Danazol

What is Danazol

Danazol is a drug that is clinically classified as a synthetic androgen and it can be naturally obtained from Ethinyl testosterone. Danazol has weak androgenic properties and it is completely antiestrogenic. It is primarily indicated for the treatment of endometriosis, but this should be done before this condition has advanced to a level where it will require a surgical operation, it is also used in the palliative treatment of fibrocystic breast disease and it has been successfully used to treat hereditary angioedema in both males and females. This drug was approved for clinical use by the FDA in 1976.

Danazol’s Mechanisms Of Action

Danazol begins its action on the pituitary glands where it facilitates a reduced production of estrogen by inhibiting the release of the Luteinizing hormone and the follicle stimulating hormone. Scientific evidence suggests that Danazol works by binding to sex hormone receptors in specific tissues where it exhibits anti-estrogenic, anabolic and weak androgenic properties. When a higher dose of this medicine is administered to a patient, it might result in amenorrhea after about six weeks of treatment, when this administration is discontinued, cyclic bleeding and ovulation may return back to their normal levels after about 90 days. Danazol is indicated for the treatment of endometriosis since some of its actions can lead to the atrophy of the ectopic endometrial tissues. This can relieve the symptoms of this condition completely. Hereditary angioedema is a genetic disorder that is characterized by a deficiency in C1INH/C1 Esterase inhibitor which is a serum inhibitor of the first activated component of a complement pathway. Danazol increases the levels and the rates of circulation of C1INH in the system which alternately increases the levels of C4 in the system. The deficiency of C1INH is what causes hereditary angioedema so the administration of danazol can be used as a solution and to prevent repeated attacks from the effects of this condition. The exact mechanism through which Danazol increases the levels of C1INH has not been clearly established but this medicine does not possess any progestogenic properties and it has not proved to have any effect on the release of corticotropin by the pituitary or the normal release of cortisol from the adrenal glands.  Danazol is used to treat fibrocystic breast disease because, in controlled doses, it can greatly reduce the growth rates of abnormal tissues in the breasts.

Pharmacokinetics of Danazol

Most danazol drugs are capsule formulated, so, it should be administered orally. Information on how this drug is distributed around the body is still inconclusive but its primary metabolite, 2-hydroxymethyltesterone is produced after it undergoes extensive hepatic metabolism. The bioavailability of danazol in the serum does not depend on the concentration of the dosage that is administered and increasing its administration does not necessarily mean that you will attain a proportional increase in its concentration in the plasma. Doubling a dose can roughly result in about 30-40% increase in its concentration in the plasma. After its administration, peak concentrations of danazol can be attained in the serum after about 2 to 3 hours but its therapeutic effects will not be realized until after 6 to 8 weeks of continuous medication. In a case where this medication is used for the treatment of a fibrocystic breast disease, a reduction in pain may start to be realized after a month of continuous medication with peak effects at 2 to 3 months of treatment.

Indications of Danazol

Danazol is clinically indicated for the treatment of hereditary angioedema prophylaxis and it can also be used to treat endometriosis, chronic immune thrombocytopenia, mastalgia that is associated with HIV or Pre-Menstrual Syndrome, purpura, PMS that is associated with weight gain and bloating, depression, anxiety, emergency post-coital contraception and finally, in the palliative treatment of fibrocystic breast disease.

Contraindications and Precautions when using Danazol

Danazol is well known to increase fluid retention in the system of human beings so it should be used very cautiously in patients with a migraine, headaches, cardiac diseases, seizure disorders and renal impairments since it can worsen the effects of these situations, it should be completely avoided in patients with severe heart diseases, severe cardiac disease, and severe renal diseases.

Danazol should never be administered to patients with severe hepatic diseases because it can lead to hepatic dysfunctions which include; peliosis of the liver, cholestatic jaundice, and benign hepatic adenoma. Adenoma and Peliosis may not be detected until a patient suffers from a life-threatening intra-abdominal bleeding. If danazol must be used in patients with this condition, then the clinician must proceed with caution and regular liver function examinations should be carried out to ascertain safety.

