Demulen

What is Demulen and how is it used?

Demulen is a prescription medicine used as Contraception to prevent pregnancy. Demulen may be used alone or with other medications.

Demulen belongs to a class of drugs called Estrogens/Progestins; Contraceptives, Oral.

It is not known if Demulen is safe and effective in children.

What are the possible side effects of Demulen?

Demulen may cause serious side effects including:

• hives,
• difficulty breathing,
• swelling of your face, lips, tongue, or throat,
• sudden numbness or weakness (especially on one side of the body),
• sudden severe headache,
• slurred speech,
• problems with vision or balance,
• sudden vision loss,
• stabbing chest pain,
• shortness of breath,
• coughing up blood,
• pain or warmth in one or both legs,
• chest pain or pressure,
• pain spreading to your jaw or shoulder,
• nausea,
• sweating,
• loss of appetite,
• upper stomach pain,
• tiredness,
• fever,
• dark urine,
• clay-colored stools,
• yellowing of the skin or eyes (jaundice),
• blurred vision,
• pounding in your neck or ears,
• swelling in your hands, ankles, or feet,
• changes in the pattern or severity of migraine headaches,
• breast lump,
• sleep problems,
• weakness,
• tiredness, and
• mood changes

Get medical help right away, if you have any of the symptoms listed above.

The most common side effects of Demulen include:

• nausea,
• vomiting,
• breast tenderness,
• breakthrough bleeding,
• acne,
• darkening of facial skin,
• weight gain, and
• problems with contact lenses

Tell the doctor if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of Demulen. For more information, ask your doctor or pharmacist.

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

DESCRIPTION

The chemical name for ethyndiol diacetate is 19-nor-17alpha-pregn-4-en-20-yne-3beta,17-diol diacetate, and for ethinyl estradiol it is 19-nor- 17alpha-pregna-1,3,5 (10)-trien-20-yne-3,17-diol.

Demulen (ethinyl estradiol and ethynodiol diacetate) 1/35-21 and Demulen (ethinyl estradiol and ethynodiol diacetate) 1/35-28: Each white tablet contains 1 mg of ethynodiol diacetate and 35 mcg of ethinyl estradiol, and the inactive ingredients include calcium acetate, calcium phosphate, corn starch, hydrogenated castor oil, and povidone. Each blue tablet in the Demulen (ethinyl estradiol and ethynodiol diacetate) 1/35-28 package is a placebo containing no active ingredients, and the inactive ingredients include calcium sulfate, corn starch, FD&C Blue No. 1 Lake, magnesium stearate, and sucrose.

Demulen (ethinyl estradiol and ethynodiol diacetate) 1/50-21 and Demulen (ethinyl estradiol and ethynodiol diacetate) 1/50-28: Each white tablet contains 1 mg of ethynodiol diacetate and 50 mcg of ethinyl estradiol, and the inactive ingredients include calcium acetate, calcium phosphate, corn starch, hydrogenated castor oil, and povidone. Each pink tablet in the Demulen (ethinyl estradiol and ethynodiol diacetate) 1/50-28 package is a placebo containing no active ingredients, and the inactive ingredients include calcium sulfate, corn starch, FD&C Red No. 3, FD&C Yellow No. 6, magnesium stearate, and sucrose.

INDICATIONS

Female Contraception.

DOSAGE AND ADMINISTRATION

Female: Contraception: Oral:

• Schedule 1 (Sunday starter): Dose begins on first Sunday after onset of menstruation; if the menstrual period starts on Sunday, take first tablet that very same day. With a Sunday start, an additional method of contraception should be used until after the first 7 days of consecutive administration:
• For 21-tablet package: 1 tablet/day for 21 consecutive days, followed by 7 days off of the medication; a new course begins on the 8th day after the last tablet is taken
• For 28-tablet package: 1 tablet/day without interruption
• Schedule 2 (Day-1 starter): Dose starts on first day of menstrual cycle taking 1 tablet/day:
• For 21-tablet package: 1 tablet/day for 21 consecutive days, followed by 7 days off of the medication; a new course begins on the 8th day after the last tablet is taken
• For 28-tablet package: 1 tablet/day without interruption
  
  If all doses have been taken on schedule and one menstrual period is missed, continue dosing cycle. If two consecutive menstrual periods are missed, pregnancy test is required before new dosing cycle is started.
  
