Danol^® (Capsules) Instructions for Use

Marketing Authorization Holder

Sanofi-Synthelabo, Ltd. (United Kingdom)

ATC Code

G03XA01 (Danazol)

Active Substance

Danazol (Rec.INN registered by WHO)

Dosage Forms

	Danol®	Capsules 100 mg: 60 or 100 pcs.
		Capsules 200 mg: 60 or 100 pcs.

Dosage Form, Packaging, and Composition

Capsules hard gelatin, opaque, size No. 3, with a white body and a gray cap, the body and cap are marked “DANOL 100”; the capsule contents are a white or almost white powder, practically odorless.

Excipients: corn starch, lactose monohydrate, talc, magnesium stearate.

Composition of the capsule body gelatin, titanium dioxide (E171).
Composition of the capsule cap gelatin, titanium dioxide (E171), iron oxide black dye (E172).
Ink composition Opacode S-1-8100HV Black 1007 (shellac, soy lecithin, dimethylpolysiloxane, iron oxide black dye (E172)).

10 pcs. – blisters (6) – cardboard packs.
10 pcs. – blisters (10) – cardboard packs.

Capsules hard gelatin, opaque, size No. 1, with a white body and a brownish-pink cap, the body and cap are marked “DANOL 200”; the capsule contents are a white or almost white powder, practically odorless.

Excipients: corn starch, lactose monohydrate, talc, magnesium stearate.

Composition of the capsule body gelatin, titanium dioxide (E171).
Composition of the capsule cap gelatin, titanium dioxide (E171), iron oxide red dye (E172), iron oxide yellow dye (E172).
Ink composition Opacode S-1-8100HV Black 1007 (shellac, soy lecithin, dimethylpolysiloxane, iron oxide black dye (E172)).

10 pcs. – blisters (6) – cardboard packs.
10 pcs. – blisters (10) – cardboard packs.

Clinical-Pharmacological Group

Gonadotropin production inhibitor

Pharmacotherapeutic Group

Gonadotropin-releasing hormone inhibitor

Pharmacological Action

An antigonadotropic agent, which is a synthetic androgen derived from ethisterone. It suppresses the production of gonadotropic hormones LH and FSH by the pituitary gland in men and women. In women, it suppresses ovarian activity, inhibits ovulation, and causes endometrial atrophy. The action is reversible, the drug lacks estrogenic or progestogenic action, and in high doses, it has weak androgenic activity with a concomitant anabolic effect.

In endometriosis, it damages both normal and ectopic endometrial tissue, leading to its inactivation and atrophy. It reduces the pain syndrome associated with endometriosis and causes regressive changes in endometriotic lesions. It has an immunosuppressive effect and suppresses lymphocyte proliferation in vitro. It significantly reduces immunoglobulin (Ig) levels and the production of autoantibodies in patients with endometriosis. In fibrocystic mastopathy, it promotes partial or complete disappearance of nodular indurations and complete relief of the pain syndrome. The clinical efficacy in hereditary angioedema is possibly due to an increase in the content of C1 esterase inhibitor (a congenital deficiency of which is characteristic of this disease) and, as a result, an increase in the plasma level of the C4 complement component.

Pharmacokinetics

Food intake (fats more than 30 g) delays absorption by 30 minutes, increases bioavailability and C_max. When administered at 100 mg twice daily, C_max is 200-800 ng/ml; at 200 mg twice daily for 2 weeks – 250 ng/ml-2 µg/ml.

Metabolized in the liver to form ethisterone and 17-hydroxymethylethisterone.

T_1/2 – up to 24 hours. Bioavailability does not increase proportionally with increasing dose. When the dose is doubled, the plasma concentration increases by 35-40%.

Indications

• Endometriosis with associated infertility;
• Benign breast neoplasms (fibrocystic mastopathy);
• Primary menorrhagia and premenstrual syndrome, precocious puberty, gynecomastia;
• Hereditary angioedema.

ICD codes

Dosage Regimen

Orally. As a rule, the lowest effective doses are used.

Adults the usual daily dose is from 200 to 800 mg, divided into 2-4 doses.

Treatment of endometriosis should start with a dose of 400 mg/day. This dose is increased or decreased as necessary. The duration of treatment is 4-6 months.

For treatment of benign breast diseases or severe cyclic mastalgia the recommended daily dose is from 100 to 400 mg (usually 300 mg), for 3-6 months.

The dose for primary menorrhagia and premenstrual syndrome is 100-400 mg/day (usually 200 mg), for 3 months.

For gynecomastia men are prescribed 200-600 mg (usually 400 mg) of the drug/day (for no more than 6 months).

For prevention of angioedema the initial dose should be 200 mg with subsequent reduction (in the absence of exacerbations) over 1-3 months.

