Compounded Progesterone Product Line Overview

Progesterone Capsules

25mg | 30mg | 35mg | 40mg | 50mg | 75mg | 100mg | 112mg | 150mg| 185mg | 200mg | 225mg | 250mg | 300mg

All strengths available in both short and long acting, as well as other custom strengths to meet specific patient need.

We also make many individual strengths of Progesterone creams, suppositories and troches to meet individual patient needs.

About Progesterone Capsules

Progesterone is a naturally occurring progestin. In the body, it is synthesized in the ovaries, testes, placenta, and adrenal cortex. Progesterone is primarily used to treat amenorrhea, abnormal uterine bleeding, or as a contraceptive. Progesterone is also used to prevent early pregnancy failure in women with corpus luteum insufficiency, including women undergoing assisted reproductive technology (ART). Additionally, the use of progesterone for preterm delivery prophylaxis is being investigated. Preliminary data indicate that progesterone may be effective in preventing preterm delivery in high-risk women, especially those with a history of preterm delivery;^[1] however, the optimal dosage and route have not been determined. The American College of Obstetricians and Gynecologists (ACOG) Committee recommends that if progesterone is to be used for the prevention of preterm delivery, it should only be used in women with a history of spontaneous birth at < 37 weeks gestation, until more data supporting its use in other high-risk women are available.^[2] A study in support of the use of vaginal progesterone in women with a short cervix has been published.^[3] Progesterone is available commercially as an intramuscular injection, an intravaginal gel, an intravaginal insert, oral capsules, or a powder for use in extemporaneous preparations (e.g., vaginal suppositories). A progesterone-releasing IUD (Progestasert®) that was inserted once yearly has been discontinued. Progesterone was approved by the FDA in 1939. In May 1998, micronized progesterone capsules for oral administration were approved for secondary amenorrhea; they received a second indication in December 1998 for the prevention of endometrial hyperplasia in postmenopausal women with an intact uterus taking estrogen replacement therapy. In May 1997, a progesterone vaginal gel (Crinone®) was approved for progesterone supplementation or replacement as part of an Assisted Reproductive Technology (ART) program for infertile women; a second intravaginal gel, Prochieve™, was released to the US market in 2002. A vaginal insert, Endometrin®, for progesterone supplementation as part of an ART program in infertile women was approved in June 2007.

Mechanisms of Action

Endogenous progesterone is responsible for inducing secretory activity in the endometrium of the estrogen-primed uterus in preparation for the implantation of a fertilized egg and for the maintenance of pregnancy. It is secreted from the corpus luteum in response to luteinizing hormone. The hormone increases basal body temperature, causes histologic changes in vaginal tissues, inhibits uterine contractions, inhibits pituitary secretion, stimulates mammary alveolar gland tissues, and precipitates withdrawal bleeding in the presence of estrogen. The administration of progesterone to women with adequate estrogen production transforms the uterus from a proliferative to a secretory phase.

The primary contraceptive effect of exogenous progestins involves the suppression of the midcycle surge of LH. The exact mechanism of action, however, is unknown. At the cellular level, progestins diffuse freely into target cells and bind to the progesterone receptor. Target cells include the female reproductive tract, the mammary gland, the hypothalamus, and the pituitary. Once bound to the receptor, progestins slow the frequency of release of gonadotropin releasing hormone (GnRH) from the hypothalamus and blunt the pre-ovulatory LH surge, thereby preventing follicular maturation and ovulation. Overall, progestin-only contraceptives prevent ovulation in 70—80% of cycles, however, the clinical effectiveness ranges 96—98%. This suggests that additional mechanisms may be involved. Other actions of progestins include alterations in the endometrium that can impair implantation and an increase in cervical mucus viscosity which inhibits sperm migration into the uterus. Progesterone administered via IUD suppresses proliferation of endometrial tissue. Following removal of the IUD, the endometrium rapidly returns to a normal cyclic pattern and can support pregnancy. Progesterone has minimal estrogenic and androgenic activity.

Contraindications & Precautions

Do not take this medicine if you have breast cancer, cardiac disease or dementia. Your health care provider needs to know if you have any of these conditions: autoimmune disease like systemic lupus erythematosus (SLE); blood vessel disease, blood clotting disorder, or suffered a stroke; breast, cervical or vaginal cancer; dementia; diabetes; kidney or liver disease; heart disease, high blood pressure or recent heart attack; high blood lipids or cholesterol; hysterectomy; tobacco smoker; vaginal bleeding; an unusual or allergic reaction to progesterone or other products; pregnant or trying to get pregnant; breast-feeding. This medicine can cause swelling, tenderness, or bleeding of the gums. Do not drive, use machinery, or do anything that needs mental alertness until you know how this drug affects you. This list may not include all possible contraindications.

Progesterone injection formulations are for intramuscular use only. Never administer via intravenous administration.

Hormonal contraceptives have been associated with the development of hepatic tumors. Although this is believed to be an estrogen-mediated effect, progesterone is contraindicated in patients with hepatic disease or hepatic dysfunction.

Progesterone is contraindicated in undiagnosed abnormal vaginal bleeding orincomplete abortion. Hormones can cause irregular menstrual bleeding in most women. In general, these irregularities diminish with continuing use. Women should be counseled regarding irregular menstrual bleeding.

Progesterone is contraindicated in patients with pre-existing breast cancer or cancer of reproductive organs, such as cervical cancer, uterine cancer, or vaginal cancer, except as palliative therapy in selected patients. Although progestins reduce the risk of endometrial cancer in patients receiving estrogen replacement therapy, it is unclear whether progestins added to estrogen therapy reduce the risk of breast cancer in postmenopausal women.^[4]

Progesterone should be used cautiously in patients with hyperlipidemia. Although hyperlipidemia is associated with estrogen-progestin combinations, the effects of progestin-only oral contraceptives on serum lipids have not been studied. Serum lipoproteins (HDL and LDL) should be monitored during therapy with progesterone.

Progesterone capsules are classified in FDA pregnancy category B. Animal studies involving oral or intravaginal or in utero administration of progesterone have, in general, not indicated evidence of fetal harm. In general, several studies of women exposed to progesterone during pregnancy for luteal support have not demonstrated a significant increase in fetal malformations. A single case of cleft palate has been reported in an infant exposed to micronized progesterone in utero. Rare cases of fetal death have been reported in women administered micronized progesterone in early pregnancy, but causality has not been established. Only select products are specifically labeled for use to provide luteal support during pregnancy.^[5]^[6] Crinone progesterone vaginal gel may be used to support early pregnancy as part of an Assisted Reproductive Technology (ART) program; if pregnancy occurs, the gel is typically continued for 10—12 weeks until placental production of progesterone is adequate to support the pregnancy. Similarly, Endometrin vaginal inserts are used for up to 10 weeks in ART. Progesterone should only be used during early pregnancy under the observation of an ART specialist; data suggest that progesterone may be effective in preventing preterm delivery, especially in high-risk populations.^[3]^[1] The American College of Obstetricians and Gynecologists (ACOG) Committee recommends that if progesterone is to be used, it should only be used in women with a history of spontaneous birth at < 37 weeks gestation; in addition, the ideal formulation or whether it should be used in other high-risk women is not yet known.^[2] Progesterone should not be used if there is ectopic pregnancy, during cases of missed abortion, or during diagnostic tests for pregnancy. In high doses, injectable progesterone is an anti-fertility drug and may chemically induce female infertility. In general, the American Academy of Pediatrics considers progesterone to be compatible with breast-feeding.^[7] Detectable amounts of progestins have been identified in the milk of nursing mothers; in general the presence of progestins in the milk are not expected to have adverse effects on lactation production. However, the effects of progestins present in breast milk on the nursing infant have not been determined.^[8]^[6] The administration of any medication to nursing mothers should take into account the benefit of the drug to the mother and the potential for risk to the breast-fed infant. The safety and effectiveness of progesterone in children have not been established. The safety and efficacy of progesterone have only been established in females of reproductive age. Use of progesterone in female children before menarche is not usually indicated, and its safety and efficacy in this population is not established. Progesterone is contraindicated in patients with a history of thrombophlebitis orthromboembolic disease (including stroke and myocardial infarction). Although thromboembolic disease is believed to be an estrogen-related effect, studies have shown that patients receiving hormonal contraceptives or hormonal replacement therapy regimens containing progestins may have a higher risk of venous thromboembolic (VTE) disease. Because of the higher risk of thromboembolic disease in tobacco smoking women, women should be advised not to smoke, particularly if they are over the age of 35 years. Hormonal contraceptives and hormone replacement therapies should also be used cautiously in patients with history of coronary artery disease, progestin intolerance, or cerebrovascular disease. Progesterone should be used cautiously in patients with diabetes mellitus. Although the effects appear to be minimal during therapy with progestins, altered glucose tolerance secondary to decreased insulin sensitivity has been reported during hormonal contraceptive therapy. Progesterone should be prescribed cautiously in patients with asthma, congestive heart failure, nephrotic syndrome or other renal disease, or cardiac disease. Hormonal contraceptives can cause fluid retention and may exacerbate any of the above conditions. Progesterone should be used cautiously in patients with a history of major depression, migraine, or seizure disorder. Progestins may exacerbate these conditions in some patients. Some cases of seizures following administration of progestins have been reported. An intrauterine device containing progesterone should not be used if there is any infection or inflammation in the female reproductive tract. There is a risk of infection progressing to pelvic inflammatory disease. Exposure to sexually transmitted disease also increases this risk. Progesterone capsules should not be used in patients with peanut hypersensitivity. This product is formulated with peanut oil. Progesterone may cause transient dizziness in some patients. Use caution when driving or operating machinery. Estrogen/progestin combination therapy has been found to fail to prevent mild cognitive impairment (memory loss) and to increase the risk of dementia in women 65 years and older. The WHIMS study, an ancillary study of the WHI trial to assess the effects of estrogen/progestin therapy on cognitive function in geriatric women (65 years of age or older), found that patients receiving either active treatment or placebo had similar rates of developing mild cognitive impairment. Patients receiving estrogen/progestin combination therapy were more likely than patients receiving placebo to be diagnosed with dementia. The applicability of this finding to women who use estrogen alone or to the typical user of HRT (i.e., younger, symptomatic women taking hormone replacement therapy to relieve menopausal symptoms) is unclear. Administration of estrogen/progestin combination therapy should be avoided in women 65 years of age and older and estrogen/progestin combination therapy should not be used to prevent or treat dementia or preserve cognition (memory).^[9] Hormonal contraceptives have been associated with retinal thrombosis. Although this effect is generally believed to be related to estrogen, patients should be monitored carefully for the development of ocular lesions. Progesterone therapy should be discontinued if any unexplained visual disturbance occurs.

