Ferring Pharmaceuticals Inc.

FERRING PHARMACEUTICALS INC.- progesterone ring
Ferring Pharmaceuticals Inc.

1 INDICATIONS AND USAGE

MILPROSA is indicated to support embryo implantation and early pregnancy (up to 10 weeks post-embryo transfer) by supplementation of corpus luteal function as part of an Assisted Reproductive Technology (ART) treatment program for infertile women up to and including 34 years of age.

Limitation of Use

Efficacy in women 35 years of age and older has not been established.

2 DOSAGE AND ADMINISTRATION

2.1 Important Dosage and Administration Information

MILPROSA is not recommended for use with other vaginal products (such as antifungal products, vaginal lubricants, diaphragms, and condoms) because this concomitant use has not been studied and may alter the progesterone release and absorption from the vaginal system [see Warnings and Precautions (5.4) and Drug Interactions (7)].

2.2 Recommended Dosage and Administration

Insert one MILPROSA vaginal system starting on the day after oocyte retrieval. Leave in place continuously (for a minimum of 23 hours per day) for 7 days, then remove the used MILPROSA and insert a new MILPROSA. Replace MILPROSA weekly for up to 10 weeks.

3 DOSAGE FORMS AND STRENGTHS

Vaginal system: 1.78 grams of progesterone in a white to off-white, flexible, non-biodegradable silicone ring (toroidal-shape). MILPROSA has a cross-sectional diameter of approximately 8.5 mm, and an outer and inner diameter of approximately 55 mm and 38 mm, respectively. Each MILPROSA releases an average of 11 mg/day of progesterone when placed in the vagina over a 7-day period.

4 CONTRAINDICATIONS

MILPROSA is contraindicated in women with:

  • Known sensitivity to progesterone or any of the ingredients of MILPROSA [see Description (11)]
  • Undiagnosed vaginal bleeding
  • Severe hepatic impairment or disease
  • Known or suspected malignancy of the breast
  • Active arterial or venous thromboembolism or severe thrombophlebitis, or a history of these events

5 WARNINGS AND PRECAUTIONS

5.1 Cardiovascular or Cerebrovascular Disorders

Be alert to early signs of myocardial infarction, cerebrovascular disorders, arterial or venous thromboembolism (venous thromboembolism or pulmonary embolism), thrombophlebitis, or retinal thrombosis in women using MILPROSA. Discontinue MILPROSA if any of these are suspected.

5.2 Depression

Observe closely women with a history of depression who use MILPROSA. Discontinue MILPROSA if symptoms of depression worsen.

5.3 Toxic Shock Syndrome

Cases of toxic shock syndrome (TSS) have been reported in women using vaginal systems with and without tampon use. No causal relationship between the use of MILPROSA and TSS has been established. Warning signs of TSS include fever, nausea, vomiting, diarrhea, muscle pain, dizziness, faintness or a sunburn-like rash on face and body. Discontinue MILPROSA if TSS is suspected. and initiate appropriate medical evaluation and treatment.

5.4 Use of Other Vaginal Products

Concomitant use of MILPROSA with other vaginal products (such as antifungal products, vaginal lubricants, diaphragms and condoms) has not been studied; these products may alter progesterone release and absorption from MILPROSA [see Drug Interactions (7) ]. If possible, avoid use of other vaginal products with MILPROSA.

6 ADVERSE REACTIONS

The following serious adverse reactions are discussed elsewhere in the labeling:

6.1 Clinical Study Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety data described in Table 1 reflect exposure to MILPROSA (up to 10 weeks) in 647 infertile women (80% Caucasian, 8% African-American, 5% Hispanic, 5% Asian) in a single prospective, randomized, active concurrently-controlled clinical trial of progesterone supplementation in women undergoing in-vitro fertilization (IVF) in the U.S. [see Clinical Studies (14)]. Adverse reactions that occurred at a rate greater than or equal to 2% in the MILPROSA treatment group are summarized in Table 1.

Table 1: Number and Frequency of Adverse Reactions in Women Treated with MILPROSA in an Assisted Reproductive Technology Study (≥2%)
Preferred Term MILPROSA(N=647)
Headache 44 (7%)
Vaginal discharge 26 (4%)
Nausea 25 (4%)
Breast tenderness 24 (4%)
Post procedural discomfort 24 (4%)
Abdominal distension 22 (3%)
Abdominal pain 19 (3%)
Pelvic pain 19 (3%)
Constipation 17 (3%)

Additional safety data following exposure to MILPROSA was collected in a multi-center, non-comparative, open-label, single-arm study of women undergoing Assisted Reproductive Technology in the U.S. The population consisted of 254 infertile women 18-34 years of age (83% Caucasian, 7% African-American, 9% Asian,1% American Indian) who were exposed up to 10 weeks. The adverse reaction profile was consistent with previous observations.

Adverse reactions associated with other drugs containing progesterone include bloating, mood swings, irritability, and drowsiness.

7 DRUG INTERACTIONS

No formal drug-drug interaction studies have been conducted for MILPROSA. Drugs known to induce the hepatic CYP3A4 enzyme (such as rifampin, carbamazepine) may increase the elimination of progesterone. The effect of concomitant vaginal products on the exposure of progesterone from MILPROSA has not been assessed. MILPROSA is not recommended for use with other vaginal products (such as antifungal products, vaginal lubricants, diaphragms and condoms) as this may alter progesterone release and absorption from the vaginal system [see Warnings and Precautions (5.4)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

MILPROSA is indicated to support embryo implantation and early pregnancy as part of an assisted reproductive technology treatment program in vitro fertilization (IVF) with or without intracytoplasmic sperm injection (ICSI) and embryo transfer for infertile women. Maternal risks are discussed throughout the labeling.

In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Human Data

MILPROSA has been used to support embryo implantation during the first trimester of pregnancy and to maintain clinical pregnancy as part of an ART regimen. Exposure in pregnancy with use of MILPROSA occurs from implantation of an embryo through week 10 of pregnancy when the placenta takes over production of progesterone.

In clinical trials, among 813 women less than 35 years of age who were treated with MILPROSA, 75 (9.2%) had a spontaneous abortion and 6 (0.7%) had an ectopic pregnancy. Of the 813 women less than 35 years of age, 559 (68.8%) were planned to be followed through birth. Among the 559 to be followed through birth, 263 (47.0%) had livebirths consisting of 154 (58.6%) singletons, 102 (38.8%) twins, and 7 (2.7%) triplets. In this same cohort of treatment, 10 (1.8%) had a second or third trimester loss. Neonatal birth defects were reported in 8 (2.1%) of infants based on 379 liveborn infants. In the 2.1% of live born infants with birth defects for women less than 35 years of age treated with MILPROSA the following were noted: Turner’s syndrome; Tetralogy of Fallot; and congenital anomalies including left foot deformity, hypospadias, pyloric stenosis, spina bifida, multiple congenital anomalies, and multiple congenital anomalies with VACTERL association.

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