0.72, 1.64)
1.15
(0.71, 1.86)
Norethindrone
1 once daily
(Ortho Novum
® )
400/100
capsule twice
daily
12
0.84
(0.75, 0.94)
0.83
(0.73, 0.94)
0.68
(0.54, 0.85)
Ombitasvir/
paritaprevir/
ritonavir+
dasabuvir
1
25/150/100 +
dasabuvir 400
400/100
tablet twice
daily
6
1.14
(1.01, 1.28)
1.17
(1.07, 1.28)
1.24
(1.14, 1.34)
2.04
(1.30, 3.20)
2.17
(1.63, 2.89)
2.36
(1.00, 5.55)
1.55
(1.16, 2.09)
2.05
(1.49, 2.81)
5.25
(3.33, 8.28)
0.99
(0.75, 1.31)
0.93
(0.75, 1.15)
0.68
(0.57, 0.80)
Pitavastatin
1
4 once daily
400/100 tablet
twice daily
23
0.96
(0.84-1.10)
0.80
(0.73-0.87)
N/A
Pravastatin
20 once daily
400/100 capsule
twice daily
12
1.26
(0.87, 1.83)
1.33
(0.91, 1.94)
N/A
Rifabutin
150 once daily
combo vs. 300
once daily
alone
400/100 capsule
twice daily
12
2.12
(1.89, 2.38)
3.03
(2.79, 3.30)
4.90
(3.18, 5.76)
25-
O -desacetyl
rifabutin
23.6
(13.7, 25.3)
47.5
(29.3, 51.8)
94.9
(74.0, 122)
Rifabutin + 25-
O -desacetyl
rifabutin
3.46
(3.07, 3.91)
5.73
(5.08, 6.46)
9.53
(7.56, 12.01)
Rilpivirine
150 once daily
400/100 capsules
twice daily
15
1.29
(1.18-1.40)
1.52
(1.36-1.70)
1.74
(1.46-2.08)
Rosuvastatin
2
20 once daily
400/100 tablet
twice daily
15
4.66
(3.4, 6.4)
2.08
(1.66, 2.6)
1.04
(0.9, 1.2)
Tenofovir
alafenamide
1
10 once daily
800/200
tablet once
daily
10
2.19
(1.72, 2.79)
1.47
(1.17, 1.85)
N/A
Tenofovir
disoproxil
fumarate
1
300 once daily
400/100 capsule
twice daily
24
No
Change
1.32
(1.26, 1.38)
1.51
(1.32, 1.66)
1 Data extracted from the U.S. prescribing information of co-administered drugs.
2 Kiser, et al. J Acquir Immune Defic Syndr. 2008 Apr 15; 47(5):570-8.
3 Parallel group design
N/A = Not available.
Mechanism of Action
Lopinavir, an inhibitor of the HIV-1 protease, prevents cleavage of the viral Gag-Pol polyprotein, resulting in the production of immature, non-infectious viral particles.
Antiviral Activity
In the absence of human serum, the mean 50% effective concentration (EC
50 ) values of lopinavir against five different HIV-1 subtype B laboratory strains in lymphoblastic cell lines ranged from 10-27 nM (0.006-0.017 µg/mL, 1 µg/mL = 1.6 µM), and ranged from 4-11 nM (0.003-0.007 µg/mL) against several HIV-1 subtype B clinical isolates in peripheral blood lymphocytes (n = 6). In the presence of 50% human serum, the mean EC
50 values of lopinavir against these five HIV-1 laboratory strains ranged from 65-289 nM (0.04-0.18 µg/mL), representing a 7 to 11-fold attenuation. The EC
50 values of lopinavir against three different HIV-2 strains ranged from 12-180 nM (0.008-113 μg/mL).
Resistance
HIV-1 isolates with reduced susceptibility to lopinavir have been selected in cell culture. The presence of ritonavir does not appear to influence the selection of lopinavir-resistant viruses in cell culture.
In a study of 653 antiretroviral treatment-naïve patients (Study 863), plasma viral isolates from each patient on treatment with plasma HIV-1 RNA >400 copies/mL at Week 24, 32, 40 and/or 48 were analyzed. No specific amino acid substitutions could be associated with resistance to KALETRA in the virus from 37 evaluable KALETRA-treated patients. The selection of resistance to KALETRA in antiretroviral treatment-naïve pediatric patients (Study 940) appears to be consistent with that seen in adult patients (Study 863).
