Progesterone (Prometrium)

1. Health Canada Product Monograph — Progesterone

• Prometrium is used in women with an intact uterus as an add-on to postmenopausal estrogen replacement therapy, to reduce the risk of estrogen-related overgrowth (hyperplasia) and cancer of the uterine lining.
• Prometrium is not a contraceptive and should not be relied on to prevent pregnancy.

Contraindicated in pregnancy. Confirm pregnancy status and discuss alternative therapy with the prescriber before dispensing.

• Prometrium is contraindicated in known or suspected pregnancy.
• Pregnancy should be ruled out before starting hormone replacement therapy, and treatment should be stopped immediately if pregnancy occurs.
• A case of cleft palate and rare cases of fetal death have been reported after use in early pregnancy, though a direct cause-and-effect link has not been established.
• Rare cases of liver disease in the mother have been reported when progesterone was used in the second or third trimester for unapproved reasons, such as threatened premature labour.

• Detectable amounts of progesterone pass into breast milk, and Prometrium is not recommended during breastfeeding.

• The safety and effectiveness of Prometrium have not been adequately studied in women over 65 years of age, so it is not indicated for this age group.
• The Women's Health Initiative Memory Study found an increased risk of probable dementia in women 65 and older taking combined estrogen and progestin therapy.

• Prometrium is not indicated for use in children.

• The usual dose of Prometrium is 200 mg once daily for the last 14 days of each estrogen treatment cycle, taken at bedtime.
• Women on higher doses of estrogen may need 300 mg daily for the last 12 to 14 days of the cycle, divided as one capsule in the morning, taken about 2 hours after breakfast, and two capsules at bedtime.
• The dose of Prometrium should be adjusted in proportion to the dose of estrogen being used; with the correct balance, patients should have either regular withdrawal bleeding or no bleeding at all.
• Hormone replacement therapy, including Prometrium, should be used at the lowest effective dose for the shortest duration needed to manage symptoms.
• Prometrium capsules must be swallowed whole and should not be chewed, crushed, or pierced.
• If a woman on the 200 mg bedtime dose forgets to take it, she should take one capsule the next morning and continue her regular schedule; women on the 300 mg regimen who miss a morning or evening dose should simply skip the missed dose rather than doubling up.

If overdose is suspected, seek emergency medical attention immediately or contact your regional Poison Control Centre without delay.

• Progesterone has very low toxicity in overdose; symptoms that may occur include nausea, vomiting, drowsiness, and dizziness.
• Overdose of related synthetic progestins has been associated with low mood, tiredness, acne, and excess hair growth.

• Breakthrough bleeding or spotting between periods may occur.
• Changes in menstrual flow or irregular periods may occur.
• Dizziness may occur.
• Drowsiness may occur, particularly 1 to 4 hours after taking a dose, especially with food.
• Abdominal cramping may occur.
• Nausea may occur.
• Breast tenderness may occur.
• Fatigue may occur.
• Headache may occur.
• Bloating may occur.
• Joint pain may occur.
• Mood changes, including low mood, may occur.
• Hot flashes may still occur despite hormone therapy.
• Vaginal discharge or dryness may occur.
• Swelling of the hands or feet may occur.

Serious side effects require immediate discussion with the prescriber or emergency care.

• Combined estrogen-progestin therapy has been associated with an increased risk of heart attack, stroke, blood clots (including deep vein thrombosis and pulmonary embolism), and invasive breast cancer.
• An increased risk of probable dementia has been reported in women 65 and older using combined hormone therapy.
• Blood clots, including in the legs, lungs, retina, or brain, can occur; symptoms include leg pain or swelling, sudden shortness of breath, chest pain, sudden vision changes, or sudden severe headache.
• Liver problems, including impaired liver function, cholestatic jaundice, and rarely hepatocellular liver disease, have been reported.
• Gallbladder disease requiring surgery occurs more often in women taking estrogen-containing hormone therapy.
• Severe allergic reactions, including hives and anaphylactic shock, can occur, particularly in patients allergic to soya or peanuts, since the capsules contain soya lecithin.
• Worsening migraine, visual disturbances, sudden weakness, difficulty speaking, or loss of consciousness can signal a serious cerebrovascular event and require immediate discontinuation of the medication.
• Severe skin reactions, including erythema multiforme and erythema nodosum, have been reported.
• Seek urgent medical attention for sudden chest pain, shortness of breath, leg swelling or pain, sudden severe headache, vision changes, yellowing of the skin or eyes, or a severe allergic reaction.

