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FDA Drug Safety Communication: Serious health problems seen in premature babies given Kaletra (lopinavir/ritonavir) oral solution


Safety Announcement

Additional Information for Patients
Additional Information for Healthcare Professionals
Data Summary


Safety Announcement

[3-8-2011] 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.
  • Be 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.
  • Do not stop giving Kaletra oral solution without talking to your healthcare professional.
  • Discuss any questions or concerns about Kaletra oral solution with your healthcare professional.
  • If 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.
  • Report 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 Professionals

  • The 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.
  • Kaletra 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.
  • If 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.
  • Calculate 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 adult dose.
  • The 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.
  • Be 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.


Data Summary
 

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 events.

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 toxicity.

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.

 

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