DIANE®-35
Berlex Canada
Cyproterone Acetate – Ethinyl Estradiol
Acne Therapy
Action And Clinical Pharmacology: Diane-35 is a combination antiandrogen-estrogen for use in the treatment of androgen-dependent dermatological conditions in females.
Cyproterone is a steroid compound with potent antiandrogenic, progestogenic and antigonadotrophic activity. It exerts its antiandrogenic effect by blocking androgen receptors. It also reduces androgen synthesis by a negative feedback effect on the hypothalamo-pituitary-ovarian systems. The estrogen component (ethinyl estradiol) of Diane-35 increases levels of sex hormone binding globulin (SHBG) and thus reduces the free circulating plasma levels of androgens. Cyproterone has no tendency to reduce SHBG levels.
If used alone in women, cyproterone leads to menstrual cycle disturbances which are avoided when combined with ethinyl estradiol. When Diane-35 is administered in a cyclic manner it has the added effect of preventing ovulation and possible conception.
The components of Diane-35 are rapidly absorbed after oral administration. Due to the long terminal half-life of cyproterone, a 4-fold increase in plasma levels occurs after 6 to 12 days of daily dosing. Long-term therapy (36 months) with Diane-35 did not have a significant influence on lipid metabolism. A trend to increased plasma cholesterol and triglyceride levels was observed. There was a slight decrease in low density lipoprotein (LDL) with a simultaneous increase in high density lipoprotein (HDL).
Indications And Clinical Uses: For the treatment of women with severe acne, unresponsive to oral antibiotic and other available treatments, with associated symptoms of androgenization, including seborrhea and mild hirsutism.
Note: Diane-35 should not be prescribed solely for its contraceptive properties. However, when taken as recommended (see Dosage), Diane-35 will provide reliable contraception in patients treated for the above clinical conditions. If patient compliance is uncertain and contraception is necessary, then a supplementary nonhormonal contraceptive method should be considered.
Diane-35 has many properties in common with estrogen/progestogen-combination oral contraceptives and the same Contraindications, Warnings and Precautions applicable to this class of drugs should be considered.
Estrogen and/or progestogen should not be taken during treatment with Diane-35.
Contra-Indications: Thrombophlebitis, thromboembolic disorders, or a history of these conditions; cerebrovascular disorders; myocardial infarction or coronary artery disease; active liver disease or hepatic adenomas or carcinomas; history of cholestatic jaundice; known or suspected carcinoma of the breast; known or suspected estrogen-dependent neoplasia; undiagnosed abnormal vaginal bleeding; any ocular lesion arising from ophthalmic vascular disease, such as partial or complete loss of vision or defect in visual fields; when pregnancy is suspected or diagnosed; previous or existing liver tumors; severe diabetes with vascular changes; a history of otosclerosis with deterioration during pregnancy.
Manufacturers’ Warnings In Clinical States: Predisposing Factors For Coronary Artery Diseases: In women with predisposing factors for coronary artery disease (such as cigarette smoking, hypertension, hypercholesterolemia, obesity, diabetes and increasing age), the use of estrogen/progestogen combinations have been reported as an additional risk factor.
After the age of 35 years, estrogen/progestogen combinations should be considered only in exceptional circumstances and when the risk/benefit ratio has been carefully weighed by both the patient and the physician.
Cigarette smoking increases the risk of serious adverse effects on the heart and blood vessels from the use of this class of medication. This risk increases with age and heavy smoking (15 or more cigarettes per day) and is more marked in women over 35 years of age. Women who use such medication should not smoke.
Estrogen/progestogen combinations may cause an increase in plasma lipoproteins and should be administered with caution to women known to have pre-existent hyperlipoproteinemia. Lipid profiles should be determined regularly in these patients.
The combination of obesity, hypertension and diabetes is particularly hazardous to women who are taking this class of medication. Should this triad of conditions develop, the patient should be placed on an alternate form of therapy.
Discontinue medication at the earliest manifestation of: A. Thromboembolic and cardiovascular disorders such as: thrombophlebitis, pulmonary embolism, cerebrovascular disorders, myocardial ischemia, mesenteric thrombosis and retinal thrombosis.
The use of estrogen/progestogen-combination products should be avoided in conditions which predispose to venous stasis and to vascular thrombosis, e.g., immobilization after accidents or confinement to bed during long-term illness. Under such conditions, other nonhormonal methods of treatment should be considered. For use when surgery is contemplated, see Precautions.
