Hydralazine hydrochloride BP Injection 20 mg

Presentation

A white friable powder which after reconstitution in 1 mL of water for injections becomes a clear colourless solution with a pH of 3.5-5.0. Each ampoule contains 20 mg of Hydralazine hydrochloride.

Uses

Actions

Hydralazine hydrochloride is a peripheral vasodilator . It exerts its peripheral vasodilating effect through a direct relaxation of smooth muscle tissue in vascular resistance vessels, predominantly in the arterioles. The cellular mechanism of action responsible for this effect is not fully understood.

The preferential dilatation of arterioles, as compared with veins, minimises postural hypotension and promotes the increase in cardiac output. The peripheral vasodilatation is widespread but not uniform.

Splanchnic, coronary, cerebral, and renal blood flow increases unless the fall in blood pressure is very marked. Vascular resistance in the cutaneous and muscle beds is not consistently affected.

In hypertension, this effect results in decreased arterial blood pressure (diastolic more than systolic) and in an increased heart rate, stroke volume, and cardiac output.

Since hydralazine exhibits no cardiodepressant or sympatholytic properties, reflex regulatory mechanisms producing an increase in stroke volume and heart rate continue to operate. Reflex-induced tachycardia, which may occur as an accompanying effect, can be counteracted by concomitant treatment with a beta-blocker or any substance that inhibits sympathetic function.

The use of hydralazine can result in sodium and fluid retention, producing oedema and reduced urinary volume. These unwanted effects are best prevented by concomitant administration of a diuretic.

Pharmacokinetics

Absorption and plasma concentrations

After intravenous administration of hydralazine no first-pass effect occurs; acetylator status therefore has no influence on the plasma levels.

Distribution

Hydralazine becomes bound to plasma proteins (chiefly albumin) to the extent of 88-90%. Hydralazine is rapidly distributed in the body and displays a specific affinity for muscle tissue of the arterial walls. Hydralazine crosses the placental barrier and also passes into the breast milk.

Elimination

The plasma half-life generally ranges from 2 to 3 hours, but in rapid acetylators it is shorter, averaging 45 minutes. In patients with impaired renal function, the plasma half-life is prolonged to up to 16 hours at a creatinine clearance of < 20 mL/min.

Hydralazine and its metabolites are rapidly excreted by the kidney. Within 24 hours after an oral dose, approx. 80% of the dose can be recovered in the urine. The bulk of the hydralazine excreted is in the form of acetylated and hydroxylated metabolites, some of which are conjugated with glucuronic acid; 2-14% is excreted as “apparent” hydralazine.

Advancing age does not affect either the blood concentration or the systemic clearance of “apparent” hydralazine. Renal elimination may however be affected insofar as kidney function diminishes with age.

Indications

Hypertensive crisis, especially during late pregnancy (pre-eclampsia and eclampsia).

Dosage and Administration

Parenteral treatment with Apresoline should always be carried out cautiously and under strict medical surveillance (if possible in hospital).

Adults

The initial dose is 5-10 mg, administered by slow intravenous injection in order to avoid precipitous fall in mean arterial pressure with a critical reduction in cerebral or utero-placental perfusion. If it is necessary to repeat the injection, this should be done after an interval of 20-30 min, throughout which the blood pressure and heart rate should be monitored. A satisfactory response can be defined as a decrease in diastolic blood pressure to 90-100 mmHg.

Apresoline may also be given by continuous intravenous infusion, beginning with a flow rate of 200-300 µg/min. Maintenance flow rates must be determined individually and are usually within the range 50-150 µg/min.

Prior to injection, the powdered active substance should be completely dissolved in 1 mL distilled water for injection and the freshly prepared solution should be used immediately. For the preparation of infusion solutions, this fresh solution should be diluted with physiological saline or with 5% sorbitol solution.

Children

In the rare cases where rapid treatment proves indispensable in a child, Apresoline ampoules should be used with extreme caution.

The initial dose is 0.1-0.5 mg/kg body weight administered intravenously over 1-2 min with repeat doses every 30-90 min as required, up to a maximum daily dose of 3.5 mg/kg body weight.

Contraindications

• Known hypersensitivity to hydralazine or dihydralazine.
• 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 heart failure due to pulmonary hypertension (cor pulmonale).
• Dissecting aortic aneurysm.

Warnings and Precautions

The overall state of the circulation induced by hydralazine may accentuate certain clinical conditions. Myocardial stimulation may provoke or aggravate uncontrolled or untreated angina pectoris. Therefore, Apresoline should only be given to patients with suspected or confirmed coronary artery disease who are already being treated with a βblocker, or in combination with other suitable sympatholytic agents. It is important that the βblocker medication should be commenced a few days before the start of treatment with Apresoline.

Patients who have survived a myocardial infarction should not receive Apresoline until a post-infarction stabilisation phase has been achieved.

