Included as part of the PRECAUTIONS section.
Risk Of Serious Adverse Reactions Due To Drug
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
- 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]. Consider the potential for drug
interactions prior to and during KALETRA therapy; review concomitant
medications during KALETRA therapy, and monitor for the adverse reactions
associated with the concomitant medications [see CONTRAINDICATIONS and DRUG
Toxicity In Preterm Neonates
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 and OVERDOSAGE].
Pancreatitis has been observed in patients receiving
KALETRA therapy, including those who developed marked triglyceride elevations.
In some cases, fatalities have been observed. Although a causal relationship to
KALETRA has not been established, marked triglyceride elevations are a risk
factor for development of pancreatitis [see Lipid Elevations]. Patients with advanced HIV-1 disease may be at
increased risk of elevated triglycerides and pancreatitis, and patients with a
history of pancreatitis may be at increased risk for recurrence during KALETRA
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
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
Appropriate laboratory testing should be conducted prior
to initiating therapy with KALETRA and patients should be monitored closely
during treatment. Increased AST/ALT monitoring should be considered in the
patients with underlying chronic hepatitis or cirrhosis, especially during the
first several months of KALETRA treatment [see Use In Specific Populations].
QT Interval Prolongation
Postmarketing cases of QT interval prolongation and
torsade de pointes have been reported although causality of KALETRA could not
be established. Avoid use in patients with congenital long QT syndrome, those
with hypokalemia, and with other drugs that prolong the QT interval [see CLINICAL
PR Interval Prolongation
Lopinavir/ritonavir prolongs the PR interval in some
patients. Cases of second or third degree atrioventricular block have been
reported. KALETRA should be used with caution in patients with underlying
structural heart disease, pre-existing conduction system abnormalities,
ischemic heart disease or cardiomyopathies, as these patients may be at
increased risk for developing cardiac conduction abnormalities.
The impact on the PR interval of co-administration of
KALETRA with other drugs that prolong the PR interval (including calcium
channel blockers, beta-adrenergic blockers, digoxin and atazanavir) has not
been evaluated. As a result, co-administration of KALETRA with these drugs
should be undertaken with caution, particularly with those drugs metabolized by
CYP3A. Clinical monitoring is recommended [see CLINICAL PHARMACOLOGY].
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
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 GravesÃ¢â¬™ disease,
polymyositis, and Guillain-BarrÃ© syndrome) have also been reported to occur in
the setting of immune reconstitution, however, the time to onset is more
variable, and can occur many months after initiation of treatment.
Treatment with KALETRA has resulted in large increases in
the concentration of total cholesterol and triglycerides [see ADVERSE
REACTIONS]. Triglyceride and cholesterol testing should be performed prior
to initiating KALETRA therapy and at periodic intervals during therapy. Lipid
disorders should be managed as clinically appropriate, taking into account any
potential drug-drug interactions with KALETRA and HMG-CoA reductase inhibitors [see
CONTRAINDICATIONS and DRUG INTERACTIONS].
Redistribution/accumulation of body fat including central
obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting,
facial wasting, breast enlargement, and “cushingoid appearance” have
been observed in patients receiving antiretroviral therapy. The mechanism and
long-term consequences of these events are currently unknown. A causal
relationship has not been established.
Patients With Hemophilia
Increased bleeding, including spontaneous skin hematomas
and hemarthrosis have been reported in patients with hemophilia type A and B
treated with protease inhibitors. In some patients additional factor VIII was
given. In more than half of the reported cases, treatment with protease
inhibitors was continued or reintroduced. A causal relationship between
protease inhibitor therapy and these events has not been established.
Because the potential for HIV 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].
Patient Counseling Information
Advise the patient to read the
FDA-approved patient labeling (Medication Guide)
General Administration Information
[see DOSAGE AND ADMINISTRATION]
- Advise patients to pay special attention to accurate
administration of their dose to minimize the risk of accidental overdose or
underdose of KALETRA.
- Advise patients and caregivers that the oral solution
should be administered using the calibrated dosing cup (supplied) or oral
- Advise caregivers to inform their healthcare provider if
the childÃ¢â¬™s weight changes in order to make sure that the childÃ¢â¬™s KALETRA dose
is adjusted as needed.
- Inform patients and caregivers that KALETRA tablets may
be taken with or without food but KALETRA oral solution should be taken with
food to enhance absorption.
- Advise patients to remain under the care of a healthcare
provider while using KALETRA and to take KALETRA in combination with other
antiretroviral drugs as prescribed.