B. Visual defects, partial or complete.
C. Papilledema, or ophthalmic vascular lesions.
D. Severe headache of unknown etiology, or worsening of pre-existing migraine headache.
E. Onset of jaundice or hepatitis.
F. Itching of the whole body.
Pregnancy: Fetal abnormalities have been reported to occur in the offspring of women who have taken estrogen/progestogen combinations in early pregnancy. Rule out pregnancy as soon as it is suspected.
Lactation: The use of estrogen/progestogen combinations during the period a mother is breast-feeding her infant may not be advisable. The hormonal components are excreted in breast milk and may reduce its quantity and quality. The long-term effects on the developing child are not known.
This drug may cause fluid retention. Conditions such as epilepsy, asthma, and cardiac or renal dysfunction require careful observation.
Recognized first-line tests of genotoxicity gave negative results when conducted with cyproterone. However, further tests showed that cyproterone was capable of producing adducts with DNA (and an increase in DNA repair activity) in liver cells from rats and monkeys and also in freshly isolated human hepatocytes. This DNA-adduct formation occurred at exposures that might be expected to occur in the recommended dose regimens for cyproterone. One in vivo consequence of cyproterone treatment was the increased incidence of focal, possibly pre-neoplastic, liver lesions in which cellular enzymes were altered in female rats.
The relevance of these findings does not appear to be clinically significant based on the results of a multicentre international liver tumor case control study which demonstrated that there is no evidence of an increased risk of hepatocellular carcinoma associated with contraceptive steroids containing cyproterone acetate, even after long-term use.
Precautions: Physical Examination and Follow-up: Before estrogen/progestogen combinations are used, a thorough history and physical examination should be made including a blood pressure determination. Breasts, liver, extremities, abdomen and pelvic organs should be examined. A Papanicolaou smear should be taken if the patient has been sexually active and a urinalysis should be done.
The first follow-up examination should be done 3 months after the initial prescription. Thereafter, examinations should be conducted at regular intervals during long-term treatment and more frequently for those patients at greater risk for adverse effects. At each annual visit, examination should include those procedures outlined above that were done at the initial visit.
Hepatic Function: Patients who have had jaundice should be given estrogen/progestogen combinations with great care and under close observation.
If there is a clear-cut history of cholestatic jaundice, especially if it occurred during pregnancy, other methods of treatment should be prescribed. The development of severe generalized pruritus or icterus requires that the medication be withdrawn until the problem is resolved. If the jaundice should prove to be cholestatic in type, therapy should not be resumed. In patients taking estrogen/progestogen combinations, changes in the composition of the bile may occur and an increased incidence of gallstones has been reported. Hepatic nodules (adenoma and focal nodular hyperplasia) have been reported, particularly in long-term users of estrogen/progestogen combinations. Although these lesions are uncommon, they have caused fatal intra-abdominal hemorrhage and should be considered in women presenting with an abdominal mass, acute abdominal pain, or evidence of intra-abdominal bleeding.
Hypertension: Patients with essential hypertension whose blood pressure is well controlled may be given the drug but only under close supervision. If a significant elevation of blood pressure in previously normotensive or hypertensive subjects occurs at any time during the administration of the drug, cessation of medication is necessary.
Migraine and Headache: The onset or exacerbation of migraine or the development of headache of a new pattern which is recurrent, persistent, or severe, requires discontinuation of medication and evaluation of the cause.
Diabetes: Diabetic patients, or those with a family history of diabetes, should be observed closely to detect any alterations in carbohydrate metabolism. Patients predisposed to diabetes who can be kept under close supervision may be given estrogen/progestogen combinations under strict medical supervision. Young diabetic patients whose disease is of recent origin, well-controlled, and not associated with hypertension or other signs of vascular disease such as ocular fundal changes, should be closely observed.
Metabolic and Endocrine Diseases: In metabolic or endocrine diseases and when metabolism of calcium and phosphorus is abnormal, careful clinical evaluation should precede medication and a regular follow-up is recommended.
Ocular Disease: Progressive astigmatic error, possibly leading to keratoconus, has been noted in some myopic women receiving drugs of the estrogen/progestogen class. In women who developed myopia at or near puberty, and in whom myopia stabilized in adult life, estrogen/progestogen combinations after some 6 months of use have increased the refractive error 2- to 3-fold. Women with a family history of myopic astigmatism or keratoconus who are using such therapy may experience rapid advancement of the ocular disorder.