• Use with caution in patients with a personal or family history of breast cancer risk factors, since combined hormone therapy has been linked to an increased risk of breast cancer.
• Use with caution in patients with diabetes or a predisposition to diabetes, since hormone therapy can worsen blood sugar and lipid control.
• Use with caution in patients with a history of blood clots, cardiovascular disease, or risk factors for these conditions.
• Use with caution in patients with liver or gallbladder disease.
• Use with caution in patients with uterine fibroids or endometriosis, since hormone therapy may cause these conditions to grow or worsen.
• Use with caution in patients with epilepsy, migraine, systemic lupus erythematosus, or otosclerosis, since hormone therapy may aggravate these conditions.
• Use with caution in patients with kidney or heart disease, or asthma, since hormone therapy can cause fluid retention.
• Use with caution when driving or operating machinery, since drowsiness or dizziness can occur 1 to 4 hours after a dose, particularly when taken with food.
• Use with caution in patients with an allergy to peanuts, given the possible cross-reaction with the soya lecithin in the capsules.

• Contraindicated in patients hypersensitive to progesterone, soya, peanut, or any ingredient in the formulation.
• Contraindicated in active liver disease or dysfunction until liver function tests return to normal.
• Contraindicated in patients with a personal history of breast cancer or other hormone-sensitive cancer.
• Contraindicated in endometrial hyperplasia.
• Contraindicated in unexplained abnormal vaginal bleeding.
• Contraindicated in known or suspected pregnancy.
• Contraindicated in active or past arterial blood clot disease, such as stroke, heart attack, or coronary heart disease.
• Contraindicated in active or past venous blood clots, such as deep vein thrombosis or pulmonary embolism.
• Contraindicated in partial or complete vision loss due to blood vessel disease of the eye.
• Contraindicated in known clotting disorders, such as protein C, protein S, or antithrombin deficiency.
• Contraindicated in porphyria.

• Progesterone may affect blood sugar control, so diabetes medication doses may need to be adjusted.
• Progesterone may slow the breakdown of ciclosporin, increasing ciclosporin levels and the risk of toxicity.
• Medicines that induce liver enzymes, such as rifampicin, rifabutin, certain seizure medicines (phenytoin, phenobarbital, carbamazepine, topiramate), some HIV medicines (nevirapine, efavirenz), barbiturates, and bosentan, can speed up the breakdown of progesterone, reducing its effect and altering bleeding patterns.
• Medicines that inhibit liver enzymes, such as the antifungals fluconazole, itraconazole, ketoconazole, and voriconazole, the antiretrovirals ritonavir and nelfinavir, and the immunosuppressant tacrolimus, can raise progesterone levels and increase the risk of side effects.
• St. John's Wort and other herbal products may affect how the body processes progesterone and estrogen, changing their efficacy and safety.

• Prometrium should generally be taken with food, since concomitant food intake significantly increases how much progesterone the body absorbs; the dosing schedule, including the bedtime dose and the morning dose timed about 2 hours after breakfast, is designed around this food effect.

• The 200 mg daily dose should be taken at bedtime; for the 300 mg daily regimen, one capsule is taken in the morning about 2 hours after breakfast and two capsules are taken at bedtime, since drowsiness or dizziness can occur 1 to 4 hours after a dose.

• Store Prometrium at controlled room temperature between 15°C and 30°C, protected from light.

• Prometrium (progesterone) is combined with estrogen therapy to protect the lining of the uterus in women who still have a uterus.
• Take this medicine consistently with food as directed, since food increases how much of the medicine your body absorbs.
• Report any unusual vaginal bleeding, leg swelling or pain, chest pain, sudden severe headache, or vision changes to your healthcare professional right away.
• Have regular check-ups, including breast exams and mammograms, while taking this medicine.