Nifedipine Capsules 5mg
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Nifedipine Capsules 5 mg
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each soft capsule contains 5 mg Nifedipine Excipient with known effect : Sunset Yellow (E110)
For the full list of excipients, see section 6.1
3 PHARMACEUTICAL FORM
Orange oval, soft gelatin capsule with a clear liquid fill material.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
For the prophylaxis of chronic stable angina pectoris, the treatment of Raynaud’s phenomenon and hypertension.
For patients suffering from essential hypertension or chronic stable angina pectoris treated with fast release forms of nifedipine, a dose dependent increase in the risk of cardiovascular complications (e.g. myocardial infarction) and mortality may occur. Because of this, nifedipine capsules should only be used for the treatment of patients with essential hypertension or chronic stable angina pectoris if no other treatment is appropriate.
4.2 Posology and method of administration
The capsules should be taken orally with a little water, either with or without food. The recommended starting dose is 5mg every 8 hours with subsequent titration of dose according to response. The dose can be increased to 20mg every 8 hours.
Co-administration with cytochrome P450 3A4 inhibitors or inducers may result in increased or reduced serum concentrations of nifedipine. The dose of nifedipine may require adjustment, or an alternative to nifedipine treatment may be necessary.
Nifedipine is metabolised primarily by the liver and therefore patients with liver dysfunction should be carefully monitored. Dose reduction may be necessary in severe liver impairment.
Patients with renal impairment should not require adjustment of dosage.
Treatment may be continued indefinitely.
Dosage in the elderly
The pharmacokinetics of nifedipine are altered in the elderly so that lower maintenance dose of nifedipine may be required compared to younger patients.
Paediatric population
The safety and efficacy of nifedipine in children under the age 18 years have not been established.
Currently available data for the use of nifedipine in hypertension are described in section 5.1
4.3 Contraindications
Nifedipine should not be administered to patients with known hypersensitivity to nifedipine, or other dihydropyridines because of the theoretical risk of cross-reactivity or to any of the excipients listed in section 6.1.
Nifedipine should not be used in cardiogenic shock, clinically significant aortic stenosis, unstable angina, or during or within one month of a myocardial infarction.
Nifedipine should not be used for the treatment of acute attacks of angina.
The safety of nifedipine in malignant hypertension has not been established.
Nifedipine should not be used for secondary prevention of myocardial infarction.
Nifedipine should not be administered concomitantly with rifampicin since effective plasma levels of nifedipine may not be achieved owing to enzyme induction (see section 4.5).
4.4 Special warnings and precautions for use
Nifedipine is not a beta-blocker and therefore gives no protection against the dangers of abrupt beta-blocker withdrawal; any such withdrawal should be gradual reduction of the dose of beta-blocker preferably over 8-10 days.
Nifedipine 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. Nifedipine will not prevent possible rebound effects after cessation of other antihypertensive therapy.
Nifedipine 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.
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 treatment.
Myocardial infarction has occurred, although it is not possible to distinguish this from the natural course of the underlying disease.
Nifedipine should not be used during pregnancy unless the clinical condition of the woman requires treatment with nifedipine. Nifedipine should be reserved for women with severe hypertension who are unresponsive to standard therapy (see Section 4.6).
Caution should be exercised in patients with severe hypotension (systolic pressure less than 90 mmHg) as there is a risk of further decrease in blood pressure.'
The use of nifedipine 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.
Careful monitoring of blood pressure must be performed when administering nifedipine with intravenous magnesium sulphate, owing to the potential for an excessive fall in blood pressure, which could harm both mother and foetus (For further information regarding use in pregnancy, refer to section 4.6).
Nifedipine is not recommended for use during breastfeeding because nifedipine has been reported to be excreted in human milk and the effects of nifedipine exposure to the infant are not known (see Section 4.6).
In patients with impaired liver function, careful monitoring, and in severe cases, a dose reduction may be necessary.
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.
Nifedipine is metabolised via the cytochrome P450 3A4 enzyme system. Concomitant use of substances that are known to inhibit or induce this enzyme system may lead to increased or reduced plasma concentrations of nifedipine. Changes in the dose of nifedipine may be required (see section 4.5).
