Symptoms
The following symptoms are observed in cases of severe nifedipine intoxication:
Disturbances of consciousness to the point of coma, a drop in blood pressure, tachycardia, bradycardia, hyperglycaemia, metabolic acidosis, hypoxia, cardiogenic shock with pulmonary oedema.
Treatment
As far as treatment is concerned, elimination of nifedipine and the restoration of stable cardiovascular conditions have priority. Elimination must be as complete as possible, including the small intestine, to prevent the otherwise inevitable subsequent absorption of the active substance.
The benefit of gastric decontamination is uncertain.
1. Consider activated charcoal (50 g for adults, 1 g/kg for children) if the patient presents within 1 hour of ingestion of a potentially toxic amount.
Although it may seem reasonable to assume that late administration of activated charcoal may be beneficial for sustained release (SR, MR) preparations there is no evidence to support this.
2. Alternatively consider gastric lavage in adults within 1 hour of a potentially life-threatening overdose.
3. Consider further doses of activated charcoal every 4 hours if a clinically significant amount of a sustained release preparation has been ingested with a single dose of an osmotic laxative (e.g. sorbitol, lactulose or magnesium sulphate).
4. Asymptomatic patients should be observed for at least 4 hours after ingestion and for 12 hours if a sustained release preparation has been taken.
Haemodialysis serves no purpose as nifedipine is not dialysable, but plasmapheresis is advisable (high plasma protein binding, relatively low volume of distribution).
Hypotension as a result of cardiogenic shock and arterial vasodilatation can be treated with calcium (10-20 ml of a 10 % calcium gluconate solution administered intravenously over 5-10 minutes). If the effects are inadequate, the treatment can be continued, with ECG monitoring. If an insufficient increase in blood pressure is achieved with calcium, vasoconstricting sympathomimetics such as dopamine or noradrenaline should be administered. The dosage of these drugs should be determined by the patient's response.
Symptomatic bradycardia may be treated with atropine, beta-sympathomimetics or a temporary cardiac pacemaker, as required.
Additional fluids should be administered with caution to avoid cardiac overload.
Adalat capsules must not be administered to patients with known hypersensitivity to the active substance, or to other dihydropyridines because of the theoretical risk of cross-reactivity, or to any of the excipients listed in sections 4.4 and 6.1.
Adalat capsules must not be used in cases of cardiogenic shock, clinically significant aortic stenosis, unstable angina, or during or within 4 weeks of an acute myocardial infarction.
Adalat capsules should not be used for the treatment of acute attacks of angina.
The safety of Adalat capsules in malignant hypertension has not been established.
Adalat capsules should not be used for secondary prevention of myocardial infarction.
Adalat capsules should not be administered concomitantly with rifampicin since effective plasma levels of nifedipine may not be achieved owing to enzyme induction.
1.Meborilan capsules must not be used in cases of cardiogenic shock, clinically significant aortic stenosis, unstable angina, or during or within 4 weeks of an acute myocardial infarction.
Meborilan capsules should not be used for the treatment of acute attacks of angina.
The safety of Meborilan capsules in malignant hypertension has not been established.
Meborilan capsules should not be used for secondary prevention of myocardial infarction.
Meborilan capsules should not be administered concomitantly with rifampicin since effective plasma levels of nifedipine may not be achieved owing to enzyme induction.
Not applicable.
Adverse drug reactions (ADRs) based on placebo-controlled studies with nifedipine sorted by CIOMS III categories of frequency (clinical trial data base: nifedipine n = 2,661; placebo n = 1,486; status: 22 Feb 2006 and the ACTION study: nifedipine n = 3,825; placebo n = 3,840) are listed below: ADRs listed under "common" were observed with a frequency below 3% with the exception of oedema (9.9%) and headache (3.9%).