Interactions

Possible interactions include: barbiturate; medicines for sleep or seizures; bexarotene; carbamazepine; ethotoin; ketoconazole; phenytoin; rifampin This list may not describe all possible interactions. Give your health care provider a list of all the medicines, herbs, non-prescription drugs, or dietary supplements you use. Also tell them if you smoke, drink alcohol, or use illegal drugs. Some items may interact with your medicine.

Vaginal preparations of progesterone (e.g., Crinone, Endometrin, and Prochieve) should not be used with other intravaginal products (e.g., vaginal antifungals, such as clotrimazole, miconazole terconazole, or tioconazole) as concurrent use may alter progesterone release and absorption from the vagina. Separate the times of administration to avoid the interaction. The manufacturers of Crinone and Prochieve indicate that other intravaginal products can be used as long as 6 hours has lapsed either before or after vaginal administration of progesterone.^[10]^[11] Endometrin is generally not recommended for use with other vaginal products (e.g., antifungal products) as this may alter progesterone release and absorption from the vaginal insert and the potential for interaction has not been formally assessed; use other vaginal products if medically necessary, but be aware that the response to Endometrin may be altered.^[5]

Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormones including hormonal contraceptives. Pregnancy has been reported during therapy with estrogens, oral contraceptives, or progestins in patients receiving phenytoin concurrently.^[12] Women taking both hormones and hepatic enzyme-inducing drugs should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants, or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on phenytoin, with dose adjustments made based on clinical efficacy.

Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormones including hormonal contraceptives. Pregnancy has been reported during therapy with estrogens, oral contraceptives, or progestins in patients receiving phenytoin (the active metabolite of fosphenytoin) concurrently.^[13]^[12] Women taking both hormones and hepatic enzyme-inducing drugs should report breakthrough bleeding to their prescribers.An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants, or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on fosphenytoin, with dose adjustments made based on clinical efficacy.

Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormones including hormonal contraceptives. Pregnancy has been reported during therapy with estrogens, oral contraceptives, or progestins in patients receiving phenytoin concurrently.^[12] A similar interaction may be expected with ethotoin.^[14] Women taking both hormones and hepatic enzyme-inducing drugs should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants, or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on ethotoin, with dose adjustments made based on clinical efficacy.

Estrogens and progestins are both susceptible to drug interactions with hepatic enzyme inducing drugs such as carbamazepine. Concurrent administration of carbamazepine with estrogens, oral contraceptives, or progestins may increase the hormone’s elimination.^[15]^[16]^[17] Women taking both hormones and hepatic enzyme-inducing drugs should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed hepatic enzyme inducing drugs, or higher-dose hormonal regimens may be indicated where acceptable or applicable as pregnancy has been reported in patients taking the hepatic enzyme inducing drug phenytoin concurrently with hormonal contraceptives. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on carbamazepine, with dose adjustments made based on clinical efficacy.

Estrogens and progestins are both susceptible to drug interactions with hepatic enzyme inducing drugs such as barbiturates. Concurrent administration of barbiturates with estrogens, oral contraceptives, non-oral combination contraceptives, or progestins may increase the hormone’s elimination.^[18]^[19]^[10] Women taking both hormones and hepatic enzyme-inducing drugs should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed hepatic enzyme inducing drugs. Higher-dose hormonal regimens may be indicated where acceptable or applicable as pregnancy has been reported in patients taking the hepatic enzyme inducing drug phenytoin concurrently with hormonal contraceptives. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Additionally, epileptic women taking both anticonvulsants and OCs may be at higher risk of folate deficiency secondary to additive effects on folate metabolism; if oral contraceptive failure occurs, the additive effects could potentially heighten the risk of neural tube defects in pregnancy.^[20] Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on barbiturates, with dose adjustments made based on clinical efficacy.

Estrogens and progestins are both susceptible to drug interactions with hepatic enzyme inducing drugs such as rifampin, rifabutin, or rifapentine. Concurrent administration of these drugs with estrogens, oral contraceptives, or progestins may increase the hormone’s elimination.^[21]^[22]^[23]^[10] In addition, free estrogen-hormone concentrations are decreased because rifampin increases estrogenic protein binding ability. Additionally, like other anti-infectives, rifampin indirectly inhibits the enterohepatic recirculation of estrogen through disruption of GI flora growth. Women taking both hormones and any of these drugs should report breakthrough bleeding to their prescribers; it is estimated that 70% of women taking oral contraceptives and rifampin experience menstrual abnormalities, and 6% become pregnant.^[24]^[25] If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed rifampin, rifabutin, or rifapentine. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of the interacting medication. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on rifampin, rifabutin, or rifapentine, with dose adjustments made based on clinical efficacy.

The metabolism of progesterone was inhibited by ketoconazole, a known inhibitor of cytochrome P450 3A4 hepatic enzymes.^[8] It has not been determined whether other drugs which inhibit CYP3A4 hepatic enzymes would have a similar effect. Other such drugs include cimetidine,^[26] clarithromycin,^[27] danazol,^[21] diltiazem,^[28] erythromycin,^[21] fluconazole,^[21] itraconazole,^[21] troleandomycin, verapamil,^[21] and voriconazole.^[29] This list is not inclusive of all drugs that inhibit CYP3A4.

Although specific studies have not been done with progesterone (including the progesterone intrauterine device, IUD), an alternative or additional non-hormonal method of birth control is recommended during aprepitant, fosaprepitant treatment and for 28 days after aprepitant treatment is discontinued to avoid potential for contraceptive failure.^[30]

Bromocriptine is used to restore ovulation and ovarian function in amenorrheic women.^[31] Progestins can cause amenorrhea and, therefore, counteract the desired effects of bromocriptine. Concurrent use is not recommended.

Food can increase the bioavailability of progesterone administered orally.^[8] Mean peak serum concentrations (Cmax) were increased slightly when progesterone was administered with or 2 hours after a high fat breakfast relative to the fasting state. In contrast, when the capsules were administered 4 hours after the high fat breakfast, there was a significant increase in Cmax. There was no effect on the time to maximum serum concentrations (Tmax). The effects of food on the pharmacokinetics of progesterone showed high intra- and intersubject variability.

In a published study, progesterone was given intravenously to patients with advanced malignancies at high doses (up to 10 g over 24 hours) concomitantly with a fixed doxorubicin dose (60 mg/m2) by IV bolus. Enhanced doxorubicin-induced neutropenia and thrombocytopenia were observed.^[32] Similar effects may occur with doxorubicin liposomal.

Based on an interaction with tamoxifen, bexarotene capsules may theoretically increase the rate of metabolism and reduce plasma concentrations of other substrates metabolized by CYP3A4, including progestins.^[33]

Bosentan is a significant inducer of CYP3A hepatic enzymes.^[21]^[34] Specific interaction studies have not been performed to evaluate the effect of coadministration of bosentan and hormonal contraceptives (oral contraceptives, estrogens, or progestins), including oral, injectable or implantable agents.^[34] Since many of these drugs are metabolized by CYP3A4, ^[21] there is a possibility of contraceptive failure when bosentan is coadministered.^[34] Women should not rely on hormonal contraception alone when taking bosentan; bosentan is teratogenic and is contraindicated during pregnancy.^[34] Since many of these drugs are metabolized by CYP3A4, a reduction in hormone replacement efficacy is possible when bosentan is coadministered.^[34]

Progesterone is known to decrease the uptake of iodide into thyroid tissue.^[35] In order to increase thyroid uptake and optimize exposure of thyroid tissue to the radionucleotide sodium iodide I-131, consider withholding progesterone prior to treatment with sodium iodide I-131.This list may not include all possible interactions. Give your health care provider a list of all the medicines, herbs, non-prescription drugs, or dietary supplements you use. Also tell them if you smoke, drink alcohol, or use illegal drugs. Some items may interact with your medicine.

