Aspen

ALDOMET® Tablets 500 mg

''Aldomet' Tablets 500 mg, contain methyldopa equivalent to 500 mg anhydrous methyldopa

Film coated tablets

Yellow coloured, round, film-coated tablets marked 'ALDOMET' on one side and '500' on the other.

In the treatment of hypertension (mild, moderate or severe).

Use in Adults: Initial dosage: Usually 250 mg two or three times a day, for two days.

Adjustment: Usually adjusted at intervals of not less than two days, until an adequate response is obtained. The maximum recommended daily dosage is 3 g.

Many patients experience sedation for two or three days when therapy with 'Aldomet' is started or when the dose is increased. When increasing the dosage, therefore, it may be desirable to increase the evening dose first.

General considerations: Methyldopa is largely excreted by the kidney, and patients with impaired renal function may respond to smaller doses.

Withdrawal of 'Aldomet' is followed by return of hypertension, usually within 48 hours. This is not complicated generally by an overshoot of blood pressure.

Therapy with 'Aldomet' may be initiated in most patients already on treatment with other antihypertensive agents by terminating these antihypertensive medications gradually, as required. Following such previous antihypertensive therapy, 'Aldomet' should be limited to an initial dose of not more than 500 mg daily and increased as required at intervals of not less than two days.

'Aldomet' may also be used concomitantly with the combination of amiloride hydrochloride and hydrochlorothiazide (such as Moduret-25) or beta-blocking agents, such as timolol maleate.

When methyldopa is given to patients on other antihypertensives the dose of these agents may need to be adjusted to effect a smooth transition.

Use in Children: initial dosage is based on 10 mg/kg of bodyweight daily in 2-4 oral doses. The daily dosage is then increased or decreased until an adequate response is achieved. The maximum dosage is 65 mg/kg or 3.0 g daily, whichever is less.

Use in the elderly: Syncope in the older patients may be related to an increased sensitivity and advanced arteriosclerotic vascular disease. This may be avoided by using lower doses.

'Aldomet' is contra-indicated in patients with:

• With active hepatic disease, such as acute hepatitis and active cirrhosis

• With hypersensitivity (including hepatic disorders associated with previous methyldopa therapy) to any component of these products

• With depression

• On therapy with monoamine oxidase inhibitors (MAOIs).

'Aldomet' is not recommended for the treatment of phaeochromocytoma (see 4.4 'Special warnings and precautions for use').

Acquired haemolytic anaemia has occurred rarely; should symptoms suggest anaemia, haemoglobin and/or haematocrit determinations should be made. If anaemia is confirmed, tests should be done for haemolysis. If haemolytic anaemia is present, 'Aldomet' should be discontinued. Stopping therapy, with or without giving a corticosteroid, has usually brought prompt remission. Rarely, however, deaths have occurred.

Some patients on continued therapy with methyldopa develop a positive Coombs test. From the reports of different investigators, the incidence averages between 10% and 20%. A positive Coombs test rarely develops in the first six months of therapy, and if it has not developed within 12 months, it is unlikely to do so later on continuing therapy. Development is also dose-related, the lowest incidence occurring in patients receiving 1 g or less of methyldopa per day. The test becomes negative usually within weeks or months of stopping methyldopa.

Prior knowledge of a positive Coombs reaction will aid in evaluating a cross-match for transfusion. If a patient with a positive Coombs reaction shows an incompatible minor cross-match, an indirect Coombs test should be performed. If this is negative, transfusion with blood compatible in the major cross-match may be carried out. If positive, the advisability of transfusion should be determined by a haematologist.

Reversible leucopenia, with primary effect on granulocytes has been reported rarely. The granulocyte count returned to normal on discontinuing therapy. Reversible thrombocytopenia has occurred rarely.

Occasionally, fever has occurred within the first three weeks of therapy, sometimes associated with eosinophilia or abnormalities in liver-function tests. Jaundice, with or without fever, also may occur. Its onset is usually within the first two or three months of therapy. In some patients the findings are consistent with those of cholestasis. Rare cases of fatal hepatic necrosis have been reported. Liver biopsy, performed in several patients with liver dysfunction, showed a microscopic focal necrosis compatible with drug hypersensitivity. Liver-function tests and a total and differential white blood-cell count are advisable before therapy and at intervals during the first six weeks to twelve weeks of therapy, or whenever an unexplained fever occurs.