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 (see section 4.5).
Nifedipine capsules contain Sunset yellow (E110) which may cause hypersensitivity reactions.
4.5 Interaction with other medicinal products and other forms of interaction
Drugs that affect nifedipine
Nifedipine is metabolised via the cytochrome P450 3A4 system, located both in the intestinal mucosa and in the liver. Drugs that are known to either inhibit or to induce this enzyme system may therefore alter the first pass (after oral administration) or the clearance of nifedipine (see Section 4.4).
The extent as well as the duration of interactions should be taken into account when administering nifedipine together with the following drugs:
Rifampicin: Rifampicin strongly induces the cytochrome P450 3A4 system. Upon co-administration with rifampicin, the bioavailability of nifedipine is distinctly reduced and thus its efficacy weakened. The use of nifedipine in combination with rifampicin is therefore contraindicated (see Section 4.3).
Upon co-administration of known inhibitors of the cytochrome P450 3A4 system the blood pressure should be monitored and, if necessary, a reduction in the nifedipine dose considered (see Sections 4.2 and 4.4). In the majority of these cases, no formal studies to assess the potential for a drug interaction between nifedipine and the drug(s) listed have been undertaken, thus far.
Drugs increasing nifedipine exposure:
• macrolide antibiotics (e.g., erythromycin)
• anti-HIV protease inhibitors (e.g., ritonavir)
• azole anti-mycotics (e.g., ketoconazole)
• fluoxetine
• nefazodone
• quinupristin/dalfopristin
• cisapride
• valproic acid
• cimetidine
• diltiazem
Upon co-administration of inducers of the cytochrome P450 3A4 system, the clinical response to nifedipine should be monitored and, if necessary, an increase in the nifedipine dose considered. If the dose of nifedipine is increased during co-administration of both drugs, a reduction of the nifedipine dose should be considered when the treatment is discontinued.
Drugs decreasing nifedipine exposure:
• rifampicin (see above)
• phenytoin
• carbamazepine • phenobarbital
Effects of nifedipine on other drugs
Nifedipine may increase the blood pressure lowering effect of concomitant applied antihypertensives.
When nifedipine is administered simultaneously with beta-receptor blockers the patient should be carefully monitored, since deterioration of heart failure is also known to develop in isolated cases.
Digoxin: The simultaneous administration of nifedipine and digoxin may lead to reduced digoxin clearance and, hence, an increase in the plasma digoxin level. The patient should therefore be subjected to precautionary checks for symptoms of digoxin overdosage and, if necessary, the glycoside dose should be reduced.
Quinidine: Co-administration of nifedipine with quinidine may lower plasma quinidine levels, and after discontinuation of nifedipine, a distinct increase in plasma quinidine levels may be observed in individual cases. Consequently, when nifedipine is either additionally administered or discontinued, monitoring of the quinidine plasma concentration, and if necessary, adjustment of the quinidine dose are recommended. Blood pressure should be carefully monitored and, if necessary, the dose of nifedipine should be decreased.
Tacrolimus: Tacrolimus is metabolised via the cytochrome P450 3A4 system. Published data indicate that the dose of tacrolimus administered simultaneously with nifedipine may be reduced in individual cases. Upon coadministration of both drugs, the tacrolimus plasma concentrations should be monitored and, if necessary, a reduction in the tacrolimus dose considered.
Drug food interactions
Grapefruit juice inhibits the cytochrome P450 3A4 system. Administration of nifedipine together with grapefruit juice thus results in elevated plasma concentrations and prolonged action of nifedipine due to a decreased first pass metabolism or reduced clearance. As a consequence, the blood pressure lowering effect of nifedipine may be increased. After regular intake of grapefruit juice, this effect may last for at least three days after the last ingestion of grapefruit juice.
Ingestion of grapefruit/grapefruit juice is therefore to be avoided while taking nifedipine (see Section 4.2).
Other forms of interaction
Nifedipine may increase the spectrophotometric values of urinary vanillylmandelic acid falsely. However, HPLC measurements are unaffected.