Contact lens wearers who develop visual changes or changes in lens tolerance should be assessed by an ophthalmologist and temporary or permanent cessation of wear considered.
Connective Tissue Disease: The use of estrogen/progestogen combinations in some women has been associated with positive lupus erythematous cell tests and with clinical lupus erythematosus. In some instances exacerbation of rheumatoid arthritis and synovitis has been observed.
Breasts: Although estrogen/progestogen-combination use has not been shown to increase the risk of developing breast cancer, particular attention should be paid to women who have an immediate family history of this disease and are therefore more prone to its development. Careful monitoring is mandatory because, if a breast cancer should develop, estrogen-containing drugs may cause a rapid progression if the malignancy is hormone-dependent.
Special judgment should be used in prescribing such medications for women with fibrocystic disease of the breast.
Women receiving such medications should be instructed in self-examination of their breasts. Their physicians should be notified whenever any masses are detected.
Vaginal Bleeding: Persistent irregular vaginal bleeding requires special diagnostic judgment to exclude the possibility of pregnancy or neoplasm.
Fibroids: Patients with fibroids (leiomyomata) should be carefully observed. Sudden enlargement, pain or tenderness require discontinuance of medication.
Age: In general, women in the later reproductive years gradually assume an increasing risk of circulatory and metabolic complications which becomes more prominent at 35 years of age. In view of this, closer observation, shorter duration of estrogen/progestogen-combination use and avoidance of cigarette smoking is advisable. Alternatively, adoption of other means of therapy should be considered for this age group.
Estrogen/progestogen combinations may mask the onset of climacteric.
Emotional Disorders: Patients with a history of emotional disturbances, especially the depressive type, are more prone to have a recurrence of depression while taking estrogen/progestogen combinations. In cases of a serious recurrence, a trial of an alternate method of therapy should be made which may help to clarify the possible relationship.
Laboratory Tests: Results of laboratory tests should be interpreted in light of the fact that the patient is taking estrogen/progestogen therapy. The laboratory tests listed below are modified.
A. Liver function tests: Aspartate serum transaminase (AST): variously reported elevations. Alkaline phosphatase and gamma glutamine transaminase (GGT): slightly elevated.
B. Coagulation tests: Minimal elevation of test values reported for such parameters as Factors VII, VIII, IX and X.
C. Thyroid function tests: Protein binding of thyroxine is increased as indicated by increased total serum thyroxine concentrations and decreased T3 resin uptake.
D. Lipoproteins: Small changes of unproven clinical significance may occur in lipoprotein cholesterol fractions.
E. Gonadotropins: LH and FSH levels are suppressed by the use of estrogen/progestogen therapy. Wait 2 weeks after discontinuing the use of estrogen/progestogen therapy before measurements are made.
Tissue Specimens: Pathologists should be advised of estrogen/progestogen therapy when specimens obtained from surgical procedures are submitted for examination.
Return to Fertility: After discontinuing therapy, the patient should delay pregnancy until at least 1 normal menstrual cycle has occurred. The patient should be instructed to use a nonhormonal method of contraception during this time period.
Amenorrhea: Women having a history of oligomenorrhea, secondary amenorrhea, or irregular cycles may remain anovulatory or become amenorrheic following estrogen/progestogen-combination therapy. Amenorrhea, especially if associated with breast secretion, that continues for 6 months or more after withdrawal, warrants a careful assessment of hypothalamic-pituitary function.
Thromboembolic Complications – Post-surgery: Retrospective studies have reported an increased risk of post-surgery thromboembolic complications in estrogen/progestogen-combination users. If feasible, such drugs should be discontinued at least 1 month prior to elective major surgery. Medication should not be resumed until at least 2 weeks after hospital discharge following surgery.
Drug Interactions: Concurrent use of the following drugs may result in reduced efficacy of Diane-35 and increased incidence of breakthrough bleeding: ampicillin, analgesics, antihistamines, antimigraine preparations, chloramphenicol, griseofulvin, isoniazid, neomycin, nitrofurantoin, penicillin V, phenylbutazone, sulfonamides and tetracycline.
Concurrent use of anticoagulants with estrogen/progestogen combinations may reduce the anticoagulant effect. Effectiveness of the following drugs may be altered when used concurrently: antihypertensives, benzodiazepines (those that undergo oxidative degradation) beta-adrenergic blockers, caffeine, corticosteroids, hypoglycemics, phenothiazines, theophyllines, tricyclic antidepressants and vitamins.
