Endometrin: Indications, Dosage, Precautions, Adverse Effects
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Endometrin - Product Information

Manufacture: Ferring Pharmaceuticals
Country: Canada
Condition: Amenorrhea, Progesterone Insufficiency
Class: Progestins
Form: Vaginal (e.g., douche, pessary, etc.), Tablets
Ingredients: Progesteronelactose, monohydrate, polyvinylpyrrolidone, adipic acid, sodium bicarbonate, sodium lauryl sulfate, magnesium stearate, pregelatinized starch, and colloidal silicone dioxide.

Summary Product Information

Route of
Administration
Dosage Form /
Strength
Clinically Relevant Nonmedicinal
Ingredients
VaginalEffervescent vaginal tablets

100 mg
lactose monohydrate, polyvinylpyrrolidone, adipic acid, sodium bicarbonate, sodium lauryl sulfate, magnesium stearate, pregelatinized starch, and colloidal silicone dioxide

For a complete listing see Dosage Forms, Composition and Packaging section.

Indications and Clinical Use

Endometrin is indicated for progesterone supplementation in women undergoing in vitro fertilization.

Geriatrics

No clinical data have been collected in patients over age 65.

Pediatrics

This drug is not intended for pediatric use and no clinical data have been collected in children.

Contraindications

Endometrin should not be used in individuals with any of the following conditions:

  • Previous allergic reactions to progesterone or any of the ingredients of Endometrin [see Summary of Product Information]
  • Known missed abortion or ectopic pregnancy
  • Severe hepatic dysfunction or disease
  • Known or suspected breast cancer or genital tract cancer
  • Active arterial or venous thromboembolism or severe thrombophlebitis or cerebro-vascular disease, or a history of these events.
  • Porphyria
  • Undiagnosed Vaginal Bleeding

Warnings and Precautions

General

  • Before starting treatment, the patient and her partner should be assessed by a doctor for causes of infertility.
  • A pretreatment physical examination should include special reference to breasts, pelvic organs as well as Papanicolaou smear.
  • In all cases of irregular vaginal bleeding adequate diagnostic measures should be undertaken.
  • Progesterone may cause fluid retention and conditions which might be influenced by this (e.g., epilepsy, migraine, asthma, cardiac or renal dysfunction) require careful observation.
  • The pathologist should be informed of progesterone therapy when relevant specimens are submitted.
  • Endometrin 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 [see Drug Interactions].
  • Sex steroid use may also increase the risk of retinal vascular lesions. To prevent these latter complications, caution is to be taken in users >35 years, in smokers, and in those with risk factors for atherosclerosis. Use should be terminated in case of transient ischemic events, appearance of sudden severe headaches, or vision impairments related to papillary edema or retinal hemorrhage.
  • Abrupt discontinuation of Endometrin may cause increased anxiety, moodiness, and increased sensibility to seizures.

Cardiovascular

The physician should be alert to earliest signs of myocardial infraction, 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.

Hepatic/Biliary/Pancreatic

Cautious use in patients with mild to moderate hepatic dysfunction.

Metabolic

Decrease in glucose tolerance has been noted in a few patients when taking oestrogen- progestin combination drugs. The mechanism for this is unknown. Diabetic patients should be carefully monitored while receiving progesterone therapy.

Psychiatric

Patients who have a history of depression should be carefully observed. Endometrin® should be discontinued if symptoms worsen.

Special Populations

Pregnancy

There is yet limited and inconclusive data on the risk of congenital anomalies, including genital abnormalities in male and female infants, following intrauterine exposure during pregnancy.

Endometrin has been used to support embryo implantation and maintain clinical pregnancy in one clinical study. The live birth 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 live births).
  • 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 live births).

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.

Nursing Mothers

Detectable amounts of progesterone have been identified in the milk of mothers receiving oral progestins. The effect of this on the nursing infant has not been determined. Endometrin should not be used during lactation.

Pediatrics

This drug is not intended for pediatric use and no clinical data have been collected in children.

Geriatrics

No clinical data have been collected in patients over age 65.

Adverse Reactions

Adverse Drug Reaction Overview

Endometrin was well tolerated after exposure in more than 860 subjects in clinical trials and in well over 6,000 cycles in clinical practice worldwide. No serious adverse events (SAEs) were assessed as being related to the Endometrin treatment. No deaths were reported during any of the trials.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

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 In Vitro Fertilization 10 week clinical study. 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 a study involving in vitro fertilization
Body System
Preferred Term
Endometrin
100 mg twice Daily
(N=404)
Endometrin
100 mg three times
daily (N=404)
Gastrointestinal Disorders
Abdominal Pain50 (12%)50 (12%)
Nausea32 (8%)29 (7%)
Abdominal Distention18 (4%)17 (4%)
Constipation9 (2%)14 (3%)
Vomiting13 (3%)9 (2%)
General disorders & Administration Site Conditions
Fatigue7 (2%)12 (3%)
Infections and Infestations
Urinary tract infection9 (2%)4 (1%)
Injury, Poisoning and Procedural Complications
Post-oocyte retrieval pain115 (28%)102 (25%)
Nervous System Disorder
Headache15 (4%)13 (3%)
Reproductive System and Breast Disorders
Ovarian hyperstimulation syndrome30 (7%)27 (7%)
Uterine spasm15 (4%)11 (3%)
Vaginal bleeding13 (3%)14 (3%)

Other less common reported adverse reactions included genital itching, vaginal burning sensation, and vaginal discomfort. These may, in part, be due to the excipient sodium lauryl sulfate. Urticaria was reported in 0.2% of the subjects in each Endometrin group and peripheral edema in 0.2% in Endometrin 100 mg three times daily group.

