Cytadren (Aminoglutethimide)


Novartis Pharmaceuticals


Adrenal Suppressant – Reversible Inhibitor of Peripheral Estrogen Synthesis

Action And Clinical Pharmacology: Cushing’s Syndrome: Aminoglutethimide is a potent reversible inhibitor of adrenal mineralocorticoid and glucocorticoid synthesis. It partially inhibits the enzymatic conversion of cholesterol to pregnenolone, the reaction that initiates steroidogenesis in the adrenal cortex. As well, aminoglutethimide blocks the C-11, C-18 and C-21 hydroxylation of steroids. In Cushing’s syndrome of all etiologies other than drug-induced, the inhibition of cortisol biosynthesis by aminoglutethimide markedly reduces excessive plasma cortisol.

Breast Carcinoma: In addition to the effect on the adrenal cortex, aminoglutethimide also inhibits the aromatization of androgens into estrogens in peripheral tissues. The aromatase mediated conversion of androgens into estrogens is the source of estrogen in the postmenopausal woman. The aromatase enzyme is present in liver, muscle, fat, and breast tissue including breast carcinoma. Aminoglutethimide does not inhibit the formation of testosterone or dehydrotestosterone. Thus, maintenance of androgen levels with relative suppression of estrogens may be of potential benefit.

In vitro studies have shown that the blockade of aromatization occurs at aminoglutethimide concentrations 10 times lower than those required to prevent steroidogenesis. It is believed that this extra-adrenal blockade of aromatization of androgens of adrenal origin into estrogens by aminoglutethimide is of overriding therapeutic importance in the treatment of breast carcinoma in the postmenopausal woman.

Inhibition of adrenal cortisol production by aminoglutethimide leads to a reflex rise in adrenocorticotrophic hormone (ACTH) secretion from the pituitary. The latter overcomes the cortisol-lowering effect of aminoglutethimide leading to the so-called “adrenal escape phenomenon”. The compensatory increase in ACTH secretion can be suppressed by the simultaneous administration of a glucocorticoid.

Aminoglutethimide increases the rate of its metabolism and that of certain glucocorticoids including dexamethasone but not of hydrocortisone. Hence, the latter is indicated as the glucocorticoid replacement therapy of choice to maintain a long-lasting adrenal suppressant effect, e.g., to prevent the “adrenal escape phenomenon”.

Aminoglutethimide causes a rapid decrease in aldosterone secretion from the adrenal cortex. In some patients, the signs and symptoms of hypoaldosteronemia occur, such as hyponatremia, dizziness, hypotension and weakness. These symptoms may be treated by administration of a mineralocorticoid such as fludrocortisone 0.1 mg orally daily or on alternate days.

Aminoglutethimide inhibits the synthesis of thyroxine by the thyroid gland. There is, however, a compensatory increase in thyroid stimulating hormone (TSH) secretion that is usually of sufficient magnitude to overcome this blockade. Thyroxine replacement therapy is therefore only occasionally required.

In spite of the TSH increase, aminoglutethimide administration, for reasons which are not entirely clear, has not been associated with an increase in prolactin secretion.

Aminoglutethimide only minimally inhibits estrogen production by the ovarian follicle in the premenopausal woman. Hence, it is not feasible to produce a chemical oophorectomy in these women with this drug.

Pharmacokinetics: Aminoglutethimide is completely absorbed from the gastrointestinal tract and its systemic availability is estimated to be 92 to 98%. Absorption is rapid, peak plasma concentrations being reached within 1 to 4 hours after oral administration. The peak concentrations of aminoglutethimide average 5.9 µg/mL (25.4 µmol/L) after ingestion of a 500 mg dose.

Mean steady state plasma concentrations in patients receiving 500 and 1 000 mg aminoglutethimide daily are variable and are approximately 4.5 µg/mL and 9.5 µg/mL respectively, after 3 months of therapy. For doses ranging from 125 to 1 000 mg/day, steady state concentrations are proportional to the dose. The major plasma metabolite, N-acetylaminoglutethimide, reaches steady state concentrations of about 25 to 35% of those of the unchanged drug. The concentration of aminoglutethimide in blood cells is 1.4 to 1.7 times that in plasma. The extent of binding to plasma proteins is 21 to 25%, with the major binding protein being albumin.