- Advise patients not to alter the dose or discontinue
therapy without consulting with their healthcare provider. If a dose of KALETRA
is missed patients should take the dose as soon as possible and then return to
their normal schedule. However, if a dose is skipped the patient should not
double the next dose.
- Inform patients that it is important to take KALETRA on a
regular dosing schedule as directed and to avoid missing doses as that can
result in development of resistance.
- Inform patients that there may be a greater chance of
developing diarrhea with the once daily regimen as compared with the twice
- Inform patients that Kaletra is not a cure for HIV-1
infection and that they may continue to experience illnesses associated with
HIV-1 infection, including opportunistic infections.
Inform patients that KALETRA may interact with some
drugs; therefore, patients should be advised to report to their healthcare
provider the use of any prescription, non-prescription medication or herbal
products such as St. JohnÃ¢â¬™s Wort [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS and DRUG
Advise patients that pancreatitis has been observed in
patients receiving KALETRA and to alert their healthcare provider if they
experience symptoms such as nausea, vomiting or abdominal pain [see WARNINGS AND PRECAUTIONS].
Inform patients that skin rash ranging in severity from
mild to toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, erythema
multiforme, urticaria, and angioedema have been reported in patients receiving
KALETRA or its components lopinavir and/or ritonavir. Advise patients to
contact their healthcare provider if they develop a rash while taking KALETRA [see
Pre-existing liver disease including Hepatitis B or C can
worsen with use of KALETRA. This can be seen as worsening of transaminase
elevations or hepatic decompensation. Advise patients that their liver function
tests will need to be monitored closely especially during the first several
months of KALETRA treatment and that they should notify their healthcare
provider if they develop the signs and symptoms of worsening liver disease
including loss of appetite, abdominal pain, jaundice, and itchy skin [see WARNINGS AND PRECAUTIONS].
QT And PR Interval Prolongation
Advise patients that KALETRA may produce changes in the
electrocardiogram (e.g., PR and/or QT prolongation) and to consult their
healthcare provider if they experience symptoms such as dizziness,
lightheadedness, abnormal heart rhythm or loss of consciousness [see WARNINGS AND PRECAUTIONS].
Advise patients that new onset of diabetes or exacerbation
of pre-existing diabetes mellitus, and hyperglycemia have been reported during
KALETRA use. Advise patients to notify their healthcare provider if they
develop the signs and symptoms of diabetes mellitus including frequent
urination, excessive thirst, extreme hunger or unusual weight loss and/or an
increased blood sugar while on KALETRA as they may require a change in their
diabetes treatment or new treatment [see WARNINGS
Immune Reconstitution Syndrome
Advise patients that immune reconstitution syndrome has
been reported in HIV-infected patients treated with combination antiretroviral
therapy, including KALETRA [see WARNINGS AND
Advise patients that treatment with KALETRA therapy can
result in substantial increases in the concentration of total cholesterol and
triglycerides [see WARNINGS AND PRECAUTIONS].
Fat Redistribution Advise patients that redistribution or accumulation of body
fat may occur in patients receiving antiretroviral therapy and that the cause
and long term health effects of these conditions are not known at this time [see
WARNINGS AND PRECAUTIONS].
Patients With Hemophilia
Advise patients with hemophilia that they may experience
increased bleeding when treated with protease inhibitors such as KALETRA [see WARNINGS AND PRECAUTIONS].
Pregnancy Exposure Registry
Inform patients that there is an antiretroviral pregnancy
registry that monitors fetal outcomes of pregnant women exposed to KALETRA [see
Use In Specific Populations]. Lactation Instruct women with HIV-1
infection not to breastfeed because HIV-1 can be passed to the baby in breast
milk [see Use In Specific Populations].
KALETRA Tablets, 200 mg lopinavir and 50 mg ritonavir
Impairment Of Fertility
was evaluated for carcinogenic potential by oral gavage administration to mice
and rats for up to 104 weeks. Results showed an increase in the incidence of
benign hepatocellular adenomas and an increase in the combined incidence of
hepatocellular adenomas plus carcinoma in both males and females in mice and
males in rats at doses that produced approximately 1.6-2.2 times (mice) and 0.5
times (rats) the human exposure (based on AUC0-24hr measurement) at the
recommended dose of 400/100 mg KALETRA twice daily. Administration of
lopinavir/ritonavir did not cause a statistically significant increase in the
incidence of any other benign or malignant neoplasm in mice or rats.