Adverse Reactions / Side Effects

The most common adverse reactions occurring during therapy with progesterone include menstrual irregularity, menstrual flow changes, and dysmenorrhea or amenorrhea. These effects may be indistinguishable from pregnancy. Progesterone also causes spotting, breakthrough bleeding, weight gain, nausea, vomiting, breast tenderness or mastalgia, and mild headache. These adverse effects occur less frequently with progestin-only OCs compared to combination OCs. Other reported adverse reactions during therapy include melasma, chloasma, libido decrease, libido increase, breast discharge, cervicitis, galactorrhea, hirsutism, leukorrhea, unusual weakness, and vaginitis. Post-marketing experiences with oral progesterone include endometrial carcinoma, hypospadia, intra-uterine death, menorrhagia, menstrual disorder, metorrhagia, ovarian cyst, and spontaneous fetal abortion.^[36] Additional adverse reactions associated with the intravaginal gel include breast enlargement, dyspareunia, nocturia, perineal pain, dysmenorrhea, premenstrual tension, vaginal dryness, and vaginal discharge.^[37] Adverse reactions associated with vaginal inserts include vaginal irritation, vaginal itching, vaginal burning, and vaginal pain/discomfort.^[5]

Fluid retention and/or edema may occur in patients receiving progesterone. Patients with heart failure and/or renal disease may experience an exacerbation of their condition. Post-marketing reports of adverse reactions with oral progesterone include facial edema, circulatory collapse, congenital heart disease, hypertension, hypotension, and sinus tachycardia.^[36]

Patients receiving progesterone or other hormonal contraceptives can experience emotional lability. This adverse effect may be manifest as mental depression, anxiety, frustration, irritability, anger, or other emotional outbursts. Additional CNS and psychiatric adverse events reported include insomnia, aggression, forgetfulness, migraine, tremor, headache, dizziness, drowsiness, and fatigue. Post-marketing experience reports include convulsions, depersonalization, disorientation, dysarthria, loss of consciousness, paresthesias, sedation, stupor, difficulty walking, syncope, transient ischemic attack, suicidal ideation, and feeling drunk.^[36]

The insertion of an intrauterine device (IUD) containing progesterone may result in infection. The risk of infection is greatest within the first 20 days after insertion. Untreated infection may lead to pelvic inflammatory disease, which requires removal of the system and appropriate antibiotic treatment. The patient’s partner may also require antibiotic treatment. Uterine pain may follow initial insertion of the progesterone IUD and usually responds to analgesic therapy. Pain should not persist for more than a few hours after IUD insertion.^[5]

Thromboembolic disease is more common in hormonal contraceptive users than in non-users. Previously, thromboembolic disease such as deep venous thrombosis (DVT), appeared to be more related to estrogen therapy than to progestin therapy, however, there is some evidence that different types of progestins are associated with differing rates of venous thromboembolism. At usual doses, women receiving third generation progestins (e.g., desogestrel or gestodene) appear to have an increased risk of venous thromboembolic disease compared to women receiving previous generation progestins.^[38]^[39] The risk is even greater in women with genetic predisposition or family history for venous thromboembolic disease.^[40] Thromboembolism or thrombus formation has also been associated with high doses of progestins. Other rare adverse reactions that may occur during progestin therapy may include pulmonary embolism, retinal thrombosis, hepatoma, hepatitis (and elevated hepatic enzymes), cholestasis, jaundice, and hyperglycemia.^[36]

Intramuscular administration of progesterone often causes an injection site reaction. Adverse local reactions include erythema, irritation, pain, and swelling at the site of injection. More general dermatological events have been reported and include alopecia, pruritus, urticaria, acne vulgaris, rash (unspecified), seborrhea, skin discoloration, fever, and hot flashes. Anaphylactoid reactions and hypersensitivity, including dyspnea, rhinitis, asthma, hyperventilation, and throat tightness have been reported.^[36]^[37]

GI adverse reactions reported with progesterone use include abdominal pain, bloating, nausea, vomiting, dyspepsia, dysphagia, eructation, flatulence, gastritis, diarrhea, constipation, anorexia, appetite stimulation, and weight loss. Acute pancreatitis and swollen tongue were reported post-marketing.^[36]

Adverse reactions reported with progesterone use include abnormal gait, arthralgia, choking (with oral formulations), cleft lip, cleft palate, tinnitus, vertigo, cystitis, dysuria, increased urinary frequency, leg pain, musculoskeletal pain, flu-like symptoms, xerophthalmia, benign cyst, purpura, anemia, infection, pharyngitis, sinusitis, urinary tract infection, and conjunctivitis.^[36]^[37]

Pregnancy & Breastfeeding

In general, the American Academy of Pediatrics considers progesterone to be compatible with breast-feeding.^[7] Detectable amounts of progestins have been identified in the milk of nursing mothers; in general the presence of progestins in the milk are not expected to have adverse effects on lactation production. However, the effects of progestins present in breast milk on the nursing infant have not been determined.^[8]^[6] The administration of any medication to nursing mothers should take into account the benefit of the drug to the mother and the potential for risk to the breast-fed infant.

Storage

Store this medication at 68°F to 77°F (20°C to 25°C) and away from heat, moisture and light. Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond-use date. Do not flush unused medications or pour down a sink or drain.

References

Meis PJ, Klebanoff M, Thom E, et al. Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. N Eng J Med 2003;348:2379-85.
ACOG Committee on Obstetric Practice. Committee Opinion: use of progesterone to reduce preterm birth. Obstet Gynecol 2003;102:1115-6.
Fonseca EB, Celik E, Parra M, et al. Progesterone and the risk of preterm birth among women with a short cervix. N Engl J Med 2007;357:462-8.
Grady D, Rubin SM, Petitti DB, et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med 1992;117:1016-37.
Endometrin (progesterone) vaginal insert package insert. Hunt Valley, MD: Pharmaceutics International, Inc.; 2014 Jun.
Crinone (progesterone vaginal gel) package insert. Parsippany, NJ: Watson Pharma, Inc.; 2011 Dec.
American Academy of Pediatrics (AAP) Committee on Drugs. Transfer of drugs and other chemicals into human milk. Pediatrics 2001;108:776-89.
Prometrium® (progesterone) package insert. Marietta, GA: Solvay Pharmaceuticals Inc.; 1998 Dec.
Shumaker SA, Legault C, Rapp SR, et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women. The Women’s Health Initiative Memory Study: A randomized controlled trial (WHIMS). JAMA 2003;289:2651-62.
Endometrin® (progesterone) package insert. Hunt Valley, MD: Pharmaceutics International, Inc.; 2007 Jun.
Prochieve® (progesterone) package insert. Livingston, NJ: Columbia Laboratories, Inc.; 2004 Oct.
Dilantin® Kapseals® (extended phenyotin sodium capsules, USP) package insert. Morris Plains, NJ: Parke Davis; 1999 Aug.
Cerebyx® (fosphenytoin sodium) package insert. New York, NY: Parke-Davis; 2002 Jun.
Peganone® (ethotoin) package insert. Deerfield, IL: Ovation Pharmaceuticals, Inc.; 2003 Sep.
Tegretol® (carbamazepine) package insert. East Hanover, NJ. Novartis Pharmaceuticals; 2003 Sept.
Carbatrol® (carbamazepine) package insert. Wayne, PA. Shire US Inc; 2006 Jul.
Crawford P. Interactions between antiepileptic drugs and hormonal contraception. CNS Drugs. 2002;16:263—72.
Berman ML, Green OC. Acute stimulation of cortisol metabolism by pentobarbital in man. Anesthesiology 1971;34:365—9.
Phenobarbital Tablets, USP package insert. Elizabeth, NJ: Purepac Pharmaceuticals; 2000 Oct.[/fnElestrin™ (estradiol) package insert. San Antonio,TX: DPT Laboratories, Ltd.; 2006 Dec.
Lewis DP, VanDyke DC, Stumbo PJ, et al. Drug and environmental factors associated with adverse pregnancy outcomes Part 1: Antiepileptic drugs, contraceptives, smoking and folate. Ann Pharmacother 1998;32:802—17.
Hansten P, Horn J. The Top 100 Drug Interactions: A Guide to Patient Management. includes table of CYP450 and drug transporter substrates and modifiers (appendices). H & H Publications, LLP 2014 edition.
Kyriazopoulou V, Parparousi O, Vagenakis A. Rifampicin-induced adrenal crisis in addisonian patients receiving corticosteroid replacement therapy. J Clin Endocrinol Metab 1984;59:1204—6.
Elestrin™ (estradiol) package insert. San Antonio,TX: DPT Laboratories, Ltd.; 2006 Dec.
Archer JSM, Archer DF. Oral contraceptive efficacy and antibiotic interaction: A myth debunked. J Am Acad Dermatol 2002;46:917—23.
Dickinson BD, Altman RD, Nielsen NH, Sterling ML, for the Council on Scientific Affairs, American Medical Association (AMA). Drug interactions between oral contraceptives and antibiotics. Obstet Gynecol 2001;98:853—60. Review.
Uniphyl® (theophylline, anhydrous) tablets package insert. Stamford, CT: Purdue Pharmaceutical Products LP; 2004 Mar.
Biaxin® (clarithromycin) package insert. North Chicago, IL: Abbott Laboratories; 2007 March.
Cardizem® CD (diltiazem) package insert. Kansas City, MO: Aventis Pharmaceuticals, Inc.; 2007 Sep.
VFEND® (voriconazole) package insert. New York,NY: Pfizer Inc; 2008 Mar.
Emend® capsules (aprepitant) package insert. Whitehouse Station, NJ: Merck & Co., Inc.; 2007 Nov.
Parlodel (bromocriptine) package insert. East Hanover, NJ: Novartis Pharmaceutical Corporation, Inc.; 2003 Mar.
Christen RD, McClay EF, Plaxe SC, et al. Phase I/pharmacokinetic study of high-dose progesterone and doxorubicin. J Clin Oncol 1993;11:2417—26.
Targretin® (bexarotene capsules) package insert. San Diego CA: Ligand Pharmaceuticals Inc.; 2003 April.
Tracleer® (bosentan) package insert. South San Francisco, CA: Actelion Pharmaceuticals US, Inc.; 2007 Feb.
Saha GB. Fundamentals of nuclear pharmacy. 3rd ed. New York: Springer-Verlag New York, Inc.; 1992.
Progesterone capsule package insert. High Point, NC: Banner Pharmacaps Inc; 2013 Nov.
Prochieve (progesterone) vaginal gel package insert. Livingston, NJ: Columbia Laboratories, Inc.; 2009 Nov.
Jick H, Jick SS, Gurewich V, et al. Risk of idiopathic cardiovascular death and nonfatal venous thromboembolism in women using oral contraceptives with differing progestagen components. Lancet 1995;346:1589-93.
World Health Organization. Effect of different progestagens in low oestrogen oral contraceptives on venous thromboembolic disease. Lancet 1995;346:1582-8.
Bloemenkamp KWM, Rosendaal FR, Helmerhorst FM, et al. Enhancement by factor V Leiden mutation of risk of deep-vein thrombosis associated with oral contraceptives containing a third-generation progestagen. Lancet 1995;346:1593-6.