Concurrent use of the following drugs may reduce the efficacy of Diane-35 because of accelerated estrogen metabolism caused by the induction of hepatic enzymes: carbamazepine, phenobarbital, phenytoin, primidone and rifampin.
Diabetics using estrogen/progestogen combinations may require adjustment of their antidiabetic medication.
Concurrent administration of vitamin C (ascorbic acid) with estrogen/progestogen combinations has been reported to result in a significant rise in plasma ethinyl estradiol levels.
Pregnancy: Rule out pregnancy before treatment is begun. Because of the antiandrogenic action of Diane-35, feminization of male fetuses has occurred in animal studies and may possibly occur in humans.
Adverse Reactions: General: An increased risk of the following serious adverse reactions has been associated with the use of estrogen/progestogen combinations: thrombophlebitis; arterial thromboembolism; pulmonary embolism; mesenteric thrombosis; neuro-ocular lesions, e.g., retinal thrombosis and optic neuritis; myocardial infarction; cerebral thrombosis; cerebral hemorrhage; hypertension; liver tumors; gallbladder disease and congenital anomalies.
The following adverse reactions also have been reported in patients receiving estrogen/progestogen-combination oral contraceptives: nausea and vomiting, usually the most common adverse reaction occurring in approximately 10% or less of patients during the first cycle. Other reactions, as a general rule, are seen less frequently or only occasionally: gastrointestinal symptoms (such as abdominal cramps and bloating); breakthrough bleeding; spotting; change in menstrual flow; dysmenorrhea; amenorrhea during and after treatment; temporary infertility after discontinuance of treatment; edema; chloasma or melasma which may persist; breast changes: tenderness, enlargement, and secretion; change in weight (increase or decrease); change in cervical erosion and secretion; endocervical hyperplasia; possible diminution in lactation when given immediately postpartum; cholestatic jaundice; migraine; increase in size of uterine leiomyomata; rash (allergic); mental depression; reduced tolerance to carbohydrates; vaginal candidiasis; premenstrual-like syndrome; intolerance to contact lenses; change in corneal curvature (steepening); cataracts; optic neuritis; retinal thrombosis; changes in libido; chorea; changes in appetite; cystitis-like syndrome; rhinitis; headache; nervousness; dizziness; hirsutism; loss of scalp hair; erythema multiforme; erythema nodosum; hemorrhagic eruption; vaginitis; porphyria; impaired renal function; Raynaud’s phenomenon; auditory disturbances; hemolytic uremic syndrome and pancreatitis.
Product-specific Adverse Reactions: Diane-35 was generally well tolerated in studies involving 1 563 women who were treated for periods of 6 to 36 cycles. The most frequently reported complaint was dysmenorrhea (10.2%) which decreased over time in a manner characteristic of treatment with estrogen/progestogen combinations. Other effects reported were also similar in nature and frequency to those reported with estrogen/progestogen combinations.
Serious postmarketing adverse reactions reported with Diane-35 include deep venous thrombosis, venous thrombosis with pulmonary embolism, arterial emboli involving the extremities and the spleen, cerebral ischemic vascular accident, cerebral venous thrombosis, sinus thrombosis, retinal vein thrombosis, hypertensive crisis, migraine, pancreatitis, focal nodular hyperplasia of the liver, subcapsular liver hematoma, liver adenoma, hepatocellular carcinoma, primary bile duct carcinoma, hepatitis, liver dystrophy, cholangitis, pseudomembranous colitis, cholestasis, abdominal pain, epileptic seizures, cerebral tumor symptoms, acute brachiofacial paresis, acute hydrocephalus, manic syndrome, hyperpathia, anaphylactoid reactions, ascites, diabetes mellitus, acute leukemia and breast cancer.
The following nonserious adverse reactions, listed according to body system, have been reported postmarketing: Cardiovascular: headaches, migraine, superficial phlebitis, palpitations, flushing.
Gastrointestinal: focal nodular hyperplasia, liver tumor, hepatitis, jaundice, hepatomegaly without abnormal liver tests, nausea, diarrhea, flatulence, stomatitis, salivary gland swelling.
Genitourinary: menstrual disorder, ovarian cyst, myoma, cervix dysplasia, vaginitis, urinary tract infection, premature birth, abortion, missed abortion and placenta insufficiency.
Metabolism: abnormal liver enzymes, hyperthyroidism, hyperprolactinemia.
