Drug Safety Communication: Serious Health
Problems Seen in Premature Babies given
Kaletra (lopinavir/ritonavir) Oral Solution
March 8, 2011 -- The U.S. Food and Drug Administration (FDA)
is notifying healthcare professionals of serious health
problems that have been reported in premature babies receiving
Kaletra (lopinavir/ritonavir) oral solution. Kaletra oral
solution contains the ingredients alcohol and propylene
glycol. Premature babies may be at increased risk for health
problems because they have a decreased ability to eliminate
propylene glycol; this could lead to adverse events such
as serious heart, kidney, or breathing problems.
A safe and effective dose for babies less than 14 days of
age (whether born premature or full term) has not been established.
Because the consequences of using Kaletra oral solution
in babies immediately after birth can be severe or possibly
fatal, the label is being revised to include a new warning.
The use of Kaletra oral solution should be avoided in premature
babies until 14 days after their due date, or in full-term
babies younger than 14 days of age unless a healthcare professional
believes that the benefit of using Kaletra oral solution
to treat HIV infection immediately after birth outweighs
the potential risks. In such cases, FDA strongly recommends
monitoring for increases in serum osmolality, serum creatinine,
and other signs of toxicity.
Kaletra oral solution is an antiviral medication used in
combination with other antiretroviral drugs for the treatment
of HIV-1 infection in pediatric patients 14 days of age
(whether premature or full term) or older and in adults.
Taking antiretroviral medications for HIV will not cure
the infection, but can help children and adults with HIV-1
infection stay healthier for a longer period of time.
(see Data Summary below)
Additional Information for Patients
Call your healthcare professional right away if your
baby appears too sleepy or their breathing has changed
while taking Kaletra oral solution. Kaletra oral solution
contains alcohol and propylene glycol, and babies less
than 14 days old (whether premature or full-term) may
develop high blood levels of these ingredients resulting
in these symptoms.
aware that the use of Kaletra oral solution should be
avoided in premature babies until 14 days after their
due date or full term babies younger than 14 days of
age unless your healthcare professional thinks it is
right for your baby.
not stop giving Kaletra oral solution without talking
to your healthcare professional.
any questions or concerns about Kaletra oral solution
with your healthcare professional.
your baby takes more than the usual dose of Kaletra
all at once, it can make them sick. Contact your local
poison control center or emergency room right away if
an overdose occurs.
any side effects you experience to the FDA MedWatch
program using the information in the "Contact Us"
box at the bottom of the page.
Additional Information for Healthcare
use of Kaletra oral solution should be avoided in neonates
before a postmenstrual age (first day of 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.
oral solution should be avoided in preterm neonates
in the immediate postnatal period because of possible
toxicities. Kaletra oral solution should also be avoided
in full term babies younger than 14 days of age. A safe
and effective dose of Kaletra oral solution in these
populations are not established.
in the judgment of the health care professional, the
benefit of using Kaletra oral solution in babies to
treat HIV infection immediately after birth outweighs
the potential risks, then the neonate should be monitored
closely for increases in serum osmolality and serum
creatinine and for toxicity related to Kaletra oral
solution. These toxicities include hyperosmolality with
or without lactic acidosis, renal toxicity, CNS depression
(including stupor, coma, and apnea), seizures, hypotonia,
cardiac arrhythmias, ECG changes and hemolysis.
the appropriate dose of Kaletra oral solution for each
child based on body weight (kg) or body surface area
(BSA) to avoid underdosing or exceeding the recommended
total amounts of alcohol and propylene glycol from all
medications that are to be given to pediatric patients
from 14 days to 6 months of age should be taken into
account in order to avoid toxicity from these excipients.
aware that toxicity in preterm neonates can be severe
or possibly fatal, and it can be mistaken for neonatal
sepsis. Immediate discontinuation of the drug is critical
in these settings.
Report adverse events involving Kaletra to the FDA MedWatch
program, using the information in the "Contact
Us" box at the bottom of the page.
Kaletra oral solution contains the excipients alcohol (42.4%
v/v) and propylene glycol (15.3% w/v). When administered
concomitantly with propylene glycol, ethanol competitively
inhibits the metabolism of propylene glycol, which may lead
to elevated concentrations of propylene glycol. 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
FDA conducted a review of the Adverse Events Reporting System
(AERS) database from the approval of Kaletra oral solution
in September 2000 through September 2010. The review yielded
10 post-marketing cases with life-threatening events reported
in neonates who were predominantly born preterm (8 of 10
neonates were born at gestational ages ranging from 28 to
almost 35 weeks) and who received Kaletra oral solution.
Post-marketing life-threatening events included cardiac
toxicity (including complete AV block, bradycardia, and
cardiomyopathy), lactic acidosis, acute renal failure, central
nervous system (CNS) depression, and respiratory complications.
Of the 10 cases, there was one death due to cardiogenic
shock related to a large overdose of Kaletra oral solution.
The temporal association between the onset of symptoms when
the drug was started and a positive dechallenge when the
drug was stopped support the association with Kaletra administration.
In addition, clinical findings were consistent with known
adverse events of one or more of the ingredients of Kaletra
oral solution. From these cases, it appears that neonates
taking Kaletra oral solution, especially those born prematurely,
were at risk of lopinavir, ethanol, and/or propylene glycol
The cases identified in the AERS review included seven neonates
who exhibited signs of cardiac toxicity, including bradycardia,
sinoatrial block, complete AV block, congestive cardiomyopathy,
cardiac failure, and cardiogenic shock. An elevated lactate
level was documented in two patients. Neuromuscular toxicity
including hypotonia, an abnormal EEG, altered state of consciousness,
somnolence, and asthenia occurred in three patients. Acute
renal failure was seen in five patients and an increased
serum creatinine was documented in one. Four patients had
hyperkalemia. Respiratory complications were present in
three neonates, and included respiratory failure and pulmonary
hemorrhage, neonatal respiratory arrest, and dyspnea and
wheezing. Gastrointestinal adverse events occurred in five
patients and included vomiting, failure to thrive, abdominal
distention, and ulcerative colitis. There was one death
among the ten infants. Eight of the ten neonates received
their first dose of Kaletra oral solution on the day of
birth or the day after birth. The onset of toxicity occurred
within 1 to 6 days in eight of the cases. A full-term infant
showed the first signs of toxicity 20 days after birth.
After Kaletra oral solution was discontinued, six infants
recovered within 5 days. Another three neonates showed improvement,
although the time course was not documented. FDA noted that
the majority of these cases occurred outside the U.S.
FDA is updating the labels with a new warning that the use
of Kaletra oral solution should be avoided in preterm infants
in the immediate postnatal period because of the possible
toxicity associated with Kaletra oral solution. A safe and
effective dose in this age group has not been established.
However, if in the judgment of the health care professional,
the benefit of using Kaletra Oral solution to treat HIV
infection immediately after birth in infants outweighs the
potential risks, then monitoring for increases in serum
osmolality and serum creatinine is strongly recommended.
Additionally, infants should be monitored closely 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.
U.S. Food and Drug Administration (FDA). Serious Health Problems
Seen in Premature Babies Given Kaletra (lopinavir/ritonavir)
Oral Solution. FDA Drug Safety Communication. March 8, 2011.
R Klein and K Struble (FDA). Kaletra (lopinavir/ritonavir) Oral
Solution label changes related to toxicity in preterm neonates.
HIV/AIDS Update. February 24, 2011.