Progesterone Cream

Other strengths available to be made to meet patient specific needs

About Progesterone Cream

Progesterone is one of several primary hormones in women that play a key role in the maintenance of pregnancy. After the rupture of the ovarian follicle and release of the ovum within the female ovary, progesterone is secreted by mature granulosa cells known as the corpus luteum. The released progesterone causes a thickening of the endometrial wall of the uterus, preparing it for the implantation of a fertilized ovum. If fertilization and implantation does not occur, the corpus luteum eventually atrophies and the serum progesterone levels fall. However, if implantation does occur, the serum progesterone levels remain elevated throughout the duration of the pregnancy as the placenta takes over the role of progesterone production.^[1]^[2]^[3]

Progesterone is a derivative of cholesterol. After interaction with cellular membrane receptors and fusion with intracellular lysozymes, it is then transported to the mitochondria where it is then converted into pregnenolone. Through the mediating action of the Cytochrome P450 group of super enzymes, pregnenolone is then converted to progesterone within the corpus luteum or the placenta, depending on the presence or absence of pregnancy.^[1]

In addition to its role in pregnancy, progesterone also plays an essential role in the central as well as peripheral nervous system. It is a neurosteroid, meaning that it is synthesized in the nervous system; this synthesis occurs in neuronal cells located with the central nervous system (CNS). Within the CNS, the pathway for progesterone synthesis is similar to that found in the corpus luteum or placenta. In the central nervous system, progesterone aids in the production of the myelin sheath, which is the layer surrounding the nerves, and is responsible for the transmission of rapid impulses along the nerve cells.^[4]

Mechanisms of Action

The traditional means by which progesterone exerts its effects within the human body, also known as the genomic mechanism, is through its interaction with the progesterone receptor, PR. The progesterone receptor, typically described as a nuclear transcription factor, acts on ribosomal RNA to regulate ribosomal transcription, resulting in the production of the corresponding proteins. There are two primary forms of progesterone receptors that are located within the body namely PR-A and PR-B. PR-A and PR-B share the same DNA binding domain but have differing amino acid sequences with PR-A having 164 more amino acids than PR-B. Some of the effects of progesterone on organs within the body through its binding with the progesterone receptors PR-A and PR-B include:

Thickening of the uterine endometrium, getting it ready for the implantation of a fertilized ovum. Progesterone is released by the corpus luteum from the granulosa cells in the ovary for this purpose.
Maintenance of pregnancy, helping to ensure that a successfully implanted fertilized ovum is carried by the mother until delivery. After the development of the placenta, one of its roles is to continue the production of progesterone for the duration of the pregnancy, making sure that serum progesterone levels are sufficient to maintain the fetus within the uterus.^[5]
In the female breast, progesterone stimulates the growth in number and size of the alveoli and lobes during pregnancy. In addition, progesterone inhibits the production of breast milk throughout the duration of the pregnancy. As progesterone levels fall after delivery, milk production within the breasts is triggered.
In the central nervous system, progesterone plays a role in the development of the myelin sheath surrounding the nerves. It has also been shown to play role in the neurological recovery from after a traumatic brain injury or a hypoxic-ischemic injury within the brain.^[6]
In addition to the genomic mechanism, progesterone can also exert its effects through non-genomic means. The non-genomic pathway involves the activation of intracellular signaling pathways, which occurs through ion channels as well as second messenger cascades. This pathway normally occurs in the central nervous system; however, it can also take place in other areas of the body.^[5]

Contraindications & Precautions

There are certain circumstances under which progesterone should not be administered or, if administered, should be done with extreme caution. Some of the absolute or relative contraindications to progesterone administration include:

Hypersensitivity: Progesterone should not be administered to individuals who have a hypersensitivity to progesterone or any of its products.
Hepatic disease: Due to the fact that progesterone is mainly metabolized in the liver, its administration to individuals with significant renal impairment should be avoided as much as possible.

Ectopic pregnancy: Ectopic pregnancy as well as missed or incomplete abortions are absolute contraindications to exogenous progesterone administration.
Breastfeeding: Caution should be exercised when administering progesterone to breastfeeding mothers as detectable amounts have been found in breast milk.

Thromboembolic diseases: Individuals with a current or previous history of thromboembolic disease such as peripheral vascular disease, stroke, or myocardial infarction should not receive progesterone therapy. Individuals with high risk factors for thromboembolic diseases need to be closely monitored if they are given progesterone.

Vaginal bleeding: Progesterone should not be administered to females presenting with vaginal bleeding of an unknown cause.

Diabetes mellitus: Diabetics may receive progesterone therapy with caution as some individuals may experience a decrease in glucose tolerance and a resultant increase in blood sugar levels.

Reproductive cancer: Progesterone therapy is contraindicated in females presenting with breast, cervical, endometrial, ovarian, uterine, or vaginal cancer. Since these cancers are usually hormonally dependent, progesterone administration may worsen these conditions.

Hyperlipidemia: Progesterone therapy has been shown to impair lipid metabolism in some individuals and so should be administered cautiously to individuals with known or suspected cases of hyperlipidemia.

Drug interactions: Care should be taken when administering progesterone with other drugs due to the likelihood of significant drug interactions. Some drugs such as barbiturates can stimulate the production of Cytochrome P450 enzymes in the liver and increase the rate of hepatic clearance of progesterone; this can result in decreased serum levels of progesterone as well as decreased effectiveness.^[9]

Adverse Reactions / Side Effects

Some side effects that individuals may experience while on progesterone therapy are mild and generalized such as nausea and vomiting, urticaria, rhinitis, fever, headache, and fatigue, among others. Other individuals, however, may experience more severe and consequential adverse effects such as:

Thromboembolic disease: This is especially the case in individuals who have risk factors for thromboembolic disease.

Emotional lability: Sudden onsets of depression, anxiety, irritability, and uncontrollable outbursts are some emotional changes that may occur in women on progesterone therapy.

Fluid retention: Progesterone administration may cause fluid retention. In individuals with cardiac or renal disease, this may result in a worsening of their condition.

Menstrual changes: Changes in menstrual flow and rhythm, dysmenorrhea, and amenorrhea are some of the changes that may be seen in women receiving progesterone therapy.^[9]

Pregnancy & Breastfeeding

Progesterone is a US FDA pregnancy category B medication. Studies in animals have not demonstrated any particular risks to fetuses. However, enough adequate and well-controlled studies about its effects have not been done in pregnant women. Current recommendations are that progesterone therapy should only be used during the first three months of therapy. It should be discontinued once there is evidence of an adequate production of placental progesterone.^[12]

Detectable levels of progesterone have been found in the milk of breastfeeding mothers. There have been no reported instances of developmental problems in neonates and toddlers of mothers with progesterone in their breast milk. As such, there are no restrictions for breastfeeding women receiving progesterone therapy. However, some degree of care should be exercised when administering progesterone to lactating females.

Storage

Store this medication in its original container at 68°F to 77°F (20°C to 25°C) and away from heat, moisture and light. Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond use date. Do not flush unused medications or pour down a sink or drain.