The frequencies of ADRs reported with nifedipine-containing products are summarised in the table below. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as common (>1/100 to < 1/10), uncommon (> 1/1,000 to < 1/100) and rare (> 1/10,000 to < 1/1,000). The ADRs identified only during the ongoing postmarketing surveillance, and for which a frequency could not be estimated, are listed under “Not knownâ€.
| System Organ Class (MedDRA) | Common | Uncommon | Rare | Not Known |
| Blood and Lymphatic System Disorders | Agranulocytosis Leucopenia | |||
| Immune System Disorders | Allergic reaction Allergic oedema/ angioedema (incl. larynx oedema*) | Pruritus Urticaria Rash | Anaphylactic/ anaphylactoid reaction | |
| Psychiatric Disorders | Anxiety reactions Sleep disorders | |||
| Metabolism and Nutrition Disorders | Hyperglycaemia | |||
| Nervous System Disorders | Headache | Vertigo Migraine Dizziness Tremor | Par-/Dysaesthesia | Hypoaesthesia Somnolence |
| Eye Disorders | Visual disturbances | Eye pain | ||
| Cardiac Disorders | Tachycardia Palpitations | Chest pain (Angina Pectoris) | ||
| Vascular Disorders | Oedema (incl. peripheral oedema) Vasodilatation | Hypotension Syncope | ||
| Respiratory, Thoracic, and Mediastinal Disorders | Nosebleed Nasal congestion | Dyspnoea Pulmonary oedema** | ||
| Gastrointestinal Disorders | Constipation | Gastrointestinal and abdominal pain Nausea Dyspepsia Flatulence Dry mouth | Gingival hyperplasia | Vomiting Gastroesophageal sphincter insufficiency |
| Hepatobiliary Disorders | Transient increase in liver enzymes | Jaundice | ||
| Skin and Subcutaneous Tissue Disorders | Erythema | Toxic Epidermal Necrolysis Photosensitivity allergic reaction Palpable purpura | ||
| Musculoskeletal and Connective Tissue Disorders | Muscle cramps Joint swelling | Arthralgia Myalgia | ||
| Renal and Urinary Disorders | Polyuria Dysuria | |||
| Reproductive System and Breast Disorders | Erectile dysfunction | |||
| General Disorders and Administration Site Conditions | Feeling unwell | Unspecific pain Chills |
* = may result in life-threatening outcome
**cases have been reported when used as tocolytic during pregnancy
In dialysis patients with malignant hypertension and hypovolaemia a distinct fall in blood pressure can occur as a result of vasodilation.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
Preclinical data reveal no special hazard for humans based on conventional studies of single and repeated dose toxicity, genotoxicity and carcinogenic potential.
Reproduction toxicology
Nifedipine has been shown to produce teratogenic findings in rats, mice and rabbits, including digital anomalies, malformation of the extremities, cleft palates, cleft sternum, and malformation of the ribs. Digital anomalies and malformation of the extremities are possibly a result of compromised uterine blood flow, but have also been observed in animals treated with nifedipine solely after the end of the organogenesis period.
Nifedipine administration was associated with a variety of embryotoxic, placentotoxic and foetotoxic effects, including stunted foetuses (rats, mice, rabbits), small placentas and underdeveloped chorionic villi (monkeys), embryonic and foetal deaths (rats, mice, rabbits) and prolonged pregnancy/decreased neonatal survival (rats; not evaluated in other species). The risk to humans cannot be ruled out if a sufficiently high systemic exposure is achieved, however, all of the doses associated with the teratogenic, embryotoxic or foetotoxic effects in animals were maternally toxic and were several times the recommended maximum dose for humans.
For the prophylaxis of chronic stable angina pectoris, the treatment of Raynaud's phenomenon and essential hypertension.
For patients suffering from essential hypertension or chronic stable angina pectoris, and treated with fast release forms of nifedipine (Adalat capsules), a dose dependent increase in the risk of cardiovascular complications (e.g., myocardial infarction) and mortality may occur. Due to this, Adalat capsules should only be used for treatment of patients with essential hypertension or chronic stable angina pectoris if no other treatment is appropriate.
For the prophylaxis of chronic stable angina pectoris, the treatment of Raynaud's phenomenon and essential hypertension.