4.6 Pregnancy and lactation
Pregnancy
Nifedipine should not be used during pregnancy unless the clinical condition of the woman requires treatment with nifedipine (see Section 4.4).
In animal studies, nifedipine has been shown to produce embryotoxicity, foetotoxicity and teratogenicity (see section 5.3).
There are no adequate and well-controlled studies in pregnant women.
From the clinical evidence available a specific prenatal risk has not been identified, although an increase in perinatal asphyxia, caesarean delivery, as well as prematurity and intrauterine growth retardation have been reported. It is unclear whether these reports are due to the underlying hypertension, its treatment, or to a specific drug effect.
The available information is inadequate to rule out adverse drug effects on the unborn and newborn child. Therefore any use in pregnancy requires a very careful individual risk benefit assessment and should only be considered if all other treatment options are either not indicated or have failed to be efficacious.
Breast-feeding
Nifedipine passes into breast milk. The nifedipine concentration in the milk is almost comparable with mother serum concentration. For immediate release formulations, it is proposed to delay breastfeeding or milk expression for 3 to 4 hours after drug administration to decrease the nifedipine exposure to the infant (see Section 4.4).
Fertility
In single cases of in vitro fertilization, calcium antagonists like nifedipine have been associated with reversible biochemical changes in the spermatozoa’s head section that may result in impaired sperm function. In those men who are repeatedly unsuccessful in fathering a child by in vitro fertilization, and where no other explanation can be found, calcium antagonists like nifedipine should be considered as possible causes.
4.7 Effects on ability to drive and use machines
Nifedipine may cause dizziness, lethargy and visual disturbances. Reactions to the drug, which vary in intensity from individual to individual, may impair the ability to drive or use machinery. This applies particularly at the start of treatment, when changing the medication, and in combination with alcohol.
4.8 Undesirable effects
Most side effects are consequences of the vasodilatory effects of nifedipine. Headache, flushing, tachycardia and palpitations may occur, most commonly in the early stages of treatment with nifedipine. Gravitational oedema, not associated with heart failure or weight gain, may also occur.
Ischaemic pain has been reported in a small proportion of patients within 30 to 60 minutes of the introduction of nifedipine therapy. Although a “steal” effect has not been demonstrated, patients experiencing this effect should discontinue nifedipine.
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%). ADRs derived from post marketing reports (status: 31 Mar 2006) are printed in bold italic.
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 known”.
|
Common > 1% to <10% |
Uncommon > 0.1% to <1% |
Rare > 0.01% to <0.1% |
Frequency Not Known |
|
Blood and Lymphatic System Disorders | |||
|
Agranulocytosis, Leucopenia | |||
|
Metabolism and Nutrition Disorders | |||
|
Hyperglycaemia | |||
|
Immune System Disorders | |||
|
Allergic reaction Allergic oedema/angioedema (incl. larynx oedema*) |
Pruritus Urticaria Rash |
Anaphylactic/anaphylactoid reaction | |
|
Psychiatric Disorders | |||
|
Anxiety reactions Sleep disorders | |||
|
Nervous System Disorders | |||
|
Headache |
Vertigo Migraine Dizziness |
Par- /Dysaesthesia |
Hypoaesthesia, Somnolence |
Tremor
|
Eye Disorders | |||
|
Visual disturbances |
Eye pain | ||
|
Cardiac Disorders | |||
|
Tachycardia |
Chest pain | ||
|
Palpitations |
(Angina Pectoris) | ||
|
Vascular Disorders | |||
|
Oedema |
Hypotension | ||
|
Vasodilatation |
Syncope | ||
|
Respiratory, Thoracic and Mediastinal Disorders | |||
|
Nasal congestion |
Dyspnoea | ||
|
Nosebleed | |||
|
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, Connective Tissue and Bone 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
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.
4.9 Overdose
The fatal dose is not known.
Clinical effects
Reports of nifedipine overdosage are limited and symptoms are not necessarily dose-related.
The most important effects are on the cardiovascular system. Severe hypotension secondary to profound peripheral vasodilation, and tachycardia or bradycardia are the most likely manifestations of overdose.
