US FDA and Bristol-Myers Squibb issue caution for combination HIV therapy with stavudine (d4T) and didanosine (ddI) in pregnant women
The US FDA and Bristol Myers Squibb are warning health care professionals that pregnant women may be at increased risk of fatal lactic acidosis when prescribed the combination of the HIV drugs stavudine and didanosine with other antiretroviral agents.
Lactic acidosis occurs when cells of the body are unable to convert food into usable energy. As a result, excess acid accumulates in the body and vital organs such as the liver or pancreas may be damaged. Severe lactic acidosis is an infrequent, but well-described complication of the class of HIV drugs known as nucleoside analogues. Pancreatitis is also a well-described complication of stavudine and didanosine.
This new warning follows three reported cases of fatal lactic acidosis, with or without pancreatitis, that occurred in pregnant women taking stavudine and didanosine in combination with other drugs used to treat HIV. Two of the cases were reported from ongoing clinical trials of an investigational HIV drug, and one was identified through worldwide post marketing surveillance. In addition FDA has received several nonfatal reports of lactic acidosis, with and without pancreatitis, occurring in pregnant women receiving only stavudine and didanosine. Although data have suggested that women may be at increased risk for the development of lactic acidosis and liver toxicity, it is unclear whether pregnancy potentiates these known side effects.
On January 5, 2001, Bristol Myers Squibb issued a letter to alert health care professionals to the potential increased risk of lactic acidosis and liver damage in pregnant women treated with the combination of stavudine and didanosine. Bristol Myers Squibb recommends that the combination of the two drugs should be prescribed for pregnant women only when the potential benefit clearly outweighs the potential risk. One situation where the benefit may outweigh the risk is the use of didanosine plus stavudine in women who have exhausted other treatment options.
The letter points out that decisions about using the drugs for pregnant women should be made by health care professionals experienced in treating HIV infection. Because of these reports, the FDA will strengthen the existing black box warnings to include this new prescribing information. Women who are prescribed the combination drug therapy should be closely monitored for clinical or laboratory signs of lactic acidosis and liver damage. This syndrome may develop abruptly, and in the absence of abnormal laboratory values in the weeks preceding its development.
Therefore, it is imperative that healthcare providers maintain a high index of suspicion when monitoring these patients. Healthcare providers in the US are encouraged to report any adverse events related to stavudine and didanosine to Bristol Myers Squibb Company (800-426-7644). Reports may be submitted to FDA by telephone (800-FDA-1088), fax (800-FDA-0178), online at
or by by mail to:
Food and Drug Administration,
5600 Fishers Lane,
A copy of the letter from Bristol Myers Squibb is attached below.
Source: Richard Klein. Office of Special Health Issues. Food and Drug Administration, Communication on FDA’s MedWatch
U.S. Food and Drug Administration
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This is the retyped text of a letter from Bristol-Myers Squibb Company. Contact the company for a copy of any referenced enclosures.
IMPORTANT DRUG WARNING
January 5, 2001
Dear Healthcare Provider,
Fatal lactic acidosis has recently been reported in pregnant women treated throughout gestation with the combination of stavudine and didanosine. Based on these cases, the combination of stavudine (ZERIT®) and didanosine (VIDEX® or VIDEX® EC) should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk, such as when there are few remaining treatment options.
This recommendation is based on three cases of fatal lactic acidosis, two with and one without pancreatitis, that occurred in women who were either pregnant or postpartum and whose antiretroviral therapy during pregnancy included stavudine and didanosine in combination with other antiretroviral agents. Two of the infants of these women died, one in utero at 32 weeks gestation and one after emergency caesarean section at 36 weeks gestation. Two of the fatal cases occurred in patients enrolled in BMS study AI424-007, an open-label, multinational, randomised, two-arm comparison of stavudine plus didanosine plus nelfinavir (Viracept®) versus stavudine plus didanosine plus BMS-232632 (an investigational protease inhibitor). A third pregnancy-related death attributed to lactic acidosis was reported through worldwide postmarketing surveillance. This patient had received long-term therapy with stavudine and didanosine together with the NNRTI nevirapine (Viramune ®). In addition, postmarketing surveillance identified several nonfatal cases of pancreatitis, with and without lactic acidosis or hepatic failure, in pregnant women receiving stavudine plus didanosine.
Stavudine and didanosine are nucleoside reverse transcriptase inhibitors indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infection. The nucleoside analogue class of antiretroviral drugs has been implicated in idiopathic lactic acidosis and severe hepatomegaly with steatosis, and all members of this class carry a warning in the label to this effect. Data have suggested that women may be at higher risk for these toxicities and it is unclear whether pregnancy potentiates these known side effects. However, the temporal occurrence of the three deaths should serve as a reminder that potential risks may be associated with use of these agents in pregnancy. Decisions regarding antiretroviral therapy for pregnant women are complex and should be made by healthcare providers experienced in the treatment of HIV infection. Although the VIDEX (didanosine), VIDEX EC (didanosine), and ZERIT (stavudine) labels have always advised of the risks of lactic acidosis, Bristol-Myers Squibb has decided to expand the Boxed Warning, Warnings, and Precautions sections to reflect the new information that has been described above. For the complete Warning on lactic acidosis and the Precaution regarding the use of these agents in pregnancy, please see the enclosed full prescribing information.
The revised Boxed Warning statements for both the didanosine and stavudine labels are stated below:
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including didanosine (stavudine) and other antiretrovirals. Fatal lactic acidosis has been reported in pregnant women who received the combination of didanosine and stavudine with other antiretroviral agents. The combination of didanosine and stavudine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk. Please see enclosed full prescribing information for VIDEX (didanosine), VIDEX EC (didanosine), and ZERIT (stavudine) for additional information regarding the recommended use of these agents.
If you have any further questions, please contact the Medical Information Department at Bristol-Myers Squibb Company at 1-800-426-7644. Sincerely,
A. Collier Smyth, M.D. Vice President, Medical Affairs
Source: FDA’s MedWatch