Danazol Polfarmex

Danazol Polfarmex capsules are recommended for the treatment of:

Endometriosis: treatment of endometriosis-associated symptoms or/and to reduce the extent of endometriosis foci. Danazol may be used either in conjunction with surgery or, as sole hormonal therapy, in patients not responding to other treatments.

Benign fibrocystic breast disease: symptomatic relief of severe pain and tenderness. Danazol should be used only in patients not responsive to other therapeutic measures or for whom such measures are inadvisable.

Endometriosis

Danazol Polfarmex is indicated for the treatment of endometriosis amenable to hormonal management.

Fibrocystic Breast Disease

Most cases of symptomatic fibrocystic breast disease may be treated by simple measures (e.g., padded brassieres and analgesics).

In infrequent patients, symptoms of pain and tenderness may be severe enough to warrant treatment by suppression of ovarian function. Danazol Polfarmex is usually effective in decreasing nodularity, pain, and tenderness. It should be stressed to the patient that this treatment is not innocuous in that it involves considerable alterations of hormone levels and that recurrence of symptoms is very common after cessation of therapy.

Hereditary Angioedema

Danazol Polfarmex is indicated for the prevention of attacks of angioedema of all types (cutaneous, abdominal, laryngeal) in males and females.

Adults:

Danazol Polfarmex capsules should be given as a continuous course, dosage being adjusted according to the severity of the condition and the patient's response. A reduction in dosage once a satisfactory response has been achieved may prove possible. In fertile females, Danazol Polfarmex capsules should be started during menstruation, preferably on the first day, to avoid exposing a pregnancy to its possible effects. Where doubt exists, appropriate checks should be made to exclude pregnancy before starting medication. Females of child-bearing age should employ non-hormonal contraception throughout the course of treatment.

In endometriosis the recommended dosage is 200mg to 800mg daily in a course of treatment lasting normally three to six months. Dosage should be increased if normal cyclical bleeding still persists after two months therapy, a higher dosage (not exceeding 800mg per day) may also be needed for severe disease.

In benign fibrocystic breast disease, treatment should commence at a dose of 300mg daily, a course of treatment normally lasting 3 to 6 months.

Elderly: Danazol Polfarmex is not recommended.

Children: Danazol Polfarmex is not recommended.

The capsules are for oral administration.

Endometriosis

In moderate to severe disease, or in patients infertile due to endometriosis, a starting dose of 800 mg given in two divided doses is recommended. Amenorrhea and rapid response to painful symptoms is best achieved at this dosage level. Gradual downward titration to a dose sufficient to maintain amenorrhea may be considered depending upon patient response. For mild cases, an initial daily dose of 200 mg to 400 mg given in two divided doses is recommended and may be adjusted depending on patient response.

Therapy should begin during menstruation. Otherwise, appropriate tests should be performed to ensure that the patient is not pregnant while on therapy with Danazol Polfarmex. (See CONTRAINDICATIONS and WARNINGS.) It is essential that therapy continue uninterrupted for 3 to 6 months but may be extended to 9 months if necessary. After termination of therapy, if symptoms recur, treatment can be reinstituted.

Fibrocystic Breast Disease

The total daily dosage of Danazol Polfarmex for fibrocystic breast disease ranges from 100 mg to 400 mg given in two divided doses depending upon patient response. Therapy should begin during menstruation. Otherwise, appropriate tests should be performed to ensure that the patient is not pregnant while on therapy with Danazol Polfarmex. A nonhormonal method of contraception is recommended when Danazol Polfarmex is administered at this dose, since ovulation may not be suppressed.

In most instances, breast pain and tenderness are significantly relieved by the first month and eliminated in 2 to 3 months. Usually elimination of nodularity requires 4 to 6 months of uninterrupted therapy. Regular menstrual patterns irregular menstrual patterns and amenorrhea each occur in approximately one-third of patients treated with 100 mg of Danazol Polfarmex. Irregular menstrual patterns and amenorrhea are observed more frequently with higher doses. Clinical studies have demonstrated that 50% of patients may show evidence of recurrence of symptoms within one year. In this event, treatment may be reinstated.

Hereditary Angioedema

The dosage requirements for continuous treatment of hereditary angioedema with Danazol Polfarmex should be individualized on the basis of the clinical response of the patient. It is recommended that the patient be started on 200 mg, two or three times a day. After a favorable initial response is obtained in terms of prevention of episodes of edematous attacks, the proper continuing dosage should be determined by decreasing the dosage by 50% or less at intervals of one to three months or longer if frequency of attacks prior to treatment dictates. If an attack occurs, the daily dosage may be increased by up to 200 mg. During the dose adjusting phase, close monitoring of the patient's response is indicated, particularly if the patient has a history of airway involvement.