  Missed doses monophasic formulations (refer to package insert for complete information):
• One dose missed: Take as soon as remembered or take 2 tablets next day
• Two consecutive doses missed in the first 2 weeks: Take 2 tablets as soon as remembered or 2 tablets next 2 days. An additional method of contraception should be used for 7 days after missed dose.
• Two consecutive doses missed in week 3 or three consecutive doses missed at any time: An additional method of contraception must be used for 7 days after a missed dose:
• Schedule 1 (Sunday starter): Continue dose of 1 tablet daily until Sunday, then discard the rest of the pack, and a new pack should be started that same day.
• Schedule 2 (Day-1 starter): Current pack should be discarded, and a new pack should be started that same day.

Administer at the same time each day.

HOW SUPPLIED

Demulen (ethinyl estradiol and ethynodiol diacetate) 1/35: Each white Demulen (ethinyl estradiol and ethynodiol diacetate) 1/35 tablet is round in shape, with a debossed SEARLE on one side and 151 and design on the other side, and contains 1 mg of ethynodiol diacetate and 35 mcg of ethinyl estradiol. (Blue placebo tablets have a debossed SEARLE on one side and a "P" on the other side.)

Demulen (ethinyl estradiol and ethynodiol diacetate) 1/50: Each white Demulen (ethinyl estradiol and ethynodiol diacetate) 1/50 tablet is round in shape, with a debossed SEARLE on one side and 71 on the other side, and contains 1 mg of ethynodiol diacetate and 50 mcg of ethinyl estradiol. (Blue placebo tablets have a debossed SEARLE on one side and a "P" on the other side.)

SIDE EFFECTS

Cardiovascular: Arterial thromboembolism, cerebral hemorrhage, cerebral thrombosis, edema, hypertension, mesenteric thrombosis, myocardial infarction

Central nervous system: Depression, dizziness, headache, migraine, nervousness, premenstrual syndrome, stroke

Dermatologic: Acne, erythema multiforme, erythema nodosum, hirsutism, loss of scalp hair, melasma (may persist), rash (allergic)

Endocrine & metabolic: Amenorrhea, breakthrough bleeding, breast enlargement, breast secretion, breast tenderness, carbohydrate intolerance, lactation decreased (postpartum), glucose tolerance decreased, libido changes, menstrual flow changes, sex hormone-binding globulins (SHBG) increased, spotting, temporary infertility (following discontinuation), thyroid-binding globulin increased, triglycerides increased

Gastrointestinal: Abdominal cramps, appetite changes, bloating, cholestasis, colitis, gallbladder disease, jaundice, nausea, vomiting, weight gain/loss

Genitourinary: Cervical erosion changes, cervical secretion changes, cystitis-like syndrome, vaginal candidiasis, vaginitis

Hematologic: Antithrombin III decreased, folate levels decreased, hemolytic uremic syndrome, norepinephrine induced platelet aggregability increased, porphyria, prothrombin increased; factors VII, VIII, IX, and X increased

Hepatic: Benign liver tumors, Budd-Chiari syndrome, cholestatic jaundice, hepatic adenomas

Local: Thrombophlebitis

Ocular: Cataracts, change in corneal curvature (steepening), contact lens intolerance, optic neuritis, retinal thrombosis

Renal: Impaired renal function

Respiratory: Pulmonary thromboembolism

Miscellaneous: Hemorrhagic eruption

For additional information refer to Ethinyl Estradiol; Norethindrone.