For patients suffering from essential hypertension or chronic stable angina pectoris, and treated with fast release forms of nifedipine (Meborilan capsules), a dose dependent increase in the risk of cardiovascular complications (e.g., myocardial infarction) and mortality may occur. Due to this, Meborilan capsules should only be used for treatment of patients with essential hypertension or chronic stable angina pectoris if no other treatment is appropriate.
Pharmacotherapeutic group: selective calcium channel blockers with mainly vascular effect, dihydropyridine derivatives, ATC code: C08CA05
Nifedipine is a calcium antagonist of the 1, 4-dihydropyridine type. Calcium antagonists reduce the transmembranal influx of calcium ions through the slow calcium channel into the cell. As a specific and potent calcium antagonist, nifedipine acts particularly on the cells of the myocardium and the smooth muscle cells of the coronary arteries and the peripheral resistance vessels. The main action of Adalat capsules is to relax arterial smooth muscle both in the coronary and peripheral circulation.
In angina pectoris, Adalat capsules relax peripheral arteries so reducing the load on the left ventricle. Additionally, Adalat capsules dilate submaximally both clear and pre-stenotic coronary arteries, and stenotic and post-stenotic coronary arteries, thus protecting the heart against coronary artery spasm and improving perfusion to the ischaemic myocardium.
Adalat capsules reduce the frequency of painful attacks and ischaemic ECG changes, irrespective of the relative contribution from coronary artery spasm or atherosclerosis.
Adalat capsules cause a reduction in blood pressure such that the percentage lowering is directly related to its initial level. In normotensive individuals, Adalat capsules have little or no effect on blood pressure.
Paediatric population:
Limited information on comparison of nifedipine with other antihypertensives is available for both acute hypertension and long-term hypertension with different formulations in different dosages. Antihypertensive effects of nifedipine have been demonstrated but dose recommendations, long term safety and effect on cardiovascular outcome remain unestablished. Paediatric dosing forms are lacking.
Pharmacotherapeutic group: selective calcium channel blockers with mainly vascular effect, dihydropyridine derivatives, ATC code: C08CA05
Nifedipine is a calcium antagonist of the 1, 4-dihydropyridine type. Calcium antagonists reduce the transmembranal influx of calcium ions through the slow calcium channel into the cell. As a specific and potent calcium antagonist, nifedipine acts particularly on the cells of the myocardium and the smooth muscle cells of the coronary arteries and the peripheral resistance vessels. The main action of Meborilan capsules is to relax arterial smooth muscle both in the coronary and peripheral circulation.
In angina pectoris, Meborilan capsules relax peripheral arteries so reducing the load on the left ventricle. Additionally, Meborilan capsules dilate submaximally both clear and pre-stenotic coronary arteries, and stenotic and post-stenotic coronary arteries, thus protecting the heart against coronary artery spasm and improving perfusion to the ischaemic myocardium.
Meborilan capsules reduce the frequency of painful attacks and ischaemic ECG changes, irrespective of the relative contribution from coronary artery spasm or atherosclerosis.
Meborilan capsules cause a reduction in blood pressure such that the percentage lowering is directly related to its initial level. In normotensive individuals, Meborilan capsules have little or no effect on blood pressure.
Paediatric population:
Limited information on comparison of nifedipine with other antihypertensives is available for both acute hypertension and long-term hypertension with different formulations in different dosages. Antihypertensive effects of nifedipine have been demonstrated but dose recommendations, long term safety and effect on cardiovascular outcome remain unestablished. Paediatric dosing forms are lacking.
Absorption
After oral administration nifedipine is almost completely absorbed. The systemic availability of orally administered nifedipine immediate release formulations (Adalat capsules) is 45 - 56 % owing to a first pass effect. Maximum plasma and serum concentrations are reached at 30 to 60 minutes. Simultaneous food intake leads to delayed, but not reduced absorption.
Distribution
Nifedipine is about 95 % bound to plasma protein (albumin). The distribution half-life after intravenous administration has been determined to be 5 to 6 minutes.
