Danazol

G03X - Other sex hormones and modulators of the genital system ATC G03XA01 Small molecule approved 1976 Oral Natural product Black-box warning

JFDA label: DANOL CAP.

⚠ Black-Box Warning

Thromboembolic events:
Pregnancy:
Hepatic effects:
Intracranial hypertension:

Mechanism of Action

Agonist of Progesterone receptor — Progesterone receptor agonist; Agonist of Androgen receptor — Androgen Receptor agonist

Target	Action	Gene / class
Androgen receptor efficacy	AGONIST	AR
Progesterone receptor efficacy	AGONIST	PGR

Indications

Approved

Endometriosis
Fibrocystic breast disease
Hereditary angioedema

Off-label

Autoimmune hemolytic anemia
Immune thrombocytopenia, refractory

Contraindications

Source: Lexicomp

Additional contraindications (not in the US labeling): Genital neoplasia Absolute
Hypersensitivity to danazol or any component of the formulation Absolute
active or history of thrombosis or thromboembolic disease Absolute
androgen-dependent tumor Absolute
breast-feeding Absolute
concomitant administration with simvastatin Absolute
markedly impaired hepatic, renal, or cardiac function Absolute
undiagnosed abnormal genital bleeding Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (7)

Not Known Edema · flushing · hypertension · myocardial infarction · palpitations · syncope · tachycardia

Nervous system disorders (9)

Not Known Depression · dizziness · emotional lability · fatigue · headache · nervousness · paresthesia · sleep disorder · voice disorder (deepening of the voice, hoarseness, instability, sore throat)

Hepatobiliary disorders (6)

Not Known Cholestatic jaundice · hepatic adenoma · hepatic neoplasm (malignant; after prolonged use) · increased liver enzymes · jaundice · peliosis hepatitis

Renal and urinary disorders (8)

Not Known Asthenospermia · breast atrophy · decreased ejaculate volume · hematuria · inhibition of spermatogenesis · spermatozoa disorder (changes in sperm count and semen viscosity) · vaginal dryness · vaginal irritation

Blood and lymphatic system disorders (12)

Not Known Abnormal erythrocytes (increased) · decreased sex hormone binding globulin · eosinophilia · increased sex hormone-binding globulin · leukocytosis · leukopenia · malignant neoplasm (after prolonged use) · petechial rash · polycythemia · purpuric rash · thrombocythemia · thrombocytopenia

Metabolism and nutrition disorders (10)

Not Known Amenorrhea (may continue post-therapy) · change in libido · decreased glucose tolerance (and glucagon changes) · decreased HDL cholesterol · decreased thyroxine binding globulin · hirsutism (mild) · increased LDL cholesterol · increased thyroxine binding globulin · menstrual disease (altered timing of cycle, spotting) · weight gain

Gastrointestinal disorders (4)

Not Known Constipation · gastroenteritis · nausea · vomiting

Skin and subcutaneous tissue disorders (9)

Not Known Acne vulgaris · alopecia · diaphoresis · maculopapular rash · papular rash · pruritus · seborrhea · urticaria · vesicular eruption

Musculoskeletal and connective tissue disorders (11)

Not Known Ankylosing spondylitis · arthralgia · back pain · increased creatine phosphokinase · joint swelling · limb pain · muscle cramps · muscle spasm · neck pain · tremor · weakness

Eye disorders (1)

Not Known Visual disturbance

Respiratory, thoracic and mediastinal disorders (1)