Danazol should not be used in patients with acute intermittent porphyria because it can induce the activity of ALA synthetase and the metabolism of porphyrin which can facilitate an attack.

Danazol is strictly contraindicated for use during pregnancy and lactation. It is under the category X for pregnancy. A lot of care should be taken and standard measures should be considered to ensure that a patient does not get pregnant during this therapy. This drug can cause teratogenic effects on a fetus and since androgens are well known for their effect of virilization of external genitalia in the female fetus, it can result in clitoromegaly, the abnormal development of the vagina and the fusion of the genital folds to form scrotal-like structures. This masculinization is dependent on the concentration of the drug, the dosage of the drug and the age of the fetus during the administration. These effects are likely to be more severe during the first tri-semester of fetal development. Female patients on this medication are advised to adopt adequate methods of contraception or commence with this treatment during their menstrual periods where possible so that they can be sure of a pregnant free state during the administration of this medication. In a case of a pregnancy, this administration should be discontinued immediately and the patient should be adequately counseled about the effects of this medication on a fetus.

Danazol can be excreted into a mother’s milk through the breasts and because of its androgenic effects on infants, it is strongly contraindicated during breastfeeding. In a case where a patient should be lactating, alternative solutions and alternative techniques to breastfeeding should be considered.

Danazol is contraindicated in any conditions with an abnormal vaginal bleeding because it can lead to more bleeding, menstrual irregularities and adverse reactions in women who might have pre-existing vaginal conditions.

Danazol should never be used to treat fibrocystic breast disease until all possibilities of breast carcinoma have been eliminated. If the nodules on the breasts enlarge or persist after this treatment, the possibilities of cancer should be evaluated.

Geriatric patients, especially those over 65 years should be treated cautiously using this medication since its safety and efficacy in patients with this condition has not been clearly established. Elderly men may be at a higher risk of developing prostate hypertrophy.

Danazol has been associated in multiple cases with benign increased intracranial pressure and the early signs of this condition can include; visual disturbances, nausea, vomiting, headaches, and papilledema. In case of any of these symptoms, a patient should be neurologically evaluated, examined and the administration of this medication discontinued immediately.

A therapy using danazol exposes one to a higher risk of developing thromboembolic diseases and thrombotic events. Sagittal sinus thrombosis and life-threatening strokes have also been reported in some cases.

This list does not include all the possible contraindications of this medication so incase of any negative results, the administration of this medication should be discontinued and medical help acquired immediately.

Interactions of Danazol

It should be noted that danazol is a CYP3A4 inhibitor which means that it inhibits the metabolism of Cytochrome P450 System Isoenzyme/CYP3A4. It should therefore never be used concurrently with drugs that contain these substrates since in can inhibit their metabolism thus decrease their efficacy or they can lead to the development of undesired results, some of these drugs are; ezetimibe, niacin, cyclosporine, carbamazepine, tacrolimus, amiodarone, disopyramide, pimozide, sildenafil, sirolimus, aprepitants, fosaprepitant, ranolazine, budesonide, sunitinib among others.

CPY3A4 inhibitors like danazol can also inhibit the 25-hydroxylation of doxercarlciferol which may alternatively decrease the formation of its active metabolite which will decrease its efficacy.

The combination of danazol and warfarin should be avoided because danazol can decrease the hepatic synthesis of coagulant factors which can greatly increase the chances of excessive bleeding when used together with platelet inhibitors, thrombolytic agents, and anticoagulants. This combination can increase the action time of prothrombin. If this combination is unavoidable, you should consider reducing your dose of warfarin.

The concurrent use of danazol and lovastatin or simvastatin should be avoided because it can increase the risk of rhabdomyolysis and myopathy. In case this combination is desired, the potential risks to benefits should be outweighed and the dosage of lovastatin should be controlled between 10 mg to a maximum of 20 mg in a day with extended use.

Theoretically, soy isoflavones like genistein and daidzein can counteract the activities of androgens like danazol because their mode of action appears to inhibit the type II 5-alpha reductase isoenzyme which results in a decreased conversion of testosterone to androgen 5-alpha-dihydotestosterone.