Carcinogenicity studies in mice
and rats have been carried out on ritonavir. In male mice, there was a dose
dependent increase in the incidence of both adenomas and combined adenomas and
carcinomas in the liver. Based on AUC measurements, the exposure at the high
dose was approximately 4-fold for males that of the exposure in humans with the
recommended therapeutic dose (400/100 mg KALETRA twice daily). There were no
carcinogenic effects seen in females at the dosages tested. The exposure at the
high dose was approximately 9-fold for the females that of the exposure in
humans. There were no carcinogenic effects in rats. In this study, the exposure
at the high dose was approximately 0.7-fold that of the exposure in humans with
the 400/100 mg KALETRA twice daily regimen. Based on the exposures achieved in
the animal studies, the significance of the observed effects is not known.
Neither lopinavir nor ritonavir
was found to be mutagenic or clastogenic in a battery of in vitro and in vivo assays
including the Ames bacterial reverse mutation assay using S. typhimurium and
E. coli, the mouse lymphoma assay, the mouse micronucleus test
and chromosomal aberration assays in human lymphocytes.
Impairment Of Fertility
Lopinavir in combination with
ritonavir at a 2:1 ratio produced no effects on fertility in male and female
rats at levels of 10/5, 30/15 or 100/50 mg/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).
Use In Specific Populations
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.
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
Dose Adjustments During Pregnancy And The Postpartum
Administer 400/100 mg of KALETRA twice daily in pregnant
patients with no documented lopinavir-associated resistance substitutions [see DOSAGE
AND ADMINISTRATION and CLINICAL PHARMACOLOGY]. 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
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%.
KALETRA was evaluated in 12 HIV-infected pregnant women
in an open-label pharmacokinetic trial [see CLINICAL PHARMACOLOGY]. 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
ritonavircontaining 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.
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).
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.
Females And Males Of Reproductive Potential
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].
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
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/m² 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 AUC12 than older
children (6 months to 12 years of age), however, despite the lower lopinavir
drug exposure observed, antiviral activity was demonstrated as reflected in the
proportion of subjects who achieved HIV-1 RNA <400 copies/mL at Week 24 [see
ADVERSE REACTIONS, CLINICAL PHARMACOLOGY, Clinical Studies].
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 naÃÂ¯ve and
experienced pediatric patients ages 6 months to 12 years. Dose selection for
patients 6 months to 12 years of age was based on the following results. The
230/57.5 mg/m² oral solution twice daily regimen without nevirapine and the
300/75 mg/m² oral solution twice daily regimen with nevirapine provided
lopinavir plasma concentrations similar to those obtained in adult patients
receiving the 400/100 mg twice daily regimen (without nevirapine) [see ADVERSE
REACTIONS, CLINICAL PHARMACOLOGY, Clinical Studies].
A prospective multicenter, open-label trial evaluated the
pharmacokinetic profile, tolerability, safety and efficacy of high-dose KALETRA
with or without concurrent NNRTI therapy (Group 1: 400/100 mg/m² twice daily +
≥ 2 NRTIs; Group 2: 480/120 mg/m² 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, CLINICAL PHARMACOLOGY].
A prospective multicenter, randomized, open-label study
evaluated the efficacy and safety of twice-daily versus once-daily dosing of
KALETRA tablets dosed by weight as part of combination antiretroviral therapy
(cART) in virologically suppressed HIV-1 infected children (n=173). Children
were eligible when they were aged < 18 years, ≥ 15 kg in weight,
receiving cART that included KALETRA, HIV-1 ribonucleic acid (RNA) < 50
copies/mL for at least 24 weeks and able to swallow tablets. At week 24,
efficacy (defined as the proportion of subjects with plasma HIV-1 RNA less than
50 copies per mL) was significantly higher in subjects receiving twice daily
dosing compared to subjects receiving once daily dosing. The safety profile was
similar between the two treatment arms although there was a greater incidence
of diarrhea in the once daily treated subjects.
Clinical studies of KALETRA did not include sufficient
numbers of subjects aged 65 and over to determine whether they respond
differently from younger subjects. In general, appropriate caution should be
exercised in the administration and monitoring of KALETRA in elderly patients
reflecting the greater frequency of decreased hepatic, renal, or cardiac
function, and of concomitant disease or other drug therapy.
KALETRA is principally metabolized by the liver;
therefore, caution should be exercised when administering this drug to patients
with hepatic impairment, because lopinavir concentrations may be increased [see
WARNINGS AND PRECAUTIONS and CLINICAL