Prometrium capsules (100 mg, 200 mg)

PROMETRIUM (progesterone, USP) Capsules contain micronized progesterone for oral administration. Progesterone has a molecular weight of 314.47 and an empirical formula of C 21 H 30 O 2 . Progesterone (pregn-4-ene-3, 20-dione) is a white or creamy white, odorless, crystalline powder practically insoluble in water, soluble in alcohol, acetone and dioxane and sparingly soluble in vegetable oils, stable in air, melting between 126° and 131°C. The structural formula is:

Progesterone is synthesized from a starting material from a plant source and is chemically identical to progesterone of human ovarian origin. PROMETRIUM Capsules are available in multiple strengths to afford dosage flexibility for optimum management. PROMETRIUM Capsules contain 100 mg or 200 mg micronized progesterone.

The inactive ingredients for PROMETRIUM Capsules 100 mg include: peanut oil NF, gelatin NF, glycerin USP, lecithin NF, titanium dioxide USP, D&C Yellow No. 10, and FD&C Red No. 40.

The inactive ingredients for PROMETRIUM Capsules 200 mg include: peanut oil NF, gelatin NF, glycerin USP, lecithin NF, titanium dioxide USP, D&C Yellow No. 10, and FD&C Yellow No. 6.

Absorption

After oral administration of progesterone as a micronized soft gelatin capsule formulation, maximum serum concentrations were attained within 3 hours. The absolute bioavailability of micronized progesterone is not known. Table 1 summarizes the mean pharmacokinetic parameters in postmenopausal women after five oral daily doses of PROMETRIUM Capsules 100 mg as a micronized soft-gelatin capsule formulation.

Serum progesterone concentrations appeared linear and dose proportional following multiple dose administration of PROMETRIUM Capsules 100 mg over the dose range 100 mg/day to 300 mg/day in postmenopausal women. Although doses greater than 300 mg/day were not studied in females, serum concentrations from a study in male volunteers appeared linear and dose proportional between 100 mg/day and 400 mg/day. The pharmacokinetic parameters in male volunteers were generally consistent with those seen in postmenopausal women.

Distribution

Progesterone is approximately 96%-99% bound to serum proteins, primarily to serum albumin (50%-54%) and transcortin (43%-48%).

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 which are excreted in the bile may be deconjugated and may be further metabolized in the gut via reduction, dehydroxylation, and epimerization.

Excretion

The glucuronide and sulfate conjugates of pregnanediol and pregnanolone are excreted in the bile and urine. Progesterone metabolites which are excreted in the bile may undergo enterohepatic recycling or may be excreted in the feces.

Special Populations

The pharmacokinetics of PROMETRIUM Capsules have not been assessed in low body weight or obese patients.

Race:

There is insufficient information available from trials conducted with PROMETRIUM Capsules to compare progesterone pharmacokinetics in different racial groups.

Hepatic Insufficiency:

No formal studies have evaluated the effect of hepatic disease on the disposition of progesterone. However, since progesterone is metabolized by the liver, use in patients with severe liver dysfunction or disease is contraindicated (see CONTRAINDICATIONS ). If treatment with progesterone is indicated in patients with mild to moderate hepatic dysfunction, these patients should be monitored carefully.

Renal Insufficiency:

No formal studies have evaluated the effect of renal disease on the disposition of progesterone. Since progesterone metabolites are eliminated mainly by the kidneys, PROMETRIUM Capsules should be used with caution and only with careful monitoring in patients with renal dysfunction. (see PRECAUTIONS )

Food-Drug Interaction:

Concomitant food ingestion increased the bioavailability of PROMETRIUM Capsules relative to a fasting state when administered to postmenopausal women at a dose of 200 mg.

Drug-Drug Interaction:

The metabolism of progesterone by human liver microsomes was inhibited by ketoconazole (IC 50 <0.1 µM). Ketoconazole is a known inhibitor of cytochrome P450 3A4, hence these data suggest that ketoconazole or other known inhibitors of this enzyme may increase the bioavailability of progesterone. The clinical relevance of the in vitro findings is unknown.

