Treatment of overdosage consists of discontinuation of Endometrin together with institution of appropriate symptomatic and supportive care.
Endometrin should not be used in individuals with any of the following conditions:
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 reflect exposure to Endometrin in 808 infertile women (74.9% White, 10.3% Hispanic, 5.4% Black, 5% Asian, and 4.6% Other) in a single Assisted Reproductive Technology 10 week clinical study conducted in the U.S. Endometrin was studied at doses of 100 mg twice daily and 100 mg three times daily. The adverse reactions that occurred at a rate greater than or equal to 2% in either Endometrin group are summarized in Table 1.
Table 1: Number and Frequency of Reported
Adverse Reactions in Women Treated with Endometrin in an Assisted Reproductive
Technology Study
| Body System Preferred Term | Endometrin 100 mg twice daily (N=404) | Endometrin 100 mg three times daily (N=404) |
| Gastrointestinal Disorders | ||
| Abdominal pain | 50 (12%) | 50 (12%) |
| Nausea | 32 (8%) | 29 (7%) |
| Abdominal distension | 18(4%) | 17(4%) |
| Constipation | 9(2%) | 14 (3%) |
| Vomiting | 13(3%) | 9(2%) |
| General Disorders and Administration Site Conditions | ||
| Fatigue | 7(2%) | 12 (3%) |
| Infections and Infestations | ||
| Urinary tract infection | 9(2%) | 4 (1%) |
| Injury, Poisoning and Procedural Complications | ||
| Post-ooctye retrieval pain | 115(28%) | 102 (25%) |
| Nervous System Disorders | ||
| Headache | 15(4%) | 13(3%) |
| Reproductive System and Breast Disorders | ||
| Ovarian hyperstimulation syndrome | 30 (7%) | 27 (7%) |
| Uterine spasm | 15(4%) | 11 (3%) |
| Vaginal bleeding | 13(3%) | 14 (3%) |
Other less common reported adverse reactions included vaginal irritation, itching, burning, discomfort, urticaria, and peripheral edema.
Expected Adverse Reaction Profile Seen with ProgesteroneEndometrin is also expected to have adverse reactions similar to other drugs containing progesterone that may include breast tenderness, bloating, mood swings, irritability, and drowsiness.
Endometrin is indicated to support embryo implantation and early pregnancy by supplementation of corpus luteal function as part of an Assisted Reproductive Technology (ART) treatment program for infertile women.
Progesterone serum concentrations increased following the administration of the Endometrin Vaginal Insert in 12 healthy pre-menopausal females. On single dosing, the mean Cmax was 17.0 ng/Ml in the Endometrin twice daily group and 19.8 ng/mL in the Endometrin three times daily group. On multiple dosing, steady-state concentrations were attained within approximately 1 day after initiation of treatment with Endometrin. Both Endometrin regimens provided average serum concentrations of progesterone exceeding 10 ng/mL on Day 5. The pharmacokinetic results are summarized in Table 2.
Table 2: Mean (±Standard Deviation) Serum
Progesterone Pharmacokinetic Parameters
| Pharmacokinetic Parameter (unit) | Endometrin 100 mg twice daily (N=6) | Endometrin 100 mg three times daily (N=6) |
| Single Dosing | ||
| Cmax (ng/mL) | 17.0 ± 6.5 | 19.8 ± 7.2 |
| Tmax (hr) | 24.0 ± 0.0 | 17.3 ± 7.4 |
| AUC0-24 (ng•hr/mL) | 217±113 | 284 ± 143 |
| Day 5 of Multiple Dosing | ||
| Cmax (ng/mL) | 18.5 ± 5.5 | 24.1 ±5.6 |
| Tmax (hr) | 18.0 ± 9.4 | 18.0 ± 9.4 |
| Cmin (ng/mL) | 8.9 ±4.5 | 10.9 ± 6.7 |
| Cavg (ng/mL) | 14.0 ±4.8 | 15.9 ±4.3 |
| AUC0-24 (ng•hr/mL) | 327±127 | 436 ± 106 |
| Cmax Maximum progesterone serum concentration. Tmax Time to maximum progesterone serum concentration. Cavg Average progesterone serum concentration. AUC0-24 Area under the drug concentration versus time curve from 0-24 hours post dose. Cmin Minimum progesterone serum concentration. |
Progesterone is approximately 96% to 99% bound to serum proteins, primarily to serum albumin and corticosteroid binding globulin.
