Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/2158
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Kaletra (Capsule, Liquid Filled)
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KALETRA capsules
and oral solution must be taken with food. The recommended oral dose of KALETRA is as follows: (Please
also refer to INDICATIONS AND USAGE and ADVERSE REACTIONS)<br/>Adults: Therapy-Na��ve Patients Therapy-experienced Patients Once-daily
administration of KALETRA is not recommended in therapy-experienced patients.<br/>Concomitant therapy: Efavirenz, nevirapine, amprenavir or nelfinavir: A dose increase of KALETRA to 533/133 mg (4 capsules
or 6.5 mL) twice-daily taken with food is recommended when used in combination
with efavirenz, nevirapine, amprenavir or nelfinavir (see CLINICAL
PHARMACOLOGY���Drug-drug Interactions
and/or PRECAUTIONS���Table 11). KALETRA should not be administered as a once-daily regimen
in combination with efavirenz, nevirapine, amprenavir or nelfinavir.<br/>Pediatric Patients: In children 6 months to 12 years of age, the recommended
dosage of KALETRA oral solution is 12/3 mg/kg for those 7 to<15 kg and
10/2.5 mg/kg for those 15 to 40 kg (approximately equivalent to 230/57.5 mg/m)
twice-daily taken with food, up to a maximum dose of 400/100 mg in children>40 kg (5.0 mL or 3 capsules) twice-daily. KALETRA once-daily has not been
evaluated in pediatric patients. It is preferred
that the prescriber calculate the appropriate milligram dose for each individual
child���12 years old and determine the corresponding volume of
solution or number of capsules. However, as an alternative, the
following table contains dosing guidelines for KALETRA oral solution based
on body weight. When possible, dose should be administered using a calibrated
dosing syringe. Note: Use adult dosage recommendation
for children>12 years of age.<br/>Concomitant Therapy: Efavirenz, nevirapine or amprenavir: A dose increase of KALETRA oral solution to 13/3.25
mg/kg for those 7 to<15 kg and 11/2.75 mg/kg for those 15 to 45 kg (approximately
equivalent to 300/75 mg/m) twice-daily taken with food, up to
a maximum dose of 533/133 mg in children>45 kg twice-daily is recommended
when used in combination with efavirenz, nevirapine or amprenavir in children
6 months to 12 years of age. The following table contains dosing guidelines
for KALETRA oral solution based on body weight, when used in combination with
efavirenz, nevirapine or amprenavir in children (see CLINICAL
PHARMACOLOGY���Drug-drug Interactions
and/or PRECAUTIONS���Table 11
). Note: Use adult dosage recommendation
for children>12 years of age.
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| dailymed-instance:descripti... |
KALETRA (lopinavir/ritonavir) is a co-formulation
of lopinavir and ritonavir. Lopinavir is an inhibitor of the HIV 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 [1S-[1R*,(R*), 3R*,
4R*]]-N-[4-[[(2,6-dimethylphenoxy)acetyl]amino]-3-hydroxy-5-phenyl-1-(phenylmethyl)pentyl]tetrahydro-alpha-(1-methylethyl)-2-oxo-1(2H)-pyrimidineacetamide.
Its molecular formula is CHNO,
and its molecular weight is 628.80. 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, [5S-(5R*,8R*,10R*,11R*)]. Its molecular formula
is CHNOS, and
its molecular weight is 720.95. Ritonavir has the following structural formula: Lopinavir is a white
to light tan powder. It is freely soluble in methanol and ethanol, soluble
in isopropanol and practically insoluble in water. KALETRA
capsules are available for oral administration in a strength of 133.3 mg lopinavir
and 33.3 mg ritonavir with the following inactive ingredients: FD&C Yellow
No. 6, gelatin, glycerin, oleic acid, polyoxyl 35 castor oil, propylene glycol,
sorbitol special, titanium dioxide, and water. KALETRA
oral solution is available for oral administration as 80 mg lopinavir and
20 mg ritonavir per milliliter with the following inactive ingredients:
Acesulfame potassium, alcohol, artificial cotton candy flavor, citric acid,
glycerin, high fructose corn syrup, Magnasweet-110 flavor, menthol, natural&artificial vanilla flavor, peppermint oil, polyoxyl 40 hydrogenated
castor oil, povidone, propylene glycol, saccharin sodium, sodium chloride,
sodium citrate, and water. KALETRA oral solution contains 42.4% alcohol (v/v).