Total plasma clearance averages 3.5 L/h following single aminoglutethimide doses. It increases to 4.4 L/h during long-term treatment of patients, owing to hepatic enzyme induction. At the same time the volume of distribution decreases from 76 to 53 L. As a result of these changes, the elimination half-life falls from about 15 hours after a single dose to 9 hours at steady state.

Aminoglutethimide is cleared from the body partly by hepatic metabolism and partly by direct renal excretion. Metabolism primarily involves oxidation and acylation of the aromatic amino group of the drug. The metabolites formed have no inhibitory effect on aromatase and desmolase, or are several times less active than aminoglutethimide.

Excretion of the drug and its metabolites is predominantly renal: 90 to 97% of a dose is recovered in urine, only 3 to 7% in bile. Urinary output of unchanged aminoglutethimide accounts for about 47% of the dose at steady state. N-hydroxylaminoglutethimide is the major urinary metabolite in patients whose liver enzymes have been induced by the drug; it constitutes 20 to 25% of a dose on average.

N-acetylaminoglutethimide is a minor product in urine, accounting for less than 5% of the dose at steady state. The actual yield of this metabolite depends on the phenotype: it is about 4% in fast acetylators and 2% in slow acetylators. Thus, acetylation is an unimportant pathway of drug clearance in either case.

Upon withdrawal of aminoglutethimide, the ability of the adrenal glands to synthesize steroids returned to normal within 36 hours, suggesting that the so-called “chemical adrenalectomy” induced by aminoglutethimide is reversible.

Cushing’s Syndrome: Data from various sources indicate that aminoglutethimide is most effective in treating Cushing’s syndrome caused by adrenal carcinoma, adrenal adenoma, and ectopic ACTH producing tumors. Clinical and biochemical improvement is manifested in 27 to 55% of these treated patients. Adrenal hyperplasia frequently responds transiently to aminoglutethimide as autonomous, high levels of ACTH reduce the efficacy of the drug.

Treatment with aminoglutethimide has been shown to be useful in reducing the widespread deleterious effects of cortisone excess on body tissues, systems and fluids prior to definitive treatment. Further, aminoglutethimide has been documented to be an effective palliative agent where widespread disease makes definitive treatment impossible.

Metastatic Breast Carcinoma: In data compiled from numerous sources, objective responses (complete response+partial response) to aminoglutethimide were seen in 28 to 37% of patients, lasting for a mean duration of 1.8 years. The responses in general are significantly higher (total 50%) when patients with stabilized disease are included in the final analysis. The remission rate has been shown to be highest in those patients with soft tissue and bone metastases; metastases in liver and lung rarely responded to aminoglutethimide.

The objective response (complete+partial response) was higher in patients with estrogen receptor positive tumors than those with estrogen receptor negative tumors.

The rate and mean duration of objective responses (complete response+partial response) to aminoglutethimide treatment are similar to those seen following surgical ablative procedures.

Aminoglutethimide is as effective as tamoxifen citrate in producing remission of metastatic breast carcinoma. Bone metastases appear to be more responsive to aminoglutethimide than to tamoxifen citrate.

Up to 30% of patients initially refractory to tamoxifen citrate may show an objective response to aminoglutethimide.

After remission and relapse on tamoxifen citrate, up to 48% of these patients may experience an objective response to aminoglutethimide.