Biotransformation
After oral administration nifedipine is metabolized in the gut wall and in the liver, primarily by oxidative processes. These metabolites show no pharmacodynamic activity. Nifedipine is excreted in the form of its metabolites predominantly via the kidneys and about 5 - 15 % via the bile in the faeces. The unchanged substance is recovered only in traces (below 0.1 %) in the urine.
Elimination
The terminal elimination half-life is 1.7 to 3.4 hours. No accumulation of the substance after the usual dose was reported during long-term treatment. In cases of impaired kidney function no substantial changes have been detected in comparison with healthy volunteers.
In a study comparing the pharmacokinetics of nifedipine in patients with mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment with those in patients with normal liver function, oral clearance of nifedipine was reduced by on average 48% (Child Pugh A) and 72% (Child Pugh B). As a result AUC and Cmax of nifedipine increased on average by 93% and 64% (Child Pugh A) and by 253% and 171% (Child Pugh B), respectively, compared to patients with normal hepatic function. The pharmacokinetics of nifedipine has not been investigated in patients with severe hepatic impairment.
Absorption
After oral administration nifedipine is almost completely absorbed. The systemic availability of orally administered nifedipine immediate release formulations (Meborilan capsules) is 45 - 56 % owing to a first pass effect. Maximum plasma and serum concentrations are reached at 30 to 60 minutes. Simultaneous food intake leads to delayed, but not reduced absorption.
Distribution
Nifedipine is about 95 % bound to plasma protein (albumin). The distribution half-life after intravenous administration has been determined to be 5 to 6 minutes.
Biotransformation
After oral administration nifedipine is metabolized in the gut wall and in the liver, primarily by oxidative processes. These metabolites show no pharmacodynamic activity. Nifedipine is excreted in the form of its metabolites predominantly via the kidneys and about 5 - 15 % via the bile in the faeces. The unchanged substance is recovered only in traces (below 0.1 %) in the urine.
Elimination
The terminal elimination half-life is 1.7 to 3.4 hours. No accumulation of the substance after the usual dose was reported during long-term treatment. In cases of impaired kidney function no substantial changes have been detected in comparison with healthy volunteers.
In a study comparing the pharmacokinetics of nifedipine in patients with mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment with those in patients with normal liver function, oral clearance of nifedipine was reduced by on average 48% (Child Pugh A) and 72% (Child Pugh B). As a result AUC and Cmax of nifedipine increased on average by 93% and 64% (Child Pugh A) and by 253% and 171% (Child Pugh B), respectively, compared to patients with normal hepatic function. The pharmacokinetics of nifedipine has not been investigated in patients with severe hepatic impairment.
Adalat capsules are not beta-blockers and therefore give no protection against the dangers of abrupt beta-blocker withdrawal; any such withdrawal should be a gradual reduction of the dose of beta-blocker, preferably over 8-10 days.
Adalat capsules may be used in combination with beta-blocking drugs and other antihypertensive agents but the possibility of an additive effect resulting in postural hypotension should be borne in mind. Adalat capsules will not prevent possible rebound effects after cessation of other antihypertensive therapy.
Care must be exercised in patients with very low blood pressure (severe hypotension with systolic pressure less than 90 mm Hg).
Treatment with short-acting nifedipine may induce an exaggerated fall in blood pressure and reflex tachycardia, which can cause cardiovascular complications such as myocardial and cerebrovascular ischaemia.
As with other vasoactive substances, angina pectoris may very rarely occur (data from spontaneous reports) with immediate release nifedipine, especially at the start of the treatment. Data from clinical studies confirm that the occurrence of angina pectoris attacks is uncommon.
In patients suffering from angina pectoris an increase in frequency, duration and severity of angina pectoris attacks may occur, especially at the start of the treatment.
The occurrence of myocardial infarction has been described in isolated cases, although it was not possible to distinguish this from the natural course of the underlying disease.