References

Taraborrelli, S., “Physiology, production and action of progesterone”, ACTA Obstetricia et Gynecologica, vol.94, pp. 8-16, 2015. Available: https://obgyn.onlinelibrary.wiley.com/doi/pdf/10.1111/aogs.12771– LinkOpens in New Tab
Graham, J. D., Clarke, C.L., “Physiological Action of Progesterone in Target Tissues” Endocrine Reviews, vol.18, pp. 502-519, 1997. Available: https://academic.oup.com/edrv/article/18/4/502/2530774– LinkOpens in New Tab
”Progesterone”, National Center for Biotechnology information, 2020. Available: https://pubchem.ncbi.nlm.nih.gov/compound/Progesterone– LinkOpens in New Tab
Schumacher, M., Hussain, R., Gago, N., Oudinet, J. P., Mattern, C., Ghoumari, A. M., “Progesterone synthesis in the nervous system: implications for myelination and myelin repair”, Frontiers in neuroscience, Vol.6, issue 10, 2012. Available: https://doi.org/10.3389/fnins.2012.00010– LinkOpens in New Tab
Singh, M, Su, C, Ng, S., “Non-genomic mechanisms of progesterone action in the brain”, Frontiers in Neuroscience, vol.7, 2013. Available: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3776940/#:~:text=The%20%E2%80%9Cclassical%E2%80%9D%20mechanism%20by%20which,region%20of%20target%20genes%20to– LinkOpens in New Tab
Gonzalez-Orozco, J.C., Camacho-Arroyo, I, “Progesterone Actions During Central Nervous System Development”, Frontiers in Neuroscience, vol.13, 2019. Available: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6533804/– LinkOpens in New Tab
”Progesterone – Drug summary”, Prescribers’ Digital Reference. Available: https://www.pdr.net/drug-summary/progesterone?druglabelid=2388– LinkOpens in New Tab
”Progesterone pregnancy and breastfeeding warnings” Available: https://www.drugs.com/pregnancy/progesterone.html#:~:text=US%20FDA%20pregnancy%20category%20B,controlled%20studies%20in%20pregnant%20women.

Progesterone Troches

100mg | 200mg

Other strengths available to make to meet specific patient needs

About Progesterone Troches

Mechanism of Action

Contraindications & Precautions

Progesterone injection formulations are for intramuscular use only. Never administer via intravenous administration.

Interactions

Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormones including hormonal contraceptives. Pregnancy has been reported during therapy with estrogens, oral contraceptives, or progestins in patients receiving phenytoin (the active metabolite of fosphenytoin) concurrently.^[13]^[12] Women taking both hormones and hepatic enzyme-inducing drugs should report breakthrough bleeding to their prescribers.An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants, or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on fosphenytoin, with dose adjustments made based on clinical efficacy.

Drugs that can induce hepatic enzymes can accelerate the rate of metabolism of hormones including hormonal contraceptives. Pregnancy has been reported during therapy with estrogens, oral contraceptives, or progestins in patients receiving phenytoin concurrently.^[12] A similar interaction may be expected with ethotoin.^[14] Women taking both hormones and hepatic enzyme-inducing drugs should report breakthrough bleeding to their prescribers. An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants, or higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on ethotoin, with dose adjustments made based on clinical efficacy.

The metabolism of progesterone was inhibited by ketoconazole, a known inhibitor of cytochrome P450 3A4 hepatic enzymes.^[8] It has not been determined whether other drugs which inhibit CYP3A4 hepatic enzymes would have a similar effect. Other such drugs include cimetidine, clarithromycin, danazol, diltiazem, erythromycin, fluconazole, itraconazole, troleandomycin, verapamil, and voriconazole.^[26]^[27]^[21]^[28]^[21]^[21]^[21] ^[21]^[29] This list is not inclusive of all drugs that inhibit CYP3A4.

Bosentan is a significant inducer of CYP3A hepatic enzymes.^[21]^[34] Specific interaction studies have not been performed to evaluate the effect of coadministration of bosentan and hormonal contraceptives (oral contraceptives, estrogens, or progestins), including oral, injectable or implantable agents.^[34] Since many of these drugs are metabolized by CYP3A4, there is a possibility of contraceptive failure when bosentan is coadministered.^[21]^[34] Women should not rely on hormonal contraception alone when taking bosentan; bosentan is teratogenic and is contraindicated during pregnancy.^[34] Since many of these drugs are metabolized by CYP3A4, a reduction in hormone replacement efficacy is possible when bosentan is coadministered.^[34]

Adverse Reactions / Side Effects

Pregnancy & Breastfeeding

Oral Progesterone is classified in FDA pregnancy category B. Animal studies involving oral or intravaginal or in utero administration of progesterone have, in general, not indicated evidence of fetal harm. In general, several studies of women exposed to progesterone during pregnancy for luteal support have not demonstrated a significant increase in fetal malformations. A single case of cleft palate has been reported in an infant exposed to micronized progesterone in utero. Rare cases of fetal death have been reported in women administered micronized progesterone in early pregnancy, but causality has not been established. Only select products are specifically labeled for use to provide luteal support during pregnancy.^[5]^[6] Crinone progesterone vaginal gel may be used to support early pregnancy as part of an Assisted Reproductive Technology (ART) program; if pregnancy occurs, the gel is typically continued for 10—12 weeks until placental production of progesterone is adequate to support the pregnancy. Similarly, Endometrin vaginal inserts are used for up to 10 weeks in ART. Progesterone should only be used during early pregnancy under the observation of an ART specialist; data suggest that progesterone may be effective in preventing preterm delivery, especially in high-risk populations.^[3]^[1] The American College of Obstetricians and Gynecologists (ACOG) Committee recommends that if progesterone is to be used, it should only be used in women with a history of spontaneous birth at < 37 weeks gestation; in addition, the ideal formulation or whether it should be used in other high-risk women is not yet known.^[2] Progesterone should not be used if there is ectopic pregnancy, during cases of missed abortion, or during diagnostic tests for pregnancy. In high doses, injectable progesterone is an anti-fertility drug and may chemically induce female infertility.

In general, the American Academy of Pediatrics considers progesterone to be compatible with breastfeeding.^[7] Detectable amounts of progestins have been identified in the milk of nursing mothers; in general the presence of progestins in the milk are not expected to have adverse effects on lactation production. However, the effects of progestins present in breastmilk on the nursing infant have not been determined.^[8]^[6] The administration of any medication to nursing mothers should take into account the benefit of the drug to the mother and the potential for risk to the breast-fed infant.

Storage

Store this medication in its original container at 68°F to 77°F (20°C to 25°C) and away from heat, moisture and light. Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond-use date. Do not flush unused medications or pour down a sink or drain.

References

Meis PJ, Klebanoff M, Thom E, et al. Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. N Eng J Med 2003;348:2379-85.
ACOG Committee on Obstetric Practice. Committee Opinion: use of progesterone to reduce preterm birth. Obstet Gynecol 2003;102:1115-6.
Fonseca EB, Celik E, Parra M, et al. Progesterone and the risk of preterm birth among women with a short cervix. N Engl J Med 2007;357:462-8.
Grady D, Rubin SM, Petitti DB, et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med 1992;117:1016-37.
Endometrin (progesterone) vaginal insert package insert. Hunt Valley, MD: Pharmaceutics International, Inc.; 2014 Jun.
Crinone (progesterone vaginal gel) package insert. Parsippany, NJ: Watson Pharma, Inc.; 2011 Dec.
American Academy of Pediatrics (AAP) Committee on Drugs. Transfer of drugs and other chemicals into human milk. Pediatrics 2001;108:776-89.
Prometrium® (progesterone) package insert. Marietta, GA: Solvay Pharmaceuticals Inc.; 1998 Dec.
Shumaker SA, Legault C, Rapp SR, et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women. The Women’s Health Initiative Memory Study: A randomized controlled trial (WHIMS). JAMA 2003;289:2651-62.
Endometrin® (progesterone) package insert. Hunt Valley, MD: Pharmaceutics International, Inc.; 2007 Jun.
Prochieve® (progesterone) package insert. Livingston, NJ: Columbia Laboratories, Inc.; 2004 Oct.
Dilantin® Kapseals® (extended phenyotin sodium capsules, USP) package insert. Morris Plains, NJ: Parke Davis; 1999 Aug.
Cerebyx® (fosphenytoin sodium) package insert. New York, NY: Parke-Davis; 2002 Jun.
Peganone® (ethotoin) package insert. Deerfield, IL: Ovation Pharmaceuticals, Inc.; 2003 Sep.
Tegretol® (carbamazepine) package insert. East Hanover, NJ. Novartis Pharmaceuticals; 2003 Sept.
Carbatrol® (carbamazepine) package insert. Wayne, PA. Shire US Inc; 2006 Jul.
Crawford P. Interactions between antiepileptic drugs and hormonal contraception. CNS Drugs. 2002;16:263—72.
Berman ML, Green OC. Acute stimulation of cortisol metabolism by pentobarbital in man. Anesthesiology 1971;34:365—9.
Phenobarbital Tablets, USP package insert. Elizabeth, NJ: Purepac Pharmaceuticals; 2000 Oct.[/fnElestrin™ (estradiol) package insert. San Antonio,TX: DPT Laboratories, Ltd.; 2006 Dec.
Lewis DP, VanDyke DC, Stumbo PJ, et al. Drug and environmental factors associated with adverse pregnancy outcomes Part 1: Antiepileptic drugs, contraceptives, smoking and folate. Ann Pharmacother 1998;32:802—17.
Hansten P, Horn J. The Top 100 Drug Interactions: A Guide to Patient Management. includes table of CYP450 and drug transporter substrates and modifiers (appendices). H & H Publications, LLP 2014 edition.
Kyriazopoulou V, Parparousi O, Vagenakis A. Rifampicin-induced adrenal crisis in addisonian patients receiving corticosteroid replacement therapy. J Clin Endocrinol Metab 1984;59:1204—6.
Elestrin™ (estradiol) package insert. San Antonio,TX: DPT Laboratories, Ltd.; 2006 Dec.
Archer JSM, Archer DF. Oral contraceptive efficacy and antibiotic interaction: A myth debunked. J Am Acad Dermatol 2002;46:917—23.
Dickinson BD, Altman RD, Nielsen NH, Sterling ML, for the Council on Scientific Affairs, American Medical Association (AMA). Drug interactions between oral contraceptives and antibiotics. Obstet Gynecol 2001;98:853—60. Review.
Uniphyl® (theophylline, anhydrous) tablets package insert. Stamford, CT: Purdue Pharmaceutical Products LP; 2004 Mar.
Biaxin® (clarithromycin) package insert. North Chicago, IL: Abbott Laboratories; 2007 March.
Cardizem® CD (diltiazem) package insert. Kansas City, MO: Aventis Pharmaceuticals, Inc.; 2007 Sep.
VFEND® (voriconazole) package insert. New York,NY: Pfizer Inc; 2008 Mar.
Emend® capsules (aprepitant) package insert. Whitehouse Station, NJ: Merck & Co., Inc.; 2007 Nov.
Parlodel (bromocriptine) package insert. East Hanover, NJ: Novartis Pharmaceutical Corporation, Inc.; 2003 Mar.
Christen RD, McClay EF, Plaxe SC, et al. Phase I/pharmacokinetic study of high-dose progesterone and doxorubicin. J Clin Oncol 1993;11:2417—26.
Targretin® (bexarotene capsules) package insert. San Diego CA: Ligand Pharmaceuticals Inc.; 2003 April.
Tracleer® (bosentan) package insert. South San Francisco, CA: Actelion Pharmaceuticals US, Inc.; 2007 Feb.
Saha GB. Fundamentals of nuclear pharmacy. 3rd ed. New York: Springer-Verlag New York, Inc.; 1992.
Progesterone capsule package insert. High Point, NC: Banner Pharmacaps Inc; 2013 Nov.
Prochieve (progesterone) vaginal gel package insert. Livingston, NJ: Columbia Laboratories, Inc.; 2009 Nov.
Jick H, Jick SS, Gurewich V, et al. Risk of idiopathic cardiovascular death and nonfatal venous thromboembolism in women using oral contraceptives with differing progestagen components. Lancet 1995;346:1589-93.
World Health Organization. Effect of different progestagens in low oestrogen oral contraceptives on venous thromboembolic disease. Lancet 1995;346:1582-8.
Bloemenkamp KWM, Rosendaal FR, Helmerhorst FM, et al. Enhancement by factor V Leiden mutation of risk of deep-vein thrombosis associated with oral contraceptives containing a third-generation progestagen. Lancet 1995;346:1593-6.