Coadministration of conjugated estrogens and PROMETRIUM Capsules to 29 postmenopausal women over a 12 day period resulted in an increase in total estrone concentrations (Cmax 3.68 ng/ml to 4.93 ng/ml) and total equilin concentrations (Cmax 2.27 ng/ml to 3.22 ng/ml) and a decrease in circulating 17(beta) estradiol concentrations (Cmax 0.037 ng/ml to 0.030 ng/ml). The half-life of the conjugated estrogens was similar with coadministration of PROMETRIUM Capsules. Table 2 summarizes the pharmacokinetic parameters.

1. Known sensitivity to PROMETRIUM Capsules or its ingredients. PROMETRIUM Capsules contain peanut oil and should never be used by patients allergic to peanuts.
2. Known or suspected pregnancy.
3. Thrombophlebitis, thromboembolic disorders, cerebral apoplexy, or patients with a past history of these conditions.
4. Severe liver dysfunction or disease.
5. Known or suspected malignancy of breast or genital organs.
6. Undiagnosed vaginal bleeding.
7. Missed abortion.
8. As a diagnostic test for pregnancy.

Endometrial Protection

Table 7 lists adverse experiences which were reported in >/=2% of patients (regardless of relationship to treatment) who received cyclic PROMETRIUM Capsules, 200 mg daily (12 days per calendar month cycle) with daily 0.625 mg conjugated estrogen, in a multicenter, randomized, double-blind, placebo-controlled clinical trial in 875 postmenopausal women.

Secondary Amenorrhea

Table 8 lists adverse experiences which were reported in >/=5% of patients receiving PROMETRIUM Capsules, 400 mg/day, in a multicenter, randomized, double-blind, placebo-controlled clinical trial in estrogen-primed (6 weeks) postmenopausal women receiving conjugated estrogens 0.625 mg/day and cyclic (10 days per calendar month cycle) PROMETRIUM Capsules at a dose of 400 mg/day, for three cycles.

The most common adverse experiences reported in >/=5% of patients in all PROMETRIUM Capsules dosage groups studied in this trial (100 mg/day to 400 mg/day) were: dizziness (16%), breast pain (11%), headache (10%), abdominal pain (10%), fatigue (9%), viral infection (7%), abdominal distention (6%), musculoskeletal pain (6%), emotional lability (6%), irritability (5%), and upper respiratory tract infection (5%).

Other adverse events reported in <5% of patients taking PROMETRIUM Capsules include:

Autonomic Nervous System Disorders:   dry mouth

Body As A Whole:   accidental injury, chest pain, fever

Cardiovascular System Disorders:   hypertension

Central and Peripheral Nervous System Disorders:   confusion, somnolence, speech disorder

Gastrointestinal System Disorders:   constipation, dyspepsia, gastroenteritis, hemorrhagic rectum, hiatus hernia, vomiting

Hearing and Vestibular Disorders:   earache

Heart Rate and Rhythm Disorders:   palpitation

Metabolic and Nutritional Disorders:   edema, edema peripheral

Musculoskeletal System Disorders:   arthritis, leg cramps, hypertonia, muscle disorder, myalgia

Myo/Endo/Pericardial and Valve Disorders:   angina pectoris

Psychiatric Disorders:   anxiety, impaired concentration, insomnia, personality disorder

Reproductive System Disorders:   leukorrhea, uterine fibroid, vaginal dryness, fungal vaginitis, vaginitis

Resistance Mechanism Disorders:   abscess, herpes simplex

Respiratory System Disorders:   bronchitis, nasal congestion, pharyngitis, pneumonitis, sinusitis

Skin and Appendages Disorders:   acne, verruca, wound debridement

Urinary System Disorders:   urinary tract infection

Vision Disorders:   abnormal vision

White Cell and Resistance Disorders:   lymphadenopathy

The following adverse experiences have been reported with PROMETRIUM Capsules in other U.S. clinical trials: increased sweating, asthenia, tooth disorder, anorexia, increased appetite, nervousness, and breast enlargement.