Should fever, abnormality in liver function, or jaundice occur, therapy should be withdrawn. If related to methyldopa, the temperature and abnormalities in liver function will then return to normal. Methyldopa should not be used again in these patients. Methyldopa should be used with caution in patients with a history of previous liver disease or dysfunction.

Tolerance to this product may occur.

Patients may require reduced doses of anaesthetics when on methyldopa. If hypotension does occur during anaesthesia, it can usually be controlled by vasopressors. The adrenergic receptors remain sensitive during treatment with methyldopa.

Dialysis removes methyldopa; therefore, hypertension may recur after this procedure.

If cerebral or myocardial infarction occurs during therapy with 'Aldomet', adjustment of dosage or temporary cessation of 'Aldomet' may be required during the acute phase. Therapy with 'Aldomet' should not be initiated during the acute phase of cerebral or myocardial infarction.

Rarely, involuntary choreoathetotic movements have been observed during therapy with methyldopa in patients with severe bilateral cerebrovascular disease. Should these movements occur, therapy should be discontinued.

Interference with laboratory tests:

Methyldopa may interfere with the measurement of urinary uric acid by the phosphotungstate method, serum creatinine by the alkaline picrate method, and AST (SGOT) by colorimetric method. Interference with spectrophotometric methods for AST (SGOT) analysis has not been reported.

As methyldopa fluoresces at the same wavelengths as catecholamines, spuriously high amounts of urinary catecholamines may be reported interfering with a diagnosis of phaeochromocytoma.

It is important to recognise this phenomenon before a patient with a possible phaeochromocytoma is subjected to surgery. Methyldopa does not interfere with measurements of VMA (vanillylmandelic acid) by those methods which convert VMA to vanillin.

Rarely, when urine is exposed to air after voiding, it may darken because of breakdown of methyldopa or its metabolites.

When methyldopa is used with other anti-hypertensive drugs or alcohol, the antihypertensive action may be enhanced. Similarly the antihypertensive effect may be modified by concurrent administration of tricyclic antidepressants, sympathomimetics, phenothiazines and monoamine oxidase inhibitors (MAOIs). Interaction with haloperidol has been reported. When methyldopa and lithium are given concomitantly the patient should be monitored carefully for symptoms of lithium toxicity. The progress of patients should be carefully followed to detect side reactions or manifestations of drug idiosyncrasy.

Iron:

Several studies demonstrate a decrease in the bioavailability of methyldopa when it is ingested with ferrous sulphate or ferrous gluconate. This may adversely affect blood pressure control in patients treated with methyldopa.

Patients may require reduced doses of anaesthetics when on methyldopa. If hypotension doses occur during anaesthesia, it can usually be controlled by vasopressor. The adrenergic receptors remain sensitive during treatment with methyldopa.

Use in pregnancy

'Aldomet' has been used under close medical supervision for the treatment of hypertension during pregnancy. There was no clinical evidence that 'Aldomet' caused foetal abnormalities or affected the neonate.

Methyldopa crosses the placental barrier and appears in cord blood and breast milk.

Although no obvious teratogenic effects have been reported, the possibility of foetal injury cannot be excluded and the use of the drug in women who are, or may become, pregnant or who are breast-feeding their newborn infant requires that anticipated benefits be weighed against possible risks.

Breast-feeding mothers

Methyldopa appears in breast milk. The use of the drug in breast-feeding mothers requires that anticipated benefits be weighed against possible risks.

Sedation, usually transient, may occur during the initial period of therapy or whenever the dose is increased. If affected, patients should not attempt to drive, or operate machinery.

Sedation, usually transient, may occur during the initial period of therapy or whenever the dose is increased. If affected, patients should not attempt to drive, or operate machinery. Headache, asthenia or weakness may be noted as early and transient symptoms.