Progesterone Gel

10 % (10mg/gram) | 20 % (20mg/gram) | 25 % (25mg/gram) |

Other strengths available to be made to meet patient specific needs

About Progesteone gel

Progesterone is a naturally occurring progestin. In the body, it is synthesized in the ovaries, testes, placenta, and adrenal cortex. Progesterone may be given orally, parenterally, or vaginally. The hormone is primarily used to treat amenorrhea and abnormal uterine bleeding, and also to prevent endometrial hyperplasia in postmenopausal women taking estrogen therapy. The drug is sometimes used off-label for premenstrual dysphoric disorder (PMDD), and has historically been used as a contraceptive. Progesterone is also used to prevent early pregnancy failure in women with corpus luteum insufficiency, including women undergoing assisted reproductive technology (ART).^[1]^[2]^[3]Progesterone also helps reduce the risk for preterm birth in selected patients. In women with single gestation pregnancy and a history of spontaneous preterm delivery, antenatal progesterone therapy effectively decreases the risk of a recurrent preterm delivery. Progesterone supplementation is beneficial in these women starting at 16 to 24 weeks gestation and continuing through 34 weeks gestation. It is not yet clear if the drug is beneficial at reducing risk for preterm birth in multiple gestation pregnancies.^[4]^[5]^[6] Progesterone was first marketed medicinally in 1939, which was prior to the modern FDA drug approval process; the injection and various bulk products for extemporaneous compounding of vaginal suppositories and other dosage forms have long been available. A progesterone-containing intrauterine device was available for contraception, but is no longer marketed. In May 1998, oral micronized progesterone capsules were first FDA-approved. In May 1997, a progesterone vaginal gel was FDA-approved for use in an Assisted Reproductive Technology (ART) program; a progesterone vaginal insert used for this purpose was FDA-approved in June 2007.

Mechnisms 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 essential for the development of decidual tissue, and the effect of progesterone on the differentiation of glandular epithelia and stroma has been extensively studied. Progesterone is necessary to increase endometrial receptivity for implantation of an embryo. Once an embryo is implanted, progesterone acts to maintain the pregnancy. Normal or near-normal endometrial responses to oral estradiol and intramuscular progesterone have been noted in functionally agonadal women through the sixth decade of life. Progesterone administration decreases the circulatory levels of gonadotropins.^[3]^[2]

Progesterone can be used to achieve normalized progesterone levels in women with secondary amenorrhea. When a woman does not produce enough progesterone, menstrual irregularities may occur. Progesterone can thus help re-establish normal menstrual cycles in pre-menopausal women with such irregularities.^[2]^[7]

The primary role of progesterone when used in the menopausal woman is for a protective effect that reductes the risk of endometrial hyperplasia when used with estrogen in the woman with an intact uterus. Micronized oral progesterone does not appear to have adverse effects on serum lipid profiles when used in regimens for hormone replacement therapy (HRT).^[7]

Progesterone has also been used historically as a contraceptive, including in intrauterine contraceptive devices (IUDs). The primary contraceptive effect of exogenous progestins involves the suppression of the midcycle surge of luteinizing hormone (LH). The exact mechanism of action, however, is unknown. At the cellular level, progestins diffuse freely into target cells and bind to the progesterone receptor. Target cells include the female reproductive tract, the mammary gland, the hypothalamus, and the pituitary. Once bound to the receptor, progestins slow the frequency of release of gonadotropin releasing hormone (GnRH) from the hypothalamus and blunt the pre-ovulatory LH surge, thereby preventing follicular maturation and ovulation. Additional mechanisms may be involved in the contraceptive effect. Other actions of progestins include alterations in the endometrium that can impair implantation and an increase in cervical mucus viscosity which inhibits sperm migration into the uterus.

Contraindications & Precautions

Progesterone is contraindicated in patients with pre-existing breast cancer or cancer of reproductive organs, such as cervical cancer, endometrial cancer, ovarian cancer, uterine cancer, or vaginal cancer. Likewise, progesterone formulations should not be used in patients with undiagnosed vaginal bleeding. Progesterone, like other hormones, can influence hormonally-dependent cancers.^[1]^[3]^[2]^[7]^[11]

Hormone Replacement Therapy (HRT): Oral progesterone labeling contains a boxed warning regarding the potential risk for breast cancer (new primary malignancy) in post-menopausal women receiving estrogen and progestin hormonal replacement therapy (HRT).^[7] The use of estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation. All women should receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results. Progestins with estrogens should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman. The most important randomized clinical trial providing information about breast cancer in patients taking combined estrogen-progestin HRT regimens is the WHI substudy of estrogen plus progestin.^[12]^[13] After a mean follow-up of 5.6 years, the WHI estrogen plus progestin substudy reported an increased risk of invasive breast cancer in women who took daily CE plus MPA vs. placebo. In this substudy, prior use of estrogen-alone or estrogen plus progestin therapy was reported by 26% of the women. The relative risk of invasive breast cancer was 1.24, and the absolute risk was 41 versus 33 cases per 10,000 women-years, for estrogen plus progestin compared with placebo. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 vs. 25 cases per 10,000 women-years for estrogen plus progestin compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 vs. 36 cases per 10,000 women-years for estrogen plus progestin compared with placebo. In the same WHI substudy, invasive breast cancers were larger, were more likely to be node positive, and were diagnosed at a more advanced stage in the combined HRT group compared with the placebo group. Metastatic disease was rare, with no apparent difference between the 2 groups. Other prognostic factors, such as histologic subtype, grade and hormone receptor status did not differ between the 2 groups.^[12] Consistent with the WHI clinical trial, observational studies have also reported an increased risk of breast cancer for estrogen plus progestin therapy, and a smaller increased risk for estrogen-alone therapy, after several years of use. The risk increased with duration of use, and appeared to return to baseline over about 5 years after stopping treatment (only the observational studies have substantial data on risk after stopping). Observational studies also suggest that the risk of breast cancer was greater, and became apparent earlier, with combined HRT as compared to estrogen-alone therapy. However, these studies have not found significant variation in the risk of breast cancer among different estrogen plus progestin combinations, doses, or routes of administration.^[7] Adding a progestin such as progesterone to estrogen HRT has been shown to reduce, but not completely eliminate, the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Clinical surveillance of all women using estrogen plus progestin HRT is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding.^[7] The WHI estrogen plus progestin substudy reported a statistically non-significant increased risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for CE plus MPA versus placebo was 1.58 (95% CI, 0.77 to 3.24). The absolute risk for CE plus MPA was 4 versus 3 cases per 10,000 women-years. In some epidemiologic studies, the use of estrogen plus progestin and estrogen-only products, in particular for 5 or more years, has been associated with increased risk of ovarian cancer. However, the duration of exposure associated with increased risk is not consistent across all epidemiologic studies and some report no association.^[7]

Progesterone products are contraindicated in patients with hepatic disease or known hepatic dysfunction.^[1]^[3]^[2]^[7]^[11]

Progesterone injections are formulated in oil and are for intramuscular use only. Never administer via intravenous administration.^[11] Oil microembolization, such as pulmonary oil microembolism, may occur if inadvertently administered intravenously, which may result in serious reactions. Some injection formulations are made from sesame oil and are not for use in patients with sesame oil hypersensitivity. Benzyl alcohol is also contained in some injection formulas, so use with caution in patients with benzyl alcohol hypersensitivity.