The following spontaneous adverse events have been reported during the marketing of PROMETRIUM Capsules: reversible cases of hepatitis and elevated transaminases. These events occurred mainly in patients receiving high doses of up to 1200 mg. Additionally, rare instances of syncope with and without hypotension have been reported.

The following additional adverse experiences have been observed in women taking progestins in general: breakthrough bleeding, spotting, change in menstrual flow, amenorrhea, changes in weight (increase or decrease), changes in the cervical squamo-columnar junction and cervical secretions, cholestatic jaundice, anaphylactoid reactions and anaphylaxis, rash (allergic) with and without pruritus, melasma or chloasma, pyrexia, and insomnia.

Prevention of endometrial hyperplasia --PROMETRIUM Capsules should be given as a single daily dose in the evening, 200 mg orally for 12 days sequentially per 28 day cycle, to postmenopausal women with a uterus who are receiving daily conjugated estrogens tablets.

Secondary Amenorrhea --PROMETRIUM Capsules may be given as a single daily dose of 400 mg in the evening for 10 days.

PROMETRIUM (progesterone, USP) Capsules 100 mg are round, peach-colored capsules branded with black imprint "SV", available in bottles of 100 capsules (NDC0032-1708-01).

PROMETRIUM (progesterone, USP) Capsules 200 mg are oval, pale yellow-colored capsules branded with black imprint "SV2", available in bottles of 100 capsules (NDC0032-1711-01).

Store at 25°C (77°F) Excursions permitted to 15-30°C (59-86°F).

Dispense in tight, light-resistant container as defined in USP/NF, accompanied by a Patient Insert.

Protect from excessive moisture.

References:

1. International Agency for Research on Cancer (IARC) V.6, 1974; IARC V.21, 1979.
2. K.S. Larrson and D. Machin, Safety requirements for contraceptive steroids. F. Michal (ed.) Cambridge University Press, Cambridge. pp. 30-269, 1989.
3. Sixth Annual Report on Carcinogens V.2, pp 693-696, 1991.
4. Med. Sci. Res. 1987; 15:703-704.
5. Johnstone, E.E. and Franklin, R.R. (1964). Assay of progestins for fetal virilizing properties using the mouse. Obstet Gynecol . 23:359-62.
6. Seegmiller, R.E., Nelson, G.W. and Johnson, C.K. (1983) Evaluation of the teratogenic potential of Delalutin (17-hydroxyprogesterone caproate) in mice. Teratology 28:201-8.
7. Suchowsky, G.K. and Junkmann, K. (1961). A study of the virilizing effects of progesterone on the female rat fetus. Endocrinolgy 68:341-9.
8. Scholer, H.F.L. and de Wachter, A.M. (1961). Evaluation of androgenic properties of progestational compounds in the rat by the female foetal masculinization test. Acta. Endocrinol. 38:128-36.
9. Hudson, R., Pharriss, B.B., Tillson, S.A. and Reno, F. (1978). Preclinical evaluation of intrauterine progesterone as a contraceptive agent. III. Embryology and toxicology. Contraception 17:489-97.
10. Foote, W.D., Foote, W.C., and Foote, L.H. (1968). Influence of certain natural and synthetic steroids on genital development in guinea pigs. Fertil. Steril. 19:606-15.
11. Wharton, L.R. Jr. and Scott, R.B. (1964). Experimental production of genital lessions with norethindrone. Am J. Obstet. Gynecol. 89:701-15
12. Scialli, A.R. (1988). Developmental effects of progesterone and its derivatives. Reproductive Toxicol. 2:3-11.

Manufactured by: R. P. Scherer North America, St. Petersburg, FL 33716

Marketed by: Solvay Pharmaceuticals, Inc., Marietta, GA 30062.

© 2000 Solvay Pharmaceuticals, Inc.

All rights reserved.

9683 4E Rev 7/2000

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