- Approval Id
- 1b87fd5bc67004a5
- Drug Approval Emc Name
- Methyldopa Tablets BP 250mg
- Drug Name
- Methyldopa Tablets BP 250mg
- Company Name
- Flamingo Pharma (UK) Ltd
- Company Address
- The BLOC, 38 Springfield Way, Kingston Upon Hull, HU10 6RJ, UK
- Company Website
- http://www.flamingopharma.co.uk
- Company Telephone
- +44 (0) 7784240228
- Company Medical Info Direct Line
- 00 800 890 13370
- Atc Code
- C02AB
- Legal Category
- Prescription only medicine
- Authorisation Holder
- Flamingo Pharma UK Ltd.
1st floor, Kirkland House,
11-15 Peterborough Road,
Harrow, Middlesex,
HA12AX, United Kingdom.
- Authorisation Number
- PL 43461/0092
- Authorisation Date
- 05/03/2011
- Instruction Authorisation Holder
- Flamingo Pharma UK Ltd.
1st floor, Kirkland House,
11-15 Peterborough Road,
Harrow, Middlesex,
HA12AX, United Kingdom.
- Instruction Authorisation Number
- PL 43461/0092
- Instruction Authorisation Date
- 05/03/2011
- Instruction Composition
- | | |
| --- | --- |
| Active: Methyldopa Ph. Eur | Per Tablet: 281.960 mg equivalent to methyldopa anhydrous 250mg |
\*\*Excipient(s) with known effect\*\*
Each tablet contains 33 mg of lactose (as monohydrate).
For the full list of excipients, see Section 6.1.
- Instruction Dosage Form
- Round, yellow film coated biconvex tablet.
- Instruction Clinical Particulars
- 4.1 Therapeutic indications
Treatment of moderate to severe hypertension.4.2 Posology and method of administration
ADULTS:
250mg 2-3 times daily for 2 days, adjusted at intervals of 2 days until adequate response is obtained. Maximum dose 3g daily (increase evening dose first). Usual effective dose 500mg to 2g daily.
Many patients experience sedation for two or three days when therapy with methyldopa is started or when the dose is increased. When increasing the dosage, therefore, it may be desirable to increase the evening dose first.
Withdrawal of methyldopa is followed by return of hypertension, usually within 48 hours. This is not complicated generally by an overshoot of blood pressure.
Patients with renal impairment:
Methyldopa is largely excreted by the kidney, and patients with impaired renal function may respond to smaller doses.
Other antihypertensives:
Therapy with methyldopa 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, methyldopa 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.
When methyldopa is given to patients on other antihypertensives the dose of these agents may need to be adjusted to effect a smooth transition.
When 500 mg of methyldopa is added to 50 mg of hydrochlorothiazide, the two agents may be given together once daily.
ELDERLY:
Initial dose should be kept as low as possible not exceeding 250mg daily. An appropriate starting dose would be 125mg twice daily, increased slowly as required but not exceeding a maximum daily dosage of 2g.
Syncope in older patients may be related to an increased sensitivity and advanced arteriosclerotic vascular disease. This may be avoided by lower doses.
CHILDREN:
10mg/kg bodyweight daily in 2-4 divided doses. The dosage is increased or decreased until adequate response is achieved. Maximum recommended daily dose is 65mg/kg bodyweight or 3g whichever is less.
Method of administration
Oral.4.3 Contraindications
Methyldopa tablets are contraindicated in patients with:
• Hypersensitivity to methyldopa or to any of the excipients listed in section 6.1 (including hepatic disorders associated with previous methyldopa therapy)
• A history of depression
• Active hepatic disease such as acute hepatitis and active cirrhosis
• On therapy with monoamine oxidase inhibitors (MAOIs)
• Porphyria
• Methyldopa Tablets are not recommended for the treatment of catecholamine-secreating tumour such as phaeochromocytoma or paraganglioma (see 4.4 'Special warnings and precautions for use').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, Methyldopa tablets 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 bloodcell 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.