DRUG INTERACTIONS

Ethinyl estradiol: Substrate of CYP3A4 (major), 3A5-7 (minor); Inhibits CYP1A2 (weak), 2B6 (weak), 2C19 (weak), 3A4 (weak)

Acetaminophen: May increase plasma concentration of synthetic estrogens, possibly by inhibiting conjugation. Combination hormonal contraceptives may also decrease the plasma concentration of acetaminophen.

Acitretin: Interferes with the contraceptive effect of microdosed progestin-containing "minipill" preparations. The effect on other progestational contraceptives (eg, implants, injectables) is unknown.

Aminoglutethimide: May increase CYP metabolism of progestins leading to possible decrease in contraceptive effectiveness. Use of a nonhormonal contraceptive product is recommended.

Antibiotics (ampicillin, tetracycline): Pregnancy has been reported following concomitant use, however, pharmacokinetic studies have not shown consistent effects with these antibiotics on plasma concentrations of synthetic steroids. Use of a nonhormonal contraceptive product is recommended.

Anticoagulants: Combination hormonal contraceptives may increase or decrease the effects of coumarin derivatives. Combination hormonal contraceptives may also increase risk of thromboembolic disorders

Anticonvulsants (carbamazepine, felbamate, phenobarbital, phenytoin, topiramate): Increase the metabolism of ethinyl estradiol and/or some progestins, leading to possible decrease in contraceptive effectiveness. Use of a nonhormonal contraceptive product is recommended.

Ascorbic acid: Doses of ascorbic acid (vitamin C) 1 g/day have been reported to increase plasma concentration of synthetic estrogens by ~47%, possibly by inhibiting conjugation; clinical implications are unclear.

Atorvastatin: Atorvastatin increases the AUC for norethindrone and ethinyl estradiol.

Benzodiazepines: Combination hormonal contraceptives may decrease the clearance of some benzodiazepines (alprazolam, chlordiazepoxide, diazepam) and increase the clearance of others (lorazepam, oxazepam, temazepam)

Clofibric acid: Combination hormonal contraceptives may increase the clearance of clofibric acid.

Cyclosporine: Combination hormonal contraceptives may inhibit the metabolism of cyclosporine, leading to increased plasma concentrations; monitor cyclosporine levels

CYP3A4 inducers: CYP3A4 inducers may decrease the levels/effects of ethinyl estradiol. Example inducers include aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin, and rifamycins.

Griseofulvin: Griseofulvin may induce the metabolism of combination hormonal contraceptives causing menstrual changes; pregnancies have been reported. Use of barrier form of contraception is suggested while on griseofulvin therapy.

Morphine: Combination hormonal contraceptives may increase the clearance of morphine.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs): Nevirapine may decrease plasma levels of combination hormonal contraceptives; use of a nonhormonal contraceptive product is recommended. No data for delavirdine; incomplete data for efavirenz

Prednisolone: Ethinyl estradiol may inhibit the metabolism of prednisolone, leading to increased plasma concentrations.

Protease inhibitors: Amprenavir, lopinavir, nelfinavir, and ritonavir have been shown to decrease plasma levels of combination hormonal contraceptives; use of a nonhormonal contraceptive product is recommended. Indinavir has been shown to increase plasma levels of combination hormonal contraceptives. No data for saquinavir.

Rifampin: Rifampin increases the metabolism of ethinyl estradiol and some progestins (norethindrone) resulting in decreased contraceptive effectiveness and increased menstrual irregularities. Use of a nonhormonal contraceptive product is recommended.

Salicylic acid: Combination hormonal contraceptives may increase the clearance of salicylic acid.

Selegiline: Combination hormonal contraceptives may increase the serum concentration of selegiline.

Theophylline: Ethinyl estradiol may inhibit the metabolism of theophylline, leading to increased plasma concentrations.

Tricyclic antidepressants (amitriptyline, imipramine, nortriptyline): Metabolism may be inhibited by combination hormonal contraceptives, increasing plasma levels of antidepressant; use caution.