Not Known Interstitial pneumonitis

Dosing

Source: Lexicomp

Note: In females, begin treatment during menstruation: Endometriosis (females): Oral: Mild disease: Initial: 200 to 400 mg/day in 2 divided doses; gradually titrate dosage downward to maintain amenorrhea; continue (uninterrupted) for 3 to 6 months (may extend up to 9 months). If symptoms recur following discontinuation, may reinitiate treatment. Moderate-to-severe disease or infertility: Initial: 800 mg/day in 2 divided doses; gradually titrate dosage downward to maintain amenorrhea; continue (uninterrupted) for 3 to 6 months (may extend up to 9 months). If symptoms recur following discontinuation, may reinitiate treatment. Fibrocystic breast disease (females): Oral: Range: 100 to 400 mg/day in 2 divided doses. If symptoms recur following discontinuation, may reinitiate treatment. Hereditary angioedema (males/females): Oral: Initial: 200 mg 2 to 3 times/day; after favorable initial response, decrease the dosage by 50% or less at intervals of 1 to 3 months or longer if the frequency of attacks dictates. If an attack occurs, increase the dosage by up to 200 mg/day. Immune thrombocytopenia, refractory (off-label use): Oral: 200 mg 2 to 4 times/day (10 to 15 mg/kg/day in divided doses) (Provan 2010); initial response is observed at 14 to 90 days; may take up to 6 months for peak response (Neunert 2011; Provan 2010) or 600 mg once daily for at least 6 months followed by 400 mg once daily for 3 months, then (if remission maintained) 200 mg once daily (Meloisel 2004).

Refer to adult dosing.

Use is contraindicated in patients with markedly impaired renal function.

Use is contraindicated in patients with markedly impaired hepatic function.

Warnings & Precautions

Source: Lexicomp

Androgenic effects

May cause nonreversible androgenic effects.

Blood lipid changes

Anabolic steroids may cause blood lipid changes (decreased high density lipoproteins and increased low density lipoproteins) with increased risk of arteriosclerosis and coronary artery disease.

Hepatotoxicity

Peliosis hepatis and benign hepatic adenoma have been reported with long-term use. Peliosis hepatis and hepatic adenoma may be silent until complicated by acute, potentially life-threatening intraabdominal hemorrhage. Use the lowest effective dose. When used for hereditary angioneurotic edema, if danazol was initiated during an exacerbation due to trauma, stress or other cause, consider periodic attempts to decrease or withdraw therapy. Monitor liver function tests and monitor closely for potential hepatotoxicity during therapy. Use is contraindicated in patients with marked hepatic impairment.

Intracranial hypertension

Danazol is associated with cases of benign intracranial hypertension (also known as pseudotumor cerebri). Early signs and symptoms include papilledema, headache, nausea and vomiting, and visual disturbances. Monitor for symptoms; if symptoms occur, screen for papilledema. Discontinue immediately and refer for neurology care if papilledema is present.

Thromboembolic events

Thromboembolism, thrombotic, and thrombophlebitic events have been reported (including sagittal sinus thrombosis and life-threatening or fatal strokes). Disease-related concerns:

Diabetes

Use with caution in patients with diabetes mellitus; insulin requirements may be increased; monitor carefully.

Edematous conditions

Use with caution in patients with conditions influenced by edema (eg, cardiovascular disease, migraine, seizure disorder, renal impairment); danazol may cause fluid retention.

Fibrocystic breast disease

Breast cancer should be ruled out prior to treatment for fibrocystic breast disease, and if fibrocystic nodules persist or enlarge during danazol treatment. The onset of relief of pain and tenderness is 1 month and symptoms are typically relieved within 2 to 3 months of treatment initiation; elimination of nodularity usually requires 4 to 6 months of continuous therapy. Symptoms of fibrocystic breast disease may recur within 1 year following discontinuation of therapy. Ovulation may not be suppressed at doses used for fibrocystic disease, therefore nonhormonal contraception is recommended.

Porphyria

May cause exacerbations of acute intermittent porphyria; use is contraindicated in patients with porphyria. Concurrent drug therapy issues:

Drug-drug interactions

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Special populations:

Pregnancy

Danazol use is contraindicated in pregnancy. Pregnancy should be ruled out immediately prior to starting treatment using a sensitive test (eg, beta subunit test if available) capable of determining early pregnancy. A nonhormonal method of contraception should also be used during therapy. If a patient becomes pregnant during danazol treatment, discontinue danazol and apprise the patient of the potential risk to the fetus. Exposure to danazol in utero may result in androgenic effects on the female fetus; reports of clitoral hypertrophy, labial fusion, urogenital sinus defect, vaginal atresia, and ambiguous genitalia have been received.

