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To update section 4.4 and 4.8 in relation to hydralazine-induced SLE; to correct a typographical error in section 2; and to update section 4.5 and 4.3 in relation to PIL user testing. Finally, to update section 10. Changes below in bold:
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
The active ingredient is 1-hydrazinophthalazine hydrochloride (hydralazine hydrochloride).
One coated tablet contains 25 mg hydralazine hydrochloride B.P.
For a full list of excipients, see section 6.1.
4.3. Contra-indications
Known hypersensitivity to hydralazine or dihydralazine or to any of the excipients. Idiopathic systemic lupus erythematosus (SLE) and related diseases.
Severe tachycardia and heart failure with a high cardiac output (e.g. in thyrotoxicosis).
Myocardial insufficiency due to mechanical obstruction (e.g. in the presence of aortic or mitral stenosis or constrictive pericarditis).
Isolated right ventricular failure due to pulmonary hypertension.
Porphyria
4.4. Special Warnings and Special Precautions for Use
Warnings
The overall ‘hyperdynamic’ state of the circulation induced by hydralazine may accentuate certain clinical conditions. Myocardial stimulation may provoke or aggravate angina pectoris. Patients with suspected or confirmed coronary artery disease should therefore be given Apresoline/Hydralazine Tablets only under cover of beta-blocker or in combination with other suitable sympatholytic agents. It is important that the beta-blocker medication should be commenced a few days before the start of treatment with Apresoline/Hydralazine Tablets.
Patients who have survived a myocardial infarction should not receive Apresoline/
Hydralazine Tablets until a post-infarction stabilisation state has been achieved.
Prolonged treatment with hydralazine (i.e. usually for more than 6 months) may provoke a systemic lupus erythematosus (SLE)-like syndrome, especially where doses exceed 100 mg daily. First symptoms are likely to be similar to rheumatoid arthritis (arthralgia, sometimes associated with fever, anaemia, leucopenia, thrombocytopenia and rash) and are reversible after withdrawal of the drug. In its more severe form it resembles acute SLE (similar manifestations as the milder form plus pleurisy, pleural effusions and pericarditis), and in rare cases renal and ocular involvement have been reported. Early detection and a timely diagnosis with appropriate therapy (i.e. treatment discontinuation and possibly long-term treatment with corticosteroids may be required to reverse these changes) are of utmost importance in this life-threatening illness to prevent more severe complications, which may sometimes be fatal.
Since such reactions tend to occur more frequently the higher the dose and the longer its duration, and since they are also more common in slow acetylators, it is recommended that for maintenance therapy the lowest effective dose should be used. If 100 mg daily fails to elicit an adequate clinical effect, the patient’s acetylator status should be evaluated. Slow acetylators and women run greater risk of developing the SLE-like syndrome and every effort should therefore be made to keep the dosage below 100 mg daily and a careful watch kept for signs and symptoms suggestive of this syndrome. If such symptoms do develop the drug should be gradually withdrawn.
Rapid acetylators often respond inadequately even to doses of 100 mg daily and therefore the dose can be raised with only a slightly increased risk of an LE like syndrome.
During long term treatment with Apresoline/Hydralazine Tablets it is advisable to determine the antinuclear factors and conduct urine analysis at intervals of approximately 6 months. Microhaematuria and / or proteinuria, in particular together with positive titres of ANF, may be initial signs of immune-complex glomerulonephritis associated with the SLE like syndrome. If overt clinical signs or symptoms develop, the drug should be withdrawn immediately.
Skin rash, febrile reactions and change in blood count occur rarely and drug should be withdrawn. Peripheral neuritis in the form of paraesthesia has been reported, and may respond to pyridoxine administration or drug withdrawal.
Precautions
In patients with renal impairment (creatinine clearance < 30 ml/min or serum creatinine concentrations > 2.5 mg / 100 ml or 221 mmol/l) and in patients with hepatic dysfunction the dose or interval between doses should be adjusted according to clinical response, in order to avoid accumulation of the ‘apparent’ active substance.
Apresoline//Hydralazine Tablets should be used with caution in patients with coronary artery disease (since it may increase angina) or cerebrovascular disease.