Adalat capsules should not be used during pregnancy unless the clinical condition of the woman requires treatment with nifedipine. Adalat capsules should be reserved for women with severe hypertension who are unresponsive to standard therapy.
Careful monitoring of blood pressure must be exercised when administering nifedipine with I.V. magnesium sulfate, owing to the possibility of an excessive fall in blood pressure, which could harm both mother and foetus.
Adalat capsules are not recommended for use during breast-feeding because nifedipine has been reported to be excreted in human milk and the effects of nifedipine exposure to the infant are not known.
In patients with mild, moderate or severe impaired liver function, careful monitoring and a dose reduction may be necessary. The pharmacokinetics of nifedipine has not been investigated in patients with severe hepatic impairment. Therefore, nifedipine should be used with caution in patients with severe hepatic impairment.
Adalat capsules should be used with caution in patients whose cardiac reserve is poor. Deterioration of heart failure has occasionally been observed with nifedipine.
At doses higher than those recommended, there is some concern about increased mortality and morbidity in the treatment of ischaemic heart disease, in particular after myocardial infarction.
The use of Adalat capsules in diabetic patients may require adjustment of their control.
In dialysis patients with malignant hypertension and hypovolaemia, a marked decrease in blood pressure can occur.
Nifedipine is metabolised via the cytochrome P450 3A4 system. Drugs that are known to either inhibit or to induce this enzyme system may therefore alter the first pass or the clearance of nifedipine.
Drugs that are known inhibitors of the cytochrome P450 3A4 system, and which may therefore lead to increased plasma concentrations of nifedipine include, for example:
- macrolide antibiotics (e.g., erythromycin)
- anti-HIV protease inhibitors (e.g., ritonavir)
- azole antimycotics (e.g., ketoconazole)
- the antidepressants, nefazodone and fluoxetine
- quinupristin/dalfopristin
- valproic acid
- cimetidine
Upon co-administration with these drugs, the blood pressure should be monitored and, if necessary, a reduction of the nifedipine dose should be considered.
Adalat capsules contains yellow orange S (E110) which may cause allergic reactions.
Meborilan capsules are not beta-blockers and therefore give no protection against the dangers of abrupt beta-blocker withdrawal; any such withdrawal should be a gradual reduction of the dose of beta-blocker, preferably over 8-10 days.
Meborilan capsules may be used in combination with beta-blocking drugs and other antihypertensive agents but the possibility of an additive effect resulting in postural hypotension should be borne in mind. Meborilan capsules will not prevent possible rebound effects after cessation of other antihypertensive therapy.
Care must be exercised in patients with very low blood pressure (severe hypotension with systolic pressure less than 90 mm Hg).
Treatment with short-acting nifedipine may induce an exaggerated fall in blood pressure and reflex tachycardia, which can cause cardiovascular complications such as myocardial and cerebrovascular ischaemia.
As with other vasoactive substances, angina pectoris may very rarely occur (data from spontaneous reports) with immediate release nifedipine, especially at the start of the treatment. Data from clinical studies confirm that the occurrence of angina pectoris attacks is uncommon.
In patients suffering from angina pectoris an increase in frequency, duration and severity of angina pectoris attacks may occur, especially at the start of the treatment.
The occurrence of myocardial infarction has been described in isolated cases, although it was not possible to distinguish this from the natural course of the underlying disease.
Meborilan capsules should not be used during pregnancy unless the clinical condition of the woman requires treatment with nifedipine. Meborilan capsules should be reserved for women with severe hypertension who are unresponsive to standard therapy.
Careful monitoring of blood pressure must be exercised when administering nifedipine with I.V. magnesium sulfate, owing to the possibility of an excessive fall in blood pressure, which could harm both mother and foetus.
Meborilan capsules are not recommended for use during breast-feeding because nifedipine has been reported to be excreted in human milk and the effects of nifedipine exposure to the infant are not known.
In patients with mild, moderate or severe impaired liver function, careful monitoring and a dose reduction may be necessary. The pharmacokinetics of nifedipine has not been investigated in patients with severe hepatic impairment. Therefore, nifedipine should be used with caution in patients with severe hepatic impairment.
