Healthcare professionals should pay special attention to accurate calculation
of the dose of Kaletra (Lopinavir; ritonavir) , transcription of the medication order, dispensing
information and dosing instructions to minimize the risk for medication errors,
overdose, and underdose.
Body surface area (BSA) can be calculated as follows:
The Kaletra (Lopinavir; ritonavir) dose can be calculated based on weight or BSA:
Patient Weight (kg) × Prescribed lopinavir dose (mg/kg) = Administered
lopinavir dose (mg)
Patient BSA (m) × Prescribed lopinavir dose
(mg/m) = Administered lopinavir dose (mg)
If Kaletra (Lopinavir; ritonavir) oral solution is used, the volume (mL) of Kaletra (Lopinavir; ritonavir) solution can be
determined as follows:
Volume of Kaletra (Lopinavir; ritonavir) solution (mL) = Administered lopinavir dose (mg) ÷ 80
(mg/mL)
The dose of the oral solution should be administered using a calibrated
dosing syringe.
Before prescribing Kaletra (Lopinavir; ritonavir) 100/25 mg tablets, children should be assessed for
the ability to swallow intact tablets. If a child is unable to reliably swallow
a Kaletra (Lopinavir; ritonavir) tablet, the Kaletra (Lopinavir; ritonavir) oral solution formulation should be
prescribed.
In pediatric patients 14 days to 6 months of age, the recommended dosage of
lopinavir/ritonavir using Kaletra (Lopinavir; ritonavir) oral solution is 16/4 mg/kg or 300/75
mg/m twice daily. Prescribers should calculate the
appropriate dose based on body weight or body surface area.
Because no data exists for dosage when administered with efavirenz,
nevirapine, amprenavir, or nelfinavir, it is recommended that Kaletra (Lopinavir; ritonavir) not be
administered in combination with these drugs in patients greater then 6 months of
age.
6 Months to 18 Years:
In children 6 months to 18 years of age, the recommended dosage of
lopinavir/ritonavir using Kaletra (Lopinavir; ritonavir) oral solution without concomitant efavirenz,
nevirapine, amprenavir, or nelfinavir is 230/57.5 mg/m
given twice daily, not to exceed the recommended adult dose (400/100 mg [5 mL]
twice daily). If weight-based dosing is preferred, the recommended dosage of
lopinavir/ritonavir for patients greater then 15 kg is 12/3 mg/kg given twice daily and
the dosage for patients less then 15 kg to 40 kg is 10/2.5 mg/kg given twice daily.
Table 1 provides the dosing recommendations for pediatric patients 6 months
to 18 years of age based on body weight or body surface area for Kaletra (Lopinavir; ritonavir)
tablets.
A dose increase of Kaletra (Lopinavir; ritonavir) to 300/75 mg/m using
Kaletra (Lopinavir; ritonavir) oral solution is needed when co-administered with efavirenz, nevirapine,
amprenavir, or nelfinavir in children (both treatment-naïve and
treatment-experienced) 6 months to 18 years of age, not to exceed the
recommended adult dose (533/133 mg [6.5 mL] twice daily). If weight-based dosing
is preferred, the recommended dosage for patients greater then 15 kg is 13/3.25 mg/kg
given twice daily and the dosage for patients less then 15 kg to 45 kg is 11/2.75
mg/kg given twice daily.
Table 2 provides the dosing recommendations for pediatric patients 6 months
to 18 years of age based on body weight or body surface area for Kaletra (Lopinavir; ritonavir) tablets
when given in combination with efavirenz, nevirapine, amprenavir, or nelfinavir.
See Tables and for listing
of drugs that are contraindicated for use with Kaletra (Lopinavir; ritonavir) due to potentially
life-threatening adverse events, significant drug interactions, or loss of
virologic activity.
Pancreatitis has been observed in patients receiving Kaletra (Lopinavir; ritonavir)
therapy, including those who developed marked triglyceride elevations. In some
cases, fatalities have been observed. Although a causal relationship to Kaletra (Lopinavir; ritonavir)
has not been established, marked triglyceride elevations are a risk factor for
development of pancreatitis . Patients with advanced HIV-1 disease
may be at increased risk of elevated triglycerides and pancreatitis, and
patients with a history of pancreatitis may be at increased risk for recurrence
during Kaletra (Lopinavir; ritonavir) therapy.
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 (Lopinavir; ritonavir) .
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 (Lopinavir; ritonavir) therapy has
not been established.
Appropriate laboratory testing should be conducted prior to initiating
therapy with Kaletra (Lopinavir; ritonavir) 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 (Lopinavir; ritonavir) treatment
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.
Lopinavir/ritonavir prolongs the PR interval in some patients.
Cases of second or third degree atrioventricular block have been reported.
Kaletra (Lopinavir; ritonavir) 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 (Lopinavir; ritonavir) 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 (Lopinavir; ritonavir) with these drugs should be undertaken with
caution, particularly with those drugs metabolized by CYP3A. Clinical monitoring
is recommended.
