Lower DMPA dose provides comparable efficacy, tolerability in adolescents




ORLANDO – Depot medroxyprogesterone acetate (DMPA) given at a dose of 75 mg provided effective contraception with rates of weight gain and unscheduled bleeding in adolescent girls that were comparable to higher doses in a small randomized controlled trial.

Of 27 girls who completed the study, 8 were treated with a 150 mg dose, 9 were treated with 104 mg, and 10 were treated with 75 mg. Weight gain was greatest with the 75 mg dose, with 28.6% of girls in that group experiencing greater than 5% weight gain, compared with 12.5% and 22.2% of those in the 150 mg and 104 mg groups, respectively. The differences between groups did not reach statistical significance, however, Dr. Andrea E. Bonny reported at the annual meeting of the North American Society for Pediatric and Adolescent Gynecology.

The combined number of days of bleeding or spotting during days 0 to 24 was lowest for those on the 75 mg dose (about 44 days vs. about 45 and 70 days for the 150 mg and 104 mg groups, respectively). These differences also failed to reach statistical significance, although the difference between the 104 mg and 75 mg groups trended toward significance, said Dr. Bonny of Nationwide Children’s Hospital, Columbus, Ohio.

Study subjects were healthy postmenarcheal females aged 12 to 21 years (mean of 18.5 years) who were initiating DMPA. Assigned doses were administered by intramuscular injection every 12 weeks. Subjects were assessed for weight/adiposity at baseline and at 12 and 24 weeks, and for serum MPA, estradiol, and progesterone weekly from 0-12 weeks, and also at 16, 20, and 24 weeks. Doses were escalated if MPA concentration was below 0.3 ng/ml, which is triple the previously demonstrated efficacy threshold of 0.1 ng/ml, Dr. Bonny said.

Doses were also escalated if progesterone concentration was 2 ng/ml or greater (which is suggestive of ovulation) at the time of an assessment. Escalations were required in 3 of the 10 girls in the 75 mg dose group, indicating 70% efficacy, but it is important to note that 98% of the measures of MPA concentration were above the standard 0.01 threshold for efficacy, she said.

All subjects kept a diary to track the number of days of spotting and bleeding.

An analysis of pharmacokinetic measures, including maximum MPA concentration, time needed to reach maximum MPA concentration, MPA elimination rate, and area under the concentration time curve from 0-12 weeks, showed a trend for an inverse relationship between MPA exposure and weight gain. The analysis also showed that time to maximum MPA concentration was a better predictor of unscheduled bleeding than was MPA dose; the time to maximum concentration was highly inversely correlated with the number of days of bleeding, Dr. Bonny said.

“The longer the time to get up to max concentration, the less bleeding they had,” she said.

Single intramuscular doses of 25, 50, and 100 mg have been shown to inhibit ovulation for at least 3 months in most individuals, but the relationship between exposure and side effects has been unclear, she said.

“We know that weight gain and unscheduled bleeding are highly variable among adolescents on DMPA, and despite a wide variety of studies examining predictors of DMPA-associated side effects, understanding of who is at risk is still limited,” she said, adding that pharmacokinetics also vary widely among patients.

“We found the 75 mg DMPA dose provided effective contraception in 70% of subjects, but that was using our very conservative cutoff of 0.03 ng/ml, and if we actually used the historical cutoff of 0.1, it would have reached 98%,” she said

The finding of a trend toward increased weight gain with the lowest dose seems counterintuitive, but has also been seen in at least one other cohort, she noted.

Aside from demonstrating the efficacy of the 75 mg dose of DMPA, this study demonstrated that adolescents “really can be enrolled in rigorous contraceptive trials,” she said, explaining that such studies rarely include individuals under age 18 years, and almost never include those under age 16 years.

“We had subjects who were 12 years old ... who were very compliant,” she said.

She also noted that the findings would be much more clinically useful if a simple clinical marker of pharmacokinetics were available.

“To that end, we have collected whole blood, and we will be analyzing it for genetic variants of the primary enzyme responsible for metabolizing DMPA to see if we can find a marker that can predict [time to maximum concentration] or some other pharmacokinetic measure,” she said.


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