Source: Health Products and Food Branch (CA) Revision Year: 2019
The overall “hyperdynamic” state of the circulation induced by hydralazine may accentuate certain clinical conditions. Hydralazine can cause anginal attacks and ECG changes indicative of myocardial ischemia. Myocardial stimulation may provoke or aggravate angina pectoris, congestive heart failure or myocardial infarction.
Patients with suspected or confirmed coronary artery disease should therefore be given APRESOLINE only under beta-blocker cover 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. Patients who have survived a myocardial infarction should not receive APRESOLINE until post-infarction stabilization has been achieved. APRESOLINE should not be used in heart failure.
Like all potent antihypertensives, APRESOLINE should be used with caution in patients suffering from cerebrovascular disease, since it can increase ischemia.
APRESOLINE (hydralazine hydrochloride USP) may provoke in a few patients a clinical picture simulating systemic lupus erythematosus (SLE) including glomerulonephritis. In its mild form this syndrome is reminiscent of rheumatoid arthritis (arthralgia, sometimes associated with fever and skin rash). When fully developed a syndrome resembling disseminated lupus erythematosus occurs.
Should this SLE-like syndrome develop, treatment should be discontinued immediately. Symptoms and signs usually regress when the drug is discontinued but residua have been detected many years later. Long-term treatment with adrenocorticosteroids may be necessary.
The frequency of these untoward effects increases with dosage and duration of exposure to the drug and is higher in slow than in fast acetylators. When treated with the same dosage, slow acetylators have higher serum concentrations than fast acetylators. The lowest effective dosage should therefore be used for maintenance therapy. Rapid acetylators, often respond inadequately even to doses of 100 mg daily. In these patients, the dosage can be raised with only a slightly increased risk of a SLElike syndrome. 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 this SLE-like syndrome. In such cases dosage should be kept below 100 mg daily and the patients carefully monitored for clinical signs and symptoms suggestive of this syndrome.
Complete blood counts, examination of lupus erythematosus cell preparations, antinuclear antibody titer determinations and urine analysis are indicated before and periodically (e.g. every 6 months) during prolonged therapy with hydralazine even though the patient is asymptomatic. Microhaematuria and/or proteinuria, in particular together with positive titres of anti-nuclear factors (ANF), may be initial signs of immunecomplex glomerulonephritis associated with the SLE-like syndrome. A positive ANF titre requires that the physician carefully weighs the implications of the test results against the benefits of continued therapy with APRESOLINE. If overt clinical signs and symptoms develop, the medicine should be withdrawn at once. A complete blood count and ANF titre determination is indicated before and periodically during prolonged therapy with APRESOLINE even if the patient is asymptomatic. These tests are also indicated if the patient develops arthralgia, fever, chest pain, continued malaise or other unexplained signs or symptoms. If the results of these tests are abnormal, treatment should be discontinued.
Antinuclear antibodies may be found in the blood of as many as 50 percent of patients receiving hydralazine who remain asymptomatic. A positive antinuclear antibody titer requires that the physician carefully weigh the implications of the test results against the benefits to be derived from antihypertensive therapy with APRESOLINE.
Treatment with APRESOLINE may induce systemic vasculitis, including ANCA (antineutrophil cytoplasm antibody)-positive vasculitis, leading to pulmonary renal syndrome which is a combination of diffuse alveolar haemorrhage and rapidly aggressive glomerulonephritis. Patients may present with severe respiratory and/or renal failure and require treatment in an intensive care unit. The syndrome is characterised by a fulminant course if left untreated and may sometimes be fatal.
Usage in Pregnancy (Category C: Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing harmful effects on human fetus or neonate without causing malformations. These effects may be reversible.
Hydralazine is known to cross the placenta following intravenous administration and has been associated with fetal distress and fetal cardiac arrhythmia in the last trimester of pregnancy. Teratogenic effects observed in humans included the cleft palate and malformations of facial and cranial bones. In view of the possible teratogenic potential in humans, use of APRESOLINE in pregnancy before the third trimester should be avoided. The medicine should only be given in the third trimester if the expected benefit justifies the potential risk to the fetus.
Animal experiments have shown hydralazine is teratogenic in mice at oral doses equal to or greater than 20 mg/kg/day; a “no effect” dose has not been clearly established. Hydralazine was teratogenic in rabbits where oral doses equal to and greater than 75 mg/kg/day caused phalangeal defects. Hydralazine was not teratogenic in rats at oral doses up to 180 mg/kg/day. Embryolethality was observed in mice at doses equal to or greater than 20 mg/kg/day. Hydralazine was, however, not embryolethal in rats and rabbits at oral doses up to 180 and 60 mg/kg/day, respectively. Delayed ossification was observed in mice and rats at maternotoxic doses greater than 20 and 60 mg/kg/day, respectively, and reduced fetal weight was seen in mice at doses greater than 20 mg/kg/day.
Postural hypotension may result from APRESOLINE (hydralazine hydrochloride USP), but is less common than with ganglionic blocking agents. The drug should be used with caution in patients with cerebral vascular disease since abrupt decreases in blood pressure should be avoided in these patients.
A pronounced lowering of the blood pressure may adversely affect the patient’s reactions (e.g. as in driving or operating machinery).
In hypertensive patients with normal kidneys who are treated with APRESOLINE, there is evidence of increased renal blood flow and a maintenance of glomerular filtration rate. In some instances, improved renal function has been noted where control values were below normal prior to APRESOLINE administration. However, as with any antihypertensive agent, APRESOLINE should be used with caution in patients with advanced renal damage.
