Development of New Tocolytics Won't Be Easy

OB/GYN News, Oct 15, 1999 by Mitchel L. Zoler

Promising new treatments for preterm labor are being studied, but some unique problems make development of new tocolytic agents an especially difficult challenge.

Most notable is the paradox that shrouds current treatment for preterm labor: The only drug approved by the Food and Drug Administration for tocolysis, ritodrine, is widely viewed as archaic, relatively ineffective, and dangerous.

Although other drugs are much more commonly used for tocolysis--magnesium sulfate, terbutaline, indomethacin, and sometimes nifedipine--their off-label status makes them unlikely benchmarks for clinical trials.

"Ritodrine is mainly used [as the control drug] in studies because it's the only drug with FDA approval. No one wants to use an off-label drug as a control," said Dr. Lawrence D. Devoe, chairman of ob.gyn. at the Medical College of Georgia in Augusta.

Skittishness among drug companies is another factor. Pharmaceutical manufacturers often don't pursue promising applications of existing drugs in pregnancy because of the safety and liability issues that come with an approved indication in pregnancy, added Dr. Devoe. Drug companies seem to prefer that such drugs get used during pregnancy on an off-label basis.

A good example was a report published last month that showed, in a British study with 245 women, that treatment with one or two nitroglycerin patches a day was at least as effective as ritodrine for tocolysis, with the advantages of a better safety profile and easier dosing (Obstet. Gynecol. 94[3]:403-08, 1999).

In this multicenter trial, women with regular uterine contractions who were between 24 and 32 weeks' gestation (or up to 36 weeks in six centers outside of the United Kingdom) were randomized to one of two tocolytic regimens. Nitroglycerin treatment was used on 120 women, who received a single 10-mg patch and then a second 10-mg patch if they had no reduction in contractions after 1 hour. The patches were left in place for a day and then the women were reassessed; treatment was halted once contractions had stopped for 24 hours.

A group of 125 women were treated with ritodrine, given as an intravenous infusion of 50 [mu]g/min.

There was no significant difference in the primary outcome measure: percentage prolongation of gestation to 37 weeks. This endpoint was achieved for 73.8% of the women in the ritodrine group, and 73.6% of the women in the nitroglycerin patch group.

But in a secondary analysis, the risk of preterm delivery was reduced from 49% with ritodrine or placebo treatment to 36% with nitroglycerin, a statistically significant difference.

In addition, the nitroglycerin patches were much easier to administer, and produced notably fewer adverse effects.

Ritodrine treatment was associated with tachycardia in 58% of women, palpitations in 13%, breathlessness in 7%, and chest pain or tightness in 6%. The only one of these effects seen with nitroglycerin was tachycardia in 2%. The most notable adverse effect of nitroglycerin was headache, which was managed with acetaminophen.

Based on these results, "I'm convinced that glycerine trinitrate [nitroglycerin]... is at least as effective as ritodrine, and it looks a lot safer," said Dr. Christoph C. Lees, who is an obstetrician at King's College Hospital in London and the study's lead researcher.

Dr. Lees noted that nitroglycerin may work even better when used along with indomethacin, a combination that he has been studying anecdotally.

But two U.S. experts commented that while nitroglycerin looked promising, its role as a tocolytic is far from established.

"The data are intriguing, but to develop all of the measures you need for safety and efficacy, you need a much larger study," Dr. Devoe told this newspaper.

"The numbers are way too small for meaningful conclusions," agreed Dr. Charles J. Lockwood, chairman of ob.gyn. at New York University. He was particularly concerned about proving that nitrate treatment has no harmful effect on uteroplacental blood flow.

Dr. Lees is not optimistic that a larger-scale trial of nitroglycerin can be done without drug company support, which has not been forthcoming. "I don't think that they're commercially interested in this. A lot of companies are terribly nervous about pregnancy"

The failure of companies to sponsor trials that are big enough to prove the safety and efficacy of new tocolytic drugs has affected several other agents.

Nifedipine, already on the market as an antihypertensive drug, was shown to be more effective and safer than ritodrine in a multicenter, randomized trial published in 1997. At that time, Dr. Lockwood called for a larger, placebo-controlled trial to confirm nifedipine's safety and efficacy as a tocolytic, but such a trial has not been done. Today Dr. Lockwood sees nifedipine as a first-line tocolytic for outpatient use or for inpatients when preterm labor recurs following treatment with magnesium sulfate or subcutaneous terbutaline.

But nifedipine's role remains limited because "large trials in the U.S. are lacking," said Dr. Devoe.