Indications And Clinical Uses: Cushing’s Syndrome: For the palliative treatment of Cushing’s syndrome of all etiologies other than drug induced. It is effective in reducing elevated plasma cortisol levels to one half or less of pretreatment levels in 30 to 60% of treated patients. A sustained response to aminoglutethimide is most frequently observed in patients with Cushing’s syndrome due to adrenal adenoma or carcinoma. However, pituitary-dependent adrenal hyperplasia responds initially to aminoglutethimide in up to 60% of cases. Aminoglutethimide has no effect on the disease processes that underlie Cushing’s syndrome. It is useful in the control of hypercortisolism as an interim measure until definitive therapy is instituted or where such therapy is not appropriate. Therapy with aminoglutethimide for longer than 3 months has been studied only in a limited number of patients.

Metastatic Breast Carcinoma: In combination with glucocorticoid replacement for the palliative treatment of metastatic breast carcinoma in the naturally or artificially induced postmenopausal woman. Patients with estrogen receptor positive tumors are most likely to benefit from aminoglutethimide therapy. The remission rates appear to be the highest in soft tissue and bone metastases; metastases in liver and lung rarely respond to aminoglutethimide.

Up to 30% of patients initially refractory to tamoxifen citrate may show an objective response to aminoglutethimide.

After remission and relapse on tamoxifen citrate, up to 48% of these patients may experience an objective response to aminoglutethimide (see Pharmacology).

Aminoglutethimide treatment should be continued only in those patients who have demonstrated a response to it within the first 3 months.

Contra-Indications: Severe manifestations of hypersensitivity to glutethimide or aminoglutethimide or its excipients, in pre-menopausal women with metastatic breast carcinoma and in inducible porphyria.

Manufacturers’ Warnings In Clinical States: Adrenocortical Insufficiency: Aminoglutethimide may cause adrenocortical insufficiency which will usually present after 24 to 48 hours of treatment. Aminoglutethimide should therefore always be combined with a glucocorticoid, such as hydrocortisone or cortisone acetate. Under conditions of stress such as surgery, trauma, or acute illness, patients should be carefully monitored and the dose of hydrocortisone or cortisone acetate increased. Mineralocorticoid supplements may be indicated. Dexamethasone, prednisone or prednisolone are not recommended because their rates of metabolism are enhanced by aminoglutethimide (see Precautions, Drug Interactions).

Suppression of Aldosterone Production: Aminoglutethimide may suppress aldosterone production by the adrenal cortex and thereby cause orthostatic or persistent hypotension. Blood pressure should be followed in all patients at appropriate intervals. Patients should be advised of the possible occurrence of weakness and dizziness as symptoms of hypotension, and of measures that could be taken should they occur.

CNS Depression: Aminoglutethimide may depress the CNS resulting in lethargy or somnolence. Ataxia has been noted in some cases. These are commonly observed at the beginning of treatment and generally abate after about 6 weeks.

Pregnancy: Aminoglutethimide can cause fetal abnormalities when administered during pregnancy. In the earlier experience with the drug, 2 cases of pseudohermaphroditism in 5 000 pregnancies were reported in female infants whose mothers took aminoglutethimide concomitantly with anticonvulsants. When administered to rats at doses of 0.5 and 1.25 times the maximum human dose, aminoglutethimide caused a decrease in fetal implantation, an increase in fetal deaths and a variety of teratogenic effects. The drug also caused pseudohermaphroditism in rats treated with approximately 3 times the highest recommended human dose. If this drug must be used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be advised of the potential hazard to the fetus and the treatment continued only if the benefits outweigh the risks.

The possibility of pregnancy should be excluded before prescribing aminoglutethimide to women of childbearing potential. During treatment such women should employ nonhormonal forms of contraception.

Carcinogenicity Studies: A 2-year carcinogenicity study conducted in rats revealed an increased incidence of benign and malignant neoplasms of the adrenal cortex and thyroid follicular cells with aminoglutethimide at a dose approximately equivalent to the maximum human daily dose, plus a small number of ovarian tubular adenomas at higher doses. These tissues are known sites for the pharmacological action of aminoglutethimide (see Pharmacology).

Precautions: Initiation of Therapy: Aminoglutethimide should be administered only by physicians who are familiar with its use; therapy should be initiated in a hospital setting until a stable dosage regimen is achieved (see Dosage).

