The Expert Committee recommended the addition of the subcutaneous injection formulation of depot medroxyprogesterone acetate to the core list of the EML. The Committee considered that the subcutaneous formulation, with appropriate training for administration, would provide an effective, safe and convenient contraceptive treatment choice. The possibility of self-administration may be an advantage in settings where availability of health-care providers is limited. The Committee also recommended the current listing of the intramuscular formulation be amended as proposed in the application, to clarify its route of administration.

Depot medroxyprogesterone acetate (DPMA) for IM injection (150 mg/mL) has been included on the EML since 1985, initially on the Complementary List and then moved to the core list in 2005.

Estimates have indicated that contraceptive use contributes to reduced maternal mortality and morbidity. In an analysis of 172 countries, contraceptive use was estimated to have reduced maternal mortality by 44%, thereby averting 272 040 maternal deaths (1). A significant unmet need for contraception exists, with an estimated 222 million women in low-income countries lacking access (2). Addressing this unmet need may avert a further 30% of maternal deaths (3).

Evidence for the clinical effectiveness of medroxyprogesterone acetate was evaluated at the time of listing. The application presented the results of two phase 3, open-label, non-comparative, multinational 1-year studies which assessed the efficacy and safety of subcutaneous DMPA (DMPA-SC) (4). In each study, participants received contraceptive injection every 3 months for up to 1 year. The combined total was 16 023 woman-cycles of exposure. No unintended pregnancies were reported in either study. Both the Pearl Index (number of pregnancies per 100 woman-years of use) and the cumulative pregnancy rate at 1 year (the primary end-point) were 0 (95% confidence intervals not calculated as no pregnancies were reported). A small comparative study in 58 women assessed efficacy, ovulation suppression and return to ovulation at 12 months after a single dose of DMPA-SC or DMPA-IM (5). Pharmacokinetic parameters of the SC formulation were also assessed. Results indicated that suppression of ovulation was immediate following single-dose SC administration. DMPA-SC consistently suppressed ovulation for the 13-week dosing interval, with the earliest return to ovulation occurring at 15 weeks. Median time to return to ovulation was 30 weeks. The cumulative rate of ovulation at 12 months post-injection (the primary efficacy end-point) was 97.4% and 94.7% in the SC and IM groups, respectively. Suppression of ovulation did not appear to be affected by body mass index or race.

Evidence for the safety of medroxyprogesterone acetate was evaluated at the time of its original listing. The overall safety profile of DMPA-SC is consistent in most respects with that of DMPA-IM and reflects the known physiological effects of medroxyprogesterone acetate. With the exception of injection site reactions, the types of adverse events seen with DMPA-SC are similar to those with DMPA-IM and include bleeding irregularities, amenorrhoea, weight gain, headache and mild, reversible loss of bone mineral density. A higher rate of injection site reactions was observed in patients receiving DMPA-SC (4).

A systematic review of 14 studies investigated the safety of DMPA-SC in women with various characteristics or medical conditions (6). The review found evidence to support DMPA-SC as a safe contraceptive treatment for use by women with conditions and characteristics that included age, obesity, endometriosis and HIV infection. The review also found that the two formulations appear to be therapeutically equivalent when used by healthy women.

The unit price for DMPA-SC is US$ 1 to qualified purchasers in 69 of the world’s poorest countries with a partnership consortium. For populations and countries not included in the agreement, prices are based on a differential pricing structure and take into consideration the local economic conditions and family planning climates. In comparison, the median supplier price of DMPA-IM, according to the International Medical Products Price Guide, is US$ 0.75 per unit (8).

The WHO Medical eligibility criteria for contraceptive use (7) states that DMPA-IM and DMPA-SC appear therapeutically equivalent, demonstrating similar pharmacokinetics, effects on serum estradiol levels and high contraceptive efficacy. It recommends that all guidance for DMPA-SC should follow the current recommendations for DMPA-IM (very low-quality evidence).

Pfizer Ltd.

Comments on the application received from Médecins Sans Frontières (MSF) indicated that the organization did not support addition of this SC formulation to the EML, based on an anticipated low probability of programmes involving self-administration and the additional cost in resource-limited settings compared with the IM formulation.

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