chapter
Danazol
Pages 6

Watch for toxic effects of ciclosporin

DANAZOL TACROLIMUS Cases of ≠ tacrolimus levels Uncertain Watch for early features of tacrolimus toxicity

DANAZOL ANTICOAGULANTS – ORAL Possible ↓ anticoagulant effect Uncertain Monitor INR at least weekly until stable

DANAZOL ANTIEPILEPTICS – CARBAMAZEPINE

≠ plasma concentrations of carbamazepine, with risk of toxic effects

Inhibition of carbamazepine metabolism

Watch for toxic effects of carbamazepine

DANAZOL OESTROGENS ↓ efficacy of both danazol and oestrogen contraceptives

Uncertain; possibly competition for same receptors

Use alternative forms of contraception

ERGOMETRINE ➣ Drugs Acting on the Nervous System, Antimigraine drugs

FEMALE HORMONES

OESTROGENS

OESTROGENS REDUCED EFFICACY OF OESTROGENS

OESTROGENS 1. ANTIBIOTICS – ampicillin, cephalosporins, chloramphenicol, clindamycin, erythromycin, metronidazole, sulphonamides, tetracyclines 2. ANTIPROTOZOALS – tinidazole

Reports of ↓ contraceptive effect Possibly alteration of the bacterial flora necessary for recycling ethinylestradiol from the large bowel, although not certain in every case

Advise patients to use additional contraception for the period of antibiotic intake and for 1 month after stopping the antibiotic

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3. ANTIEPILEPTICS – barbiturates, carbamazepine, oxcarbazepine, phenytoin, topiramate 4. ANTIFUNGALS – griseofulvin, terbinafine 5. ANTIVIRALS – nelfinavir, nevirapine, ritonavir 6. CNS STIMULANTS – modafinil

↓ Induction of metabolism of oestrogens. Modafinil is moderate inducer of CYP1A2 in a concentration-dependent manner

Advise patients to use additional contraception for the period of intake and for 1 month after stopping co-administration of these drugs (4-8 weeks after stopping rifabutin or rifampicin). Barrier methods are necessary to prevent transmission of infection from patients with HIV. Avoid co-administration of oestrogens with St John’s wort

OESTROGENS 1. ANTICANCER AND IMMUNOMODULATING DRUGS – mycophenolate 2. ANTIEMETICS – aprepitant 3. ANXIOLYTICS AND HYPNOTICS – BZDs, meprobamate 4. PROTON PUMP INHIBITORS – lansoprazole

Possible altered efficacy of contraceptive; reports of breakthrough bleeding when BZDs or meprobamate were co-administered with oral contraceptives

Unclear Clinical significance uncertain. It would seem to be wise to advise patients to use an alternative form of contraception during and for 1 month after stopping co-administration of these drugs

OBSTETRICS AND GYNAECOLOGY FEMALE HORMONES Oestrogens

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Mechanism Precautions

KETOCONAZOLE, POSACONAZOLE, VORICONAZOLE

of pill cycle disturbances 2-3 weeks after the start of the pill cycle, delayed bleeding and pregnancy. Effects of either or both of oestrogen excess and progestogen excess may occur (migraine headaches, thromboembolic episodes, breast tenderness, bloating, weight gain)

The metabolism of oral contraceptives is complex, dependent on composition, constituents and doses. Ethylene oestradiol (EE), a common constituent, as well as progestogens are substrates of CYP3A4, which is inhibited by itraconazole. The inhibition of ethinylestradiol and progestogens could lead to effects of oestrogen and progestogen excess. Triazole antifungals inhibit the biotransformation of steroids, and such an ≠ may cause delay of withdrawal bleeding

Due to the complex metabolic pathways of oral contraceptives, dependent on constituents, doses and the reported adverse effects during concomitant use, it is advisable to avoid the use of azole antifungals and advise alternative methods of contraception

OESTROGENS INCREASED EFFICACY OF OESTROGENS

OESTROGENS 1. ANTICANCER AND IMMUNOMODULATING DRUGS – ciclosporin, tacrolimus 2. CALCIUM CHANNEL BLOCKERS – nicardipine, nisoldipine, verapamil 3. DIURETICS – spironolactone

Risk of gynaecomastia Inhibition of 2-hydroxylation or 17-oxidation of oestradiol in the liver, causing ≠ oestradiol pool in the body

Watch for gynaecomastia and warn patients

OESTROGENS – ESTRADIOL, POSSIBLY ETHINYLESTRADIOL

GRAPEFRUIT JUICE ≠ efficacy and ≠ adverse effects of oestrogens

Oral administration only. ≠ bioavailability and ↓ presystemic metabolism. Constituents of grapefruit juice irreversibly inhibit intestinal cytochrome CYP3A4. Transport via P-gp and MRP-2 efflux pumps is also inhibited

Monitor for ≠ side-effects

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OBSTETRICS AND GYNAECOLOGY FEMALE HORMONES Oestrogens

Etoricoxib inhibits sulphotransferase activity

Consider using a formulation with a lower dose of ethinylestradiol

OESTROGENS OPIOIDS Effect of morphine may be ↓ by combined oral contraceptives

≠ hepatic metabolism of morphine Be aware that the morphine dose may need to be ≠. Consider using an alternative opioid such as pethidine

OESTROGENS ANTICANCER AND IMMUNOMODULATING DRUGS – ciclosporin, corticosteroids, tacrolimus