Prolonged treatment with hydralazine i.e. usually treatment for more than 6 months, may provoke a systemic lupus erythematosus (SLE)-like syndrome, especially where dosages exceeding 100 mg daily are prescribed. In its mild form this syndrome is reminiscent of rheumatoid arthritis (arthralgia, sometimes associated with fever, anaemia, leucopenia, thrombocytopenia and skin rash) and proves 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; whereas nervous system and renal involvement are more rare than in idiopathic lupus), long-term treatment with corticosteroids may be required to reverse it completely. In particular, renal symptoms are less frequent than in idiopathic SLE and pleuro-pulmonary symptoms, as well as pericarditis, are more frequent. Since such reactions tend to occur more frequently the higher the dosage and the longer the duration of the medication, and since they are also more common in slow acetylators, it is recommended that for maintenance therapy the lowest dosage that still proves effective 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 a greater risk of developing an SLE-like syndrome. In such patients every effort should therefore be made not to exceed a dosage of 100 mg daily; a careful watch should also be kept for clinical signs and symptoms suggestive of SLE-like syndrome.

Rapid acetylators, by contrast, often respond inadequately even to dosages of 100 mg daily. In these patients, the dosage can be raised with only a slightly increased risk of an SLE-like syndrome.

During long-term treatment with Apresoline it is advisable to determine the antinuclear factors (ANF) and to carry out urine analyses at intervals of approx. 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 and symptoms develop, the drug should be withdrawn at once.

Isolated cases of peripheral neuritis have been reported. Published evidence suggests an antipyridoxine effect, which may respond to pyridoxine administration or drug withdrawal.

Laboratory tests: A complete blood count and ANF titre determination is indicated before and periodically during prolonged therapy with hydralazine even if the patient is asymptomatic. These studies are also indicated if the patient develops arthralgia, fever, chest pain, persistent malaise, or other unexplained signs or symptoms. A positive ANF titre requires that the physician carefully weighs the implications of the test results against the benefits of continued therapy with hydralazine.

Adverse haematological effects, such as a reduction in haemoglobin and red cell count, leucopenia, agranulocytosis and purpura, have been reported in a very few cases. If such abnormalities develop, therapy should be discontinued.

Hydralazine can cause anginal attacks and ECG changes indicative of myocardial ischaemia. It must therefore be used with caution in patients with suspected coronary artery disease.

In patients with moderate to severe renal impairment (creatinine clearance < 30 mL/min or serum creatinine concentration > 2.5 mg/100 mL or 221 µmol/L) or hepatic dysfunction, the dosage or the dosing interval must be adapted according to the clinical response to avoid accumulation of the “apparent” active substance.

Like all potent antihypertensives, Apresoline should be used with caution in patients with coronary artery disease or acute cerebrovascular disease, since it can increase ischaemia.

When undergoing surgery, patients treated with Apresoline 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.

Preclinical safety data

Teratogenicity

Hydralazine is teratogenic in mice, causing cleft palate and malformations of the facial and cranial bones at doses 20-30 times the maximum human daily dose of 200-300 mg. It is not teratogenic in rats or rabbits, however, and perinatal and postnatal growth of the rats’ offspring is not affected.

Mutagenicity

Hydralazine, in cyto-toxic concentrations, induces gene mutations in bacteria, yeasts and Drosophila, and in mammalian cells in vitro. No clear mutagenic effects including chromosomal aberrations have been detected in vivo in a large number of test systems.

Under in vitro conditions, the formation of reactive metabolites/intermediates is favoured, so that DNA damage may occur. In vivo, however, i.e. under normal metabolic conditions, there is intense detoxification of potentially toxic intermediates. Consequently, the genotoxic/mutagenic risk for man is estimated to be very low.

Carcinogenicity

Hydralazine, in carcinogenicity studies in mice and rats caused small but statistically significant increases in some types of tumours, but these also occur spontaneously with fairly high frequency in aged rodents.

Studies of the carcinogenic potential of hydralazine in rodents do not suggest a specific carcinogenic risk at therapeutic doses.

In a 2-year carcinogenicity study in rats, microscopic examination of the liver revealed some increase in the incidence of benign neoplastic nodules at oral doses (gavage) of 30 and 60 mg/kg. No such nodules were found at 15 mg/kg. The results of 3 other carcinogenicity studies (2 in mice, 1 in rats) are considered inconclusive with respect to increases in the frequency of compound-related neoplastic changes. Moreover, many years of clinical experience have not suggested that hydralazine use is associated with human cancer.