The concurrent use of ATRA, systemic tretinoin and danazol should be carried out cautiously because there is an increased risk of intracranial pressure and benign intracranial hypertension.

Danazol can reduce the hypoglycemic effects of insulin, so any patient who is receiving insulin together with this drug should be closely monitored for any changes in their blood sugar level control even after the administration of this drug is discontinued. Androgens that are administered exogenously have variable effects on blood sugar control in patients with diabetes mellitus since low testosterone concentrations are associated with an increased resistance to insulin.

Administering anabolic steroids to a patient can also facilitate an insulin resistance. It is only logical to monitor any patient with type II diabetes for any changes in glycemic controls. In a case of hypoglycemia or hyperglycemia, the administration of this medication should be stopped immediately and dosage adjustments should be considered.

 

Adverse Reactions and Side Effects of Danazol

 

Danazol can facilitate the development of irreversible androgenic effects on a female patient who is on this medication. These effects can include acne vulgaris, weight gain, seborrhea, edema, hirsutism, deepening of the voice, alopecia, pharyngitis, and hoarseness. Testicular atrophy and clitorial hypertrophy can also occur, but these are very rare. Male patients can experience abnormalities in their sperm count, semen viscosity, and motility. In some situations, the inhibition of spermatogenesis may be evident.

Female patients can also experience hypoestrogenic effects which can be manifested through a reduction in breast size, breakthrough bleeding, menstrual irregularities, emotional lability, vaginal dryness, flushing and ovulatory changes which can include anovulation. Amenorrhea can also occur and its effects may be prolonged even after the administration of this medicine has been discontinued. Additionally, nipple discharge and hematuria can also be experienced. All hypoestrogenic effects that can be experienced by females are reversible.

Danazol is associated with hepatotoxicity. Elevated levels of hepatic enzymes can be realized in patients receiving more than 400 mg of danazol but this is reversible. Severe toxicity can result in the development of jaundice, cholestasis, and peliosis hepatis. During treatment with danazol, all hepatic functions should be monitored in order to maintain normal physiological functions.

Danazol also exhibits some adverse effects on the gastro intestines which might include; constipation, vomiting, nausea, gastroenteritis and splenic peliosis.

Hypercholesterolemia which involves an increase in LDL cholesterol and a decrease in HDL cholesterol levels has been reported in some cases and this effect should be seriously considered in patients with coronary artery diseases and other risk factors that may facilitate its development.

Allergic reactions to danazol can be manifested in the forms of a vesicular rash, pruritus, urticaria, petechiae, purpura, and amacolopura rash. Erythema,

nasal congestion and photosensitivity are also some effects that can be experienced.

Teratogenesis is one of the most serious effects of danazol so this medication should never be administered during a pregnancy. It can lead to severe pseudohermaphroditism in female fetus’ but it showcases no adverse effects on a male fetus.

Some effects of danazol on the central nervous system can include spasms, muscle cramps, joint pains, pelvic pains, back pains, neck pains, and carpel tunnel syndrome which might be as a result of fluid retention in the system.

Hematologic reactions can include; leukopenia, eosinophilia, thrombocytopenia and an increase in blood platelet count. A reversible erythrocytosis, leukocytosis, and polycythemia can also be provoked by this medication.

This list does not include all the possible side effects of this medication so in case you experience any adverse reactions after the administration of this medicine, i.e. swelling, chest pains/chest tightness,wheezing, difficulty in breathing, red painful swollen spots, and itching/hives, contact emergency care services or your health care service provider immediately.

 

How is this medication best taken?

 

This medication should be taken according to your prescribed dosage and this will depend on your condition. You can choose to divide it throughout the day using a regime of anywhere around two to four times in a day. This medicine should be stored at room temperature, away from moisture and away from the reach of children.

This medicine is available at our pharmacy and it can be compounded in doses that are specific for a patient’s benefits. For more information about this medication and its administration, feel free to contact us.

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