ANARGIL Capsule, hard Ref.[28101] Active ingredients: Danazol

Special warnings

In the event of virilisation, danazol should be withdrawn.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

Anargil 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, 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.

Precautions

In view of its pharmacology, known interactions and side effects, particular care should be observed when using danazol 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 in the presence of known or suspected malignant disease (see also section 4.3). 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. An effective, non-hormonal method of contraception should be employed (see section 4.2 and 4.6).

The lowest effective dose of Anargil should always be sought.

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

• Anti-convulsant therapy: Danazol may affect the plasma level of carbamazepine and possibly the patient’s response to this agent and to phenytoin. With phenobarbital it is likely that similar interaction would occur.
• Anti-diabetic therapy: Danazol can cause insulin resistance.
• Oral anti-coagulant therapy: Danazol can potentiate the action of warfarin.
• Anti-hypertensive therapy: Possibly through promotion of fluid retention, danazol can oppose the action of anti-hypertensive agents.
• Ciclosporin and tacrolimus: Danazol can increase the plasma level of ciclosporin and tacrolimus, leading to an increase of the renal toxicity of these drugs.
• Concomitant steroids: Although specific instances have not been described, it is likely that interactions will occur between danazol and gonadal steroid therapy.
• Migraine therapy: Danazol may itself provoke migraine and possibly reduce the effectiveness of medication to prevent that condition.
• Ethyl alcohol: Subjective intolerance in the form of nausea and shortness of breath has been reported.
• Alpha calcidol: Danazol may increase the calcaemic response in primary hypoparathyroidism necessitating a reduction in dosage of this agent.
• Interactions with laboratory function tests: Danazol treatment may interfere with laboratory determination of testosterone or plasma proteins (see also section 4.8)
• Statins: The risk of myopathy and rhabdomyolysis is increased by concomitant administration of danazol with statins metabolised by CYP3A 4 such as simvastatin, atorvastatin and lovastatin.

Pregnancy

There is epidemiological and toxicological evidence of hazard in human pregnancy. Danazol is known to be associated with the risk of virilisation to the female foetus if administered during human pregnancy. Danazol should not be used during pregnancy. Women of childbearing age should be advised to use an effective, non-hormonal, method of contraception. If the patient conceives during therapy, danazol should be stopped.

Breast-feeding

Danazol has the theoretical potential for androgenic effects in breast-fed infants and therefore either danazol therapy or breast-feeding should be discontinued.

Danazol has no or negligible influence on the ability to drive and use machines.

The undesirable effects are displayed by system organ class and frequency using the following convention: Very common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1 000 to <1/100), Rare (≥1/10 000 to <1/1000), Very rare (<1/10 000), Not known (cannot be estimated from the available data).

Blood and lymphatic system disorders

Not known: Increase in red cell and platelet count. Reversible polycythaemia, leucopoenia, thrombocytopenia, eosinophilia and splenic peliosis.

Endocrine disorders

Not known:

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

Not known: 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

Not known: Emotional lability, anxiety, depressed mood and nervousness.

Nervous system disorders

Not known: Dizziness, headache, vertigo, benign intracranial hypertension, migraine.

Aggravation of epilepsy, carpal tunnel syndrome.

Eye disorders

Not known: 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

Not known: Pleuritic pain, interstitial pneumonitis.

Gastrointestinal disorders

Not known: Nausea, epigastric pain.

Cardiac disorders

Not known: Hypertension, palpitations and tachycardia.

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

Hepatobiliary disorders

Not known: 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.

Skin and subcutaneous tissue disorders

Not known: 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

Not known: 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

Not known: Haematuria with prolonged use in patients with hereditary angioedema.

General disorders and administration site conditions

Not known: Fatigue.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions is an important way to gather more information to continuously monitor the benefit/risk balance of the medicinal product. Any suspected adverse reactions should be reported to Pharmaceutical Services, Ministry of Health, CY-1475, www.moh.gov.cy/phs, Fax: +357 22608649.

None.