Pulmonary Hypersensitivity: Pulmonary hypersensitivity and allergic alveolitis may occur (see Adverse Effects). If these conditions are suspected, aminoglutethimide should be withdrawn immediately.

Hypothyroidism: Hypothyroidism may occur in association with aminoglutethimide; hence, appropriate clinical observations should be undertaken and laboratory evaluations of thyroid function performed when indicated. Supplementary thyroid hormone may be required.

Hematologic Abnormalities: Hematologic abnormalities in patients receiving aminoglutethimide have been reported especially within the first 7 weeks of therapy (see Adverse Effects). Therefore, white blood cell and platelet counts should be performed at weeks 4, 8 and 12 after starting aminoglutethimide. Thereafter, blood counts are indicated in the presence of clinical symptoms. If blood dyscrasias develop, aminoglutethimide should be withdrawn.

Laboratory Abnormalities: Since elevations in AST, GGT, alkaline phosphatase, and bilirubin have been reported, appropriate clinical observations and regular laboratory tests should be performed before and during therapy.

Electrolyte Status: Serum electrolytes should be determined periodically and mineralocorticoids should be administered depending upon the clinical and/or the electrolyte status.

Information for the Patient: Occupational Hazards: Patients should be warned that drowsiness may occur, and when present, they should not drive, operate potentially dangerous machinery, or engage in other activities which require mental alertness. Patients should be warned not to consume alcohol since the effects of aminoglutethimide may be potentiated with this combination.

Patients should also be warned of the possibility of hypotension and its symptoms (see Warnings).

Aminoglutethimide may cause a maculopapular, generalized or urticarial skin rash, often associated with fever which commonly begins on day 10 and subsides by day 15 or 16 of treatment. Forewarning patients of this problem alleviates anxiety should the rash appear (see Dosage).

Drug Interactions: Aminoglutethimide induces hepatic enzymes, increasing its own metabolism and also that of several drugs including synthetic glucocorticoids such as dexamethasone, prednisone and prednisolone; warfarin and other oral anticoagulants; digitoxin; theophylline; medroxyprogesterone and oral antidiabetics. Appropriate laboratory tests must therefore be performed and the dosage adjusted, as necessary.

Concomitant therapy with diuretics may lead to hyponatremia.

The effects of aminoglutethimide may be potentiated if taken in combination with alcohol.

Children: The safety and effectiveness have not been established by adequate and well-controlled studies in children.

Adverse Reactions: Adverse reactions reported in patients treated for Cushing’s syndrome and metastatic breast cancer include observations in patients who received aminoglutethimide for periods ranging from a few days to several years. Patients concurrently received glucocorticoid and occasionally mineralocorticoid replacement therapy. Approximately 60% of patients reported one or more unwanted effects, most of which disappeared spontaneously with continued administration of aminoglutethimide.

Although some of these symptoms may not be necessarily ascribed to aminoglutethimide therapy, they are listed as alerting information.

CNS: Frequent: drowsiness, lethargy; Occasional: dizziness (vertigo); Rare: ataxia, headache, depression; Isolated cases: insomnia, confusion, anxiety, hallucinations, poor memory, seizures.

Skin and Appendages: Frequent: morbilliform, maculopapular skin rash (sometimes accompanied by fever); Rare: pruritus, urticaria; Isolated cases: exfoliative dermatitis, Stevens-Johnson syndrome, Lyell’s syndrome.

Gastrointestinal: Occasional: nausea; Rare: diarrhea, vomiting, constipation, anorexia; Isolated cases: indigestion.

Systemic: Rare: fever, sweating; Isolated cases: chills.

Hepatic: Isolated cases: hepatitis (cholestatic type, associated with itching and skin rash), jaundice.

Endocrine: Rare: adrenal insufficiency (hyponatremia, hypotension, dizziness, hypoglycemia); Isolated cases: hypothyroidism, inappropriate ADH secretion, masculinization and hirsutism in females, precocious sexual development in males in cases where aminoglutethimide has been given without a glucocorticoid.

