Methyldopa Tablets Bp 250mg
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Methyldopa Tablets 250 mg.
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains Methyldopa 250mg For excipients see 6.1.
3 PHARMACEUTICAL FORM
Buff, circular biconvex tablet engraved with AM on one side and A336 on the other.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Methyldopa tablets are indicated for the treatment of moderate to severe hypertension.
4.2 Posology and method of administration
Adult: Initia1 dose: 250 mg 2-3 times daily for 2 days, adjusted at intervals of 2 days until adequate response is obtained. Maximum recommended daily dose is 3 g.
Children: 10 mg/kg body weight daily in 2-4 divided doses.
The dosage is increased or decreased until adequate response is achieved. Maximum recommended daily dose is 65 mg/kg body weight or 3 g, whichever is less.
Use in the elderly: Initial dose in the elderly should be kept as low as possible not exceeding 250 mg daily. An appropriate starting dose would be 125 mg twice daily. Increased slowly as required but not exceeding a maximum daily dosage of 2 g.
Route of administration: Oral
4.3 Contraindications
Hypersensitivity to methyldopa or any of the ingredients.
Acute hepatic disease such as acute hepatitis and active cirrhosis. Phaeochromocytoma.
Depression
Therapy with monoamine oxidase inhibitors (MAOIs)
4.4 Special warnings and precautions for use
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 Should fever, abnormality in liver function, or jaundice occur, therapy should be withdrawn.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.
The development of a positive direct Coombs' test occurs in 10-20% of patients and is dose related, the lowest incidence occurring in patients receiving 1g or less of methyldopa daily. It rarely develops in the first six months of treatment and if not encountered within twelve months is unlikely to occur. The test becomes negative usually within weeks or months of cessation of methyldopa.
Prior knowledge of a positive Coombs reaction will aid in evaluating a crossmatch 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.
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 made for haemolysis; if present therapy should be discontinued. Stopping therapy with or without giving corticosteroid has usually brought prompt remission, however, rarely deaths have occurred.
Reversible leucopenia with primary effect on granulocytes has been reported rarely, but the granulocyte count has reverted back to normal on discontinuing therapy. Reversible thrombocytopenia has occurred rarely.
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 is contraindicated in patients with hepatic porphyria. It should be used with extreme caution in near relatives of patients with hepatic porphyria.
4.5 Interaction with other medicinal products and other forms of interaction
The hypotensive effect of Methyldopa may be enhanced by: - alcohol, alprostadil, anaesthetics (patients may require reduced doses of anaesthetics when on methyldopa. If hypotension does occur during anaesthesia, it can usually be controlled by vasopressors), linezolid, antidepressants, other antihypertensives (The progress of patients should be carefully monitored to detect side-effects or manifestations of drug idiosyncrasy), antipsychotics (concomitant use can also increase the risk of extrapyrimidal effects), anxiolytics, hypnotics, beta-blockers, calcium channel blockers, diuretics, moxisylyte, muscel relaxants such as baclofen or tizanidine, levodopa, entacapone , nitrates beta-2 sympathomimetics (acute hypotension has been reported with salbutamol infusion).
The hypotensive effect of Methyldopa may be diminished by corticosteroids, estrogens and combined oral contraceptives and carbonoxolone.
The hypotensive effect of Methyldopa may be diminished by:- Analgesics such as NSAIDs, iron (several studies demonstrate a decrease in the bioavailability of methyldopa when it is ingested with ferrous sulphate or ferrous gluconate), corticosteroids, estrogens, combined oral contraceptives and carbonoxolone.
Concomitant use with MAOIs should be avoided
Methyldopa may antagonise the antiparkinson effect of dopaminergics.
When Methyldopa and lithium are given concomitantly the patient should be monitored carefully for symptoms of lithium toxicity.
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 the colorimetric method. Interference of the latter with spectrophotometric methods have 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.
4.6 Fertility, Pregnancy and lactation
No teratogenic effects have been reported, however the possibility of foetal injury cannot be excluded and use of the drug during pregnancy and in nursing mothers requires that anticipated benefits be weighed against possible risks.
It has been used under medical supervision for the treatment of hypertension. There is no evidence of foetal abnormalities. Methyldopa crosses the placental barrier and is present in cord blood and in breast milk.
4.7 Effects on ability to drive and use machines
Extreme caution should be observed when driving or operating machinery, as methyldopa therapy may result in drowsiness, dizziness, lightheadedness, involuntary choreoathetotic movements. In patients with severe cerebrovascular disease the patient should be advised accordingly.
4.8 Undesirable effects
The most common side-effect of methyldopa is drowsiness. This is usually transient and may occur during the initial period of therapy or when the dose is increased.
Other side-effects are rare, but the following have been reported:
Blood and lymphatic system disorders: Positive Coombs test, haemolytic anaemia, bone marrow depression, leucopenia, granulocytopenia,
thrombocytopenia, eosinophilia, uraemia. Positive tests for antinuclear antibody, LE cells, and rheumatoid factor.
Immune system disorders:
Hypersensitivity reactions including drug-related fever, lupus-like syndrome, myocarditis, pericarditis.
Endocrine disorders:
Hyperprolactinaemia.
Nervous system disorders: 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).
