Regulatory Decision Summary for Inprosub

Progesterone is currently approved in Canada in the forms of a vaginal gel, a vaginal table and a vaginal capsule for progesterone supplementation in women undergoing in vitro fertilization. There are also other available drug products that are used “off-label” for luteal supplementation though these are not specifically approved for this indication.

Inprosub represents a new dosage strength (25 mg) with a new route of administration (subcutaneous), not available on the Canadian market. The sponsor proposes that Inprosub will provide additional benefit to women through avoidance of the discharge, discomfort, and irritation associated with local vaginal administration and through the self-injection by patients at home after proper training.

For efficacy, two pivotal trials were conducted. In both trials, the primary efficacy was assessed on the endpoint of ongoing pregnancies, defined as identification of at least one gestational sac with foetal heart motion on ultrasound scan 10 weeks after the start of treatment. In both studies, the ongoing pregnancy rates for subjects treated with Inprosub were declared non-inferior (lower bounds of the 95% confidence interval [CI] of the difference between Inprosub and the active comparators excluded a difference greater than 10%) to the ongoing pregnancy rates for subjects treated with the active comparators. In Study 07EU/Prg06, ongoing pregnancy rates were 27.4% in the Inprosub group and 30.6 % in the active progesterone gel comparator group for the ITT population (difference vs. comparator -3.09; 95% confidence interval [CI]: -9.91%, 3.73%). In Study 07US/Prg05, ongoing pregnancy rates were 40.8% in the Inprosub group and 43.3% in the active progesterone tablet comparator group for the ITT population (difference vs. comparator -2.5; 95% CI: -9.4%, 4.4%). Although in these two pivotal studies, Inprosub was demonstrated to be non-inferior to the active controls (as pre-defined in the statistical protocols), the lower limit of the 95% CI is quite close to the chosen 10% margin. In addition, subjects participating in the two pivotal studies were not stratified at randomization by age (i.e., women under 35 years of age vs. women greater than or equal to 35 years of age) and/or by ovarian reserve (as measured by serum FSH levels). The mean age of enrolled patients for both pivotal studies was 34 years of age for the Inprosub groups. Thus, the efficacy of Inprosub in the subgroup of women 35-42 years of age has not been sufficiently demonstrated. This older subgroup represents approximately 50%-60% of the infertile women for whom this drug is intended to use. Women of advanced reproductive age (greater than or equal to 35 years of age) represent a different patient population from that of women under age 35 who undergo these procedures. To address these, it is recommended appropriate labeling for the indication, which includes the statements on the limitation of use for the age and for women who are unable to use or tolerate vaginal preparations. Thus, the recommended indication is as follows:

Inprosub (25 mg progesterone injection) is indicated for progesterone supplementation in women up to and including 34 years of age who are unable to use or tolerate vaginal preparations and undergoing in vitro fertilization (IVF) with or without intracytoplasmic sperm injection (ICSI).

The most concerning serious adverse events associated with progesterone therapy in general can be grouped into adverse events as a result of the pharmacologic action of the drug (including severe allergic reactions) and adverse events as a result of drug administration (including injection site reactions). The risks associated with the use of progestogens are well-defined with possible increases in the risk of stroke, myocardial infarction, deep vein thrombosis, and invasive breast cancer when used in conjunction with estrogens for hormone therapy. The overall risk of these serious outcomes is low as defined by the Women’s Health Initiative trial of conjugated estrogens and conjugated estrogens plus progestins (2002).

Important potential risks with the use of Inprosub include: conditions affected by fluid retention (such as for instance), epilepsy, cardiac or renal dysfunctions; arterial or venous thromboembolism including cerebrovascular disorders, myocardial infarction, thrombophlebitis, retinal thrombosis; depression; diabetes and reduced glucose tolerance, fetal congenital malformations and severe allergic reactions (anaphylaxis, anaphylactoid reactions).

Inprosub is also expected to have adverse reactions similar to other drugs containing progesterone that may include breast tenderness, bloating, mood swings, depression, irritability, drowsiness, insomnia, jaundice, urticaria, acne, hirsutism, alopecia, weight gain and vaginal bleeding.

In the two pivotal trials, there was numerical difference in fetal congenital malformations seen between the Inprosub treatment groups and the active control groups. In the consult review report, the Bureau of Medical Sciences recommended that this numerical difference in congenital malformations should not by itself preclude the decision to authorize this medications for assisted reproductive technology.

Progesterone has been approved under multiple NDS in various formulations for various indications including for contraception and amenorrhea. Inprosub use in IVF with or without ICSI is for short-term use until the role of producing progesterone in early pregnancy is taken over by the fetal placenta around 10-weeks post-embryo transfer (or 12^th gestational week). The duration of exposure (up to 10 weeks) of Inprosub is less than the duration of already approved products on Canadian Market.

Overall, the Benefit-Harm-Uncertainty profile is considered favorable for the limited, non-chronic use of Inprosub in the intended population of women 18 to 34 years of age who are unable to use or tolerate vaginal preparations. The available evidence supports a positive benefit-risk balance for Inprosub, in appropriately-chosen patients, when it is prescribed under the conditions of use recommended in the Product Monograph.