1. Pregnancy

2. Breast feeding

3. Markedly impaired hepatic, renal or cardiac function

4. Porphyria

5. Active thrombosis or thromboembolic disease and a history of such events

6. Androgen dependent tumour

7. Undiagnosed abnormal genital bleeding

8. Hypersensitivity to danazol or to any of the excipients

9. Concomitant administration with simvastatin

Danazol Polfarmex should not be administered to patients with:

1. Undiagnosed abnormal genital bleeding.
2. Markedly impaired hepatic, renal, or cardiac function.
3. Pregnancy. (See WARNINGS.)
4. Breast feeding.
5. Porphyria-Danazol Polfarmex can induce ALA synthetase activity and hence porphyrin metabolism.
6. Androgen-dependent tumor.
7. Active thrombosis or thromboembolic disease and history of such events.
8. Hypersensitivity to danazol.

Special warnings

In the event of virilisation, Danazol Polfarmex should be withdrawn. Androgenic reactions generally prove reversible, but continued use of Danazol Polfarmex after evidence of androgenic virilisation increases the risk of irreversible androgenic effects.

Danazol Polfarmex should be stopped if any clinically significant adverse event arises, and particularly if there is evidence of papilloedema, headache, visual disturbances or other signs or symptoms of raised intracranial pressure, jaundice or other indication of significant hepatic disturbance, thrombosis or thromboembolism.

Whilst a course of therapy may need to be repeated, care should be observed as no safety data are available in relation to repeated courses of treatment over time. The long-term risk of 17-alkylated steroids (including benign hepatic adenomata, hepatocellular focal nodular hyperplasia, peliosis hepatis and hepatic carcinoma), should be considered when danazol, which is chemically related to those compounds, is used.

Data, from two case-control epidemiological studies, were pooled to examine the relationship between endometriosis, endometriosis treatments and ovarian cancer. These preliminary results suggest that the use of danazol might increase the baseline risk of ovarian cancer in - patients treated for endometriosis.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Precautions

In view of its pharmacology, known interactions and side effects, particular care should be observed when using Danazol Polfarmex in patients with hepatic or renal disease, hypertension or other cardiovascular disease and in any state which may be exacerbated by fluid retention as well as in diabetes mellitus, polycythaemia, epilepsy, lipoprotein disorder, and in those who have shown marked or persistent androgenic reaction to previous gonadal steroid therapy.

Caution is advised in patients with migraine.

Until more is known, caution is advised in the use of Danazol Polfarmex in the presence of known or suspected malignant disease (see also contra-indications). Before treatment initiation, the presence of hormone-dependent carcinoma should be excluded at least by careful clinical examination, as well as if breast nodules persist or enlarge during danazol treatment.

In addition to clinical monitoring in all patients, appropriate laboratory monitoring should be considered which may include periodic measurement of hepatic function and haematological state. For long-term treatment (> 6 months) or repeated courses of treatment, biannual hepatic ultrasonography is recommended.

Danazol should be initiated during menstruation.6 Fertility, Pregnancy and Lactation).

The lowest effective dose of Danazol Polfarmex should always be sought.

WARNINGS

Use of danazol in pregnancy is contraindicated. A sensitive test (e.g., beta subunit test if available) capable of determining early pregnancy is recommended immediately prior to start of therapy. Additionally a non-hormonal method of contraception should be used during therapy. If a patient becomes pregnant while taking danazol, administration of the drug should be discontinued and the patient should be apprised of the potential risk to the fetus. Exposure to danazol in utero may result in androgenic effects on the female fetus; reports of clitoral hypertrophy, labial fusion, urogenital sinus defect, vaginal atresia, and ambiguous genitalia have been received. (See PRECAUTIONS: Pregnancy, Teratogenic Effects.)

Thromboembolism, thrombotic and thrombophlebitic events including sagittal sinus thrombosis and life-threatening or fatal strokes have been reported.

Experience with long-term therapy with danazol is limited. Peliosis hepatis and benign hepatic adenoma have been observed with long-term use. Peliosis hepatis and hepatic adenoma may be silent until complicated by acute, potentially life-threatening intraabdominal hemorrhage. The physician therefore should be alert to this possibility. Attempts should be made to determine the lowest dose that will provide adequate protection. If the drug was begun at a time of exacerbation of hereditary angioneurotic edema due to trauma, stress or other cause, periodic attempts to decrease or withdraw therapy should be considered.

