Apreszine 25/Apreszine 50

Apreszine 25: Orange round, convex with film coated tablet. One side has letter "H" and another side has figure 25.
Each film-coated tablet contains: Hydralazine hydrochloride 25 mg.
Apreszine 50: Round, biconvex white film-coated tablets. Score line on one side and debossed with "50" on another side.
Each tablet contains 50 mg hydralazine hydrochloride.
Excipients/Inactive Ingredients: Apreszine 50: Microcrystalline cellulose, Copovidone, Disodium edetate, Sodium starch glycolate, Colloidal silicon dioxide, Magnesium stearate, Polyvinyl alcohol, Titanium dioxide, Lecithin, Talcum, Polyethylene glycol, Purified water.

Pharmacotherapeutic group: Apreszine 50: Arteriolar smooth muscle, agents acting on; hydrazinophthalazine derivatives. ATC code: C02DB02.
Pharmacology: Pharmacodynamics: Apreszine 25: Mechanism of action: Hydralazine reduces peripheral resistance and blood pressure as a result of direct vasodilatory effect on vascular smooth muscle; the effect on arterioles is greater than on veins.
Apreszine 50: Mechanism of action: Hydralazine is a direct acting vasodilator which exerts its effects primarily on the arterioles, with little effect on veins. Its exact mechanism of action is unknown.
Pharmacodynamic effects: Administration of hydralazine decreases peripheral resistance and arterial blood pressure, producing a reflex increase in heart rate and cardiac output. These reflex effects can be reduced by concomitant administration of a beta-blocker, thus enhancing the antihypertensive effect. Increased plasma renin activity and sodium and water retention, producing oedema and reduced urinary volume, may also occur with hydralazine administration attenuating its antihypertensive action. These effects can be prevented by concomitant administration of a diuretic.
Pharmacokinetics: Apreszine 25: Absorption: Rapidly absorbed after oral administration.
Metabolism: Hepatically acetylate; extensive first-pass effect (oral).
Excretion: Urine (as metabolite).
Time to peak: 1-2 hours.
Half-life elimination: 3-7 hours.
Protein-binding: 87%.
Bioavailability: Increase with food.
Apreszine 50: Absorption: Hydralazine is well absorbed (up to 90%) after oral administration but is subject to a dose-dependent first-pass effect. Systemic bioavailability ranges from 26-55% and is dependent on individual acetylator status. Food may enhance the bioavailability of hydralazine by reducing first-pass metabolism in the gut wall. Peak plasma concentrations are reached after 0.5-1.5 hours.
Distribution: Hydralazine is rapidly distributed in the body and displays a particular affinity for the blood vessel walls. It is highly protein bound (~90%) in the plasma. Within 24 hours after an oral dose, the quantity recovered in the urine averages 80% of the dose.
Elimination: Hydralazine appears in the plasma chiefly in the form of a readily hydrolysable conjugate with pyruvic acid. Its plasma half-life averages 2-3 hours but is prolonged up to 16 hours in severe renal failure (creatinine clearance <20 mL/min) and shortened to approximately 45 minutes in rapid acetylators.
The bulk of the dose excreted as acetylated and hydroxylated metabolites, some of which are conjugated with glucuronic acid.
Toxicology: Apreszine 50: Preclinical safety data: Studies in animals found hydralazine to be teratogenic in mice at oral doses ranging from 20-120 mg/kg (20-30 times the maximum human daily dose). Teratogenic effects included cleft palate and malformations of facial and cranial bones. Hydralazine was not found to be teratogenic in rats or rabbits.
In high (cyto-) toxic concentrations, hydralazine induces gene mutations in single cell organisms and in mammalian cells in vitro. No unequivocally mutagenic effects have been detected in-vivo in a great number of test systems.
In lifetime carcinogenicity studies, hydralazine, towards the end of the experiments, caused small but statistically significant increase in lung tumours in mice and hepatic and testicular tumours in rats. These tumours also occur spontaneously with fairly high frequency in aged rodents.
With due consideration of these toxicological findings, hydralazine in therapeutic doses does not appear to bear a risk that would necessitate a limitation of its administration.
Years of clinical experience have not suggested that the use of hydralazine is associated with any risk of cancer in humans.

Apreszine 25: Management of moderate to severe hypertension as an adjunct to other antihypertensive agents such as diuretics and β-blockers, when this has not obtained a satisfactory effect.
Apreszine 50: For the treatment of moderate to severe hypertension as an adjunct to other antihypertensive agents.
Due to the complementary mechanism of action the combination of hydralazine with β-blockers and diuretics may enable antihypertensive efficacy at lower dose levels and counteract accompanying hydralazine effects such as reflex tachycardia and oedema.
As supplementary medication for use in combination with long-acting nitrates in moderate to severe chronic congestive cardiac failure in patients in whom optimal doses of conventional therapy have proved insufficient.

