Progesterone

Progesterone comes as a capsule to take by mouth. It is usually taken once a day in the evening or at bedtime. You will probably take progesterone on a rotating schedule that alternates 10 to 12 days when you take progesterone with 16 to 18 days when you do not take the medication. Your doctor will tell you exactly when to take progesterone. To help you remember to take progesterone, take it around the same time in the evening. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take progesterone exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Continue to take progesterone as directed even if you feel well. Do not stop taking progesterone without talking to your doctor.

In case of overdose, call your local poison control center at 1-800-222-1222. If the victim has collapsed or is not breathing, call local emergency services at 911.

Use the missed dose as soon as you remember. If it is almost time for your next dose, skip the missed dose and use the medicine at the next regularly scheduled time. Do not use extra medicine to make up the missed dose.

Call your doctor if you miss more than one dose of this medication.

Progesterone can cause side effects that may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be awake and alert.

Progesterone may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

Progesterone is a prescription medication used to promote normal menstrual periods in women who are premenopausal but have stopped having periods due to low progesterone levels. Progesterone is also used in combination with estrogen-containing medications in postmenopausal women with a uterus to reduce the risk of developing cancer of the uterus and to prevent abnormal thickening of the lining of the uterus in women taking estrogen. Progesterone is also used to promote embryo implantation and pregnancy in conjunction with fertility treatments in women. 

Progesterone belongs to a group of drugs called progestins. These work to acheive various effects in the body by mimicking the effects of naturally occuring hormones.

This medication comes in a capsule form and is typically taken once a day, at bedtime, for 10 or 12 continuous days, depending on the condition being treated.

This medication is also available in a vaginal insert form that is typically inserted into the vagina 2 to 3 times daily for up to 10 weeks of treatment.

This medication is also available in a gel form that is typically applied to the vagina once or twice a day. The frequency of application depends on the condition being treated. 

This medication is also available in an injectable form to be given directly into a muscle by a healthcare provider, typically daily, for 6 to 8 days.

Common side effects of progesterone include headaches, breast pain, and irregular vaginal bleeding or spotting.

Progesterone can also cause dizziness and/or drowsiness. Do not drive or operate heavy machinery until you know how progesterone affects you.

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

Progesterone falls into category B. There are no well-designed studies that have been done in humans with progesterone. In animal studies, pregnant animals were given this medication, and the babies did not show any medical issues related to this medication.

Progesterone may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

Amenorrhea

Treatment of secondary amenorrhea.101 102 103 105

Assisted Reproductive Technology

Used to support embryo implantation and early pregnancy as part of assisted reproductive technology (ART) treatment of infertile women.104 105 106

Prevention of Endometrial Changes Associated with Estrogens

Reduction of the incidence of endometrial hyperplasia and the attendant risk of endometrial carcinoma in postmenopausal women receiving estrogen replacement therapy.103

Uterine Bleeding

Treatment of abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology such as fibroids or uterine cancer.101 102

Contraindications

• Undiagnosed vaginal bleeding.101 102 103 105

• Known or suspected breast or genital cancer; history of breast cancer.101 102 103 104 105

• Active DVT or pulmonary embolism; history of DVT or pulmonary embolism.103

• Active or recent arterial thromboembolic disease (e.g., stroke, MI), thrombophlebitis, or cerebral apoplexy.101 102 103 104 105

• Liver disease or dysfunction.101 102 103 104 105

• Missed abortion or ectopic pregnancy.101 102 104 105

• Use as a pregnancy test.101

• Progesterone capsules are contraindicated in pregnant women and those with suspected pregnancy.103 Not effective for any purpose during pregnancy.103

• Known hypersensitivity to progesterone or any ingredient in the formulation.101 102 103 104 105

• Progesterone capsules (Prometrium): Known hypersensitivity to peanuts because the capsules contain peanut oil.103

Warnings/Precautions

Warnings

Possible cardiac disorders (MI) or thromboembolic and thrombotic disorders (e.g., thrombophlebitis, pulmonary embolism, cerebrovascular disorders, retinal thrombosis).101 102 103 104 105 Observe patients for these effects; discontinue immediately and do not readminister if these disorders occur or are suspected.101 102 103 104 105 (See Contraindications under Cautions.)

Progesterone capsules (Prometrium): Syncope and hypotension reported.103

If unexplained, sudden or gradual, partial or complete loss of vision; proptosis or diplopia; papilledema; migraine; or retinal vascular lesions occur, discontinue and initiate appropriate diagnostic and therapeutic measures.101 102 103 Do not reinitiate therapy if ocular examination reveals evidence of papilledema or retinal vascular lesions.101 102 103

Sensitivity Reactions

Progesterone capsules (Prometrium) contain peanut oil.103 Do not use in patients with peanut allergy.103 (See Contraindications under Cautions.)