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Microbiology:<br/>Mechanism of Action: Lopinavir, an inhibitor of the HIV protease, prevents
cleavage of the Gag-Pol polyprotein, resulting in the production of immature,
non-infectious viral particles.<br/>Antiviral Activity: The antiviral activity of lopinavir against laboratory
HIV strains and clinical HIV isolates was evaluated in acutely infected lymphoblastic
cell lines and peripheral blood lymphocytes, respectively. In the absence
of human serum, the mean 50% effective concentration (EC) values
of lopinavir against five different HIV-1 subtype B laboratory strains ranged
from 10-27 nM (0.006-0.017��g/mL, 1��g/mL = 1.6��M) and ranged
from 4-11 nM (0.003-0.007��g/mL) against several HIV-1 subtype B clinical
isolates (n = 6). In the presence of 50% human serum, the mean ECvalues
of lopinavir against these five HIV-1 laboratory strains ranged from 65-289
nM (0.04-0.18��g/mL), representing a 7- to 11-fold attenuation. Combination
antiviral drug activity studies with lopinavir in cell cultures demonstrated
additive to antagonistic activity with nelfinavir and additive to synergistic
activity with amprenavir, atazanavir, indinavir, saquinavir and tipranavir.
The ECvalues of lopinavir against three different HIV-2 strains
ranged from 12-180 nM (0.008-113��g/mL).<br/>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. The selection of resistance to KALETRA
in antiretroviral treatment-naive patients has not yet been characterized.
In a Phase III study of 653 antiretroviral treatment-naive patients (Study
863), plasma viral isolates from each patient on treatment with plasma HIV>400 copies/mL
at Week 24, 32, 40 and/or 48 were analyzed. No evidence of resistance to
KALETRA was observed in 37 evaluable KALETRA-treated patients (0%). The selection
of resistance to KALETRA in antiretroviral treatment-naive 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 Phase II studies of 227 antiretroviral treatment-naive 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. Three of these patients had
previously received treatment with a single protease inhibitor (indinavir,
nelfinavir, or saquinavir) and one patient had received treatment with multiple
protease inhibitors (indinavir, ritonavir, and saquinavir). All four of these
patients had at least 4 mutations associated with protease inhibitor resistance
immediately prior to KALETRA therapy. Following viral rebound, isolates from
these patients all contained additional mutations, some of which are recognized
to be associated with protease inhibitor resistance. However, there are insufficient
data at this time to identify lopinavir-associated mutational patterns in
isolates from patients on KALETRAtherapy. The assessment of these mutational
patterns is under study.<br/>Cross-resistance���Preclinical Studies: Varying degrees of cross-resistance have been
observed among HIV protease inhibitors. Little information is available on
the cross-resistance of viruses that developed decreased susceptibility to
lopinavir during KALETRA therapy. The antiviral
activity in cell culture of lopinavir against clinical isolates from patients
previously treated with a single protease inhibitor was determined. Isolates
that displayed>4-fold reduced susceptibility to nelfinavir (n = 13) and saquinavir
(n = 4), displayed<4-fold reduced susceptibility to lopinavir. Isolates
with>4-fold reduced susceptibility to indinavir (n = 16) and ritonavir
(n = 3) displayed a mean of 5.7- and 8.3-fold reduced susceptibility to lopinavir,
respectively. Isolates from patients previously treated with two or more
protease inhibitors showed greater reductions in susceptibility to lopinavir,
as described in the following paragraph.<br/>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 1 shows the 48-week virologic
response (HIV RNA<400 copies/mL) according to the number of the above
protease inhibitor resistance mutations at baseline in studies 888 and 765
(see INDICATIONS AND USAGE) and study
957 (see below). Virologic response to KALETRA therapy with respect to
phenotypic susceptibility to lopinavir at baseline was examined in Study 957.
In this study 56 NNRTI-na��ve patients with HIV 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 ECvalues of lopinavir against the 56
baseline viral isolates ranged from 0.5- to 96-fold the wild-type ECvalue.
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 2.<br/>Pharmacokinetics: The pharmacokinetic properties of lopinavir co-administered
with ritonavir have been evaluated in healthy adult volunteers and in HIV-infected
patients; no substantial differences were observed between the two groups.
Lopinavir is essentially completely metabolized by CYP3A. Ritonavir inhibits
the metabolism of lopinavir, thereby increasing the plasma levels of lopinavir.
Across studies, administration of KALETRA 400/100 mg twice-daily yields mean
steady-statelopinavir plasma concentrations 15- to 20-fold higher than those
of ritonavir in HIV-infected patients. The plasma levels of ritonavir are
less than 7% of those obtained after the ritonavir dose of 600 mg twice-daily.
The in vitro antiviral ECof
lopinavir is approximately 10-fold lower than that of ritonavir. Therefore,
the antiviral activity of KALETRA is due to lopinavir. Figure 1 displays the mean steady-state plasma concentrations
of lopinavir and ritonavir after KALETRA 400/100 mg twice-daily with food
for 3 weeks from a pharmacokinetic study in HIV-infected adult subjects (n
= 19).<br/>Absorption: In a pharmacokinetic study in HIV-positive subjects
(n = 19), multiple dosing with 400/100 mg KALETRA twice-daily with food for
3 weeks produced a mean��SD lopinavir peak plasma concentration (C)
of 9.8��3.7��g/mL, occurring approximately 4 hours after administration.