Apreszine 25: Adult: Initial dosage: 25 mg 2 times daily for the first 2-4 days; increase to 25 mg 4 times daily for balance of the first week.
Dosage titration: 50 mg 4 times daily from the second week on.
Maintenance dosage: Adjust dosage to the lowest effective levels. Up to 300 mg/day may be required in resistant patients.
Mode of Administration: Administered without regard to meals. However, food enhances bioavailability; administer consistently with regard to meals.
Apreszine 50: Posology: The dosage should be adjusted to the individual requirements of the patient. Treatment should commence with low doses which, depending on the patient's response, should be increased stepwise to achieve optimal therapeutic effect, whilst minimising unwanted effects.
Adults: Hypertension: The initial dose is 25 mg twice daily. This may be increased gradually to a maximum dose of 200 mg daily. The patient's acetylator status must be checked prior to increasing the daily dose beyond 100 mg.
Chronic congestive heart failure: Doses vary greatly between individual patients and are generally higher than those used to treat hypertension. Treatment should be initiated in hospital where the patient's individual haemodynamic values can be determined with the help of invasive monitoring. Treatment should continue in hospital until the patient has been established on the required maintenance dose. After progressive titration (initially 25 mg three or four times daily, increasing every second day) maintenance dosage averages 50-75 mg four times daily.
Children: Hydralazine is not recommended.
Elderly: There is no special dosage requirement. Systemic clearance and blood concentration of hydralazine are not affected by advanced age, though renal elimination may be affected due to diminished kidney function with age. The elderly may also be more sensitive to the hypotensive effects of hydralazine.
Method of administration: For oral administration only. Swallow the tablets with a glass of water.

Apreszine 25: Overdosage of hydralazine may produce hypotension, tachycardia, headache and generalized skin flushing. Myocardial ischemia and cardiac arrhythmia may develop; profound shock can occur in severe overdosage.
There is no specific antidote for the treatment of hydralazine overdosage. Support of the cardiovascular system is most important for the treatment of hydralazine overdosage. Evacuation of gastric contents using adequate precautions to protect the airway and prevent aspiration should be done only after cardiovascular status has been stabilized.
Apreszine 50: Symptoms: The signs and symptoms of hydralazine overdose include hypotension, tachycardia, headache and generalised skin flushing. Complications can include myocardial ischemia and subsequent myocardial infarction, cardiac arrhythmias, profound shock and coma.
Management: There is no specific antidote. Gastric lavage should be instituted as soon as possible, taking adequate precautions against aspiration and for protection of the airway. An activated charcoal slurry may be instilled if conditions permit. These procedures may have to be omitted or carried out after cardiovascular status has been stabilised since they might precipitate cardiac arrhythmias or increase the depth of shock.
Support of the cardiovascular system is of primary importance. Shock should be treated with plasma expanders if possible, rather than vasopressors. Supportive measures including intravenous fluids are also indicated. If hypotension is present, an attempt should be made to raise the blood pressure without increasing the tachycardia. If a vasopressor is used, one should be chosen that is least likely to precipitate or aggravate cardiac arrhythmia. Tachycardia responds to beta-blockers. Digitalisation may be necessary. Fluid and electrolyte status and renal function should be monitored.

Apreszine 25: Hypersensitivity to hydralazine; coronary artery disease; mitral valvular rheumatic heart disease.
Hydralazine is contraindicated in patients with severe tachycardia, dissecting aortic aneurysm, heart failure with high cardiac output, cor pulmonale, or myocardial insufficiency due to mechanical obstruction, for example aortic or mitral stenosis or constrictive.
Hydralazine is also contraindicated in patients with idiopathic systemic lupus erythematosus (SLE) and related disorders.
Apreszine 50: Hydralazine is contraindicated in patients with: Hypersensitivity to the active substance, dihydralazine or to any of the excipients listed in Description.
Idiopathic systemic lupus erythematosus (SLE) and related diseases.
Severe tachycardia.
High output cardiac failure (e.g. in thyrotoxicosis).
Myocardial insufficiency due to mechanical obstruction (e.g. in the presence of mitral or aortic stenosis or constrictive pericarditis).
Cor pulmonale.
Dissecting aortic aneurysm.
Porphyria.