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.
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.
Methyldopa Tablets should be used with extreme caution in patients, or in near relatives of patients, with hepatic porphyria.
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 or paraganglioma.
It is important to recognise this phenomenon before a patient with a possible phaeochromocytoma or paraganglioma is subjected to surgery. Methyldopa does not interfere with measurements of VMA (vanillylmandelic acid) by those methods which convert VMA to vanillin. Methyldopa is contraindicated for the treatment of patients with a catecholamine-secreting tumour such as phaeochromocytoma or paraganglioma.
Rarely, when urine is exposed to air after voiding, it may darken because of breakdown of methyldopa or its metabolites.
Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.4.5 Interaction with other medicinal products and other forms of interaction
\*\*Lithium:\*\*
When methyldopa and lithium are given concomitantly the patient should be monitored carefully for symptoms of lithium toxicity.
\*\*Other antihypertensive drugs:\*\*
When methyldopa is used with other antihypertensive drugs, potentiation of antihypertensive action may occur. The progress of patients should be carefully followed to detect side reactions or manifestations of drug idiosyncrasy. Concurrent use of verapamil and methyldopa can intensify sinus bradycardia.
\*\*Other classes of drugs:\*\*
The antihypertensive effect of methyldopa may be diminished by sympathomimetics, tricyclic antidepressants, phenothiazine derivatives and monoamine oxidase inhibitors (MAOIs), when administered concomitantly with these drugs (see 4.3 'Contra-indications'). In addition, phenothiazines may have additive hypotensive effects.
Concomitant administration of methyldopa with thiazide diuretics and other antihypertensive agents, general anaesthetics and levodopa enhances the antihypertensive effect.
The toxicity of haloperidol may be increased by concurrent use. Monoamine oxidase inhibitors should be discontinued before treatment with methyldopa.
\*\*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.4.6 Fertility, pregnancy and lactation
\*\*Pregnancy\*\*
Methyldopa has been used under close medical supervision for the treatment of hypertension during pregnancy. There is no clinical evidence of foetal abnormalities or effect on the neonate.
Published reports of the use of methyldopa during all trimesters indicate that if this drug is used during pregnancy the possibility of foetal harm appears remote.
\*\*Breast-feeding\*\*
Methyldopa crosses the placental barrier and is present in cord blood and appears in 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.4.7 Effects on ability to drive and use machines
Caution should be observed when driving or operating machinery, as methyldopa therapy may result in drowsiness, dizziness, light headedness, involuntary choreoathetotic movements in patients with severe cerebrovascular disease. The patient should be advised accordingly on initiation of therapy and/or increase in dosage.4.8 Undesirable effects
The following convention has been utilised for the classification of frequency: Very common (≥1/10), common (≥1/100 and <1/10), uncommon (≥1/1000 and <1/100), rare (≥1/10,000 and <1/1000), very rare (< 1/10,000) and not known (cannot be estimated from the available data).