The mean steady-state trough concentration prior to the morning dose was
7.1��2.9��g/mL and minimum concentration within a dosing interval
was 5.5��2.7��g/mL. Lopinavir AUC over a 12 hour dosing
interval averaged 92.6��36.7��g���h/mL. The absolute bioavailability of lopinavir co-formulated
with ritonavir in humans has not been established. Under nonfasting conditions
(500 kcal, 25% from fat), lopinavir concentrations were similar following
administration of KALETRA co-formulated capsules and liquid. When administered
under fasting conditions, both the mean AUC and Cof lopinavir
were 22% lower for the KALETRA liquid relative to the capsule formulation.<br/>Distribution: At steady state, lopinavir is approximately 98-99%
bound to plasma proteins. Lopinavir binds to both alpha-1-acid glycoprotein
(AAG) and albumin; however, it has a higher affinity for AAG. At steady state,
lopinavir protein binding remains constant over the range of observed concentrations
after 400/100 mg KALETRA twice-daily, and is similar between healthy volunteers
and HIV-positive patients.<br/>Metabolism: In vitro
experiments with human hepatic microsomes indicate that lopinavir
primarily undergoes oxidative metabolism. Lopinavir is extensively metabolized
by the hepatic cytochrome P450 system, almost exclusively by the CYP3A isozyme.
Ritonavir is a potent CYP3A inhibitor which inhibits the metabolism of lopinavir,
and therefore increases plasma levels of lopinavir. AC-lopinavir
study in humans showed that 89% of the plasma radioactivity after a single
400/100 mg KALETRA dose was due to parent drug. At least 13 lopinavir oxidative
metabolites have been identified in man. Ritonavir has been shown to induce
metabolic enzymes, resulting in the induction of its ownmetabolism. Pre-dose
lopinavir concentrations decline with time during multiple dosing, stabilizing
after approximately 10 to 16 days.<br/>Elimination: Following a 400/100 mgC-lopinavir/ritonavir
dose, approximately 10.4��2.3% and 82.6��2.5% of an administered
dose ofC-lopinavir can be accounted for in urine and feces,
respectively, after 8 days. Unchanged lopinavir accounted for approximately
2.2 and 19.8% of the administered dose in urine and feces, respectively.
After multiple dosing, less than 3% of the lopinavir dose is excreted unchanged
in the urine. The apparent oral clearance (CL/F) of lopinavir is 5.98��5.75 L/hr (mean��SD, n = 19).<br/>Once Daily Dosing: The pharmacokinetics of once daily KALETRA have
been evaluated in HIV-infected subjects na��ve to antiretroviral treatment.
KALETRA 800/200 mg was administered in combination with emtricitabine
200 mg and tenofovir DF 300 mg as part of a once daily regimen. Multiple
dosing of 800/200 mg KALETRA once-daily for 4 weeks with food (n = 24)
produced a mean��SD lopinavir peak plasma concentration (C)
of 11.8��3.7��g/mL, occurring approximately 6 hours after administration.
The mean steady-state lopinavir trough concentration prior to the morning
dose was 3.2��2.1��g/mL and minimum concentration within a dosing
interval was 1.7��1.6��g/mL. Lopinavir AUC over a 24 hour dosing
interval averaged 154.1��61.4��g���h/mL.<br/>Special Populations:
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KALETRA is contraindicated in patients with known
hypersensitivity to any of its ingredients, including ritonavir. Co-administration of 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 events.
These drugs are listed in Table 9.
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KALETRA (lopinavir/ritonavir) capsules are orange
soft gelatin capsules imprinted with the corporate Abbott���A���logo and the Abbo-Code PK. KALETRA is available
as 133.3 mg lopinavir/33.3 mg ritonavir capsules in the following package
sizes: Bottles of 180 capsules each���.���������������(NDC 0074-3959-77) Recommended
storage: Store KALETRA soft gelatin capsules at 36��F - 46��F (2��C - 8��C)
until dispensed. Avoid exposure to excessive heat. For patient use, refrigerated
KALETRA capsules remain stable until the expiration date printed on the label.