ETHANOL / NUTRITION / HERB INTERACTIONS

Food: CNS effects of caffeine may be enhanced if combination hormonal contraceptives are used concurrently with caffeine. Grapefruit juice increases ethinyl estradiol concentrations and would be expected to increase progesterone serum levels as well; clinical implications are unclear.

Herb/Nutraceutical: St John's wort may decrease the effectiveness of combination hormonal contraceptives by inducing hepatic enzymes. Avoid dong quai and black cohosh (have estrogen activity). Avoid saw palmetto, red clover, ginseng.

WARNINGS

Combination hormonal contraceptives do not protect against HIV infection or other sexually-transmitted diseases. The risk of cardiovascular side effects increases in women who smoke cigarettes, especially those who are >35 years of age; women who use combination hormonal contraceptives should be strongly advised not to smoke. Combination hormonal contraceptives may lead to increased risk of myocardial infarction, use with caution in patients with risk factors for coronary artery disease. May increase the risk of thromboembolism. Combination hormonal contraceptives may have a dose-related risk of vascular disease, hypertension, and gallbladder disease. Women with hypertension should be encouraged to use a nonhormonal form of contraception. The use of combination hormonal contraceptives has been associated with a slight increase in frequency of breast cancer, however, studies are not consistent. Combination hormonal contraceptives may cause glucose intolerance. Retinal thrombosis has been reported (rarely). Use with caution in patients with renal disease, conditions that may be aggravated by fluid retention, depression, or history of migraine. Not for use prior to menarche.

The minimum dosage combination of estrogen/progestin that will effectively treat the individual patient should be used. New patients should be started on products containing <50 mcg of estrogen per tablet.

PRECAUTIONS

Included as part of the WARNINGS section.

OVERDOSE

Toxicity is unlikely following single exposures of excessive doses. Treatment following emesis and charcoal administration should be supportive and symptomatic.

CONTRAINDICATIONS

Hypersensitivity to ethinyl estradiol, ethynodiol diacetate, or any component of the formulation; history of or current thrombophlebitis or venous thromboembolic disorders (including DVT, PE); active or recent (within 1 year) arterial thromboembolic disease (eg, stroke, MI); cerebral vascular disease, coronary artery disease, valvular heart disease with complications, severe hypertension; diabetes mellitus with vascular involvement; severe headache with focal neurological symptoms; known or suspected breast carcinoma, endometrial cancer, estrogen-dependent neoplasms, undiagnosed abnormal genital bleeding; hepatic dysfunction or tumor, cholestatic jaundice of pregnancy, jaundice with prior combination hormonal contraceptive use; major surgery with prolonged immobilization; heavy smoking ( 15 cigarettes/day) in patients >35 years of age; pregnancy.

CLINICAL PHARMACOLOGY

MECHANISM OF ACTION — Combination hormonal contraceptives inhibit ovulation via a negative feedback mechanism on the hypothalamus, which alters the normal pattern of gonadotropin secretion of a follicle-stimulating hormone (FSH) and luteinizing hormone by the anterior pituitary. The follicular phase FSH and midcycle surge of gonadotropins are inhibited. In addition, combination hormonal contraceptives produce alterations in the genital tract, including changes in the cervical mucus, rendering it unfavorable for sperm penetration even if ovulation occurs. Changes in the endometrium may also occur, producing an unfavorable environment for nidation. Combination hormonal contraceptive drugs may alter the tubal transport of the ova through the fallopian tubes. Progestational agents may also alter sperm fertility.

PATIENT INFORMATION

Report signs or symptoms of any of the following: Thromboembolic or thrombotic disorders including sudden severe headache or vomiting, disturbance of vision or speech, loss of vision, numbness or weakness in an extremity, sharp or crushing chest pain, calf pain, shortness of breath, severe abdominal pain or mass, mental depression or unusual bleeding. Discontinue taking the medication if you suspect you are pregnant or become pregnant.