When undergoing surgery, patients treated with Apresoline/Hydralazine Tablets may show a fall in blood pressure, in which case one should not use adrenaline to correct the hypotension, since it enhances the cardiac-accelerating effects of hydralazine.
When initiating therapy in heart failure, particular caution should be exercised and the patient kept under surveillance and/or haemodynamic monitoring for early detection of postural hypotension or tachycardia. Where discontinuation of therapy in heart failure is indicated, Apresoline/Hydralazine Tablets should be withdrawn gradually (except in serious situations, such as SLE-like syndrome or blood dyscrasias) in order to avoid precipitation and/or exacerbation of heart failure.
4.5. Interactions with other Medicinal Products and other forms of Interaction
Potentiation of effects: Concurrent therapy with other antihypertensives (vasodilators, calcium antagonists, ACE inhibitors, diuretics), anaesthetics, tricyclic antidepressants, major tranquillisers, nitrates or drugs exerting central depressant actions (including alcohol).
Administration of Apresoline/Hydralazine Tablets shortly before or after diazoxide may give rise to marked hypotension.
MAO inhibitors should be used with caution in patients receiving Apresoline/Hydralazine Tablets.
Concurrent administration of Apresoline/Hydralazine Tablets with beta-blockers subject to a strong first pass effect (e.g. propranolol) may increase their bioavailability. Downward adjustment of these drugs may be required when they are given concomitantly with Apresoline/Hydralazine Tablets.
There is potential for the hypotensive effect of hydralazine to be antagonised when used concomitantly with oestrogens or non-steroidal anti-inflammatory drugs.
4.8. Undesirable Effects
Some of the adverse effects listed below e.g. tachycardia, palpitations, angina symptoms, flushing, headache, dizziness, nasal congestion and gastro-intestinal disturbances are commonly seen at the start of treatment, especially if the dose is raised quickly. However such effects generally subside in the further course of treatment.
(The following frequency estimates are used: frequent > 10 %, occasional 1-10%, rare 0.001-1%, isolated cases < 0.001%)
Cardiovascular system:
Frequently: tachycardia, palpitations.
Occasionally: flushing, hypotension, anginal symptoms.
Rarely: oedema, heart failure.
Isolated cases: paradoxical pressor responses.
Central and peripheral nervous system:
Frequently: headache.
Rarely: dizziness.
Isolated cases: peripheral neuritis, polyneuritis, paraesthesiae (these unwanted effects may be reversed by administering pyridoxine).
Musculo-skeletal system:
Occasionally: arthralgia, joint swelling, myalgia.
Skin and appendages:
Rarely: rash.
Urogenital system:
Rarely: proteinuria, increased plasma creatinine, haematuria sometimes in association with glomerulonephritis.
Isolated cases: acute renal failure, urinary retention.
Gastrointestinal tract:
Occasionally: gastro-intestinal disturbances, diarrhoea, nausea, vomiting.
Rarely: jaundice, liver enlargement, abnormal liver function sometimes in association with hepatitis.
Isolated cases: paralytic ileus.
Blood:
Rarely: anaemia, leucopenia, neutropenia, thrombocytopenia with or without purpura.
Isolated cases: haemolytic anaemia, leucocytosis, lymphadenopathy, pancytopenia, splenomegaly, agranulocytosis.
Psychiatric reactions:
Rarely: agitation, anorexia, anxiety.
Isolated cases: depression, hallucinations.
Sense organs:
Rarely: increased lacrimation, conjunctivitis, nasal congestion.
Hypersensitivity reactions:
Occasionally: SLE-like syndrome (sometimes resulting in a fatal outcome see section 4.4 Special warnings and precautions for use).
Rarely: hypersensitivity reactions such as pruritus, urticaria, vasculitis, eosinophilia, hepatitis.
Respiratory tract:
Rarely: dyspnoea, pleural pain.
Miscellaneous:
Rarely: fever, weight decrease, malaise.
Isolated cases: exophthalmos.
10. DATE OF (PARTIAL) REVSION OF THE TEXT
November 2009
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