Progesterone at high doses is an antifertility drug and high doses of progesterone injection would be expected to impair fertility until the cessation of treatment. Women of childbearing age may expect some degree of infertility during treatment with progesterone injection at high doses.^[11]

Select progesterone products are specifically labeled for use to provide luteal support during early pregnancy.^[1]^[3]^[2] Animal studies involving oral, vaginal, or in utero administration of progesterone have not indicated evidence of fetal harm. Progesterone vaginal gel may be used to support early pregnancy as part of an Assisted Reproductive Technology (ART) program; if pregnancy occurs, the gel is typically continued for 10 to 12 weeks until placental production of progesterone is adequate to support the pregnancy. Similarly, progesterone vaginal inserts are used for up to 10 weeks in ART. Progesterone should only be used during early pregnancy under the observation of an ART specialist.^[1]^[3]^[2] Data suggest that vaginal progesterone is effective in preventing preterm delivery and associated neonatal complications, especially during high-risk singleton pregnancy; administration usually is initiated at 16 to 24 weeks gestation and continues through 34 weeks gestation.^[4]^[5]^[10]^[6]^[9] Progesterone should not be used if there is ectopic pregnancy, missed/ incomplete abortion, or during diagnostic tests for pregnancy.^[1]^[3]^[2]^[11] Progesterone capsules are only indicated in postmenopausal women, and thus this dosage form is specifically contraindicated for use during pregnancy.^[7]

Detectable amounts of drug have been identified in the milk of mothers receiving progestational drugs. The effect of this on the breast-feeding infant has not been determined.^[1]^[3]^[2]^[7]^[11] In general, use of progestins has not had adverse effects on lactation.^[14] Consider the developmental and health benefits of breast-feeding along with the mother’s clinical need for progesterone and the potential adverse effects on the breast-fed infant.

The safety and effectiveness of progesterone formulations have not been established in children or infants. The safety and efficacy of progesterone have only been established in females of reproductive age. Use of progesterone in female children before menarche is not usually indicated. In neonates, inadvertent exposure to progesterone injections, which may contain benzyl alcohol, can result in a “gasping syndrome”.

Progesterone is contraindicated in patients with a history of thrombophlebitis, active or previous history of thromboembolism or thromboembolic disease (including stroke and myocardial infarction). Patients with risk factors for heart disease, thromboembolism, and stroke (e.g., known cerebrovascular disease, hypertension, diabetes mellitus, tobacco smoking, hypercholesterolemia, obesity, etc.) should be monitored closely and managed appropriately. During use of progesterone in patients without a history of thrombosis, the provider should be alert to the earliest manifestations of thrombotic disorder (thrombophlebitis, heart attack, cerebrovascular disorder such as stroke or focal headache with symptoms consistent with cerebral ischemia, pulmonary embolism, or unexplained visual disturbance with ocular pain, which might indicate retinal thrombosis). Should any of these occur or be suspected, progesterone therapy should be discontinued immediately.^[1]^[3]^[2]^[7]^[11] Hormone Replacement Therapy (HRT): Progesterone, when used with estrogen therapy for postmenopausal hormone replacement, is associated with cardiovascular and thromboembolic risks, which are highlighted in the oral progesterone boxed warnings. The Women’s Health Initiative (WHI) estrogen plus progestin substudy reported an increased risk of deep vein thrombosis (DVT), pulmonary embolism (PE), stroke and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with estrogen-progestin therapy, relative to placebo.^[7] In the WHI estrogen plus progestin substudy, a statistically significant 2-fold greater rate of VTE was reported in women receiving estrogen plus progestin HRT vs. women receiving placebo (35 vs. 17 per 10,000 women-years). Statistically significant increases in risk for both DVT (26 vs. 13 per 10,000 women-years) and PE (18 vs. 8 per 10,000 women-years) were also demonstrated. The increase in VTE risk was demonstrated during the first year and persisted.^[15]^[13] Estrogens with or without a progestin such as progesterone should not be used for the prevention of cardiac disease or cardiovascular disease (e.g., coronary artery disease) in postmenopausal women. In the WHI estrogen plus progestin substudy, there was a statistically non-significant increased risk of CHD events reported in women receiving daily estrogen plus progestin compared to women receiving placebo (41 vs. 34 per 10,000 women-years). An increase in relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5.^[13] ^[16] Studies have also shown no cardiovascular benefit to the use of estrogen-progestin therapy for secondary prevention in women with documented cardiac disease or CHD.^[17]^[18] In the WHI estrogen plus progestin substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving estrogen plus progestin HRT compared to women in the same age group receiving placebo (33 vs. 25 per 10,000 women-years). The increase in risk was demonstrated after the first year and persisted. Women over the age of 65 years were at increased risk for non-fatal stroke.^[19]^[13]^[7]

Progesterone should be used cautiously in patients with diabetes mellitus. A decrease in glucose tolerance has been observed in a small percentage of patients on estrogen-progestin combination treatment. There are possible risks which may be associated with the use of progestin treatment, including adverse effects on carbohydrate and lipid metabolism. The dosage used may be important in minimizing these adverse effects. Use with caution in patients with known hyperlipidemia.

Progesterone should be prescribed cautiously in patients with asthma, congestive heart failure, nephrotic syndrome or other renal disease, or cardiac disease. Hormonal contraceptives can cause fluid retention and may exacerbate any of the above conditions.

Progesterone should be used cautiously in patients with a history of major depression, migraine, or seizure disorder. Progestins may exacerbate these conditions in some patients. If a patient receiving progesterone develops changes in migraine patterns, or a focal migraine with symptoms consistent with cerebral ischemia, or a severe headache pattern that may indicate a cerebrovascular disorder, consider discontinuation of the drug. Some cases of seizures following administration of progestins have been reported.

An intrauterine device containing progesterone should not be used if there is any infection or inflammation in the female reproductive tract. There is a risk of infection progressing to pelvic inflammatory disease. Exposure to sexually transmitted disease also increases this risk.

Progesterone may cause transient dizziness in some patients. Use caution when driving or operating machinery.

Estrogen/progestin combination therapy has been found to fail to prevent mild cognitive impairment (memory loss) and to increase the risk of dementia in women 65 years and older. The WHIMS study, an ancillary study of the WHI trial to assess the effects of estrogen/progestin therapy on cognitive function in geriatric women (65 years of age or older), found that patients receiving either active treatment or placebo had similar rates of developing mild cognitive impairment. Patients receiving estrogen/progestin combination therapy were more likely than patients receiving placebo to be diagnosed with dementia. The applicability of this finding to women who use estrogen alone or to the typical user of HRT (i.e., younger, symptomatic women taking hormone replacement therapy to relieve menopausal symptoms) is unclear. Administration of estrogen/progestin combination therapy should be avoided in women 65 years of age and older and estrogen/progestin combination therapy should not be used to prevent or treat dementia or preserve cognition (memory).^[20]^[7]

Adverse Reactions / Side Effects

The most common adverse reactions occurring during therapy with progesterone include menstrual irregularity, menstrual flow changes, and dysmenorrhea or amenorrhea. These effects may be indistinguishable from pregnancy. Progesterone also causes spotting, breakthrough bleeding, weight gain, nausea, vomiting, breast tenderness or mastalgia, and mild headache. These adverse effects occur less frequently with progestin-only OCs compared to combination OCs. Other reported adverse reactions during therapy include melasma, chloasma, libido decrease, libido increase, breast discharge, cervicitis, galactorrhea, hirsutism, leukorrhea, unusual weakness, and vaginitis. Post-marketing experiences with oral progesterone include endometrial carcinoma, hypospadia, intra-uterine death, menorrhagia, menstrual disorder, metorrhagia, ovarian cyst, and spontaneous fetal abortion.^[21]Additional adverse reactions associated with the intravaginal gel include breast enlargement, dyspareunia, nocturia, perineal pain, dysmenorrhea, premenstrual tension, vaginal dryness, and vaginal discharge.^[2] Adverse reactions associated with vaginal inserts include vaginal irritation, vaginal itching, vaginal burning, and vaginal pain/discomfort.^[1]

