Danol 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.

Adults:
Danol 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, Danol
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 childbearing
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: Danol is not recommended.
Children: Danol is not recommended.
The capsules are for oral administration.

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.

Special warnings
In the event of virilisation, Danol should be withdrawn. Androgenic reactions generally
prove reversible, but continued use of Danol after evidence of androgenic virilisation
increases the risk of irreversible androgenic effects.
Danol 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.
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 Danol 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 Danol 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. An effective, non-hormonal method of
contraception should be employed (see Section 4.2 Posology and Method of
Administration and 4.6 Fertility, Pregnancy and Lactation).

The lowest effective dose of Danol should always be sought.

Anti-convulsant therapy: Danol 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: Danol can cause insulin resistance.
Oral anti-coagulant therapy: Danol can potentiate the action of warfarin.
Anti-hypertensive therapy: Possibly through promotion of fluid retention, Danol can
oppose the action of anti-hypertensive agents.
Ciclosporin and tacrolimus: Danol 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 Danol and gonadal steroid therapy.
Migraine therapy: Danol 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: Danol 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
Undesirable effects)
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.

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.

Danol 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.
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

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.

Pharmacotherapeutic group: sex hormones and modulators of the genital system,
antigondotropics and similar agents, ATC code: G03XA01
Danazol, 17a-pregna-2,4-dien-20-yno(2,3-d)-isoxazol-17-ol, is a synthetic steroid
derived from ethisterone. Its pharmacological properties include:
1. Relatively marked affinity for androgen receptors, less marked affinity for
progesterone receptors and least affinity for oestrogen receptors. Danazol is a
weak androgen but in addition antiandrogenic, progestogenic,
antiprogestogenic, oestrogenic and antioestrogenic actions have been observed.
2. Interference with the synthesis of gonadal steroids, possibly by inhibition of the
enzymes of steroidogenesis, including 3 hydroxysteroid dehydrogenase,17
hydroxysteroid dehydrogenase, 17 hydroxylase, 17, 20 lyase, 11 hydroxylase,
21 hydroxylase and cholesterol side chain cleavage enzymes, or alternatively by
inhibition of the cyclic AMP accumulation usually induced by gonadotrophic
hormones in granulosa and luteal cells.
3. Inhibition of the mid-cycle surge of FSH and LH as well as alterations in the
pulsatility of LH. Danazol can also reduce the mean plasma levels of these
gonadotrophins after the menopause.
4. A wide range of actions on plasma proteins, including increasing prothrombin,
plasminogen, antithrombin III, alpha-2 macroglobulin, C1 esterase inhibitor, and
erythropoietin and reducing fibrinogen, thyroid binding and sex hormone
binding globulins. Danazol increases the proportion and concentration of
testosterone carried unbound in plasma.
5 The suppressive effects of danazol on the hypothalmic-pituitary-gonadal axis
are reversible, cyclical activity reappearing normally within 60-90 days after
therapy.

Danazol is absorbed from the gastrointestinal tract, peak plasma concentrations of 50-
80ng/ml being reached approximately 2-3 hours after dosing. Compared to the fasting
state, the bioavailability has been shown to increase 3 fold when the drug is taken with a
meal with a high fat content. It is thought that food stimulates bile flow which facilitates
the dissolution and absorption of danazol, a highly lipophilic compound.
The apparent plasma elimination half life of danazol in a single dose is approximately 3-
6 hours. With multiple doses this may increase to approximately 26 hours.
None of the metabolites of danazol, which have been isolated, exhibits pituitary
inhibiting activity comparable to that of danazol.
Few data on excretion routes and rates exist. In the monkey 36% of a radioactive dose
was recoverable in the urine and 48% in the faeces within 96 hours.

There are no preclinical data of relevance to the prescriber, which are additional to
those already included in other sections of the SmPC.

Capsule
Maize starch
Lactose monohydrate
Purified talc
Magnesium stearate
Cap
Gelatin
Titanium dioxide (E171)
Red iron oxide (E172)
Yellow iron oxide (E172)
Capsule Shell Body (size 1)
Titanium dioxide (E171)
Gelatin
Ink
S-1-27794 Opacode Black
Iron oxide black (E172)
Propylene glycol (E1520)
Industrial methylated spirit 74 OP
Or
TekPrint SW-9008 Black Ink
Shellac
Dehydrated alcohol
Propylene glycol
Strong ammonia solution
Potassium hydroxide
Black iron oxide (E172)

Not applicable.

5 years

None.

PVC blister pack compound of polyvinyl chloride (thickness 250μm) sealed to
aluminium foil (thickness 20μm). The blisters are then packed in a cardboard carton.
Pack sizes: 50, 60 and 100 capsules.
Not all pack sizes may be marketed.

No special requirements.