MetabolismProgesterone is metabolized primarily by the liver largely to pregnanediols and pregnanolones. Pregnanediols and pregnanolones are conjugated in the liver to glucuronide and sulfate metabolites. Progesterone metabolites that are excreted in the bile may be deconjugated and may be further metabolized in the gut via reduction, dehydroxylation, and epimerization.
ExcretionProgesterone undergoes renal and biliary elimination. Following injection of labeled progesterone, 50-60% of the excretion of metabolites occurs via the kidney; approximately 10% occurs via the bile and feces. Overall recovery of the labeled material accounts for 70% of an administered dose. Only a small portion of unchanged progesterone is excreted in the bile.
Endometrin has been used to support embryo implantation and maintain clinical pregnancy in one clinical study. The livebirth outcomes of these pregnancies were as follows:
Among the 404 subjects treated with Endometrin twice daily, 143 subjects had livebirths consisting of 85 singletons, 56 twins, and 2 triplets. In this treatment group, 13 subjects had a spontaneous abortion, 1 subject had an ectopic pregnancy, and 7 subjects reported fetal birth defects (3.4% based on 203 livebirths).
Among the 404 subjects treated with Endometrin three times daily, 155 subjects had livebirths consisting of 91 singletons, 60 twins, and 4 triplets. In this treatment group, 22 subjects had a spontaneous abortion, 4 subjects had an ectopic pregnancy, and 7 subjects reported fetal birth defects (3.1% based on 223 livebirths).
Birth defects reported in the Endometrin twice daily group included: one fetus with a cleft palate and intrauterine growth retardation, one fetus with spina bifida, three fetuses with congenital heart defects, one fetus with an umbilical hernia, and one fetus with an intestinal anomaly.
Birth defects reported in the Endometrin three times daily group included: one fetus with an esophageal fistula, one fetus with hypospadias and an underdeveloped right ear, one fetus with Down's and an atrial septal defect, one fetus with congenital heart anomalies, one fetus with DiGeorge's syndrome, one fetus with a hand deformity, and one fetus with cleft palate.
For additional information on the pharmacology of Endometrin and pregnancy outcome information.
100 mg vaginal insert is a white to off-white oblong-shaped tablet debossed with “FPI” on one side and “100” on the other side.
Storage And HandlingEach Endometrin Vaginal Insert is a white to off-white oblong-shaped insert debossed with “FPI” on one side and “100” on the other side. Each Endometrin® (progesterone) Vaginal Insert, 100 mg, is packed individually in a sealed foil pouch. These pouches are available in cartons packed:
21 vaginal inserts with 21 disposable vaginal applicators (NDC 55566-6500-3)
Store at 20 - 25°C (68 - 77°F); excursions permitted between 15 - 30°C (59 - 86°F).
Manufactured For: Ferring Pharmaceuticals Inc. Parsippany, NJ 07054. Revised: 04/2012
Included as part of the PRECAUTIONS section.
PRECAUTIONS Cardiovascular or Cerebrovascular DisordersThe physician should be alert to earliest signs of myocardial infarction, cerebrovascular disorders, arterial or venous thromboembolism (venous thromboembolism or pulmonary embolism), thrombophlebitis, or retinal thrombosis. Endometrin should be discontinued if any of these are suspected.
DepressionPatients with a history of depression need to be closely observed. Consider discontinuation if symptoms worsen.
Use of Other Vaginal ProductsEndometrin should not be recommended for use with other vaginal products (such as antifungal products as this may alter progesterone release and absorption from the vaginal insert.
Patient Counseling InformationSee FDA-Approved Patient Labeling
Vaginal BleedingInform patients of the importance of reporting irregular vaginal bleeding to their doctor as soon as possible.
Common Adverse Reactions with ProgesteroneInform patients of the possible side effects of progesterone therapy such as headaches, breast tenderness, bloating, mood swings, irritability, and drowsiness.
Coadministration of Vaginal ProductsInform patients that Endometrin is not recommended for use with other vaginal products.
Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of FertilityNonclinical toxicity studies to determine the potential of Endometrin to cause carcinogenicity or mutagenicity have not been performed. The effect of Endometrin on fertility has not been evaluated in animals.