During use of progesterone, the provider should be alert to the earliest manifestations of a thrombotic disorder (e.g., thrombophlebitis, deep vein thrombosis, migraine /headache or other neurologic event with focal symptoms that suggest cerebral ischemia, pulmonary embolism, heart attack, or unexplained visual disturbance with ocular pain, which might indicate retinal thrombosis). Should any of these occur or be suspected, progesterone therapy should be discontinued immediately.^[7]^[1]^[3]^[2]^[11] Hormone Replacement Therapy (HRT): Progesterone, when used with estrogen therapy for postmenopausal hormone replacement, is associated with cardiovascular and thromboembolism risks in postmenopausal women, which are highlighted in the oral progesterone boxed warnings. The Women’s Health Initiative (WHI) estrogen plus progestin substudy reported an increased risk of deep vein thrombosis (DVT), pulmonary embolism (PE), stroke and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with estrogen-progestin therapy, relative to placebo.^[7] In the WHI estrogen plus progestin substudy, a statistically significant 2-fold greater rate of VTE was reported in women receiving estrogen plus progestin HRT vs. women receiving placebo (35 vs. 17 per 10,000 women-years). Statistically significant increases in risk for both DVT (26 vs. 13 per 10,000 women-years) and PE (18 vs. 8 per 10,000 women-years) were also demonstrated. The increase in VTE risk was demonstrated during the first year and persisted.^[15]^[13] Estrogens with or without a progestin such as progesterone should not be used for the prevention of cardiac disease or cardiovascular disease (e.g., coronary artery disease) in postmenopausal women. In the WHI estrogen plus progestin substudy, there was a statistically non-significant increased risk of CHD events reported in women receiving daily estrogen plus progestin compared to women receiving placebo (41 vs. 34 per 10,000 women-years). An increase in relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5.^[13] ^[16] Studies have also shown no cardiovascular benefit to the use of estrogen-progestin therapy for secondary prevention in women with documented cardiac disease or CHD.^[17]^[18] In the WHI estrogen plus progestin substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving estrogen plus progestin HRT compared to women in the same age group receiving placebo (33 vs. 25 per 10,000 women-years). The increase in risk was demonstrated after the first year and persisted. Women over the age of 65 years were at increased risk for non-fatal stroke.^[19]^[13]^[7]

Gastrointestinal (GI) adverse reactions reported with progesterone use include abdominal pain, bloating, nausea, vomiting, dyspepsia, eructation, flatulence, diarrhea, constipation, anorexia, appetite stimulation, and weight loss.^[7]^[1]^[3]^[2]^[11] Gastritis and dysphagia have been reported with oral progesterone capsules and acute pancreatitis, hepatic failure, hepatic necrosis, hepatitis, and swollen tongue (glossitis) were reported postmarketing.^[7]

Estrogen/progestin combination hormone replacement therapy (HRT) has been found to fail to prevent mild impaired cognition (memory loss) and to increase the risk of dementia in women 65 years and older. The WHIMS study, an ancillary study of the WHI trial to assess the effects of estrogen/progestin therapy on cognitive function in geriatric women (65 years of age or older), found that patients receiving either active treatment or placebo had similar rates of developing mild cognitive impairment. Patients receiving estrogen/progestin combination therapy were more likely than patients receiving placebo to be diagnosed with dementia. The applicability of this finding to women who use estrogen alone or to the typical user of HRT (i.e., younger, symptomatic women taking hormone replacement therapy to relieve menopausal symptoms) is unclear. Administration of estrogen/progestin combination therapy should be avoided in women 65 years of age and older and estrogen/progestin combination therapy should not be used to prevent or treat dementia or preserve cognition (memory).^[20]^[7]

The issue of hormonal influences on the development of cancers (new primary malignancy) has been widely researched for many decades. The risks of various cancers for progestins used for infertility or for short term treatment of irregular uterine bleeding are expected to differ from the risks associated with postmenopausal hormone replacement therapy (HRT). Undiagnosed vaginal bleeding should be evaluated in any patient using progesterone as is clinically appropriate, since female genital cancers may be influenced by hormonal therapy. HORMONE REPLACEMENT THERAPY POSTMENOPAUSE: Numerous epidemiologic studies have examined the effects of estrogen and estrogen-progestin hormone replacement therapy (HRT) on the development of new primary malignancy (e.g., breast cancer, endometrial cancer, ovarian cancer) in postmenopausal women. The Women’s Health Initiative (WHI) estrogen plus progestin study reported increased risks of invasive breast cancer in patients taking combined estrogen-progestin HRT vs. placebo. The potential risk of breast cancer may increase with longer duration of use. Due to breast cancer and other cancer risks, combined HRT should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.^[7]^[13]^[22]^[23]^[24] There is an association of unopposed estrogen therapy and endometrial cancer in women with an intact uterus. Adding a progestin to estrogen therapy has been shown to reduce, but not eliminate, the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Clinical surveillance of all women using estrogen-alone or estrogen plus progestin therapy is important. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal vaginal bleeding. The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12-times greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with use of estrogens for less than 1 year. The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for 5 to 10 years or more, and this risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Among combined estrogen/progestin HRT users, roughly 10% will have some endometrial thickening. Postmarketing reports of endometrial hyperplasia have been reported in women receiving combined estrogen/progestin HRT; however, the incidence of endometrial hyperplasia is estimated to be 1% or less in these patients.^[7]^[24]^[25]^[13] Women who used HRT for menopausal symptoms also had an increased risk for ovarian cancer, but data are still uncertain if risk is associated with a specific duration of use. The contraindications and precautions sections for progesterone HRT product labels more fully discuss the data and what is known about HRT use with respect to risks for various cancers.^[7]^[13]^[22]^[23]^[24]

Pregnancy & Breastfeeding

Detectable amounts of drug have been identified in the milk of mothers receiving progestational drugs. The effect of this on the breast-feeding infant has not been determined.^[1]^[3]^[2]^[7]^[11] In general, use of progestins has not had adverse effects on lactation.^[14] Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for progesterone and the potential adverse effects on the breast-fed infant.

Storage

References

Endometrin (progesterone) vaginal insert package insert. Hunt Valley, MD: Pharmaceutics International, Inc.; 2014 Jun.
Prochieve (progesterone) vaginal gel package insert. Livingston, NJ: Columbia Laboratories, Inc.; 2009 Nov.
Crinone (progesterone vaginal gel) package insert. Parsippany, NJ: Watson Pharma, Inc.; 2011 Dec.
Fonseca EB, Celik E, Parra M, et al. Progesterone and the risk of preterm birth among women with a short cervix. N Engl J Med 2007;357:462-8.
ACOG Committee on Obstetric Practice. Committee Opinion: use of progesterone to reduce preterm birth. Obstet Gynecol 2003;102:1115-6.
Rode L, Tabor A. Prevention of preterm delivery in twin pregnancy. Best Pract Res Clin Obstet Gynaecol 2014;28:273-83.
Prometrium (micronized progesterone capsules) package insert. North Chicago, IL: AbbVie Inc.; 2013 Sept.
Tavaniotou A, Smitz J, Bourgain C, et al. Comparison between different routes of progesterone administration as luteal phase support in infertility treatments. Hum Reprod Update 2000;6:139-48.
Hassan SS, Romero R, Vidyadhari D, et al; PREGNANT Trial. Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial. Ultrasound Obstet Gynecol. 2011;38:18-31.
da Fonseca EB, Bittar RE, Carvalho MB, et al. Prophylactic administration of progesterone by vaginal suppository to reduce the incidence of spontaneous preterm birth in women at increased risk: a randomized, placebo-controlled double-blind study. Am J Obstet Gynecol 2003;188:419-24.
Progesterone in sesame oil injection package insert. Parsippany, NJ: Actavis Pharmaceuticals; 2014 Sept.
Chlebowski RT, Hendrix SL, Langer RD, et al. Influence of Estrogen Plus Progestin on Breast Cancer and Mammography in Healthy Postmenopausal Women: The Women’s Health Initiative Randomized Trial. JAMA 2003;289:3243-53.
Rossouw JE, Anderson GL, Prentice RL, et al. The Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA 2002;288:321-333.
American Academy of Pediatrics (AAP) Committee on Drugs. Transfer of drugs and other chemicals into human milk. Pediatrics 2001;108:776-89.
Cushman M, Kuller LH, Prentice R, et al. Estrogen plus progestin and risk of venous thrombosis. JAMA. 2004;292:1573-1580.
Hsia J, Langer RD, Manson JE, et al. Conjugated equine estrogens and coronary heart disease. The Women’s Health Initiative. Arch Intern Med. 2006;166:357-365.
The Heart and Estrogen/progestin Replacement Study (HERS) Research Group. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998;280:605-13.
Grady D, Herrington D, Bittner V, et al. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA 2002;288:49-57.
Rossoun JE, Prentice RL, Manson JE. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA. 2007;297:1465-1477.
Shumaker SA, Legault C, Rapp SR, et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women. The Women’s Health Initiative Memory Study: A randomized controlled trial (WHIMS). JAMA 2003;289:2651-62.
Progesterone capsule package insert. High Point, NC: Banner Pharmacaps Inc; 2013 Nov.
Stefanick ML, Anderson GL, Margolis KL, et al. Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy. JAMA 2006;295:1647-57.
Lacey JV, Mink PJ, Lubin JH, et al. Menopausal hormone replacement therapy and risk of ovarian cancer. JAMA 2002;288:334-341.
The 2017 hormone therapy position statement of The North American Menopause Society. Menopause. 2017 Jun 22.
Grady D, Rubin SM, Petitti DB, et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med 1992;117:1016-37.

Compounded Progesterone Product Line Overview

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