| | | |
| --- | --- | --- |
| \*\*System Organ Class\*\* | \*\*Adverse event term\*\* | \*\*Frequency\*\* |
| Cardiac disorders | Bradycardia, aggravation of angina pectoris, myocarditis, pericarditis, atrioventricular block | Not known |
| Blood and lymphatic system disorders | Haemolytic anaemia, bone-marrow depression, leucopenia, granulocytopenia, thrombocytopenia, eosinophilia | Not known |
| Nervous system disorders | Sedation (usually transient)\\*, headache\\*\\*, paraesthesia, Parkinsonism, VIIth nerve paralysis, choreoathetosis\\*, mental impairment, carotid sinus syndrome, dizziness\\*, light-headedness\\*, symptoms of cerebrovascular insufficiency (may be due to lowering of blood pressure) | Not known |
| Respiratory, thoracic and mediastinal disorders | Nasal Stuffiness | Not known |
| Gastrointestinal disorders | Nausea, vomiting, abdominal distension, constipation, flatus, diarrhoea, colitis, mild dryness of mouth, glossodynia, sore or 'black' tongue, pancreatitis | Not known |
| Skin and subcutaneous tissue disorders | Rash as in eczema or lichenoid eruption, toxic epidermal necrolysis, angioedema, urticaria | Not known |
| Musculoskeletal and connective tissue disorders | Lupus-like syndrome, mild arthralgia with or without joint swelling, myalgia | Not known |
| Endocrine disorders | Hyperprolactinaemia | Not known |
| Infections and Infestations | Sialadentis | Not known |
| Vascular disorders | Orthostatic hypotension (decrease daily dosage) | Not known |
| General disorders and administrative site conditions | Asthenia or weakness\\*\\*, oedema (and weight gain) usually relieved by use of a diuretic. (Discontinue methyldopa if oedema progresses or signs of heart failure appear.), drug-related fever | Not known |
| Hepatobiliary disorders | Liver disorders including hepatitis, jaundice | Not known |
| Reproductive system and breast disorders | Breast enlargement, gynaecomastia, amenorrhoea, lactation, impotence, failure of ejaculation | Not known |
| Psychiatric disorders | Psychic disturbances including nightmares, reversible mild psychoses or depression, decreased libido | Not known |
| Investigations | Positive Coombs test, positive tests for antinuclear antibody, LE cells, and rheumatoid factor, abnormal liver-function tests, rise in blood urea | Not known |
\\*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.
\*\*Reporting of suspected adverse reactions\*\*
Reporting of suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.4.9 Overdose
Symptoms of overdose may include acute hypotension, sedation, weakness, bradycardia, dizziness, gastrointestinal disturbances, lightheadedness, constipation, distension, flatus, diarrhoea, nausea and vomiting.
Stomach emptied by aspiration, lavage and emesis may be induced if ingestion is recent. There is no specific antidote. Methyldopa is dialyzable. Treatment is symptomatic. Intravenous infusion may be given to promote urinary excretion and pressor agents such as metaraminol or noradrenaline given. Special care is needed with cardiac rate and output, blood volume, electrolyte balance, paralytic ileus, urinary function and cerebral activity. When chronic overdosage is suspected, methyldopa should be discontinued.
- Instruction Pharmacology
- 5.1 Pharmacodynamic properties
\*\*Pharmacotherapeutic group: antiadrenergic agents; ATC code: C02AB\*\*
\*\*Mechanism of action\*\*
It appears that several mechanisms of action account for the clinically useful effects of methyldopa and the current generally accepted view is that its principal action is on the central nervous system. The antihypertensive effect of methyldopa is probably due to its metabolism to alpha-methylnoradrenaline, which lowers arterial pressure by stimulation of central inhibitory alpha-adrenergic receptors, false neurotransmission, and/or reduction of plasma renin activity. Methyldopa has been shown to cause a net reduction in the tissue concentration of serotonin, dopamine, epinephrine (adrenaline) and norepinephrine (noradrenaline).5.2 Pharmacokinetic properties
Methyldopa is incompletely absorbed from the gastrointestinal tract. Methyldopa is extensively metabolised through pathways common to the catecholamines utilising dopa decarboxylates and dopamine B-hydroxylase.
Decarboxylation is stereospecific. The bioavailability of an oral dose averages 25% (± 16%) and peak plasma levels occur 2 to 3 hours later. Elimination is biphasic. It is partly conjugated mainly to the o-sulphate and is excreted by the kidneys.
The elimination half-life is 1.8 ± 0.2 hours, methyldopa has been shown to cross the placental barrier and is found in the lungs, heart and muscles after 24 hours, detectable quantities are present in the liver and kidneys. Renal excretion accounts for about two thirds of drug clearance from plasma.5.3 Preclinical safety data
None.
