Modrenal®

1. Name Of The Medicinal Product

Modrenal Capsules – 60 mg and 120 mg

2. Qualitative And Quantitative Composition

Each Modrenal capsule contains either 60 mg or 120 mg Trilostane (4α, 5-epoxy -17β - hydroxy -3 -OXO -5α -androstane -2α -carbonitrile.) (For excipients see 6.1)

3. Pharmaceutical Form

60 mg capsules: opaque pink/black Size 3 hard gelatine capsules marked with 60 on one end.

120 mg capsules: opaque pink/yellow Size 1 hard gelatine capsules marked with 120 on one end.

4. Clinical Particulars

4.1 Therapeutic Indications

(a) For the control of the manifestation of adrenal cortical hyperfunction in such conditions as hypercortisolism and primary aldosteronism.

(b) For the treatment of postmenopausal advanced breast cancer following relapse to initial hormone therapy e.g. oestrogen receptor antagonists.

4.2 Posology And Method Of Administration

Modrenal for oral administration only.

Adrenal Cortical Hyperfunction - 240 mg/day in divided doses for at least three days, then dose adjustment according to the patient's clinical response and appropriate biochemical monitoring. The usual dose is 120–480 mg/day but may be increased to 960 mg.

Postmenopausal Breast Cancer - The daily dose given in divided doses should increase stepwise every three days from 240 mg to 480 mg to 720 mg to 960 mg. This dose should be maintained but if it cannot be tolerated it may be reduced to 720 mg/day. From the start of Trilostane therapy a physiological replacement dose of a glucocorticoid (e.g. Hydrocortisone 30 mg/day in divided doses) should be given to prevent activation of the HPA axis.

Elderly - There are no special dosage recommendations.

4.3 Contraindications

Trilostane is contraindicated in pregnancy and children.

4.4 Special Warnings And Precautions For Use

Pregnancy should be excluded before beginning treatment and nonhormonal contraceptive methods should be used during therapy where appropriate.

As with all drugs that are metabolised by the liver and excreted by the kidney, caution should be exercised when treating patients with gross hepatic or renal impairment. It is advisable to monitor response when treating adrenal cortical hyperfunction, by regular assays of blood electrolytes and circulating corticosteroids, and adjust the dose accordingly. In some patients the suppression of aldosterone production may cause hyperkalaemia and hyponatraemia with subsequent hypotension – under these circumstances a mineralocorticoid should be given, e.g. Fludro-cortisone 0.1 mg/day. In other patients it is possible to produce corticosteroid insufficiency, especially if the production of ACTH is limited, and then a glucocorticoid may be necessary.

When treating hypercortisolism due to excess ACTH production (whether ectopic or pituitary), an initial response may be followed by a relapse if the hypophyseal/pituitary/adrenal (HPA) axis is still intact and is not suppressed. If, however, the excessive steroid production is due to an adrenal cortical tumour, or the HPA axis is no longer able to respond to lowered levels of circulating glucocorticoids, the condition will remain responsive to Trilostane.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

When administered concurrently with thiazide diuretics the inhibition of aldosterone production caused by Trilostane reduces potassium loss whilst maintaining the natriuretic effect.

4.6 Pregnancy And Lactation

The production of progesterone, which is necessary for the maintenance of pregnancy, is suppressed by Trilostane and so pregnancy may be limited.

No information is available on the secretion of Trilostane in breast milk.

4.7 Effects On Ability To Drive And Use Machines

Although there have been occasional reports of lethargy or drowsiness, Trilostane is unlikely to impair ability.

4.8 Undesirable Effects

Flushing, tingling in mouth, palatal swelling, rhinorrhoea, sickness, vomiting, diarrhoea, and cramps have been reported commonly. These are generally mild and reversible on adjusting dose, administering with food, stopping therapy and/or symptomatic treatment (e.g. antacid, antidiarrhoeal with a small dose of aspirin). More severe signs of stomach upset, e.g. bleeding or ulcer, usually occur with concurrent administration of nonsteroidal anti-inflammatory drugs – reducing the dose of these latter drugs and/or adding an H2 blocker will usually resolve these problems.