Possibly ≠ plasma concentrations of these immunomodulating drugs

Inhibition of metabolism Monitor blood levels of these drugs; warn patients to report symptoms such as fever and sore throat

OESTROGENS ANTICOAGULANTS – ORAL ≠ anticoagulant effect Uncertain at present Oestrogens are usually not recommended in patients with a history of thromboembolism; if they are used, monitor INR closely

OESTROGENS ANTIDIABETIC DRUGS Altered glycaemic control Uncertain at present Monitor blood glucose closely

OESTROGENS 1. ANTIHYPERTENSIVES AND HEART FAILURE DRUGS 2. BETA-BLOCKERS 3. CALCIUM CHANNEL BLOCKERS 4. NITRATES

↓ hypotensive effect Oestrogens cause sodium and fluid retention

Monitor BP at least weekly until stable; the routine prescription of oestrogens in patients with ≠ BP is not advisable

OESTROGENS ANTIEPILEPTICS – LAMOTRIGINE

↓ lamotrigine levels ≠ metabolism Monitor levels

OESTROGENS ANTIPARKINSON’S DRUGS – ROPINIROLE, SELEGILINE

≠ levels of ropinirole and selegiline Inhibition of metabolism (possibly N-demethylation)

Watch for early features of toxicity (nausea, drowsiness) when starting oestrogens in a patient stabilized on these dopaminergics. Conversely, watch for a poor response to them if oestrogens are stopped

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Mechanism Precautions

↓ clearance of theophylline in a

dose-dependent manner Be aware; watch for features of theophylline toxicity and measure levels

OESTROGENS DANAZOL ↓ efficacy of both danazol and oestrogen contraceptives

Uncertain; possibly competition for the same receptors

Use alternative forms of contraception

OESTROGENS SOMATROPIN Possible ↓ efficacy of somatropin Uncertain ≠ dose of somatropin may be needed OESTROGENS VASODILATOR

ANTIHYPERTENSIVES Risk of hyperglycaemia when diazoxide is co-administered with combined oral contraceptives

Additive effect; both drugs have a hyperglycaemic effect

Monitor blood glucose closely, particularly with diabetics

PROGESTOGENS

PROGESTOGENS REDUCED EFFICACY OF PROGESTOGENS

PROGESTOGENS 1. ANTIBIOTICS – rifabutin, rifampicin 2. ANTIDEPRESSANTS – St John’s wort 3. ANTIEPILEPTICS – barbiturates, carbamazepine, oxcarbazepine, phenytoin, topiramate 4. ANTIFUNGALS – griseofulvin, terbinafine 5. ANTIVIRALS – amprenavir, nelfinavir, nevirapine, ritonavir 6. VASODILATOR ANTIHYPERTENSIVES – bosentan

↓ progesterone levels, which may lead to failure of contraception or poor response to treatment of menorrhagia

Possibly induction of metabolism of progestogens

Advise patients to use additional contraception for the period of intake and for 1 month after stopping co-administration with these drugs. Barrier methods are necessary to prevent transmission of infection from patients with HIV. Avoid co-administration of progestogens with St John’s wort

PROGESTOGENS ANTIEMETICS – APREPITANT ↓ progestogen levels, with risk of contraceptive failure

Uncertain Advise patients to use an alternative form of contraception during and for 1 month after discontinuing the aprepitant

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OBSTETRICS AND GYNAECOLOGY FEMALE HORMONES Progestogens

AND HEART FAILURE DRUGS – ACE inhibitors, angiotensin II receptor antagonists 3. DIURETICS – potassium-sparing

Drospirenone (component of the Yasmin brand of combined contraceptive pill) is a progestogen derived from spironolactone that can cause potassium retention

Monitor serum potassium weekly until stable and then every 6 months

PROGESTOGENS ANALGESICS – OPIOIDS Gestodene ≠ effect of buprenorphine

Gestodene ↓ CYP3A4-mediated metabolism of buprenorphine

The dose of buprenorphine needs to be ↓ (by up to 50%)

PROGESTOGENS ANTICANCER AND IMMUNOMODULATING DRUGS – CICLOSPORIN

≠ plasma concentrations of ciclosporin

Inhibition of metabolism of ciclosporin

Monitor blood ciclosporin concentrations. Monitor renal function prior to concurrent therapy. Be aware that infections in immunocompromised patients carry a serious threat to life

PROGESTOGENS ANTICOAGULANTS – ORAL ↓ anticoagulant effect Uncertain at present Monitor INR closely PROGESTOGENS ANTIDIABETIC DRUGS Altered glycaemic control Uncertain at present Monitor blood glucose closely

PROGESTOGENS ANTIEPILEPTICS – LAMOTRIGINE

↓ lamotrigine levels ≠ metabolism Monitor level

PROGESTOGENS ANTIPARKINSON’S DRUGS – SELEGILINE

≠ selegiline levels Inhibition of metabolism Watch for early features of toxicity (nausea, drowsiness) when starting progestogens in a patient stabilized on these dopaminergics. Conversely, watch for a poor response to them if progestogens are stopped

NORETHISTERONE ANTIVIRALS – PROTEASE INHIBITORS

≠ adverse effects with amprenavir and atazanavir

Uncertain Watch for early features of toxicity of amprenavir and atazanavir, and adjust the dose accordingly