- Instruction Pharmaceutical Particulars
- 6.1 List of excipients
lactose monohydrate, maize starch, citric acid, talc, magnesium stearate, stearic acid, hypromellose, macrogol 400, titanium dioxide (E171), iron oxide yellow (E172).6.2 Incompatibilities
None known.6.3 Shelf life
30 months in Blister strips6.4 Special precautions for storage
Do not store above 25°C. Store in the original package in order to protect from light.6.5 Nature and contents of container
Aluminium / PVC (opaque) blister strips of 14 tablets in cartons containing 28 or 56 tablets.6.6 Special precautions for disposal and other handling
No special instruction necessary.
- Instruction Content
- ## Composition
| | |
| --- | --- |
| Active: Methyldopa Ph. Eur | Per Tablet: 281.960 mg equivalent to methyldopa anhydrous 250mg |
\*\*Excipient(s) with known effect\*\*
Each tablet contains 33 mg of lactose (as monohydrate).
For the full list of excipients, see Section 6.1.
## Pharmaceutical Form
Round, yellow film coated biconvex tablet.
## Clinical Particulars
4.1 Therapeutic indications
Treatment of moderate to severe hypertension.4.2 Posology and method of administration
ADULTS:
250mg 2-3 times daily for 2 days, adjusted at intervals of 2 days until adequate response is obtained. Maximum dose 3g daily (increase evening dose first). Usual effective dose 500mg to 2g daily.
Many patients experience sedation for two or three days when therapy with methyldopa is started or when the dose is increased. When increasing the dosage, therefore, it may be desirable to increase the evening dose first.
Withdrawal of methyldopa is followed by return of hypertension, usually within 48 hours. This is not complicated generally by an overshoot of blood pressure.
Patients with renal impairment:
Methyldopa is largely excreted by the kidney, and patients with impaired renal function may respond to smaller doses.
Other antihypertensives:
Therapy with methyldopa 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, methyldopa 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.
When methyldopa is given to patients on other antihypertensives the dose of these agents may need to be adjusted to effect a smooth transition.
When 500 mg of methyldopa is added to 50 mg of hydrochlorothiazide, the two agents may be given together once daily.
ELDERLY:
Initial dose should be kept as low as possible not exceeding 250mg daily. An appropriate starting dose would be 125mg twice daily, increased slowly as required but not exceeding a maximum daily dosage of 2g.
Syncope in older patients may be related to an increased sensitivity and advanced arteriosclerotic vascular disease. This may be avoided by lower doses.
CHILDREN:
10mg/kg bodyweight daily in 2-4 divided doses. The dosage is increased or decreased until adequate response is achieved. Maximum recommended daily dose is 65mg/kg bodyweight or 3g whichever is less.
Method of administration
Oral.4.3 Contraindications
Methyldopa tablets are contraindicated in patients with:
• Hypersensitivity to methyldopa or to any of the excipients listed in section 6.1 (including hepatic disorders associated with previous methyldopa therapy)
• A history of depression
• Active hepatic disease such as acute hepatitis and active cirrhosis
• On therapy with monoamine oxidase inhibitors (MAOIs)
• Porphyria
• Methyldopa Tablets are not recommended for the treatment of catecholamine-secreating tumour such as phaeochromocytoma or paraganglioma (see 4.4 'Special warnings and precautions for use').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, Methyldopa tablets 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 bloodcell 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.
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.
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.
Methyldopa Tablets should be used with extreme caution in patients, or in near relatives of patients, with hepatic porphyria.
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 or paraganglioma.
It is important to recognise this phenomenon before a patient with a possible phaeochromocytoma or paraganglioma is subjected to surgery. Methyldopa does not interfere with measurements of VMA (vanillylmandelic acid) by those methods which convert VMA to vanillin. Methyldopa is contraindicated for the treatment of patients with a catecholamine-secreting tumour such as phaeochromocytoma or paraganglioma.