Pregnancy & Lactation

Pregnancy

FDA category X Contraindicated

[US Boxed Warning]: Danazol use is contraindicated in pregnancy. Pregnancy should be ruled out immediately prior to starting treatment using a sensitive test (eg, beta subunit test if available) capable of determining early pregnancy. A nonhormonal method of contraception should also be used during therapy. If a patient becomes pregnant during danazol treatment, discontinue danazol and apprise the patient of the potential risk to the fetus. Exposure to danazol in utero may result in androgenic effects on the female fetus; reports of clitoral hypertrophy, labial fusion, urogenital sinus defect, vaginal atresia, and ambiguous genitalia have been received. Therapy should be discontinued for 2 months prior to attempting pregnancy (Caballero 2012).

Lactation

Contraindicated

Use of danazol in nursing women is contraindicated.

Monitoring

Clinical pearl	Liver and renal function tests (periodically); hematologic parameters; lipid panel. Signs and symptoms of intracranial hypertension (papilledema, headache, nausea, vomiting), androgenic changes, and/or fluid retention.

Chemistry & Properties

Formula	C22H27NO2
Molecular weight	337.46 g/mol
IUPAC name	(1S,2R,13R,14S,17R,18S)-17-ethynyl-2,18-dimethyl-7-oxa-6-azapentacyclo[11.7.0.02,10.04,8.014,18]icosa-4(8),5,9-trien-17-ol
CAS	17230-88-5
PubChem CID	28417
InChIKey	`POZRVZJJTULAOH-LHZXLZLDSA-N`
logP	4.22 (XLogP 3.8)
Polar surface area	46.26 Å²
H-bond acceptors / donors	3 / 1
Drug-likeness (QED)	0.72
Lipinski violations	0

SMILES

C#C[C@]1(O)CC[C@H]2[C@@H]3CCC4=Cc5oncc5C[C@]4(C)[C@H]3CC[C@@]21C

Biology & Pharmacokinetics

Pharmacokinetics predicted

Bioavailability	70.0%
Half-life	1.846 h
Volume of distribution	4.691 L/kg
Protein binding	97.4%
BBB penetrant	Yes

Enzyme interactions

Enzyme	Role	Detail
CYP1A2	Substrate	—
CYP2B6	Inhibitor	—
CYP2C19	Inhibitor	—
CYP2C19	Substrate	—
CYP2C8	Inhibitor	IC₅₀ 1.9499999999999993 µM
CYP2C9	Inhibitor	IC₅₀ 0.6572670690061999 µM
CYP2D6	Inhibitor	IC₅₀ 2.74 µM
CYP3A4	Inhibitor	—
CYP3A4	Substrate	—

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)BSEP (Inhibitor)MRP1 (Inhibitor)MRP2 (Inhibitor)MRP3 (Inhibitor)MRP4 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)P-gp (Inhibitor)MDR1 (Substrate)P-gp (Substrate)

Drug–drug interactions (100+, DDInter)

Interacting drug	Severity	Management
Carfilzomib	major
Cisapride	major
Dicoumarol	major
Halofantrine	major
Hemin	major
Leflunomide	major
Naloxegol	major
Simvastatin	major
Teriflunomide	major
Warfarin	major
Acalabrutinib	moderate
Acarbose	moderate
Acetohexamide	moderate
Albiglutide	moderate
Alogliptin	moderate
Asparaginase Escherichia coli	moderate
Axitinib	moderate
Bosutinib	moderate
Brentuximab vedotin	moderate
Brigatinib	moderate
Budesonide	moderate
Budesonide (nasal)	moderate
Canagliflozin	moderate
Ceritinib	moderate
Chlorpropamide	moderate
Cilostazol	moderate
Clofarabine	moderate
Cobimetinib	moderate
Conestat alfa	moderate
Crizotinib	moderate
Cyclosporine	moderate
Dapagliflozin	moderate
Dasatinib	moderate
Docetaxel	moderate
Dulaglutide	moderate
Elagolix	moderate
Eliglustat	moderate
Empagliflozin	moderate
Entrectinib	moderate
Enzalutamide	moderate

Showing 40 of 100+.

Registered Products (1)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
DANOL CAP.	Capsule 200 mg	60 cap	Ulfa Pharma Co.	41.910