Children may be prescribed only to children with precocious puberty in a daily dose from 100 to 400 mg depending on age and severity of the disease.

Adverse Reactions

From the endocrine system acne, edema, hyperseborrhea, hirsutism, virilism, reduction in breast size, voice deepening, weight gain, hair loss (alopecia), impaired spermatogenesis, flushing, profuse sweating, increased sweating, increased nervous excitability, emotional lability, change in libido, migraine-like headache, menstrual cycle disorders, dysmenorrhea, absence of menstruation, vaginitis.

From the hematopoietic system leukocytosis, increase in the number of red blood cells or platelets, leukopenia or thrombocytopenia.

From the blood coagulation system bleeding in patients with hemophilia.

From the cardiovascular system: worsening of arterial hypertension, tachycardia.

From the CNS increased intracranial pressure.

From the digestive system increased activity of liver enzymes, rarely cholestasis or cholestatic jaundice, hepatitis, nausea, increased insulin requirement, hypoglycemia, increased creatine kinase activity, dyslipidemia.

Rarely visual impairment, nausea, increased appetite, skeletal muscle spasm, low back pain, paresthesia, skin rash, photosensitivity, dizziness, increased fatigue, sleep disorders, depressive states and worsening of epilepsy, fluid retention.

Contraindications

• Pregnancy, breastfeeding period,
• Porphyria;
• Breast cancer;
• Carcinoma;
• Androgen-dependent tumors;
• Vaginal bleeding of unknown origin;
• Hepatic and/or renal failure;
• Chronic heart failure;
• Thromboembolism;
• Hypersensitivity to danazol or any other ingredients of the drug.

With caution: epilepsy, migraine, diabetes mellitus, impaired plasma hemostasis mechanisms.

Use in Pregnancy and Lactation

During pregnancy and breastfeeding, the use of danazol is contraindicated, as it may cause virilization of female fetuses.

Pregnancy must be ruled out before starting therapy with the drug. If a woman becomes pregnant during treatment, danazol treatment must be discontinued, and the patient should be informed about the potential risk to the fetus.

Use in Hepatic Impairment

Contraindication: hepatic failure.

Use in Renal Impairment

Contraindication: renal failure.

Pediatric Use

Children: may be prescribed only to children with precocious puberty in a daily dose from 100 to 400 mg depending on age and severity of the disease.

Special Precautions

Treatment with danazol requires careful monitoring of patients, especially in the presence of liver and kidney diseases, arterial hypertension and/or other cardiovascular diseases, conditions accompanied by fluid retention, epilepsy, lipoprotein metabolism disorders, thrombosis (also in history) and migraine.

All patients receiving Danazol require regular examination of liver function, including liver enzymes and peripheral blood cell counts. With prolonged treatment (6 months) and with repeated courses of treatment, it is recommended to perform ultrasound examination of the pelvic organs and liver (at least 2 times a year). Caution is required when using in patients with a previous androgenic reaction to treatment with sex hormones. Danazol affects some laboratory parameters of sex hormones (for example, increases testosterone levels).

When prescribing to patients with diabetes mellitus, dose adjustment of insulin is necessary. Administration of high doses of danazol prevents ovulation. However, ovulation is possible at low doses, so non-hormonal methods of contraception should be used during treatment with danazol.

Due to the possible androgenic effect on the fetus, Danazol should not be prescribed during pregnancy, therefore, treatment with the drug in all cases should be started, after excluding pregnancy, on the first day of menstruation. In patients with amenorrhea, a pregnancy test must be performed before starting therapy.

Effect on ability to drive vehicles and operate machinery

No data available.

Overdose

Symptoms headache, dizziness, tremor, convulsions, nausea, vomiting.

Treatment removal of the drug from the gastrointestinal tract by induced vomiting or gastric lavage, symptomatic therapy. Dynamic observation.

Drug Interactions

Danazol enhances the effect of coumarin anticoagulants and indandione derivatives (increases the risk of bleeding).

Weakens the effect of insulin and oral hypoglycemic drugs (by affecting carbohydrate metabolism, increases blood glucose concentration).

Increases the concentration of glucagon in blood plasma.

Danazol may reduce the effectiveness of antihypertensive agents, possibly by stimulating fluid retention in the body.

Suppresses the metabolism of antiepileptic drugs (carbamazepine, phenytoin and phenobarbital) and increases their concentration in the blood.

Increases the plasma concentration of cyclosporine and tacrolimus (increases the risk of nephrotoxicity).

Danazol may increase the calcemic response to alfacalcidol in primary hypoparathyroidism, which requires a reduction in the dose of this drug.

Storage Conditions

List B. In a dry place at a temperature not exceeding 25°C (77°F). Keep out of reach of children.

Shelf Life

Shelf life – 5 years.

Dispensing Status

By prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.