Cardiac disorders: Bradycardia, prolonged carotid sinus hypersensitivity, aggravation of angina pectoris.
Vascular disorders: 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).
Respiratory, thoracic and mediastinal disorders: Nasal stuffiness.
Gastrointestinal disorders: Gastrointestinal disturbance, nausea, vomiting, distension, constipation, flatus, diarrhoea, colitis, mild dryness of mouth, stomatitis, sore or “black” tongue, pancreatitis, sialadenitis.
Hepatobiliary disorders: Liver disorders including hepatitis, jaundice, abnormal liver function tests.
Skin and subcutaneous tissue disorders: Rash such as in eczema or lichenoid eruption, toxic epidermal necrolysis.
Musculoskeletal, connective tissue and bone disorders: Mild arthralgia with or without joint swelling, myalgia.
Reproductive system and breast disorders: Amenorrhoea, breast enlargement, gynaecomastia, lactation, failure of ejaculation, impotence, decreased libido.
4.9 Overdose
Acute overdosage may produce acute hypotension with other responses attributable to brain and gastrointestinal malfunction (excessive sedation, weakness, bradycardia, dizziness, light-headedness, constipation, distension, flatus, diarrhoea, nausea and vomiting).
If ingestion is recent emesis may be induced or gastric lavage performed. There is no specific antidote, but methyldopa is dialysable.
Treatment is largely symptomatic but if necessary intravenous infusion may be given to promote urinary excretion and pressor agents given cautiously.
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 methyldopa should be discontinued.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic Group: Antiadrenergic agents. centrally acting ATC Code: C02A B02
Methyldopa is an antihypertensive agent acting centrally by stimulating alpha adrenergic receptors.
It inhibits the decarboxylation of dopa to dapamine but this action is not responsible for the hypotensive effect.
It is suggested that a metabolite, alpha methylnoradrenaline may act as a false transmitter in the CNS.
It reduces tissue concentration of dopamine, noradrenaline, adrenaline and serotonin.
Pharmacokinetic properties
5.2
Methyldopa is incompletely absorbed from the gastro-intestinal tract. It is partially conjugated mainly to o-sulphate. Sulphation to a-methyldopa-mono-o-sulphate probably occurs during absorption in the intestinal wall.
Peripheral decarboxylation is not essential for hypotensive action of a-methyldopa in man.
D-methyldopa is less well absorbed than the L-methyldopa. There is stereoselective absorption. It is minimally bound to plasma proteins and is distributed early to the kidneys. Small amount are found in the lungs, heart and muscles after 24 hours, detectable quantities are present in the liver and kidneys.
Methyldopa is extensively metabolised through pathways common to the catecholamines utilising dopa decarboxylases and dopamine ^-hydroxylase. Decarboxylation is stereospecific. D-methylation (catechol-o-methyl transferase) and sulphation are quantitatively important routes. Metabolites include 3-o-methyl-a-methyldopa, a-methyldopaniine, 3-o-methyl-a-methyldopamine, a-methylnorepinephrine, and 3,4-dihydroxyphenylacetone. cz-a-methyldopamine and a-methylnorepinephrine are pharmacologically active.
The plasma elimination half-life of a-methyldopa in normal adult subjects is 106 ± 12 minutes and 3.6 hours in patients with advanced renal failure. Following the elimination of most bf the drug (95%), a second elimination phase appears with a half-life of 7 to 16 hours. It is excreted through the kidneys.
5.3 Preclinical safety data
There are no pre-clinical data of relevance to the prescriber that are additional to that already included in other sections of the SmPC.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Ethylcellulose Sodium starch glycolate
Magnesium stearate
Film Coating Hypromellose Polyethylene Glycol 6000
Mastercote Yellow Contains (Quinoline Yellow Aluminium Lake E104 Erythrosine Aluminium Lake E127, Vegetable Carbon Black, Titanium Dioxide E171, Hypromellose)
6.2 Incompatibilities
None known.
6.3 Shelf life
3 years for opaque plastic containers. 2 years for blister packs.
6.4 Special precautions for storage
Keep out of the reach of children. Protect from heat, light and moisture.
6.5 Nature and contents of container
Opaque plastic containers in pack sizes of 28, 30, 42, 50, 56, 60, 84, 90, 100, 112, 250, 500, 1000 and bulk tablets.
Opaque plastic container composed of either high density polypropylene or high density polyethylene with a tamper evident or child resistant tamper evident closure composed of high density polyethylene for all pack sizes (28, 30,42, 50, 56, 60, 84, 90, 100, 112,250, 500, 1000 and bulk with a packing inclusion of polyether foam or polyethylene or polypropylene made-filler.
Blister packs of aluminium/opaque PVC. It is packed in printed cartons in pack sizes of 28, 30, 42, 56, 60, 84, 90 and 112.
Not all packs may be marketed.
6.6 Special precautions for disposal
No special instructions
7 MARKETING AUTHORISATION HOLDER
Crescent Pharma Limited
3&4 Quidhampton Business Units
Polhampton Lane
Overton
Hampshire
RG25 3ED
UK
8 MARKETING AUTHORISATION NUMBER(S)
PL 20416/0405
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
29/09/1977 / 27/09/2005
10 DATE OF REVISION OF THE TEXT
20/03/2015