Danazol has been associated with several cases of benign intracranial hypertension also known as pseudotumor cerebri. Early signs and symptoms of benign intracranial hypertension include papilledema, headache, nausea and vomiting, and visual disturbances. Patients with these symptoms should be screened for papilledema and, if present, the patients should be advised to discontinue danazol immediately and be referred to a neurologist for further diagnosis and care.

A temporary alteration of lipoproteins in the form of decreased high density lipoproteins and possibly increased low density lipoproteins has been reported during danazol therapy. These alterations may be marked, and prescribers should consider the potential impact on the risk of atherosclerosis and coronary artery disease in accordance with the potential benefit of the therapy to the patient.

Before initiating therapy of fibrocystic breast disease with Danazol Polfarmex, carcinoma of the breast should be excluded. However, nodularity, pain, tenderness due to fibrocystic breast disease may prevent recognition of underlying carcinoma before treatment is begun. Therefore, if any nodule persists or enlarges during treatment, carcinoma should be considered and ruled out.

Patients should be watched closely for signs of androgenic effects some of which may not be reversible even when drug administration is stopped.

PRECAUTIONS

Because Danazol Polfarmex may cause some degree of fluid retention, conditions that might be influenced by this factor, such as epilepsy, migraine, or cardiac or renal dysfunction, polycythemia and hypertension require careful observation. Use with caution in patients with diabetes mellitus.

Since hepatic dysfunction manifested by modest increases in serum transaminases levels has been reported in patients treated with Danazol Polfarmex, periodic liver function tests should be performed (see WARNINGS and ADVERSE REACTIONS).

Administration of danazol has been reported to cause exacerbation of the manifestations of acute intermittent porphyria. (See CONTRAINDICATIONS.)

Laboratory monitoring of the hematologic state should be considered.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Current data are insufficient to assess the carcinogenicity of danazol.

Pregnancy, Teratogenic Effects

(See CONTRAINDICATIONS.) Pregnancy Category X. Danazol Polfarmex administered orally to pregnant rats from the 6th through the 15th day of gestation at doses up to 250 mg/kg/day (7-15 times the human dose) did not result in drug-induced embryotoxicity or teratogenicity, nor difference in litter size, viability or weight of offspring compared to controls. In rabbits, the administration of Danazol Polfarmex on days 6-18 of gestation at doses of 60 mg/kg/day and above (2-4 times the human dose) resulted in inhibition of fetal development.

Nursing Mothers

(See CONTRAINDICATIONS.)

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of Danazol Polfarmex did not include sufficient numbers of subjects aged 65 and over to determine the safety and effectiveness of Danazol Polfarmex in elderly patients.

Blood and lymphatic system disorders

Increase in red cell and platelet count. Reversible polycythaemia, leucopoenia, thrombocytopenia, eosinophilia and splenic peliosis.

Endocrine disorders

Androgenic effects:

Acne, weight gain, increased appetite, seborrhoea, hirsutism, hair loss, voice change, which may take the form of hoarseness, sore throat or of instability or deepening of pitch. Hypertrophy of the clitoris, fluid retention.

Other endocrine effects:

Menstrual disturbances in the form of spotting, alteration of the timing of the cycle and amenorrhoea. Flushing, vaginal dryness, changes in libido, vaginal irritation and reduction in breast size.

Modest reduction in spermatogenesis.

Metabolism and nutrition disorders

Increased insulin resistance, increase in plasma glucagon, mild impairment of glucose tolerance.

Increase in LDL cholesterol, decrease in HDL cholesterol, affecting all subfractions, and decrease in apolipoproteins AI and AII.

Induction of aminolevulinic acid (ALA) synthetase, and reduction in thyroid binding globulin, T4, with increased uptake of T3 but without disturbance of thyroid stimulating hormone or free levothyroxine index.

Psychiatric disorders

Emotional lability, anxiety, depressed mood and nervousness.

Nervous system disorders

Dizziness, headache, vertigo, benign intracranial hypertension, migraine.

Aggravation of epilepsy, carpal tunnel syndrome.

Eye disorders

Visual disturbances such as blurring of vision, difficulty in focusing, difficulty in wearing contact lenses and refraction disorders requiring correction.

Respiratory, thoracic and mediastinal disorders

Pleuritic pain, interstitial pneumonitis.

Gastrointestinal disorders

Nausea, epigastric pain.

Cardiac disorders

Hypertension, palpitations and tachycardia.

