Key points from the evidence

Key points from the evidence

The content of this evidence summary was up-to-date in January 2014. See summaries of product characteristics (SPCs), British national formulary (BNF) or the MHRA or NICE websites for up-to-date information.

Summary

A new formulation of depot medroxyprogesterone acetate (DMPA) for subcutaneous administration (DMPA‑SC 104 mg/0.65 ml, Sayana Press) was shown to be as effective as DMPA given by intramuscular administration (DMPA‑IM 150 mg/ml, Depo-Provera) for preventing pregnancy. Bone mineral density (BMD) loss and weight gain were similar with both methods of administration.

Effectiveness

  • The Pearl Index (number of pregnancies per 100 woman-years exposure) was 0 (3 studies including 3565, 5616 and 10,407 woman-cycles excluding months when barrier contraception was used or no intercourse occurred).

  • Contraceptive efficacy was maintained in women who were overweight or obese (6.3–25.1% of women in the studies had a BMI >30 kg/m2).

Safety

  • Use of DMPA is associated with significant loss of BMD, which is greater with increasing duration of use, but BMD appears to increase after DMPA is stopped.

  • There was no significant difference between DMPA‑IM and DMPA‑SC in the decrease in BMD density after 3 years' use.

  • Weight gain is possible with DMPA‑SC but there is wide variation between individual women.

User factors

  • Contraceptive efficacy does not depend on daily concordance.

  • Subcutaneous injection may be more acceptable than intramuscular administration to some women, including those at risk of haematoma due to bleeding disorders or anticoagulation.

  • The return to fertility (ovulation) may be delayed for up to 1 year after DMPA is stopped.

Resource implications

  • The cost of each DMPA‑SC injection is £6.90, administered every 13 weeks (±7 days).

  • The cost of each DMPA‑IM injection is £6.01, administered every 12 weeks (±5 days).

Key points

Sayana Press is a formulation of DMPA for subcutaneous administration (DMPA–SC) for use as long-term female contraception, administered every 13 weeks. It is an alternative to DMPA administered by intramuscular injection (DMPA‑IM, Depo-Provera) and was launched in the UK in June 2013. DMPA works by inhibiting gonadotrophin secretion, which, in turn, prevents ovulation.

This evidence summary is based on 3 trials that evaluated the contraceptive efficacy and safety of DMPA‑SC. One of these was a randomised controlled trial that compared subcutaneous and intramuscular administration of DMPA over 2 years with an optional 1‑year extension, and also evaluated the effect of DMPA on BMD (Kaunitz et al. 2009); the other 2 studies were 1‑year non-comparative studies (Jain et al. 2004).

The trials used DMPA–SC presented in a pre-filled syringe. The brand name for this product is Sayana, but Sayana was never marketed in the UK (Pfizer, personal communication, 2013). The UK public assessment report for Sayana Press (the same formulation of DMPA‑SC as in Sayana but presented in a Uniject injection device) concluded that there was no clinically important difference in pharmacokinetics between the 2 presentations.

In all 3 studies, no pregnancies were recorded with DMPA‑SC during use up to 3 years (a total of 19,588 woman-cycles excluding months when barrier contraception was used or no intercourse occurred). In the comparative trial, 1 woman in the DMPA‑IM group became pregnant. Rates of decrease of BMD were not statistically significantly different in the DMPA‑SC and DMPA‑IM intervention groups after up to 3 years of use in the comparative trial; during this period, 55.6% (35/63) of DMPA‑SC recipients and 51.9% (28/54) of DMPA‑IM recipients had decreases of at least 5% in total hip BMD from baseline.

In the comparative trial, after 3 years' use, women in the DMPA‑SC group had a mean (± standard deviation) weight gain of 4.5±8.5 kg and women in the DMPA‑IM group had a mean weight gain of 5.8±8.7 kg. There were large individual variations in weight over 1 year, with some women losing and some women gaining more than 9 kg. The summary of product characteristics (SPC) for Sayana Press states that body weight was monitored for 12 months in phase III studies; 50% of women remained within 2.2 kg of their initial body weight, 12% of women lost more than 2.2 kg and 38% of women gained more than 2.3 kg.

The SPC advises that, because loss of BMD may occur in women of all ages who use DMPA‑SC long term, a risk/benefit assessment should be considered, which also takes into consideration the decrease in BMD that occurs during pregnancy and lactation. In particular, in women with significant lifestyle and/or medical risk factors for osteoporosis, other methods of contraception should be considered before use of DMPA‑SC. In adolescents, use of DMPA‑SC is indicated only when other contraceptive methods are considered unsuitable or unacceptable, because of unknown long-term effects of bone loss associated with DMPA‑SC in the critical period of bone accretion. The SPC advises careful re-evaluation of the risks and benefits of use in women who wish to continue use for more than 2 years.

Limitations to the evidence for DMPA SC include the lack of comparisons with other contraceptive options and the high discontinuation rate in the study by Kaunitz et al. (2009). However, the UK public assessment report for Sayana accepted that the studies provided sufficient evidence of contraceptive efficacy. This is because they were large enough that the calculated 2‑sided 95% confidence interval for the overall Pearl Index (number of pregnancies per 100 woman-years) was sufficiently narrow (in accordance with the European Medicines Agency's guideline on clinical investigation of steroid contraceptives in women). The UK public assessment report for Sayana Press concluded that there was no clinically important difference in pharmacokinetics between Sayana and Sayana Press.

In addition, the 2 non-comparative studies lasted only 1 year and only 66 women in the study by Kaunitz et al. (2009) received DMPA‑SC for 3 years. Thus, there is limited evidence of long-term safety data from clinical studies, although it is reasonable to expect that experience from long-term use of DMPA‑IM is likely to give an indication of potential harms.

The NICE clinical guideline on long-acting reversible contraception (LARC) gives recommendations on the use of DMPA, and Sayana Press provides an alternative route of administration for DMPA from the intramuscular route, at a similar cost. A review of this product from the Faculty of Sexual and Reproductive Healthcare (FSRH) commented that DMPA–SC may be a preferable form of administration compared with intramuscular DMPA in women at risk of haematoma. The FSRH review also noted that it has potential for self-administration, although it is not licensed for this indication.

Local decision-makers will need to consider the evidence for DMPA‑SC with that for DMPA‑IM and other LARC methods. Factors relating to individual women, and the licensed indications, dosage intervals and costs of the various LARC methods will need to be taken into account in the context of NICE guidance.

Key evidence

Kaunitz AM, Darney PD, Ross D et al. (2009). Subcutaneous DMPA vs. intramuscular DMPA: a 2-year randomized study of contraceptive efficacy and bone mineral density. Contraception 80: 7–17.

Jain J, Jakimiuk AJ, Bode FR et al. (2004). Contraceptive efficacy and safety of DMPA-SC. Contraception 70: 269–275.

About this evidence summary

'Evidence summaries: new medicines' provide summaries of key evidence for selected new medicines, or for existing medicines with new indications or formulations, that are considered to be of significance to the NHS. The strengths and weaknesses of the relevant evidence are critically reviewed within this summary to provide useful information for those working on the managed entry of new medicines for the NHS, but this summary is not NICE guidance.