General Precautions

May cause some degree of fluid retention.101 102 103 105 Use with caution and careful monitoring in patients with conditions (e.g., asthma, seizure disorders, migraine headache, cardiac or renal impairment) that might be aggravated by fluid retention.101 102 103 105

Possible breakthrough or irregular vaginal bleeding.101 102 103 105 Perform adequate diagnostic tests in patients with undiagnosed vaginal bleeding.101 102 103 105

Possible depression.101 102 103 104 105 Exercise caution in women with a history of depression; discontinue if severe depression recurs during use.101 102 103 104 105

Physical examination prior to initiation of therapy advised.101 102 103 105 Physical examination should include special attention to the breasts and pelvic organs and should include a Papanicolaou test (Pap smear) and relevant laboratory tests.101 102 103 105

Addition of progesterone to estrogen replacement therapy may increase the risk of breast cancer beyond that associated with estrogen use alone.103

Possible adverse effects on carbohydrate and lipid metabolism.101 102 105 Monitor patients with hyperlipidemias or diabetes mellitus carefully.101 102 105

Effect of long-term therapy on pituitary, ovarian, adrenal, hepatic, or uterine function not determined.103

Onset of climacteric may be masked in women.101 102

When used in combination with an estrogen, consider the cautions, precautions, and contraindications associated with estrogens.103

Progesterone capsules (Prometrium): Transient dizziness reported.103 Use caution when driving or operating machinery.103

Progesterone capsules (Prometrium): Extreme dizziness and/or drowsiness, blurred vision, slurred speech, difficulty walking, loss of consciousness, vertigo, confusion, disorientation, and shortness of breath reported; women who experience these adverse effects should consult their healthcare provider.103

Specific Populations

Used to support embryo implantation and maintain pregnancy as a component of ART treatment in infertile women.104 105 106 Such use is associated with increased ongoing pregnancy rates.104 105 106

Progesterone capsules (Prometrium): Category B.103

Progestins are distributed into milk.102 103 104 105 Caution advised.102 103 104 105

Safety and efficacy not established.102 103 104 105 Not indicated in pediatric patients.103 104

Vaginal inserts (Endometrin): Efficacy not established in women ≥35 years of age.104

Progesterone injection, vaginal inserts, and gel: Safety and efficacy not established in patients >65 years of age.102 104 105

Progesterone capsules (Prometrium): Insufficient experience in those ≥65 years of age to determine whether they respond differently than younger adults.103 Select dose with caution; start at the lower end of the dosing range due to the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy.103

Contraindicated in patients with liver dysfunction or disease.101 102 103 104 105

Progesterone capsules (Prometrium): If indicated in patients with mild to moderate hepatic dysfunction, monitor patient closely.103

Progesterone injection and capsules: Safety and efficacy not established in patients with renal impairment.102 103 Use with caution; carefully monitor patients with renal impairment.103

Common Adverse Effects

Menstrual abnormalities (amenorrhea; breakthrough bleeding and/or spotting; changes in menstrual flow), weight changes, dizziness, headache, abdominal pain and/or distention, breast tenderness and/or pain, fatigue, musculoskeletal pain, joint pain.101 102 103 104 105

Injection site pain.101 102

In the U.S.

• Prometrium

Available Dosage Forms:

• Capsule, Liquid Filled
• Capsule

Therapeutic Class: Endocrine-Metabolic Agent

Pharmacologic Class: Progestin

It is very important that your doctor check your progress at regular visits to make sure progesterone is working properly and does not cause unwanted effects. Pelvic exam, breast exam, and mammogram (breast x-ray) may be needed to check for unwanted effects, unless your doctor tells you otherwise.

Using progesterone while you are pregnant can harm your unborn baby. Use an effective form of birth control to keep from getting pregnant. If you think you have become pregnant while using the medicine, tell your doctor right away.

Stop using progesterone and check with your doctor right away if you have pain in the chest, groin, or legs, especially the calves; difficulty with breathing; a sudden, severe headache; slurred speech; a sudden, unexplained shortness of breath; a sudden loss of coordination; or vision changes while using progesterone.

There is a very slight chance that progesterone could increase the risk of breast cancer and endometrial (lining of the uterus) cancer in some women. Talk to your doctor about this risk. Make sure your doctor knows if anyone in your family has had breast cancer or endometrial cancer.

Using large doses of progesterone over a long period of time and using it with an estrogen medicine may increase your risk of heart attack, stroke, blood clots, or dementia. Talk with your doctor about these risks.