Use during Pregnancy and Lactation

Category C

No serious adverse effects in human pregnancy have been observed to date with Apresoline, although experience in the third trimester is extensive. However, animal experiments have shown teratogenic potential in mice but not in other animal species. Hydralazine crosses the placenta. Use of Apresoline in pregnancy, before the third trimester should be avoided, but the drug may be employed in later pregnancy if there is no safer alternative or when the disease itself carries serious risks for the mother or child, e.g. pre-eclampsia and/or eclampsia.

Hydralazine passes into breast milk, but reports available so far do not suggest an adverse effect on the infant. Mothers taking Apresoline may breast-feed their infant, provided that the infant is observed for possible unexpected adverse effects.

Effects on ability to drive and use machines

Apresoline, especially at the start of treatment, may impair the patient’s reactions when driving or operating machines.

Adverse Effects

Frequency estimates: very common ≥ 10%, common ≥ 1% to < 10%, uncommon ≥ 0.1% to < 1%, rare ≥ 0.01% to < 0.1%, very rare < 0.01%

Some of the unwanted effects listed below such as tachycardia, palpitation, anginal symptoms, flushing, headache, dizziness, nasal congestion and gastrointestinal disturbances are commonly seen at the start of treatment, especially if the dosage is raised rapidly. However, such reactions generally subside in the further course of treatment.

Cardiovascular system

Very common: tachycardia, palpitation.
Common: flushing, hypotension, anginal symptoms.
Uncommon: oedema, congestive heart failure.
Very rare: paradoxical pressor responses.

Central and peripheral nervous system

Very common: headache.
Uncommon: dizziness.
Very rare: peripheral neuritis, polyneuritis, paraesthesiae (these may be reversed by giving pyridoxine), and tremor.

Musculoskeletal system

Common: arthralgia, joint swelling, myalgia.

Skin and appendages

Uncommon: rash.

Urogenital system

Uncommon: proteinuria, increased plasma creatinine, haematuria, sometimes in association with glomerulonephritis .
Very rare: acute renal failure, urinary retention.

Gastrointestinal tract

Common: gastrointestinal disturbances, diarrhoea, nausea, vomiting.
Uncommon: jaundice, liver enlargement, abnormal liver function, sometimes in association with hepatitis
Very rare: paralytic ileus.

Blood

Uncommon: anaemia, leucopenia, neutropenia, thrombocytopenia with or without purpura.
Very rare: haemolytic anaemia, leucocytosis, lymphadenopathy, pancytopenia, splenomegaly, agranulocytosis.

Psychic effects

Uncommon: agitation, anorexia , anxiety.
Very rare: depression, hallucinations.

Sense organs

Uncommon: increased lacrimation, conjunctivitis, nasal congestion.

Hypersensitivity reactions

Common: SLE-like syndrome (see Special warnings and special precautions for use), Uncommon: hypersensitivity reactions such as pruritus, urticaria , vasculitis, eosinophilia, hepatitis.

Respiratory tract

Uncommon: dyspnoea, pleural pain.

Miscellaneous

Uncommon: fever, weight loss, malaise
Very rare: exophthalmos.

Interactions

Concomitant treatment with other vasodilators, calcium antagonists, ACE inhibitors, diuretics, antihypertensives, tricyclic antidepressants, and major tranquillisers, as well as the consumption of alcohol, may potentiate the blood-pressure-lowering effect of Apresoline. In particular, administration of Apresoline shortly before or after diazoxide may give rise to marked hypotension. MAO inhibitors should be used with caution in patients receiving Apresoline.

Concurrent administration of Apresoline with beta-blockers, subject to a strong first-pass effect, may increase their bioavailability. Downward dosage adjustment of these drugs may be required when they are given concomitantly with Apresoline.

Overdosage

Symptoms

The chief manifestations are cardiovascular disorders such as pronounced tachycardia and hypotension, which are accompanied by nausea, dizziness, and sweating, and which can result in circulatory collapse; also possible are myocardial ischaemia with angina pectoris and cardiac arrhythmias. Further signs and symptoms may include impairment of consciousness, headache, and vomiting, as well as possibly tremor, convulsions, oliguria, and hypothermia.

Treatment

Since no specific antidote is known, – in addition to attempts to eliminate the drug from the gastrointestinal tract (early induction of vomiting, later gastric lavage; administration of activated charcoal and possibly laxatives) – treatment should be supportive including use of a plasma expander or intravenous fluids as indicated.

Pharmaceutical Precautions

Protect from light and heat and store below 30°C. Store the reconstituted solution below 25°C and use within 24 hours.

Apresoline should be kept out of the reach of children.

Incompatibilities

Hydralazine hydrochloride can form complexes with various types of metal ions, causing discolouration of the solution. If possible the solution should be prepared using a non-metallic filter and contact with metal parts should be minimised. If not used immediately, the reconstituted solution should not be stored in a container with metal parts.

Glucose infusion solutions are not compatible because contact between hydralazine and glucose causes the active substance to be rapidly broken down.