Danazol

Subjective intolerance in the form of nausea and shortness of breath has been reported.

Danazol can cause insulin resistance.

Possibly through promotion of fluid retention, danazol can oppose the action of anti-hypertensive agents.

The risk of myopathy and rhabdomyolysis is increased by concomitant administration of danazol with statins metabolised by CYP3A4.

Although specific instances have not been described, it is likely that interactions will occur between danazol and gonadal steroid therapy.

Danazol may increase the calcaemic response in primary hypoparathyroidism necessitating a reduction in dosage of this agent.

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.

Danazol can increase the plasma level of ciclosporin and tacrolimus, leading to an increase of the renal toxicity of these drugs.

Danazol can potentiate the action of warfarin.

Danazol may itself provoke migraine and possibly reduce the effectiveness of medication to prevent that condition.

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.

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.

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.

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.