Resistance to KALETRA has been noted to emerge in patients treated with other protease inhibitors prior to KALETRA therapy. In studies of 227 antiretroviral treatment-naïve and protease inhibitor experienced patients, isolates from 4 of 23 patients with quantifiable (>400 copies/mL) viral RNA following treatment with KALETRA for 12 to 100 weeks displayed significantly reduced susceptibility to lopinavir compared to the corresponding baseline viral isolates. All four of these patients had previously received treatment with at least one protease inhibitor and had at least 4 substitutions associated with protease inhibitor resistance immediately prior to KALETRA therapy. Following viral rebound, isolates from these patients all contained additional substitutions, some of which are recognized to be associated with protease inhibitor resistance.
Cross-resistance - Nonclinical Studies
Varying degrees of cross-resistance have been observed among HIV-1 protease inhibitors. The antiviral activity in cell culture of lopinavir against clinical isolates from patients previously treated with a single protease inhibitor was determined (Table 18).
Table 18. Susceptibility Reduction to Lopinavir Against Isolates from Patients Previously Treated With a Single Protease Inhibitor
Susceptibility reduced by >4 fold
Susceptibility reduced to LPV
Indinavir (n=16)
5.7 fold
Nelfinavir (n=13)
<4 fold
Ritonavir (n=3)
8.32 fold
Saquinavir (n=4)
<4 fold
Isolates from patients previously treated with two or more protease inhibitors showed greater reductions in susceptibility to lopinavir, as described in the following section.
Clinical Studies - Antiviral Activity of KALETRA in Patients with Previous Protease Inhibitor Therapies
The clinical relevance of reduced susceptibility in cell culture to lopinavir has been examined by assessing the virologic response to KALETRA therapy in treatment-experienced patients, with respect to baseline viral genotype in three studies and baseline viral phenotype in one study.
Virologic response to KALETRA has been shown to be affected by the presence of three or more of the following amino acid substitutions in protease at baseline: L10F/I/R/V, K20M/N/R, L24I, L33F, M36I, I47V, G48V, I54L/T/V, V82A/C/F/S/T, and I84V. Table 19 shows the 48-week virologic response (HIV-1 RNA <400 copies/mL) according to the number of the above protease inhibitor resistance-associated substitutions at baseline in studies 888 and 765
[see Clinical Studies (
14.2 )
and
(
14.3 )]
and study 957 (see below). Once daily administration of KALETRA for adult patients with three or more of the above substitutions is not recommended.
Table 19. Virologic Response (HIV-1 RNA <400 copies/mL) at Week 48 by Baseline KALETRA Susceptibility and by Number of Protease Substitutions Associated with Reduced Response to KALETRA
1
Number of protease inhibitor substitutions at baseline
1
Study 888 (Single protease inhibitor-experienced
2 , NNRTI-naïve) n=130
Study 765 (Single protease inhibitor-experienced
3 , NNRTI-naïve) n=56
Study 957 (Multiple protease inhibitor-experienced
4 , NNRTI-naïve) n=50
0-2
76/103 (74%)
34/45 (76%)
19/20 (95%)
3-5
13/26 (50%)
8/11 (73%)
18/26 (69%)
6 or more
0/1 (0%)
N/A
1/4 (25%)
1 Substitutions considered in the analysis included L10F/I/R/V, K20M/N/R, L24I, L33F, M36I, I47V, G48V, I54L/T/V, V82A/C/F/S/T, and I84V.
2 43% indinavir, 42% nelfinavir, 10% ritonavir, 15% saquinavir.
3 41% indinavir, 38% nelfinavir, 4% ritonavir, 16% saquinavir.
4 86% indinavir, 54% nelfinavir, 80% ritonavir, 70% saquinavir.
Virologic response to KALETRA therapy with respect to phenotypic susceptibility to lopinavir at baseline was examined in Study 957. In this study 56 NNRTI-naïve patients with HIV-1 RNA >1,000 copies/mL despite previous therapy with at least two protease inhibitors selected from indinavir, nelfinavir, ritonavir, and saquinavir were randomized to receive one of two doses of KALETRA in combination with efavirenz and nucleoside reverse transcriptase inhibitors (NRTIs). The EC
50 values of lopinavir against the 56 baseline viral isolates ranged from 0.5- to 96-fold the wild-type EC
50 value. Fifty-five percent (31/56) of these baseline isolates displayed >4-fold reduced susceptibility to lopinavir. These 31 isolates had a median reduction in lopinavir susceptibility of 18-fold. Response to therapy by baseline lopinavir susceptibility is shown in Table 20.
Table 20. HIV-1 RNA Response at Week 48 by Baseline Lopinavir Susceptibility
1
Lopinavir susceptibility
2 at baseline
HIV-1 RNA <400 copies/mL (%)
HIV-1 RNA <50 copies/mL (%)
< 10 fold
25/27 (93%)
22/27 (81%)
> 10 and < 40 fold
11/15 (73%)
9/15 (60%)
≥ 40 fold
2/8 (25%)
2/8 (25%)
1 Lopinavir susceptibility was determined by recombinant phenotypic technology performed by Virologic.
2 Fold change in susceptibility from wild type.
Nonclinical toxicology
Carcinogenesis
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 AUC
0-24hr 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.