In patients with renal impairment (creatinine clearance <30 mL/min or serum creatinine >2.5 mg/100 mL or 221 µmol/L), serum levels of hydralazine increased as compared to those in patients with normal renal function, therefore the dose or the interval between doses should be adjusted according to the clinical response, in order to avoid accumulation of the “apparent” active substance.
In patients with hepatic dysfunction, serum levels of hydralazine increased as compared to those in patients with normal hepatic function, therefore the dose or the dosing interval should be adjusted according to the clinical response, in order to avoid accumulation of the “apparent” active substance.
When undergoing surgery, patients treated with Hydralazine 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 hydrochloride.
Peripheral neuritis, evidenced by paresthesias, numbness and tingling in the extremities has been observed. Published evidence suggests an antipyridoxine effect and the addition of pyridoxine to the regimen or medicine withdrawal if symptoms develop. Blood dyscrasias consisting of reduction in hemoglobin and red cell count, leukopenia, agranulocytosis and purpura have been reported. Periodic blood counts are advised during therapy. If such abnormalities develop, therapy should be discontinued.
Skin rash and febrile reactions occur rarely, in which case the medicine should be withdrawn.
Hydralazine hydrochloride in chronic toxicity studies has been shown to increase the incidence of some tumours in aging rodents. A mutagenic potential was observed in some but not all mutagenicity tests (see TOXICOLOGY). The extent to which these findings indicate a risk to man is uncertain. While long-term clinical observations have not suggested that human cancer is associated with hydralazine use, epidemiologic studies have so far been insufficient to arrive at any conclusion (see TOXICOLOGY).
Hydralazine passes into breast milk. Alternatives to hydralazine should be considered in nursing mothers.
The elderly may be more sensitive to the hypotensive effects. In addition, the risk of hydralazine-induced hypothermia may be increased in elderly patients. Concurrent hepatic and renal insufficiency should be taken into account.
Safety and efficacy of hydralazine hydrochloride has not been established in children. APRESOLINE is not recommended for paediatric use.
Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. The most common adverse reactions are tachycardia, palpitation, anginal symptoms, flushing, headache, dizziness, nasal congestion and gastrointestinal disturbances.
These are more frequent at the start of treatment, especially if the dosage is raised rapidly. However, such reactions generally subside in the further course of treatment or following a reduction of dosage. Isolated cases of peripheral neuritis, polyneuritis and paraesthesia have also been reported.
The most severe reactions are neuropathy, blood dyscrasias, and an acute rheumatoid state resulting in a syndrome resembling disseminated lupus erythematosus (see WARNINGS AND PRECAUTIONS).
(The following frequency estimates are used: frequent >10%; occasional 1-10%; rare 0.001-1%; isolated cases <0.001%)
Frequent: Tachycardia, palpitations,
Occasional: flushing, hypotension, anginal symptoms,
Rare: edema, heart failure,
Isolated cases: paradoxical pressor responses.
Frequent: Headache,
Rare: dizziness,
Isolated cases: peripheral neuritis evidenced by paresthesia numbness and tingling, polyneuritis, tremor.
Occasional: Arthralgia, joint swelling, myalgia, muscle cramps.
Rare: Rash.
Rare: Proteinuria, increased plasma creatinine, hematuria sometimes in association with glomerulonephritis,
Isolated cases: acute renal failure, urinary retention, difficulty in micturition.
Occasional: Gastrointestinal disturbances, diarrhea, constipation, nausea, vomiting,
Rare: jaundice, liver enlargement, abnormal liver function sometimes in association with hepatitis,
Isolated cases: paralytic ileus.
Rare: Anemia, leukopenia, neutropenia, thrombocytopenia with or without purpura,
Isolated cases: hemolytic anemia, leucocytosis, lymphadenopathy, pancytopenia, splenomegaly, agranulocytosis, antinuclear antibodies.
Rare: Agitation, anorexia, anxiety,
Isolated cases: depression, hallucinations, disorientation, sleep disturbances Sense Organs
Rare: Increased lacrimation, conjunctivitis, nasal congestion, blurred vision.
Occasional: SLE-like syndrome (sometimes resulting in a fatal outcome; see WARNINGS), chills, eosinophilia,
Rare: hypersensitivity reactions such as pruritus, urticaria, vasculitis, hepatitis.
Rare: Dyspnea, pleural pain.
Rare: Fever, weight decrease, malaise,
Isolated cases: exophthalmos, decreased libido, pancreatitis.
Hyperuricemia, hyperglycemia and hypokalemia have been reported.
Concomitant treatment with other vasodilators, calcium antagonists, ACE inhibitors, diuretics, antihypertensives, anaesthetics, tricyclic antidepressants and major tranquilizers, nitrates or drugs exerting central depressant actions (including alcohol), may potentiate the hypotensive effect of APRESOLINE.
Administration of APRESOLINE shortly before or after diazoxide may lead to marked hypotension. When potent antihypertensive drugs, such as diazoxide, are used in combination with APRESOLINE, patients should be continuously observed for several hours for any excessive fall in blood pressure. MAO inhibitors should be used with caution in patients receiving hydralazine.
Hydralazine hydrochloride may reduce the pressor responses to epinephrine.
Concurrent administration of APRESOLINE with beta blockers subject to a strong first pass effect (e.g. propanolol) may increase their bioavailability. Download adjustment of these drugs may be required when they are given concomitantly with hydralazine hydrochloride.
There is potential for the hypotensive effect of hydralazine to be antagonised when used concomitantly with oestrogens or non-steroidal anti-inflammatory drugs (NSAIDs).
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