Postmarketing cases of QT interval prolongation and torsade de
pointes have been reported although causality of Kaletra (Lopinavir; ritonavir) 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 .
Immune reconstitution syndrome has been reported in patients
treated with combination antiretroviral therapy, including Kaletra (Lopinavir; ritonavir) . During the
initial phase of combination antiretroviral treatment, patients whose immune
system responds may develop an inflammatory response to indolent or residual
opportunistic infections (such as
infection, cytomegalovirus,
pneumonia [PCP], or tuberculosis) which may necessitate further evaluation and
treatment.
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.
Treatment with Kaletra (Lopinavir; ritonavir) has resulted in large increases in the
concentration of total cholesterol and triglycerides . Triglyceride and
cholesterol testing should be performed prior to initiating Kaletra (Lopinavir; ritonavir) 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 (Lopinavir; ritonavir) and HMG-CoA reductase inhibitors
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 (Lopinavir; ritonavir) -treated patients, it is
unknown what effect therapy with Kaletra (Lopinavir; ritonavir) will have on the activity of
subsequently administered protease inhibitors
The following adverse reactions are discussed in greater detail
in other sections of the labeling.
Because clinical trials are conducted under widely varying conditions,
adverse reactions rates observed in the clinical trials of a drug cannot be
directly compared to rates in the clinical trials of another drug and may not
reflect the rates observed in practice.
The safety profile of Kaletra (Lopinavir; ritonavir) in adults is primarily based on
1964 HIV-1 infected patients in clinical trials.
The most common adverse reaction was diarrhea, which was generally of mild to
moderate severity. In study 730, the incidence of diarrhea of any severity
during 48 weeks of therapy was 60% in patients receiving Kaletra (Lopinavir; ritonavir) tablets once
daily compared to 57% in patients receiving Kaletra (Lopinavir; ritonavir) tablets twice daily. More
patients receiving Kaletra (Lopinavir; ritonavir) tablets once daily (14, 4.2%) had ongoing diarrhea at
the time of discontinuation as compared to patients receiving Kaletra (Lopinavir; ritonavir) tablets
twice daily (6, 1.8%). In study 730, discontinuations due to any adverse
reaction were 4.8% in patients receiving Kaletra (Lopinavir; ritonavir) tablets once daily as compared
to 3% in patients receiving Kaletra (Lopinavir; ritonavir) tablets twice daily. In study 802, the
incidence of diarrhea of any severity during 48 weeks of therapy was 50% in
patients receiving Kaletra (Lopinavir; ritonavir) tablets once daily compared to 39% in patients
receiving Kaletra (Lopinavir; ritonavir) tablets twice daily. Moderate or severe drug-related diarrhea
occurred in 14% of patients receiving Kaletra (Lopinavir; ritonavir) tablets once daily as compared to
11% in patients receiving Kaletra (Lopinavir; ritonavir) tablets twice daily. At the time of
discontinuation, 19 (6.3%) patients receiving Kaletra (Lopinavir; ritonavir) tablets once daily had
ongoing diarrhea, as compared to 11 (3.7%) patients receiving Kaletra (Lopinavir; ritonavir) tablets
twice daily. Discontinuations due to any adverse reaction occurred in 4.3% of
patients receiving Kaletra (Lopinavir; ritonavir) tablets once daily compared to 7.0% in patients
receiving Kaletra (Lopinavir; ritonavir) tablets twice daily. In study 863, discontinuations of
randomized therapy due to adverse reactions were 3.4% in Kaletra (Lopinavir; ritonavir) -treated and
3.7% in nelfinavir-treated patients.
Treatment-emergent clinical adverse reactions of moderate or severe intensity
in less then 2% of patients treated with combination therapy for up to 48 weeks (Studies
863 and 730) and for up to 360 weeks (Study 720) are presented in Table 4
(treatment-naïve patients); and for up to 48 weeks (Studies 888 and 802), 84
weeks (Study 957) and 144 weeks (Study 765) in Table 5 (protease
inhibitor-experienced patients).
Less Common Adverse Reactions
Treatment-emergent adverse reactions occurring in less than 2% of adult
patients receiving Kaletra (Lopinavir; ritonavir) in the clinical trials supporting approval and of at
least moderate intensity are listed below by system organ class.
Anemia, leukopenia, lymphadenopathy, neutropenia, and splenomegaly.
Angina pectoris, atrial fibrillation, atrioventricular block, myocardial
infarction, palpitations, and tricuspid valve incompetence.
Hyperacusis, tinnitus, and vertigo.
Cushing's syndrome and hypothyroidism.
Eye disorder and visual disturbance.
Abdominal discomfort, abdominal distension, abdomen pain lower, constipation,
duodenitis, dry mouth, enteritis, enterocolitis, enterocolitis hemorrhagic,
eructation, esophagitis, fecal incontinence, gastric disorder, gastric ulcer,
gastritis, gastroesophageal reflux disease, hemorrhoids, mouth ulceration,
pancreatitis, periodontitis, rectal hemorrhage, stomach discomfort, and
stomatitis.