If stored at room temperature up to 77��F (25��C), capsules should
be used within 2 months. KALETRA (lopinavir/ritonavir)
oral solution is a light yellow to orange colored liquid supplied in amber-colored
multiple-dose bottles containing 400 mg lopinavir/100 mg ritonavir per 5 mL
(80 mg lopinavir/20 mg ritonavir per mL) packaged with a marked dosing cup
in the following size: 160 mL bottle������������������������������������.(NDC 0074-3956-46) Recommended
storage: Store KALETRA oral solution at 36��F - 46��F (2��C -
8��C) until dispensed. Avoid exposure to excessive heat. For patient
use, refrigerated KALETRA oral solution remains stable until the expiration
date printed on the label. If stored at room temperature up to 77��F
(25��C), oral solution should be used within 2 months. Abbott Laboratories North Chicago,
IL 60064, U.S.A. --------------------------------------------(Perforation)-----------------------------------------
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dailymed-ingredient:FD&C_Yellow_No._6,
dailymed-ingredient:gelatin,
dailymed-ingredient:glycerin,
dailymed-ingredient:oleic_acid,
dailymed-ingredient:polyoxyl_35_castor_oil,
dailymed-ingredient:propylene_glycol,
dailymed-ingredient:sorbitol_special,
dailymed-ingredient:titanium_dioxide,
dailymed-ingredient:water
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KALETRA oral solution contains 42.4% alcohol (v/v).
Accidental ingestion of the product by a young child could result in significant
alcohol-related toxicity and could approach the potential lethal dose of alcohol. Human experience of acute overdosage with KALETRA is limited.
Treatment of overdose with KALETRA should consist of general supportive measures
including monitoring of vital signs and observation of the clinical status
of the patient. There is no specific antidote for overdose with KALETRA.
If indicated, elimination of unabsorbed drug should be achieved by emesis
or gastric lavage. Administration of activated charcoal may also be used
to aid in removal of unabsorbed drug. Since KALETRA is highly protein bound,
dialysis is unlikely to be beneficial in significant removal of the drug.
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lopinavir and ritonavir
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Kaletra (Capsule, Liquid Filled)
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Adults:<br/>Treatment-Emergent Adverse Events: KALETRA has been studied in 891 patients as combination
therapy in Phase I/II and Phase III clinical trials. The most common adverse
event associated with KALETRA therapy was diarrhea, which was generally of
mild to moderate severity. Rates of discontinuation of randomized therapy
due to adverse events were 5.8% in KALETRA-treated and 4.9% in nelfinavir-treated
patients in Study 863. The incidence of diarrhea was greater for KALETRA
once-daily compared to KALETRA twice-daily in Study 418 (see Table
12 and INDICATIONS AND USAGE). Treatment-Emergent clinical adverse events of moderate
or severe intensity in���2% of patients treated with combination therapy
for up to 48 weeks (Phase III) and for up to 360 weeks (Phase I/II) are presented
in Table 12. For other information regarding observed or potentially serious
adverse events, please see WARNINGS and PRECAUTIONS. Treatment-emergent adverse events
occurring in less than 2% of adult patients receiving KALETRA in all phase
II/III clinical trials and considered at least possibly related or of unknown
relationship to treatment with KALETRA and of at least moderate intensity
are listed below by body system.<br/>Post-marketing Experience: The following adverse reactions have been reported
during post-marketing use of KALETRA. Because these reactions are reported
voluntarily from a population of unknown size, it is not possible to reliably
estimate their frequency or establish a causal relationship to KALETRA exposure.<br/>Laboratory Abnormalities: The percentages of adult patients treated with
combination therapy with Grade 3-4 laboratory abnormalities are presented
in Table 14 and Table 15.<br/>Pediatrics:<br/>Treatment-Emergent Adverse Events: KALETRA has been studied in 100 pediatric patients
6 months to 12 years of age. The adverse event profile seen during a clinical
trial was similar to that for adult patients. Taste
aversion, vomiting, and diarrhea were the most commonly reported drug related
adverse events of any severity in pediatric patients treated with combination
therapy including KALETRA for up to 48 weeks in Study 940. A total of 8 children
experienced moderate or severe adverse events at least possiblyrelated to
KALETRA. Rash (reported in 3%) was the only drug-related clinical adverse
event of moderate to severe intensity observed in���2% of children
enrolled.<br/>Laboratory Abnormalities: The percentages of pediatric patients treated
with combination therapy including KALETRA with Grade 3-4 laboratory abnormalities
are presented in Table 16.
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| dailymed-instance:indicatio... |
KALETRA is indicated in combination with other antiretroviral
agents for the treatment of HIV-infection. Once-daily administration of KALETRA is not
recommended in therapy-experienced patients. When initiating treatment with KALETRA in therapy-na��ve
patients, it should be noted that the incidence of diarrhea was greater for
KALETRA once-daily compared to KALETRA twice-daily in Study 418 (57% vs. 35%
- events of all grades and probably or possibly related to drug; 16% vs. 5%
- events of at least moderate severity and probably or possibly related to
drug) (see CLINICAL PHARMACOLOGY, ADVERSE REACTIONS, and DOSAGE
AND ADMINISTRATION ).<br/>Description of Clinical Studies:<br/>Patients Without Prior Antiretroviral Therapy:<br/>Patients with Prior Antiretroviral Therapy:<br/>Other Studies:
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Kaletra
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