The following reactions have been reported:

Central nervous system: Sedation (usually transient), headache, asthenia or weakness, paraesthesiae, Parkinsonism, Bell's palsy, involuntary choreoathetotic movements. Psychic disturbances including nightmares, impaired mental acuity and reversible mild psychoses or depression. Dizziness, light-headedness, and symptoms of cerebrovascular insufficiency (may be due to lowering of blood pressure).

Cardiovascular: Bradycardia, prolonged carotid sinus hypersensitivity, aggravation of angina pectoris. Orthostatic hypotension (decrease daily dosage). Oedema (and weight gain) usually relieved by use of a diuretic. (Discontinue methyldopa if oedema progresses or signs of heart failure appear.)

Gastro-intestinal: Nausea, vomiting, distension, constipation, flatus, diarrhoea, colitis, mild dryness of mouth, sore or 'black' tongue, pancreatitis, sialadenitis.

Hepatic: Liver disorders including hepatitis, jaundice, abnormal liver-function tests.

Haematological: Positive Coombs test, haemolytic anaemia, bone-marrow depression, leucopenia, granulocytopenia, thrombocytopenia, eosinophilia. Positive tests for antinuclear antibody. LE cells, and rheumatoid factor.

Allergic: Drug-related fever and lupus-like syndrome, myocarditis, pericarditis.

Dermatological: Rash as in eczema or lichenoid eruption, toxic epidermal necrolysis.

Other: Nasal stuffiness, rise in blood urea, breast enlargement, gynaecomastia, hyperprolactinaemia, amenorrhoea, lactation, impotence, decreased libido, failure of ejaculation, mild arthralgia with or without joint swelling, myalgia.

If ingestion is recent, emesis may be induced or gastric lavage performed. Treatment is symptomatic. Infusions may be helpful to promote urinary excretion. Special attention should be directed towards cardiac rate and output, blood volume, electrolyte balance, paralytic ileus, urinary function and cerebral activity.

Administration of sympathomimetic agents may be indicated. When chronic overdosage is suspected, 'Aldomet' should be discontinued.

Methyldopa reduces both supine and standing blood pressure. It usually produces highly effective lowering of the supine pressure with infrequent symptomatic postural hypotension. Exercise hypotension and diurnal blood pressure variations rarely occur.

The maximum decrease in blood pressure occurs four to six hours after oral dosage. Once an effective dosage level is attained, a smooth blood- pressure response occurs in most patients in 12 to 14 hours. After withdrawal, blood pressure usually returns to ore-treatment levels within 24 t0 48 hours.

Methyldopa has no direct effect on cardiac function and usually does not reduce glomerular filtration rate, renal blood flow, or filtration traction, cardiac output usually is maintained without cardiac acceleration. In some patients the heart rate is slowed.

Normal or elevated plasma renin activity may decrease in the course of methyldopa therapy.

Absorption of oral methyldopa is variable and incomplete. Bioavailability after oral administration averages 25%. Peak concentrations in plasma occur at two to three hours, and elimination of the drug is biphasic. Plasma half-life is 1.8 ± 0.2 hours. Approximately 70% of the oral form of the drug which is absorbed is excreted in the urine as methyldopa and its mono-O-sulphate conjugate.

Methyldopa crosses the placental barrier, appears in cord blood and appears in breast milk.

No relevant information.

Tablet-core: cellulose powder, anhydrous citric acid; collodial silicon dioxide; ethylcellulose; guar gum; magnesium stearate; sodium calcium edetate;

Tablet-coating: propylene glycol; anhydrous citric acid; hypromellose; quinoline yellow aluminium lake E104; red iron oxide E172; talc; titanium dioxide, carnauba wax.

Not applicable

3 years

Bottle

Do not store above 25°C.

Keep container tightly closed in order to protect from light

Blister

Do not store above 25°C.

Store in original package in order to protect from light

White polyethylene bottle of 100 and 500 tablets with turquoise polyethylene closure. PVC blister packs with aluminimum lids contain 60 and 90 tablets (in strips of 10 tablets).

Not all pack sizes may be marketed.

None

Aspen Europe Gmbh

Industriestrasse 32-36

D-23843 Bad Oldesloe

Germany

Tablets 500 mg: PA 1568/004/002

Licence first granted: 21 February 1974

March 2011