Chest pain, cyst, drug interaction, edema, edema peripheral, face edema,
fatigue, hypertrophy, and malaise.
Cholangitis, cholecystitis, cytolytic hepatitis, hepatic steatosis,
hepatitis, hepatomegaly, jaundice, and liver tenderness.
Drug hypersensitivity, hypersensitivity, and immune reconstitution
syndrome.
Bacterial infection, bronchopneumonia, cellulitis, folliculitis, furuncle,
gastroenteritis, influenza, otitis media, perineal abscess, pharyngitis,
rhinitis, sialoadenitis, sinusitis, and viral infection.
Drug level increased, glucose tolerance decreased, and weight increased.
Decreased appetite, dehydration, diabetes mellitus, hypovitaminosis,
increased appetite, lactic acidosis, lipomatosis, and obesity.
Arthralgia, arthropathy, back pain, muscular weakness, osteoarthritis,
osteonecrosis, and pain in extremity.
Benign neoplasm of skin, lipoma, and neoplasm.
Ageusia, amnesia, ataxia, balance disorder, cerebral infarction, convulsion,
dizziness, dysgeusia, dyskinesia, encephalopathy, extrapyramidal disorder,
facial palsy, hypertonia, migraine, neuropathy, neuropathy peripheral,
somnolence, and tremor.
Abnormal dreams, affect lability, agitation, anxiety, apathy, confusional
state, disorientation, mood swings, nervousness, and thinking abnormal.
Hematuria, nephritis, nephrolithiasis, renal disorder, urine abnormality, and
urine odor abnormal.
Breast enlargement, ejaculation disorder, erectile dysfunction, gynecomastia,
and menorrhagia.
Asthma, cough, dyspnea, and pulmonary edema.
Acne, alopecia, dermatitis acneiform, dermatitis allergic, dermatitis
exfoliative, dry skin, eczema, hyperhidrosis, idiopathic capillaritis, nail
disorder, pruritis, rash generalized, rash maculo-papular, seborrhea, skin
discoloration, skin hypertrophy, skin striae, skin ulcer, and swelling face.
Deep vein thrombosis, orthostatic hypotension, thrombophlebitis, varicose
vein, and vasculitis.
The percentages of adult patients treated with combination therapy with Grade
3-4 laboratory abnormalities are presented in Table 6 (treatment-naïve patients)
and Table 7 (treatment-experienced patients).
Kaletra (Lopinavir; ritonavir) oral solution dosed up to 300/75 mg/m has been studied in 100 pediatric patients 6 months to 12
years of age. The adverse reaction profile seen during Study 940 was similar to
that for adult patients.
Dysgeusia (22%), vomiting (21%), and diarrhea (12%) were the most common
adverse reactions of any severity reported in pediatric patients treated with
combination therapy for up to 48 weeks in Study 940. A total of 8 patients
experienced adverse reactions of moderate to severe intensity. The adverse
reactions meeting these criteria and reported for the 8 subjects include:
hypersensitivity (characterized by fever, rash and jaundice), pyrexia, viral
infection, constipation, hepatomegaly, pancreatitis, vomiting, alanine
aminotransferase increased, dry skin, rash, and dysgeusia. Rash was the only
event of those listed that occurred in 2 or more subjects (N = 3).
Kaletra (Lopinavir; ritonavir) oral solution dosed at 300/75 mg/mhas been
studied in 31 pediatric patients 14 days to 6 months of age. The adverse
reaction profile in Study 1030 was similar to that observed in older children
and adults. No adverse reaction was reported in greater than 10% of subjects.
Adverse drug reactions of moderate to severe intensity occurring in 2 or more
subjects included decreased neutrophil count (N=3), anemia (N=2), high potassium
(N=2), and low sodium (N=2).
Kaletra (Lopinavir; ritonavir) oral solution and soft gelatin capsules dosed at higher than
recommended doses including 400/100 mg/m (without
concomitant NNRTI) and 480/120 mg/m (with concomitant
NNRTI) have been studied in 26 pediatric patients 7 to 18 years of age in Study
1038. Patients also had saquinavir mesylate added to their regimen at Week 4.
Rash (12%), blood cholesterol abnormal (12%) and blood triglycerides abnormal
(12%) were the only adverse reactions reported in greater than 10% of subjects.
Adverse drug reactions of moderate to severe intensity occurring in 2 or more
subjects included rash (N=3), blood triglycerides abnormal (N=3), and
electrocardiogram QT prolonged (N=2). Both subjects with QT prolongation had
additional predisposing conditions such as electrolyte abnormalities,
concomitant medications, or pre-existing cardiac abnormalities.
The percentages of pediatric patients treated with combination therapy
including Kaletra (Lopinavir; ritonavir) with Grade 3-4 laboratory abnormalities are presented in Table
8.
The following adverse reactions have been reported during
postmarketing use of Kaletra (Lopinavir; ritonavir) . 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 (Lopinavir; ritonavir) exposure.