Cardiac effects may include heart block, AV dissociation and asystole, and cardiogenic shock with pulmonary oedema.
Features of overdosage with calcium channel blockers may include nausea, vomiting, drowsiness, dizziness, agitation, confusion, lethargy, flushing, hypoxia and occasionally coma in the case of severe poisoning. Metabolic acidosis and hyperglycaemia may be present.
Treatment
As far as treatment is concerned, elimination of nifedipine and the restoration of stable cardiovascular conditions have priority.
The benefit of gastric decontamination is uncertain.
1. Activated charcoal (50g for adults, 1g/kg for children) should be considered 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).
Blood pressure, ECG, central arterial pressure, pulmonary wedge pressure, urea and electrolytes should be monitored.
Hypotension as a result of cardiogenic shock and arterial vasodilation should be treated with elevation of the feet and plasma expanders. If these measures are ineffective, hypotension may be treated with 10% calcium gluconate 1020ml intravenously over 5-10 minutes. If the effects are inadequate, the treatment can be continued, with ECG monitoring. In addition, beta sympathomimetics may be given, eg isoprenaline 0.2mg slowly iv, or as a continuous infusion of 5pg/min. If an insufficient increase in blood pressure is achieved with calcium and isoprenaline, vasoconstricting sympathomimetics such as dopamine or noradrenaline should be administered. The dosage of these drugs should be determined by the patient’s response.
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.
5.1 Pharmacodynamic properties
C08C A - Selective calcium channel blockers
Nifedipine is a specific and potent 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. Nifedipine acts particularly on the cells of the myocardium and the smooth muscle cells of the coronary arteries and the peripheral resistance vessels. Its main action is to relax arterial smooth muscle both in the coronary and peripheral circulation.
In angina pectoris, nifedipine capsules relax peripheral arteries so reducing the load on the left ventricle. Additionally, nifedipine dilates submaximally both clear and pre-stenotic, stenotic and post-stenotic coronary arteries, thus protecting the heart against coronary artery spasm and improving perfusion to the ischaemic myocardium.
Nifedipine capsules reduce the frequency of painful attacks and ischaemic ECG changes, irrespective of the relative contribution from coronary artery spasm or atherosclerosis.
Nifedipine causes a reduction in blood pressure such that the percentage lowering is directly related to its initial height. In normotensive individuals, nifedipine has 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.
5.2 Pharmacokinetic properties
Absorption
After oral administration nifedipine is almost completely absorbed. The systemic availability of orally administered nifedipine immediate release formulations 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 cases of impaired liver function the elimination half-life is distinctly prolonged and the total clearance is reduced. A dose reduction may be necessary in severe cases (see Section 4.4).
5.3 Preclinical safety data
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 maximum dose for humans.
6. PHARMACEUTICAL PARTICULARS
6.1. List of Excipients
Polyethylene Glycol 400 Propylene Glycol Purified Water Peppermint Oil Saccharin Sodium
Shell ingredients:
Gelatin
Glycerol
Water
Andrisorb
Sunset Yellow E110 Titanium Dioxide E171
6.2 Incompatibilities
None known.
6.3. Shelf-Life
24 months.
6.4. Special Precautions for Storage
Protect from light. Store below 25°C.
6.5. Nature and Contents of Container
PVC/PVdC (285pm)/aluminium foil (25pm) blister strips in a cardboard container.
Pack sizes: 5, 7, 10, 14, 15, 20, 21, 25, 28, 30, 56, 60, 84, 90, 100, 112, 120, 168, 180, 250, 500.
6.6. Instructions for Use/Handling
No specific instructions for use/handling.
7. MARKETING AUTHORISATION HOLDER
Strides Shasun (UK) Ltd Unit 4 Metro Centre Tolpits Lane Watford Hertfordshire
WD18 9SS
Trading as: Co-pharma
8. MARKETING AUTHORIZATION NUMBER
PL 13606/0056
9. DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION
04th March 1998
10 DATE OF REVISION OF THE TEXT
19/05/2016