Mutagenesis
Neither lopinavir nor ritonavir was found to be mutagenic or clastogenic in a battery of
in vitro and
in vivo assays including the Ames bacterial reverse mutation assay using
S. typhimurium and
E. coli , the mouse lymphoma assay, the mouse micronucleus test and chromosomal aberration assays in human lymphocytes.
Impairment of Fertility
Lopinavir in combination with ritonavir at a 2:1 ratio produced no effects on fertility in male and female rats at levels of 10/5, 30/15 or 100/50 mg/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).
Clinical studies
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
3 (range: 2 to 949 cells/mm
3 ) and mean baseline plasma HIV-1 RNA was 4.9 log
10 copies/mL (range: 2.6 to 6.8 log
10 copies/mL).
Treatment response and outcomes of randomized treatment are presented in Table 21.
Table 21. 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
2
Rebound
Never suppressed through Week 48
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 22.
Table 22. 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
3 for the KALETRA arm and 195 cells/mm
3 for the nelfinavir arm.
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
3 (range: 20 to 775 cells/mm
3 ) and mean baseline plasma HIV-1 RNA was 5.0 log
10 copies/mL (range: 1.7 to 7.0 log
10 copies/mL).
Treatment response and outcomes of randomized treatment through Week 48 are presented in Table 23.
Table 23. 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
2
Rebound
Never suppressed through Week 48
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
3 for the KALETRA once daily arm and 198 cells/mm
3 for the KALETRA twice daily arm.
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
3 (range: 10 to 1059 cells/mm
3 ) and mean baseline plasma HIV-1 RNA was 4.1 log
10 copies/mL (range: 2.6 to 6.0 log
10 copies/mL).
Treatment response and outcomes of randomized treatment through Week 48 are presented in Table 24.
Table 24. 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
2
Rebound
Never suppressed through Week 48
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
3 for the KALETRA arm and 112 cells/mm
3 for the investigator-selected protease inhibitor(s) arm.
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
3 (range: 4 to 952 cells/mm
3 ) and mean baseline plasma HIV-1 RNA was 4.3 log
10 copies/mL (range: 1.7 to 6.6 log
10 copies/mL).
Treatment response and outcomes of randomized treatment through Week 48 are presented in Table 25.
Table 25. 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
3 for the once daily group and 122 cells/mm
3 for the twice daily group.
Study 720: KALETRA twice daily + stavudine + lamivudine
Study 765: KALETRA twice daily + nevirapine + NRTIs
Study 720 (patients
without prior antiretroviral therapy) and study 765 (patients
with 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
3 , 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
10 copies/mL, respectively.
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
3 . Thirty-nine patients (39%) discontinued the study, including 13 (13%) discontinuations due to adverse reactions and 1 (1%) death.
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
3 . Twenty-seven patients (39%) discontinued the study, including 5 (7%) discontinuations secondary to adverse reactions and 2 (3%) deaths.
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
2 twice daily plus 2 NRTIs in HIV-1 infected infants ≥14 days and <6 months of age.
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
10 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.
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
10 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
[see Clinical Pharmacology (
12.3 ) for pharmacokinetic results]
.
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
2 or 300 mg lopinavir/75 mg ritonavir per m
2 . Naïve 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 m
2 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
3 and mean baseline plasma HIV-1 RNA was 4.7 log
10 copies/mL.
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
3 for antiretroviral naïve and 284 cells/mm
3 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.
Dose selection in pediatric patients was based on the following:
Among patients 14 days to 6 months of age receiving 300/75 mg/m
2 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).
Among patients 6 months to 12 years of age, the 230/57.5 mg/m
2 oral solution twice daily regimen without nevirapine and the 300/75 mg/m
2 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.
Among patients 12 to 18 years of age receiving 400/100 mg/m
2 or 480/120 mg/m
2 (with efavirenz) twice daily, plasma concentrations were 60-100% higher than among 6 to 12 year old patients receiving 230/57.5 mg/m
2 . 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.
For all age groups, the body surface area dosing was converted to body weight dosing using the patient’s prescribed lopinavir dose.
Package label
PDP
4 organizations
2 products
Product
Lopinavir + RitonavirOrganization
Rebel Distributors Corp.Organization
AbbVie Inc.Product
Lopinavir and RitonavirOrganization
REMEDYREPACK INC. Organization
NuCare Pharmaceuticals,Inc.