Endometrin is also expected to have adverse reactions similar to other drugs containing progesterone that may include breast tenderness, bloating, mood swings, irritability, drowsiness and fluid retention.

Drug Interactions

Drug-Drug Interactions

No formal drug-drug interaction studies have been conducted for Endometrin. Drugs known to induce the hepatic cytochrome-P450-3A4 system (such as rifampin, carbamazepine and also herbal products containing St. John’s wort (Hypericum perforatum) may increase the elimination of progesterone. Ketoconazole and other inhibitors of cytochrome P450-3A4 may increase the bioavailability 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 [see Warnings and Precautions].

Drug- Food Interactions

Food can increase the bioavailability of progesterone administered orally. However, this is not relevant to Endometrin since it is administered vaginally.

Dosage and Administration

Dosing Considerations

The dose of Endometrin is 100 mg administered vaginally two or three times daily starting at the day after oocyte retrieval and continuing for up to 10 weeks total duration.

Recommended Dose and Dosage Adjustment

Endometrin administered into the vagina twice daily (BID) and three times daily (TID) dosing have both been shown to be efficacious. However specific populations may derive greater benefits from BID or TID dosing regimen and the clinician can tailor treatment to the patient. For women <35 years of age and those patients with adequate ovarian reserve, Endometrin BID would be the appropriate dose. For patients aged 35 and older and those with diminished ovarian reserve, TID dosing would be the preferred regimen. Serum progesterone levels may be measured 7 days post fertilization and used to guide therapy.

Missed Dose

If a patient misses a dose, the patient should be instructed to take the dose as soon as she remembers. The patient should also be instructed not to use more than her daily dose and not to double dose.

Administration

The patient should also be instructed not to use any other vaginal products when using Endometrin and to follow the steps below.

  1. Unwrap the applicator.
  2. Put one insert in the space provided at the end of the applicator. The insert should fit snugly and not fall out.
  3. Whilst you are standing, sitting, or when lying on your back with your knees bent, gently place the thin end of the applicator well into the vagina.
  4. Push the plunger to release the insert.
  5. Remove the applicator and throw it away in the trash.

Overdosage

High doses of progesterone may cause drowsiness.
Treatment of overdosage consists of discontinuation of Endometrin together with institution of appropriate symptomatic and supportive care.

Action and Clinical Pharmacology

Mechanism of Action

Progesterone is a naturally occurring steroid that is secreted by the ovary, placenta, and adrenal gland. In the presence of adequate estrogen, progesterone transforms a proliferative endometrium into a secretory endometrium. Progesterone is necessary to increase endometrial receptivity for implantation of an embryo. Once an embryo is implanted, progesterone acts to maintain a pregnancy.

Pharmacokinetics

A pharmacokinetic study was performed to assess the pharmacokinetics of 2 dose regimen of Endometrin, 100 mg BID and 100 mg TID. A summary of the pharmacokinetic parameters results is presented 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 (nmol/L)54.06 ± 20.6762.96 ± 22.89
Tmax (hr)24.0 ± 0.017.3 ± 7.4
AUC0-24 (nmol·hr/L)690.06 ± 359.18903.12 ± 454.74
Day 5 of Multiple Dosing
Cmax (nmol/L)58.83 ± 17.4976.64 ± 17.80
Tmax (hr)18.0 ± 9.418.0 ± 9.4
Cmin (nmol/L)28.30 ± 14.3134.66 ± 21.30
Cavg (nmol/L)44.52 ± 15.2650.56 ± 13.64
AUC0-24 (nmol·hr/L)1039.86 ± 403.861386 ± 337.08

Cmax Maximum progesterone serum concentration.
Tmax Time to maximum progesterone 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.

Absorption

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 54.06 ± 20.67 nmol/L in the Endometrin twice daily group and 62.96 ± 22.89 nmol/L 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 31.45 nmol/L on Day 5.

Distribution

Progesterone is approximately 96 % to 99 % bound to serum proteins, primarily to serum albumin and corticosteroid binding globulin.

Metabolism

Progesterone 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.

Excretion

Progesterone 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.

Storage and Stability

Endometrin (progesterone) is available as 100 mg effervescent vaginal tablets packed individually in a sealed foil pouch. Store Endometrin at 20-25 C. Excursions permitted to 15-30ºC.

Dosage Forms, Composition and Packaging

Endometrin (progesterone) effervescent vaginal tablets contain micronized progesterone. Each Endometrin effervescent vaginal tablet delivers 100 mg of progesterone in a base containing lactose monohydrate, polyvinylpyrrolidone, adipic acid, sodium bicarbonate, sodium lauryl sulfate, magnesium stearate, pregelatinized starch, and colloidial silicone dioxide.

Each Endometrin effervescent vaginal tablet is a white to off-white oblong-shaped tablet debossed with “FPI” on one side and “100” on the other side. Endometrin is supplied with polyethylene vaginal applicators. Endometrin is available as 100 mg effervescent vaginal tablets packed individually in a sealed foil pouch.