Thrombotic events including sagittal sinus, cerebrovascular thrombosis as well as arterial thrombosis. Myocardial infarction.

Hepatobiliary disorders

Isolated increases in serum transaminase levels, cholestatic jaundice, benign hepatic adenomata and pancreatitis. Peliosis hepatitis as well as malignant hepatic tumour observed with long term use.

Hepatocellular injury, hepatic failure, jaundice hepatocellular, hepatocellular focal nodular hyperplasia.

Skin and subcutaneous tissue disorders

Rashes, which may be maculopapular, petechial or purpuric and may be accompanied by fever or may take an urticarial form and may be accompanied by facial oedema. Sun-sensitive rash.

Inflammatory erythematosus nodules, changes in skin pigmentation, exfoliative dermatitis and erythema multiforme.

Musculoskeletal and connective tissue disorders

Backache and muscle cramps which can be severe, with elevation of creatine phosphokinase levels. Muscle tremors, fasciculation, limb pain, joint pain and joint swelling.

Renal and urinary disorders

Haematuria with prolonged use in patients with hereditary angioedema.

General disorders and administration site conditions

Fatigue.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

The following events have been reported in association with the use of Danazol Polfarmex:

Androgen like effects include weight gain, acne and seborrhea. Mild hirsutism, edema, hair loss, voice change, which may take the form of hoarseness, sore throat or of instability or deepening of pitch, may occur and may persist after cessation of therapy. Hypertrophy of the clitoris is rare.

Other possible endocrine effects are menstrual disturbances including spotting, alteration of the timing of the cycle and amenorrhea. Although cyclical bleeding and ovulation usually return within 60-90 days after discontinuation of therapy with Danazol Polfarmex, persistent amenorrhea has occasionally been reported.

Flushing, sweating, vaginal dryness and irritation and reduction in breast size, may reflect lowering of estrogen. Nervousness and emotional lability have been reported. In the male a modest reduction in spermatogenesis may be evident during treatment. Abnormalities in semen volume, viscosity, sperm count, and motility may occur in patients receiving long-term therapy.

Hepatic dysfunction, as evidenced by reversible elevated serum enzymes and/or jaundice, has been reported in patients receiving a daily dosage of Danazol Polfarmex of 400 mg or more. It is recommended that patients receiving Danazol Polfarmex be monitored for hepatic dysfunction by laboratory tests and clinical observation. Serious hepatic toxicity including cholestatic jaundice, peliosis hepatis, and hepatic adenoma have been reported. (See WARNINGS and PRECAUTIONS.)

Abnormalities in laboratory tests may occur during therapy with Danazol Polfarmex including CPK, glucose tolerance, glucagon, thyroid binding globulin, sex hormone binding globulin, other plasma proteins, lipids and lipoproteins.

The following reactions have been reported, a causal relationship to the administration of Danazol Polfarmex has neither been confirmed nor refuted; allergic: urticaria, pruritus and rarely, nasal congestion; CNS effects: headache, nervousness and emotional lability, dizziness and fainting, depression, fatigue, sleep disorders, tremor, paresthesias, weakness, visual disturbances, and rarely, benign intracranial hypertension, anxiety, changes in appetite, chills, and rarely convulsions, Guillain-Barre syndrome; gastrointestinal: gastroenteritis, nausea, vomiting, constipation, and rarely, pancreatitis and splenic peliosis; musculoskeletal: muscle cramps or spasms, or pains, joint pain, joint lockup, joint swelling, pain in back, neck, or extremities, and rarely, carpal tunnel syndrome which may be secondary to fluid retention; genitourinary: hematuria, prolonged posttherapy amenorrhea; hematologic: an increase in red cell and platelet count. Reversible erythrocytosis, leukocytosis or polycythemia may be provoked. Eosinophilia, leukopenia and thrombocytopenia have also been noted. Skin: rashes (maculopapular, vesicular, papular, purpuric, petechial), and rarely, sun sensitivity, Stevens-Johnson syndrome and erythema multiforme; other: increased insulin requirements in diabetic patients, change in libido, myocardial infarction, palpitation, tachycardia, elevation in blood pressure, interstitial pneumonitis, and rarely, cataracts, bleeding gums, fever, pelvic pain, nipple discharge. Malignant liver tumors have been reported in rare instances, after long-term use.

Available evidence suggests that acute overdosage would be unlikely to give rise to immediate serious reaction.

In the case of acute overdose consideration should be given to reducing the absorption of the drug with activated charcoal and the patient should be kept under observation in case of any delayed reactions.

No information provided.