Your risk of heart disease or stroke from progesterone is higher if you smoke. Your risk is also increased if you have diabetes or high cholesterol, or if you are overweight. Talk with your doctor about ways to stop smoking. Keep your diabetes under control. Ask your doctor about diet and exercise to control your weight and blood cholesterol level.

Tell the medical doctor or dentist in charge that you are using progesterone before any kind of surgery (including dental surgery) or emergency treatment. Your doctor will decide whether you should continue using progesterone.

Stop using progesterone and check with your doctor immediately if sudden loss of vision or any other change in vision occurs while you are using progesterone. Your doctor may want you to have your eyes checked by an ophthalmologist (eye doctor).

progesterone may cause some people to become dizzy or drowsy. Make sure you know how you react to progesterone before you drive, use machines, or do anything else that could be dangerous if you are not alert.

Before you have any medical tests, tell the medical doctor in charge that you are taking progesterone. The results of some tests may be affected by progesterone.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Chest pain
• chills
• cold or flu-like symptoms
• cough or hoarseness
• fever
• problems with urination

• Clear or bloody discharge from the nipple
• dimpling of the breast skin
• inverted nipple
• lump in the breast or under the arm
• persistent crusting or scaling of the nipple
• redness or swelling of the breast
• sore on the skin of the breast that does not heal

• Abdominal or stomach pain
• bloating
• blurred vision
• change in vaginal discharge
• clay-colored stools
• cleft lip or palate
• confusion
• constipation
• darkened urine
• diarrhea
• difficult or labored breathing
• difficulty with swallowing
• difficulty with walking
• dizziness
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• fainting
• fast, pounding, or irregular heartbeat or pulse
• headache
• hives
• indigestion
• irregular heartbeat
• irritation
• itching
• joint pain, stiffness, or swelling
• lightheadedness
• loss of appetite
• nausea
• nervousness
• noisy breathing
• numbness or tingling in the face, arms, or legs
• pain or feeling of pressure in the pelvis
• pains in the stomach, side, or abdomen, possibly radiating to the back
• pounding in the ears
• puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue
• rash
• redness of the skin
• shortness of breath
• slow heartbeat
• spontaneous abortion
• stomach or pelvic discomfort, aching, or heaviness
• sweating
• swelling of the eyelids, face, lips, hands, or feet
• tightness in the chest
• trouble speaking, thinking, or walking
• unpleasant breath odor
• unusual tiredness or weakness
• vaginal bleeding
• vomiting
• vomiting of blood
• wheezing
• yellow eyes or skin

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Breast pain or tenderness
• depression
• muscle or joint pain
• white or brownish vaginal discharge
• worry

• Attack, assault, or force
• blurred or loss of vision
• change in walking and balance
• changes in behavior
• changes in patterns and rhythms of speech
• choking
• clumsiness or unsteadiness
• confusion about identity, place, and time
• continuing ringing or buzzing or other unexplained noise in the ears
• decreased awareness or responsiveness
• difficulty with moving
• disturbed color perception
• double vision
• drowsiness
• extreme dizziness or drowsiness
• feeling drunk
• feeling of constant movement of self or surroundings
• feeling of unreality
• hair loss or thinning of the hair
• halos around lights
• hearing loss
• hives or welts
• longer or heavier menstrual periods
• loss of consciousness
• muscle cramps
• muscle stiffness
• night blindness
• normal menstrual bleeding occurring earlier, possibly lasting longer than expected
• overbright appearance of lights
• redness of the skin
• relaxed and calm
• sensation of spinning
• sense of detachment from self or body
• severe sleepiness
• sleepiness
• slurred speech
• swollen tongue
• thoughts of killing oneself
• tunnel vision
• weight changes

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Progesterone injection, a progestin, is a sterile solution of Progesterone in a suitable vegetable oil available for intramuscular use.

Progesterone occurs as a white or creamy white, crystalline powder.  It is odorless and is stable in air.  Practically insoluble in water, it is soluble in alcohol, acetone, and dioxane and sparingly soluble in vegetable oils.

It has the following structural formula:

C21H30O2                                              M.W. 314.47

                  Pregn-4-ene-3, 20-dione

Each mL contains: Progesterone 50 mg, benzyl alcohol 10% as preservative in sesame oil q.s.

This drug is indicated in amenorrhea and abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology, such as submucous fibroids or uterine cancer.

