Lactic acidosis in pregnant women receiving d4T (stavudine) and ddI (didanosine): EMEA issue statement

The US FDA issued a statement on January 5th 2001 cautioning on the use of d4T and ddI during pregnancy. This statement and an accompanying letter to healthcare providers from Bristol Myers Squibb was reproduced in full:
www.i-base.info/htb/4145

On January 26th the European Agency for the Evaluation of Medicinal Products (EMEA) also issued a statement concerning this issue and concluded that “at present there is insufficient information to decide whether pregnancy is an additional risk for lactic acidosis.”

Public Statement

Reports of lactic acidosis in pregnant women treated with Zerit® and Videx®

The EMEA’s scientific committee, the CPMP, has been made aware of seven cases of lactic acidosis in pregnant women treated during pregnancy with the combination of Zerit¨ (stavudine) and Videx¨ (didanosine). Three of these cases were fatal. Stavudine and didanosine are nucleoside reverse transcriptase inhibitors (NRTIs) indicated for use in combination with other antiretroviral agents for the treatment of HIV- 1 infection.

Of the three women who died, one also had pathologically confirmed hepatic steatosis and two had pancreatitis. Two of these maternal deaths occurred in a multinational, randomised clinical study. One patient was taking the triple combination therapy of didanosine/stavudine/nelfinavir whilst the other was treated with the triple combination didanosine/stavudine plus an investigational protease inhibitor. The third death and the four additional non-fatal cases of lactic acidosis were identified through worldwide post-marketing surveillance. Of the three women who died, one baby survived; the other two died prior to the mother’s death, at between 32-36 weeks gestation.

Lactic acidosis, sometimes fatal, is a known side effect of NRTIs. Consequently the Summaries of Product Characteristics of all NRTIs used in the treatment of HIV infection (stavudine, lamivudine, abacavir, zidovudine, didanosine and zalcitabine’) warn of the risk of lactic acidosis, which may be fatal. Prescribers are also informed of the need for caution when prescribing to any patient (particularly obese women) with a history of hepatomegaly, hepatitis or other known risk factors for liver disease.

Lactic acidosis is usually associated with severe hepatic damage and other organs may also be affected. Lactic acidosis can occur a few weeks to several years after the beginning of treatment with NRTIs. Symptoms which may be indicative of the development of lactic acidosis include: digestive symptoms (nausea, vomiting, anorexia, abdominal pain, diarrhoea), respiratory symptoms (dyspnea), neuromuscular symptoms (cramp, myalgia, paraesthesia) or a non specific general deterioration (asthenia, weight loss).

The CPMP has carefully reviewed the available data and considers that at present there is insufficient information to decide whether pregnancy is an additional risk for lactic acidosis. It is also uncertain whether any increased risk of lactic acidosis is specific to stavudine and didanosine or whether it might be increased with all combinations of nucleoside analogues. The EMEA also wishes to draw attention to the fact that, except for the use of zidovudine in the prevention of materno-foetal transmission of HIV, the use of nucleoside analogues during pregnancy is not recommended unless the potential clinical benefit clearly outweighs the potential risks.

The CPMP and National Agencies have requested additional information from all concerned marketing authorisation holders and these issues will be evaluated further by the CPMP for the whole class of NRTIs.

These NRTIs are marketed under the following tradenames (in brackets): lamivudine (Epivir¨); abacavir (Ziagen¨); zidovudine (Retrovir¨); zalcitabine (Hivid¨); the combination product lamivudine/zidovudine (Combivir¨) ; and the combination product lamivudine/zidovudine/abacavir (Trizivir¨)

EMEA, 7 Westferry Circus, Canary Wharf, London, E14 4HB, UK. Tel: +44 (0)20 7418 8400