Apreszine 50: The "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 be given Hydralazine only under cover of a beta-blocker or in combination with other suitable sympatholytic agents. Beta-blocker medication should be started a few days prior to commencing treatment with Hydralazine.
Patients who have survived a myocardial infarction should not receive Hydralazine until a post-infarction stabilization phase 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 with doses exceeding 100 mg daily. Initial symptoms are likely to be similar to rheumatoid arthritis (arthralgia, sometimes associated with rash, anaemia, leucopenia, thrombocytopenia and fever) and are reversible upon 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 with higher doses and longer duration of treatment and since they are also more common in slow acetylators, the lowest effective dose should be used for maintenance therapy. If 100 mg daily fails to elicit an adequate response, the patient's acetylator status should be evaluated. Slow acetylators and women are at greater risk of developing the SLE-like syndrome and every effort should therefore be made to keep the dosage below 100 mg daily. The patient should be watched for signs and symptoms of the syndrome and if such symptoms develop, the drug should be gradually withdrawn. Rapid acetylators often respond inadequately even to doses of 100 mg daily and therefore the dose may be raised with only a slightly increased risk of an SLE-like syndrome.
During long-term treatment with Hydralazine, it is advisable to determine the antinuclear factors and conduct urine analysis at intervals of approximately 6 months. Microhaematuria and/or proteinuria, in particular along with positive ANF titres, may be initial signs of immune-complex glomerulonephritis associated with the SLE-like syndrome. If overt clinical signs or symptoms develop, hydralazine should be withdrawn immediately.
Skin rash, febrile reactions and change in blood count occur rarely and the drug should be withdrawn. Peripheral neuritis in the form of paraesthesia has been reported and may respond to pyridoxine administration or withdrawal of the drug.

Apreszine 25: May cause a drug-induced lupus-like syndrome including glomerulonephritis, especially in patients receiving higher doses.
Postural hypotension may occur.
Use with caution in patients with cerebral vascular accidents and suspected coronary artery disease (CAD); myocardial stimulation produced by hydralazine can cause angina attacks and electrocardiogram (ECG) changes of myocardial ischemia; has been implicated in the production of myocardial infarction.
Use with caution in patients with mitral valvular disease; may increased pulmonary artery pressure in these patients.
Use with caution in patients with advanced renal impairment; dosage adjustment.
Hydralazine has been associated with peripheral neuritis (eg, paresthesia, numbness, tingling), possibly due to an antipyridoxine effect. Pyridoxine therapy should be initiated with onset of such symptoms.
Blood dyscrasias (eg, reduction in haemoglobin and red blood cell count, leucopenia, agranulocytosis, purpura) may occur, discontinue therapy if these hematologic effects occur.
Apreszine 50: Hydralazine dose or interval between doses should be adjusted according to clinical response in patients with hepatic dysfunction or renal impairment (creatinine clearance <30 mL/min or serum creatinine >2.5 mg/100 mL) in order to avoid accumulation of the drug.
Hydralazine should be used with caution in patients with coronary artery disease (since it may increase angina) or cerebrovascular disease.
Patients on Hydralazine who undergo surgery, may show a fall in blood pressure. Adrenaline should not be used 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 monitored for early detection of postural hypotension or tachycardia. Where discontinuation of therapy in heart failure is necessary, Hydralazine 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.
Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Effects on ability to drive and use machines: Hydralazine may cause headache and difficulty in concentration, especially at the start of treatment, which can impair the patient's reactions. If symptoms are severe, the patient should not drive or operate machinery.

Pregnancy: Apreszine 25: Safety use of hydralazine in pregnancy has not been established. Hydralazine should not be used during pregnancy unless the possible benefits outweigh the potential risks to the fetus.
Apreszine 50: Hydralazine readily crosses the placenta with serum concentrations in the foetus being equal to or greater than those in the mother. Animal studies have shown reproductive toxicity (see Pharmacology: Toxicology: Preclinical safety data under Actions). No serious adverse effects in human pregnancy have been reported with hydralazine use during the third trimester. Thrombocytopenia, leucopenia, petechial bleeding and haematomas have been reported in new-borns whose mother took hydralazine, though these symptoms resolved spontaneously in one to three weeks. Hydralazine should be avoided during the first and second trimesters of pregnancy but may be used later in pregnancy if the mother or foetus is at risk (e.g. pre-eclampsia, eclampsia) or if no safer alternative is available.
Lactation: Apreszine 25: It is not known whether hydralazine is distributed into breast milk. Because many drugs are distributed into milk, the drug should be used with caution in nursing women.
Apreszine 50: Hydralazine passes into breast milk but reports to date have not indicated adverse effects on the infant. Breast-fed infants of mothers taking hydralazine should be observed for possible adverse effects.