Nervous system: depression, decreased libido, nervousness, insomnia, somnolence, confusion, hypesthesia, paresthesia, seizures (in patients with a history of epilepsy), visual disturbances, symptoms of conjunctival irritation, hearing disorder.
Skin: alopecia, acne, chloasma, exanthema, erythema nodosum, striae, neurodermitis, skin allergy, urticaria, facial edema, pruritus, photosensitivity, pigmentation, dry skin, Herpes zoster, cellulitis, s.c. lumps, eczema, livedo, blue spots.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: There have been no reports of overdose with Diane-35. There are no specific antidotes and treatment should be symptomatic, based on the knowledge of the pharmacological action of the constituents.
Dosage And Administration: Diane-35 should not be prescribed solely for its contraceptive properties. If patient compliance is uncertain and contraception is necessary, then a supplementary nonhormonal contraceptive method should be considered.
Diane-35 is supplied in blister pack units consisting of 21 tablets; each tablet containing cyproterone acetate 2 mg and ethinyl estradiol 0.035 mg. Each cycle consists of 21 days on medication and a 7-day interval without medication (3 weeks on, 1 week off).
First Treatment Course: The patient is instructed to take 1 tablet daily for 21 consecutive days beginning on day 1 of her menstrual cycle. (For the first cycle only the first day of menstrual flow is considered Day 1.) The tablets are then discontinued for 7 days (1 week). Withdrawal bleeding should usually occur during the period that the patient is off the tablets. The first cycle will be somewhat shorter than usual, whereas all following cycles will last 4 weeks.
Subsequent Courses: The patient begins her next and all subsequent 21-day course of tablets (following the same 21 days on, 7 days off) on the same day of the week that she began her first course. She begins taking her tablets 7 days after discontinuation, regardless of whether or not withdrawal bleeding is still in progress.
Treatment should be continued for several months, since improvement may not be observed with 4 or 5 cycles. It is recommended to continue treatment with Diane-35 for at least another 3 to 4 cycles after signs have subsided.
Pregnancy should be ruled out before continuing treatment with Diane-35 in patients who have missed a menstrual period. If pregnancy is suspected, medication should be discontinued.
Special Notes on Administration: It is recommended that Diane-35 tablets be taken at the same time each day. Irregular tablet-taking, vomiting or intestinal affections with diarrhea, very rare individual metabolic disturbances or prolonged simultaneous use of certain medical preparations can affect the contraceptive action (see Precautions, Drug Interactions).
If spotting or breakthrough bleeding occurs during the 3 weeks in which Diane-35 is being taken, the patient is instructed to continue taking the medication. This type of bleeding usually is transient and without significance. However, if the bleeding is persistent or prolonged, the patient is advised to consult her physician.
In exceptional cases, menstruation may fail to occur during the 7-day tablet-free interval. The patient is advised not to resume tablet-taking and to consult her physician.
Although the occurrence of pregnancy is highly unlikely if the tablets are taken according to directions, the possibility of pregnancy should be ruled out before continuing treatment with Diane-35 in patients who have missed a period of withdrawal bleeding. The patient should consult her physician and, in the meantime, a supplementary nonhormonal method of contraception should be employed.
If the patient forgets to take a tablet at the usual time, the tablet may be taken within the next 12 hours. If more than 12 hours have elapsed from the time of usual administration, the patient must discard the missed tablet and continue to take the remaining tablets in the pack at the usual time in order to avoid a premature withdrawal bleeding during this cycle. A supplementary nonhormonal method of contraception must be employed until the pack is empty to prevent pregnancy which would necessitate immediate discontinuation of Diane-35 treatment.
Use of the Blister Pack: The patient should be instructed to take the first tablet from the blister pack out of the section marked with the corresponding day of the week (for example “MO” for Monday), and swallow it whole with some liquid. The patient should be instructed to take the tablet at the same time each day.
Availability And Storage: Each beige, round, biconvex, sugar-coated tablet contains: cyproterone acetate 2 mg and ethinyl estradiol 0.035 mg. Nonmedicinal ingredients: cornstarch, lactose, magnesium stearate, povidone and talc; tablet coating: calcium carbonate, ferric oxide yellow, glycerol, polyethylene glycol, povidone, sucrose, talc, titanium dioxide and wax. Blister pack units of 21. Store at room temperature (15 to 25°C).
DIANE®-35 Berlex Canada Cyproterone Acetate – Ethinyl Estradiol Acne Therapy
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