Rarely, when urine is exposed to air after voiding, it may darken because of breakdown of methyldopa or its metabolites.
Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.4.5 Interaction with other medicinal products and other forms of interaction
\*\*Lithium:\*\*
When methyldopa and lithium are given concomitantly the patient should be monitored carefully for symptoms of lithium toxicity.
\*\*Other antihypertensive drugs:\*\*
When methyldopa is used with other antihypertensive drugs, potentiation of antihypertensive action may occur. The progress of patients should be carefully followed to detect side reactions or manifestations of drug idiosyncrasy. Concurrent use of verapamil and methyldopa can intensify sinus bradycardia.
\*\*Other classes of drugs:\*\*
The antihypertensive effect of methyldopa may be diminished by sympathomimetics, tricyclic antidepressants, phenothiazine derivatives and monoamine oxidase inhibitors (MAOIs), when administered concomitantly with these drugs (see 4.3 'Contra-indications'). In addition, phenothiazines may have additive hypotensive effects.
Concomitant administration of methyldopa with thiazide diuretics and other antihypertensive agents, general anaesthetics and levodopa enhances the antihypertensive effect.
The toxicity of haloperidol may be increased by concurrent use. Monoamine oxidase inhibitors should be discontinued before treatment with methyldopa.
\*\*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.4.6 Fertility, pregnancy and lactation
\*\*Pregnancy\*\*
Methyldopa has been used under close medical supervision for the treatment of hypertension during pregnancy. There is no clinical evidence of foetal abnormalities or effect on the neonate.
Published reports of the use of methyldopa during all trimesters indicate that if this drug is used during pregnancy the possibility of foetal harm appears remote.
\*\*Breast-feeding\*\*
Methyldopa crosses the placental barrier and is present in cord blood and appears in 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.4.7 Effects on ability to drive and use machines
Caution should be observed when driving or operating machinery, as methyldopa therapy may result in drowsiness, dizziness, light headedness, involuntary choreoathetotic movements in patients with severe cerebrovascular disease. The patient should be advised accordingly on initiation of therapy and/or increase in dosage.4.8 Undesirable effects
The following convention has been utilised for the classification of frequency: Very common (≥1/10), common (≥1/100 and <1/10), uncommon (≥1/1000 and <1/100), rare (≥1/10,000 and <1/1000), very rare (< 1/10,000) and not known (cannot be estimated from the available data).
| | | |
| --- | --- | --- |
| \*\*System Organ Class\*\* | \*\*Adverse event term\*\* | \*\*Frequency\*\* |
| Cardiac disorders | Bradycardia, aggravation of angina pectoris, myocarditis, pericarditis, atrioventricular block | Not known |
| Blood and lymphatic system disorders | Haemolytic anaemia, bone-marrow depression, leucopenia, granulocytopenia, thrombocytopenia, eosinophilia | Not known |
| Nervous system disorders | Sedation (usually transient)\\*, headache\\*\\*, paraesthesia, Parkinsonism, VIIth nerve paralysis, choreoathetosis\\*, mental impairment, carotid sinus syndrome, dizziness\\*, light-headedness\\*, symptoms of cerebrovascular insufficiency (may be due to lowering of blood pressure) | Not known |
| Respiratory, thoracic and mediastinal disorders | Nasal Stuffiness | Not known |
| Gastrointestinal disorders | Nausea, vomiting, abdominal distension, constipation, flatus, diarrhoea, colitis, mild dryness of mouth, glossodynia, sore or 'black' tongue, pancreatitis | Not known |
| Skin and subcutaneous tissue disorders | Rash as in eczema or lichenoid eruption, toxic epidermal necrolysis, angioedema, urticaria | Not known |
| Musculoskeletal and connective tissue disorders | Lupus-like syndrome, mild arthralgia with or without joint swelling, myalgia | Not known |
| Endocrine disorders | Hyperprolactinaemia | Not known |
| Infections and Infestations | Sialadentis | Not known |
| Vascular disorders | Orthostatic hypotension (decrease daily dosage) | Not known |
| General disorders and administrative site conditions | Asthenia or weakness\\*\\*, oedema (and weight gain) usually relieved by use of a diuretic. (Discontinue methyldopa if oedema progresses or signs of heart failure appear.), drug-related fever | Not known |
| Hepatobiliary disorders | Liver disorders including hepatitis, jaundice | Not known |
| Reproductive system and breast disorders | Breast enlargement, gynaecomastia, amenorrhoea, lactation, impotence, failure of ejaculation | Not known |
| Psychiatric disorders | Psychic disturbances including nightmares, reversible mild psychoses or depression, decreased libido | Not known |
| Investigations | Positive Coombs test, positive tests for antinuclear antibody, LE cells, and rheumatoid factor, abnormal liver-function tests, rise in blood urea | Not known |
\\*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.