Apreszine 25: Common: Headache, anorexia, nausea, vomiting, diarrhea, palpitations, tachycardia, angina pectoris.
Less frequent: Cardiovascular: Hypotension, paradoxical pressor response, edema.
Central nervous system: Peripheral neuritis, evidenced by paresthesia, numbness and tingling, dizziness, tremors, muscle cramps, psychotic reactions characterized by depression, disorientation or anxiety.
Apreszine 50: Some side effects of hydralazine such as palpitations, tachycardia, angina symptoms, flushing, headaches, dizziness, gastrointestinal disturbances and nasal congestion are commonly seen at the start of therapy especially if the dose is raised quickly but generally subside as treatment continues.
Adverse reactions are categorised by frequencies as follows: very common (>1/10), common (>1/100 to <1/10), rare (>1/10,000 to <1/1,000) and very rare (<1/10,000).
Blood and lymphatic system disorders: Rare: leucopenia, neutropenia, thrombocytopenia with or without purpura, anaemia.
Very rare: haemolytic anaemia, lymphadenopathy, leucocytosis, pancytopenia, splenomegaly and agranulocytosis.
Immune system disorders: Rare: hypersensitivity reactions such as urticaria, pruritus, vasculitis, eosinophilia, hepatitis.
Psychiatric disorders: Rare: anorexia, agitation, anxiety.
Very rare: depression, hallucinations.
Nervous system disorders: Very common: headache.
Common: dizziness.
Very rare: peripheral neuritis, polyneuritis and paraesthesia (which may be reversed by administering pyridoxine).
Cardiac disorders: Very common: palpitations and tachycardia.
Common: angina symptoms.
Rare: heart failure.
Very rare: paradoxical pressor responses.
Vascular disorders: Common: hypotension, flushing.
Respiratory, thoracic and mediastinal disorders: Common: nasal congestion.
Rare: dyspnoea and pleural pain.
Eye disorders: Rare: increased lacrimation, conjunctivitis.
Very rare: exophthalmos.
Gastrointestinal disorders: Common: gastrointestinal disturbances, diarrhoea, nausea and vomiting.
Very rare: paralytic ileus.
Hepatobiliary disorders: Rare: jaundice, hepatomegaly, abnormal liver function sometimes in association with hepatitis.
Skin and subcutaneous tissue disorders: Rare: skin rash.
Musculoskeletal and connective tissue disorders: Common: arthralgia, myalgia, joint swelling, SLE-like syndrome (sometimes resulting in a fatal outcome, see Warnings).
Renal and urinary disorders: Rare: proteinuria, haematuria sometimes associated with glomerulonephritis.
Very rare: acute renal failure and urinary retention.
General disorders and administration site conditions: Rare: fever, weight loss, malaise, oedema.
Investigations: Rare: increased plasma creatinine.

Apreszine 25: Hydralazine may increase the levels/effects of Amifostine, Antipsychotic agents (second generation), Bromperidol, Duloxetine, Hypotension associated agents, Levodopa, Nitroprusside, Pholcodine.
The levels/effects of Hydralazine may be increased by Afuzosine, Barbiturates, Benperidol, Brigatinib, Brimonidine (Topical), Dapoxetine, Diazoxide, Herbs (Hypotensive properties), Lormetazepam, Molsidomine, Naftofpidil, Nicergoline, Nicorandil, Obinutuzumab, Pentoxifylline, Phosphodiesterase 5 inhibitors, Prostacyclin analogues, Quinegolide.
The levels/effects of Hydralazine may be decreased by Amphetamines, Brigatinib, Bromperidol, Herbs (Hypertensive properties), Methylphenidate, Nonsteroidal anti-inflammatory agents, Yohimbine.
Apreszine 50: The following drugs enhance the hypotensive effects of hydralazine: Other antihypertensives (diuretics, ACE inhibitors, calcium channel blockers, vasodilators*); Anaesthetics; Tricyclic antidepressants; Major tranquillisers; Nitrates or drugs exerting central depressant actions (including alcohol).
*Administration of Hydralazine within an hour or two of diazoxide may give rise to marked hypotension.
The following drugs antagonise the effects of hydralazine: Non-steroidal anti-inflammatory agents (especially indometacin); Corticosteroids; Carbenoxolone; Oestrogens and combined oral contraceptives.
Concurrent administration of hydralazine and beta-blockers which are subject to significant first-pass metabolism (e.g. propranolol) may result in increased bioavailability of the beta-blocker. Dosage reduction of the beta-blocker may be necessary in such cases.
MAOI's should be used with caution in patients receiving hydralazine.

Apreszine 50: Incompatibilities: Not applicable.
Special precautions for disposal: Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Apreszine 25: Do not store above 30°C.
Apreszine 50: Shelf life: 2 years.
Special precautions for storage: Store below 30°C.

Other Antihypertensives

C02DB02 - hydralazine ; Belongs to the class of hydrazinophthalazine derivatives. Used in the treatment of hypertension.

D