1.       Current or past history of thrombophlebitis, thromboembolic disorders, or cerebral apoplexy.

2.       Liver dysfunction or disease.

3.       Known or suspected malignancy of breast or genital organs.

4.       Undiagnosed vaginal bleeding.

5.       Missed abortion.

6.       Known sensitivity to Progesterone injection.

Oral: Prevention of endometrial hyperplasia in nonhysterectomized, postmenopausal women who are receiving conjugated estrogens; treatment of secondary amenorrhea

IM: Treatment of amenorrhea or abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology, such as submucous fibroids or uterine cancer

Intravaginal gel: Part of assisted reproductive technology (ART) for infertile women with progesterone deficiency; treatment of secondary amenorrhea

Vaginal insert: To support embryo implantation and early pregnancy by supplementation of corpus luteal function as part of ART for infertile women

Oral: Hypersensitivity to progesterone or any component of the formulation, including peanuts/peanut oil; undiagnosed abnormal genital bleeding; breast cancer (known, suspected, or history of); active deep vein thrombosis, pulmonary embolism, or history of these conditions; active or history of arterial thromboembolic disease (eg, stroke, MI); hepatic impairment or disease; pregnancy.

IM: Hypersensitivity to progesterone or any component of the formulation, including sesame oil/seeds; active or history of thrombophlebitis, thromboembolic disorders, or cerebral apoplexy; undiagnosed vaginal bleeding; hepatic impairment or disease; known or suspected malignancy of the breast or genital organs; missed abortion.

Intravaginal gel: Hypersensitivity to progesterone or any component of the formulation, including palm oil; undiagnosed vaginal bleeding; hepatic impairment or disease; known or suspected malignancy of the breast or genital organs; missed abortion; active thrombophlebitis or thromboembolic disorders, or a history of hormone-associated thrombophlebitis or thromboembolic disorders.

Vaginal insert: Hypersensitivity to progesterone or any component of the formulation; undiagnosed vaginal bleeding; known missed abortion or ectopic pregnancy; hepatic disease; known or suspected malignancy of the breast or genital organs; active or history of arterial or venous thromboembolism or severe thrombophlebitis.

Canadian labeling: Additional contraindications (not in the US labeling):

Capsules: Hypersensitivity to soya; endometrial hyperplasia; classical migraine; partial or complete loss of vision due to ophthalmic vascular disease

Intravaginal gel: Acute porphyria, cerebral apoplexy

Vaginal insert/tablet: Porphyria; undiagnosed vaginal bleeding

Documentation of allergenic cross-reactivity for progestins is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Use is contraindicated in hepatic impairment or disease.

IM: Administer deep IM only. May cause injection-site irritation.

Intravaginal:

Vaginal gel: A small amount of gel will remain in the applicator following insertion. Administer into the vagina directly from sealed applicator. Remove applicator from wrapper; holding applicator on each side, push plunger into applicator until it snaps into place; twist off cap counterclockwise; gently insert into vagina and push plunger.

Vaginal insert: Insert tablet in vagina using disposable applicator provided.

Oral: For patients who experience difficulty swallowing the capsules, taking with a full glass of water in the standing position may be beneficial.

Anticoagulants: Progestins may diminish the therapeutic effect of Anticoagulants. More specifically, the potential prothrombotic effects of some progestins and progestin-estrogen combinations may counteract anticoagulant effects. Management: Carefully weigh the prospective benefits of progestins against the potential increased risk of procoagulant effects and thromboembolism. Use is considered contraindicated under some circumstances. Refer to related guidelines for specific recommendations. Consider therapy modification

Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Antifungal Agents (Vaginal): May diminish the therapeutic effect of Progesterone. Avoid combination

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

C1 inhibitors: Progestins may enhance the thrombogenic effect of C1 inhibitors. Monitor therapy

CYP2C19 Inducers (Strong): May increase the metabolism of CYP2C19 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP2C19 Substrates. Management: Seek alternatives to the CYP2C19 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Enzalutamide: May decrease the serum concentration of CYP2C19 Substrates. Conversely, concentrations of active metabolites may be increased for those drugs activated by CYP2C19. Management: Concurrent use of enzalutamide with CYP2C19 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP2C19 substrate should be performed with caution and close monitoring. Consider therapy modification

Herbs (Progestogenic Properties) (eg, Bloodroot, Yucca): May enhance the adverse/toxic effect of Progestins. Monitor therapy

Mitotane: May decrease the serum concentration of CYP3A4 Substrates. Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Pomalidomide: Progestins may enhance the thrombogenic effect of Pomalidomide. Management: Canadian pomalidomide labeling recommends caution with use of hormone replacement therapy and states that hormonal contraceptives are not recommended. US pomalidomide labeling does not contain these specific recommendations. Consider therapy modification

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

St John's Wort: May decrease the serum concentration of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Ulipristal: May diminish the therapeutic effect of Progestins. Progestins may diminish the therapeutic effect of Ulipristal. Management: Ulipristal for uterine fibroids (Canadian indication): avoid progestins within 12 days of stopping ulipristal; as emergency contraceptive (U.S. indication): avoid progestins within 5 days of stopping ulipristal. Avoid combination