Meborilan capsules should be used with caution in patients whose cardiac reserve is poor. Deterioration of heart failure has occasionally been observed with nifedipine.
At doses higher than those recommended, there is some concern about increased mortality and morbidity in the treatment of ischaemic heart disease, in particular after myocardial infarction.
The use of Meborilan capsules in diabetic patients may require adjustment of their control.
In dialysis patients with malignant hypertension and hypovolaemia, a marked decrease in blood pressure can occur.
Nifedipine is metabolised via the cytochrome P450 3A4 system. Drugs that are known to either inhibit or to induce this enzyme system may therefore alter the first pass or the clearance of nifedipine.
Drugs that are known inhibitors of the cytochrome P450 3A4 system, and which may therefore lead to increased plasma concentrations of nifedipine include, for example:
- macrolide antibiotics (e.g., erythromycin)
- anti-HIV protease inhibitors (e.g., ritonavir)
- azole antimycotics (e.g., ketoconazole)
- the antidepressants, nefazodone and fluoxetine
- quinupristin/dalfopristin
- valproic acid
- cimetidine
Upon co-administration with these drugs, the blood pressure should be monitored and, if necessary, a reduction of the nifedipine dose should be considered.
Meborilan capsules contains yellow orange S (E110) which may cause allergic reactions.
Reactions to the drug, which vary in intensity from individual to individual, may impair the ability to drive or to operate machinery. This applies particularly at the start of treatment, on changing the medication and in combination with alcohol.
Posology
The maximum total daily dose is 60 mg. The recommended starting dose is 5 mg every eight hours with subsequent titration of dose according to response permitting an increase to a maximum of 20 mg every eight hours.
Co-administration with CYP 3A4 inhibitors or CYP 3A4 inducers may result in the recommendation to adapt the nifedipine dose or not to use nifedipine at all.
Duration of treatment
Treatment may be continued indefinitely.
Additional information for special populations
Paediatric population
The safety and efficacy of Adalat capsules in children below 18 years of age has not been established.
Older people (>65 years)
The pharmacokinetics of Adalat capsules are altered in the older people so that lower maintenance doses of nifedipine may be required.
Patients with hepatic impairment
Nifedipine is metabolised primarily by the liver and therefore patients with mild, moderate or severe liver dysfunction should be carefully monitored and a dose reduction may be necessary. The pharmacokinetics of nifedipine has not been investigated in patients with severe hepatic impairment.
Patients with renal impairment
Based on pharmacokinetic data, no dosage adjustment is required in patients with renal impairment.
Method of administration
Oral use.
Adalat capsules should be swallowed whole with a little liquid, either with or without food.
Adalat capsules should not be taken with grapefruit juice.
Posology
The maximum total daily dose is 60 mg. The recommended starting dose is 5 mg every eight hours with subsequent titration of dose according to response permitting an increase to a maximum of 20 mg every eight hours.
Co-administration with CYP 3A4 inhibitors or CYP 3A4 inducers may result in the recommendation to adapt the nifedipine dose or not to use nifedipine at all.
Duration of treatment
Treatment may be continued indefinitely.
Additional information for special populations
Paediatric population
The safety and efficacy of Meborilan capsules in children below 18 years of age has not been established.
Older people (>65 years)
The pharmacokinetics of Meborilan capsules are altered in the older people so that lower maintenance doses of nifedipine may be required.
Patients with hepatic impairment
Nifedipine is metabolised primarily by the liver and therefore patients with mild, moderate or severe liver dysfunction should be carefully monitored and a dose reduction may be necessary. The pharmacokinetics of nifedipine has not been investigated in patients with severe hepatic impairment.
Patients with renal impairment
Based on pharmacokinetic data, no dosage adjustment is required in patients with renal impairment.
Method of administration
Oral use.
Meborilan capsules should be swallowed whole with a little liquid, either with or without food.
Meborilan capsules should not be taken with grapefruit juice.
No additional information.