Genitourinary: Isolated cases: renal function abnormalities, urinary retention.

Cardiovascular: Rare: hypotension; Isolated cases: tachycardia.

Hematology: Rare: agranulocytosis, leukopenia, thrombocytopenia; Isolated cases: pancytopenia, anemia, neutropenia, reduction in hemoglobin and transient decrease in white blood cell counts with chronic administration.

Allergy: Isolated cases: allergic/anaphylactic reaction, allergic alveolitis with interstitial alveolar infiltrates (see Precautions).

Laboratory Abnormalities: Rare: increased GGT (due to the enzyme-inducing effect of aminoglutethimide and usually not a sign of liver damage), hyponatremia, hyperkalemia, hypoglycemia; Isolated cases: hypercholesterolemia, increased bilirubin, elevation of alkaline phosphatase and AST.

Other: Isolated cases: nystagmus, unstable gait, arthralgia.

Adverse Reactions due to Glucocorticoid/Mineralocorticoid Replacement Therapy: Isolated cases: Cushingoid symptoms (moon face, weight gain, edema), hyperadrenalism, hypercalcemia, muscle cramps, hypertension and congestive heart failure due to its marked effect on sodium retention.

Symptoms And Treatment Of Overdose: Symptoms: The most common signs to be expected with overdosage are lethargy, dizziness, respiratory depression, ataxia, sedation, and deep coma with hypoventilation and hypotension.

Extreme weakness has been reported when patients received 3 g/day in divided doses.

Deaths have not been reported following administration of doses up to 7 g.

The signs and symptoms of acute overdosage may be aggravated or modified if alcohol, hypnotics, tranquilizers or tricyclic antidepressants have been taken at the same time.

Treatment: Gastric lavage and supportive treatment have been employed. Full consciousness following deep coma was regained 40 hours or less after ingestion of 3 or 4 g of aminoglutethimide without lavage. No evidence of hematologic, renal, or hepatic effects were subsequently found.

Close monitoring should be provided, and appropriate measures taken to support vital functions, if necessary: a parenteral glucocorticoid, preferably hydrocortisone or cortisone acetate, and/or a mineralocorticoid, such as fludrocortisone, may be indicated in the event of extreme prostration as this may be the result of adrenocortical insufficiency; measures to increase plasma volume; i.v. vasoactive drugs (e.g., norepinephrine); artificial respiration; oxygen administration.

Dialysis may be considered in severe intoxication.

Dosage And Administration: Cushing’s Syndrome: Adults: Treatment should be instituted in a hospital setting until a stable dosage regimen is achieved. Therapy should be initiated with a daily dose of 1 000 mg in 4 equally divided doses, preferably at 6-hour intervals.

The response of cortisol secreting tissue to aminoglutethimide should be followed by carefully monitoring plasma cortisol levels until the desired level of suppression is achieved. (When glucocorticoid replacement therapy is instituted, monitoring of DHEA-S (dehydroepiandrosterone sulfate) levels will provide a measure of suppression of cortisol secretion.)

If adrenal suppression is inadequate, the daily dose may be increased in increments of 250 mg each week to a maximum daily dose of 2 000 mg (2 g) in equally divided doses.

Dose reduction or temporary discontinuation may be required in the event of adverse reactions, including extreme drowsiness or severe skin rash. Incremental increases to maintenance level can then be achieved as the patient’s condition allows. If a skin rash persists for longer than 5 to 8 days, or becomes severe, the drug should be discontinued. It may be possible to reinstate therapy at a lower dosage following the disappearance of a mild to moderate rash.

Hydrocortisone: 40 mg/day or cortisone acetate 50 mg/day in equally divided doses orally is suggested as replacement therapy for frank adrenal insufficiency or when cortisol levels drop to a level where increased pituitary ACTH secretion is likely.