\*\*Reporting of suspected adverse reactions\*\*
Reporting of suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.4.9 Overdose
Symptoms of overdose may include acute hypotension, sedation, weakness, bradycardia, dizziness, gastrointestinal disturbances, lightheadedness, constipation, distension, flatus, diarrhoea, nausea and vomiting.
Stomach emptied by aspiration, lavage and emesis may be induced if ingestion is recent. There is no specific antidote. Methyldopa is dialyzable. Treatment is symptomatic. Intravenous infusion may be given to promote urinary excretion and pressor agents such as metaraminol or noradrenaline given. Special care is needed with cardiac rate and output, blood volume, electrolyte balance, paralytic ileus, urinary function and cerebral activity. When chronic overdosage is suspected, methyldopa should be discontinued.
## Pharmacological Properties
5.1 Pharmacodynamic properties
\*\*Pharmacotherapeutic group: antiadrenergic agents; ATC code: C02AB\*\*
\*\*Mechanism of action\*\*
It appears that several mechanisms of action account for the clinically useful effects of methyldopa and the current generally accepted view is that its principal action is on the central nervous system. The antihypertensive effect of methyldopa is probably due to its metabolism to alpha-methylnoradrenaline, which lowers arterial pressure by stimulation of central inhibitory alpha-adrenergic receptors, false neurotransmission, and/or reduction of plasma renin activity. Methyldopa has been shown to cause a net reduction in the tissue concentration of serotonin, dopamine, epinephrine (adrenaline) and norepinephrine (noradrenaline).5.2 Pharmacokinetic properties
Methyldopa is incompletely absorbed from the gastrointestinal tract. Methyldopa is extensively metabolised through pathways common to the catecholamines utilising dopa decarboxylates and dopamine B-hydroxylase.
Decarboxylation is stereospecific. The bioavailability of an oral dose averages 25% (± 16%) and peak plasma levels occur 2 to 3 hours later. Elimination is biphasic. It is partly conjugated mainly to the o-sulphate and is excreted by the kidneys.
The elimination half-life is 1.8 ± 0.2 hours, methyldopa has been shown to cross the placental barrier and is found in the lungs, heart and muscles after 24 hours, detectable quantities are present in the liver and kidneys. Renal excretion accounts for about two thirds of drug clearance from plasma.5.3 Preclinical safety data
None.
## Pharmaceutical Particulars
6.1 List of excipients
lactose monohydrate, maize starch, citric acid, talc, magnesium stearate, stearic acid, hypromellose, macrogol 400, titanium dioxide (E171), iron oxide yellow (E172).6.2 Incompatibilities
None known.6.3 Shelf life
30 months in Blister strips6.4 Special precautions for storage
Do not store above 25°C. Store in the original package in order to protect from light.6.5 Nature and contents of container
Aluminium / PVC (opaque) blister strips of 14 tablets in cartons containing 28 or 56 tablets.6.6 Special precautions for disposal and other handling
No special instruction necessary.