Skin rashes can occur occasionally but are usually self limiting.

Very rarely, in cancer patients whose bone marrow is compromised by disease or chemotherapy, granulocytopenia has been reported - it is reversible on stopping therapy.

4.9 Overdose

The LD50 in rats and mice is more than 16 grams/ kilogram.

In humans, if recently ingested, the drug should be removed by emesis or gastric lavage. Subsequent treatment will depend on the effect of the drug on blood electrolytes and corticosteroids.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Trilostane selectively and reversibly inhibits the enzyme system - 3β- hydroxysteroid dehydrogenase ∆5-4 isomerase – essential for the synthesis of all steroids in the adrenals, ovaries, testes and placenta. When used to treat adrenal cortical hyperfunction, it therefore lowers both glucocorticoid and mineralocorticoid steroids; however, providing there is a functioning HPA axis, when treating primary aldosteronism, the normal feedback mechanism prevents excessive lowering of glucocorticoids: equally a normally functioning renin/angiotensin/adrenal system prevents undue lowering of mineralocorticoids when treating hypercortisolism.

Trilostane's mechanism of action in postmenopausal breast cancer is attributed to similar inhibition of oestrogen biosynthesis, since oestrogen is a known growth promoter in breast tumours. Oestrogen also affects cell proliferation in breast cancer directly. The Two major pathways of oestrogen-dependent regulation of gene transcription and cell proliferation are:

- Ligand-bound oestrogen receptors (ERs) dimerise and bind to oestrogen response elements (EREs) in the promoter region of target genes.

- ERs also affect the transcriptional potency of the growth factor/tyrosine kinase activated growth promoting pathways by blocking activation of AP-1 protein (a heterodimer of c-fos/c-jun proto-oncogene products) at the AP1 activation site in target gene promoters.

In vitro study findings show that trilostane non-competitively inhibits the actions of oestrogen/ERs at both of these locations. This dual mode of action is achieved by (1) direct inhibition of ERα promoted transcription at EREs; (2) modulating ERβ so that the binding preference of oestrogen changes from the ERα subtype to favour binding to ERβ. This ERβ-modulation is particularly important at theAP-1 site, where ERβ is thought to inhibit the stimulatory actions of ERα.

5.2 Pharmacokinetic Properties

After oral administration, Trilostane is widely distributed, metabolised by the liver and excreted by the kidney. The major metabolite is 17-oxo Trilostane which has the same enzyme inhibiting activity as Trilostane. Following 120 mg orally, the Cmax is 0.69 µg/ml for Trilostane and 1.64 µg/ml for 17-oxo Trilostane at 2 hours; the half life of both is 1.2 hours.

5.3 Preclinical Safety Data

All species tested display a hyperplasia of the adrenal cortex due to compensatory overproduction of ACTH to correct the enzyme block. This is not a problem unless the HPA axis is compromised (see 4.4).

6. Pharmaceutical Particulars

6.1 List Of Excipients

Lactose, maize starch, magnesium stearate and, in capsule shell, gelatine, E171 and E172.

6.2 Incompatibilities

None.

6.3 Shelf Life

5 years

6.4 Special Precautions For Storage

The product should be stored below 25ºC.

6.5 Nature And Contents Of Container

60 mg capsules – brown, glass bottles containing 100 capsules with metal or LDPE screw top.

120 mg capsules – brown, glass bottles containing 100 capsules with metal or LDPE screw cap; or HDPE tablet containers with LDPE closure.

6.6 Special Precautions For Disposal And Other Handling

None

7. Marketing Authorisation Holder

Bioenvision Limited

Bassett House, 5 Southwell Park Road, Camberley, Surrey GU15 3PU

8. Marketing Authorisation Number(S)

60 mg capsules - PL 19999/0002

120 mg capsules - PL 19999/0003

9. Date Of First Authorisation/Renewal Of The Authorisation

27 June 1990

10. Date Of Revision Of The Text

05 February 2007