Fludrocortisone: If patients show the signs and symptoms of hypoaldosteronemia (e.g., hypotension, dizziness, and/or hyponatremia), fludrocortisone at a daily dose of 0.1 mg orally should be administered daily or on alternate days depending on the severity of symptoms. As fludrocortisone may have a marked effect on sodium retention, physicians should monitor patients closely for signs and symptoms of fluid retention, hypertension, congestive heart failure and related conditions.

Metastatic Breast Cancer: In order to achieve optimal therapeutic effects and to encounter the fewest side effects, aminoglutethimide should be administered orally in escalating doses together with hydrocortisone or cortisone acetate.

Aminoglutethimide: Aminoglutethimide should be administered orally in gradually increasing doses as follows: 125 mg b.i.d. during the first week; 250 mg b.i.d. during the second week; and if needed 250 mg t.i.d. the third week and 250 mg q.i.d. the fourth week. Gradually increasing the dose allows time for aminoglutethimide to induce its own metabolism and for patients to accommodate to the soporific side effects. In exceptional cases the daily dose may be increased to a maximum of 2 000 mg in equally divided doses.

Hydrocortisone: 100 mg/day orally (20 mg a.m.; 20 mg p.m. and 60 mg hs) during the first 2 weeks; thereafter 40 mg daily (20 mg a.m. and 20 mg p.m.).

Cortisone Acetate: 125 mg/day orally (25 mg a.m.; 25 mg p.m. and 75 mg hs) during the first 2 weeks; thereafter 37.5 to 50 mg daily (25 mg a.m. and 12.5 or 25 mg p.m.). The initial high dose of hydrocortisone or cortisone acetate reduces the severity of the skin rash that is highly steroid sensitive and which usually occurs 10 to 15 days after initiation of therapy. If the supplementary glucocorticoid medication gives rise to Cushing-like symptoms, the dosage of the glucocorticoid should be reduced.

Fludrocortisone: If patients show the signs and symptoms of hypoaldosteronemia (e.g., hypotension, dizziness, and/or hyponatremia), fludrocortisone at a daily dose of 0.1 mg orally should be administered daily or on alternate days depending on the severity of symptoms. As fludrocortisone may have a marked effect on sodium retention, physicians should monitor patients closely for signs and symptoms of fluid retention, hypertension, congestive heart failure and related conditions.

Infrequently, patients receiving aminoglutethimide continue to complain of persistent lethargy, somnolence or mild lack of alertness during chronic therapy. If facilities are available to measure plasma levels of aminoglutethimide, allow reduction in dosage to maintain drug concentrations in the therapeutic range of 10 to 15 µg/mL. If unavailable, reduction in dosage to 750 mg daily with 500 mg just before sleep and 250 mg in the morning will often alleviate this problem. It should be remembered that aminoglutethimide is excreted largely unchanged in the urine and patients with compromised renal function may have high blood levels. Five percent of patients cannot tolerate aminoglutethimide in any dosage.

Aminoglutethimide may cause a maculopapular, generalized or urticarial skin rash often associated with fever which commonly begins on day 10 and subsides by day 15 or 16 of treatment. Forewarning patients of this problem alleviates anxiety should the rash appear. The rash is responsive to a daily dose of hydrocortisone or cortisone acetate and improves with concurrent administration of an antihistamine, e.g., diphenhydramine, 25 mg b.i.d. to q.i.d. daily. If the rash persists beyond day 16, the drug should be discontinued until the rash subsides, then restarted at 125 to 250 mg daily with gradual increments to full dosage.

Availability And Storage: Each off-white, round, biconvex tablet, engraved CIBA on one side and GG on the other, fully bisected between G and G, contains: aminoglutethimide 250 mg. Nonmedicinal ingredients: cornstarch, silicon dioxide, stearic acid and talc. Energy: 0.96 kJ (0.23 kcal). Bottles of 100. Protect the tablets from heat (i.e., store between 15 to 30°C), light and humidity. Keep out of reach of children. (Shown in Product Recognition Section)

CYTADREN® Novartis Pharmaceuticals Aminoglutethimide Adrenal Suppressant – Reversible Inhibitor of Peripheral Estrogen Synthesis

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