Use In Specific Populations PregnancyEndometrin has been used to support embryo implantation and maintain clinical pregnancy in one clinical study. The livebirth outcomes of these pregnancies were as follows:
Among the 404 subjects treated with Endometrin twice daily, 143 subjects had livebirths consisting of 85 singletons, 56 twins, and 2 triplets. In this treatment group, 13 subjects had a spontaneous abortion, 1 subject had an ectopic pregnancy, and 7 subjects reported fetal birth defects (3.4% based on 203 livebirths).
Among the 404 subjects treated with Endometrin three times daily, 155 subjects had livebirths consisting of 91 singletons, 60 twins, and 4 triplets. In this treatment group, 22 subjects had a spontaneous abortion, 4 subjects had an ectopic pregnancy, and 7 subjects reported fetal birth defects (3.1% based on 223 livebirths).
Birth defects reported in the Endometrin twice daily group included: one fetus with a cleft palate and intrauterine growth retardation, one fetus with spina bifida, three fetuses with congenital heart defects, one fetus with an umbilical hernia, and one fetus with an intestinal anomaly.
Birth defects reported in the Endometrin three times daily group included: one fetus with an esophageal fistula, one fetus with hypospadias and an underdeveloped right ear, one fetus with Down's and an atrial septal defect, one fetus with congenital heart anomalies, one fetus with DiGeorge's syndrome, one fetus with a hand deformity, and one fetus with cleft palate.
For additional information on the pharmacology of Endometrin and pregnancy outcome information.
Nursing MothersDetectable amounts of progesterone have been identified in the milk of nursing mothers. The effect of this on the nursing infant has not been determined.
Pediatric UseThis drug is not intended for pediatric use and no clinical data have been collected in children. Therefore, the safety and effectiveness of Endometrin in pediatric patients have not been established.
Geriatric UseNo clinical data have been collected in patients over age 65.
The dose of Endometrin is 100 mg administered vaginally two or three times daily starting the day after oocyte retrieval and continuing for up to 10 weeks total duration. Efficacy in women 35 years of age and older has not been clearly established. The appropriate dose of Endometrin in this age group has not been determined.
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 reflect exposure to Endometrin in 808 infertile women (74.9% White, 10.3% Hispanic, 5.4% Black, 5% Asian, and 4.6% Other) in a single Assisted Reproductive Technology 10 week clinical study conducted in the U.S. Endometrin was studied at doses of 100 mg twice daily and 100 mg three times daily. The adverse reactions that occurred at a rate greater than or equal to 2% in either Endometrin group are summarized in Table 1.
Table 1: Number and Frequency of Reported
Adverse Reactions in Women Treated with Endometrin in an Assisted Reproductive
Technology Study
| Body System Preferred Term | Endometrin 100 mg twice daily (N=404) | Endometrin 100 mg three times daily (N=404) |
| Gastrointestinal Disorders | ||
| Abdominal pain | 50 (12%) | 50 (12%) |
| Nausea | 32 (8%) | 29 (7%) |
| Abdominal distension | 18(4%) | 17(4%) |
| Constipation | 9(2%) | 14 (3%) |
| Vomiting | 13(3%) | 9(2%) |
| General Disorders and Administration Site Conditions | ||
| Fatigue | 7(2%) | 12 (3%) |
| Infections and Infestations | ||
| Urinary tract infection | 9(2%) | 4 (1%) |
| Injury, Poisoning and Procedural Complications | ||
| Post-ooctye retrieval pain | 115(28%) | 102 (25%) |
| Nervous System Disorders | ||
| Headache | 15(4%) | 13(3%) |
| Reproductive System and Breast Disorders | ||
| Ovarian hyperstimulation syndrome | 30 (7%) | 27 (7%) |
| Uterine spasm | 15(4%) | 11 (3%) |
| Vaginal bleeding | 13(3%) | 14 (3%) |
Other less common reported adverse reactions included vaginal irritation, itching, burning, discomfort, urticaria, and peripheral edema.
Expected Adverse Reaction Profile Seen with ProgesteroneEndometrin is also expected to have adverse reactions similar to other drugs containing progesterone that may include breast tenderness, bloating, mood swings, irritability, and drowsiness.
DRUG INTERACTIONSNo formal drug-drug interaction studies have been conducted for Endometrin. Drugs known to induce the hepatic cytochrome-P450-3A4 system (such as rifampin, carbamazepine) may increase the elimination of progesterone. The effect of concomitant vaginal products on the exposure of progesterone from Endometrin has not been assessed. Endometrin is not recommended for use with other vaginal products (such as antifungal products) as this may alter progesterone release and absorption from the vaginal insert.
