Enfed Xl 30 Mg Prolonged-Release Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
ENFED XL 30 mg Prolonged-release Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each prolonged-release tablet contains 30 mg nifedipine.
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Prolonged-release tablet
Pink Coloured, film coated circular biconvex tablet, having orifice on one side and plain on other side.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
ENFED XL prolonged release tablet is indicated in adults for:
Treatment of hypertension Chronic stable angina pectoris
4.2 Posology and method of administration
Posology
In mild to moderate hypertension, the recommended initial dose is one 20 mg tablet once-daily (use of other nifedipine containing medicinal products available in this strength is recommended). In severe hypertension, the recommended initial dose is one 30 mg tablet once-daily. If necessary, the dosage can be increased according to individual requirements up to a maximum of 60 mg once-daily.
For the prophylaxis of angina pectoris, the recommended initial dose is one 30 mg tablet once-daily. The dosage can be increased according to individual requirements up to a maximum of 90 mg once-daily.
Patients in whom hypertension or anginal symptoms are controlled on nifedipine capsules or nifedipine modified release tablets may be safely switched to nifedipine prolonged-release tablets.
Prophylactic anti-anginal efficacy is maintained when patients are switched from other calcium antagonists such as diltiazem or verapamil to nifedipine prolonged-release tablets. Patients switched from other calcium antagonists should initiate therapy at the recommended initial dose of 30 mg once-daily. Subsequent titration to a higher dose may be initiated as warranted clinically.
Duration of treatment
Treatment may be continued indefinitely.
Children and adolescents
The safety and efficacy of ENFED XL prolonged-release tablets in children below 18 years has not been established. Currently available data for the use of nifedipine in hypertension are described in section 5.1.
Geriatric patients
The pharmacokinetics of nifedipine are altered in the elderly so that lower maintenance doses of nifedipine may be required compared to younger patients.
Patients with hepatic impairment
In patients with impaired hepatic function, close monitoring is required and, in severe cases, dose reduction may be necessary
Patients with renal impairment
Based on pharmacokinetic data, no dosage adjustment is required in patients with renal impairment (see section 5.2).
CYP 3A4 inhibitors or CYP 3A4 inducers
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 (see section 4.5).
Method of administration
The tablets should be swallowed whole with a glass of water, either with or without food. The tablets should be taken at approximately 24-hour intervals,
i.e. at the same time each day, preferably during the morning. ENFED XL prolonged-release tablets must be swallowed whole; under no circumstances should they be bitten, chewed or broken up.
Tablets should not be taken with grapefruit juice. (See section 4.5).
4.3 Contraindications
Following is the list of contraindication for ENFED XL prolonged release tablets:
— Patients with known hypersensitivity to nifedipine, or to other
dihydropyridines because of the theoretical risk of cross-reactivity, or to any of the excipients listed in section 6.1.
— Cardiogenic shock, clinically significant aortic stenosis, unstable angina, or during or within one month of a myocardial infarction.
— Treatment of acute attacks of angina.
— Secondary prevention of myocardial infarction.
— Patients with a Kock pouch (ileostomy after proctocolectomy).
— 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
ENFED XL prolonged release tablets must be swallowed whole; under no circumstances should they be bitten, chewed or broken up.
Care must be exercised in patients with very low blood pressure (severe hypotension with systolic blood pressure less than 90 mm Hg), in cases of manifest heart failure and in the case of severe aortic stenosis.
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).
Nifedipine is not recommended for use during breastfeeding because nifedipine has been reported to be excreted in human milk and the effects of oral absorption of small amounts of nifedipine are not known (see section 4.6).
Careful monitoring of blood pressure must be exercised when administering nifedipine with intravenous magnesium sulphate, owing to the possibility of 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 prolonged release may be used in combination with - beta-blocking medicinal products and other antihypertensive agents but the possibility of an additive effect resulting in postural hypotension should be borne in mind. Nifedipine prolonged release will not prevent possible rebound effects after cessation of other antihypertensive therapy.
Nifedipine prolonged release should be used with caution in patients whose cardiac reserve is poor. Deterioration of heart failure has occasionally been observed with nifedipine.
Diabetic patients taking nifedipine prolonged release may require adjustment of their control.
The safety of ENFED XL prolonged release tablets in malignant hypertension has not been established.
In dialysis patients with malignant hypertension and hypovolaemia, a marked decrease in blood pressure can occur.
In patients with impaired hepatic function, close monitoring may be required and, in severe cases, dose reduction may be necessary (see section 4.2 and 5.2).
Nifedipine is metabolised via the cytochrome P450 3A4 system. Medicinal products that are known to either inhibit or to induce this enzyme system may therefore alter the first pass or the clearance of nifedipine (see section 4.5). Medicinal products, which are inhibitors of the cytochrome P450 3A4 system and therefore may lead to increased plasma concentrations of nifedipine are, e.g. 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 and cimetidine. Upon co-administration with these medicinal products, the blood pressure should be monitored and, if necessary, a reduction of the nifedipine dose should be considered.
As the outer membrane of the ENFED XL prolonged release tablet is not digested, what appears to be the complete tablet may be seen in the toilet or associated with the patient's stools. Also, as a result of this, care should be exercised when administering ENFED XL prolonged release to patients with pre-existing severe gastrointestinal narrowing/stenosis, as symptoms of bowel obstruction, may occur. Bezoars can occur in very rare cases and may require surgical intervention.
ENFED XL prolonged release tablets should be used cautiously in patients with history of gastro-intestinal obstruction, oesophageal obstruction, or any degree of decreased lumen diameter of the gastro-intestinal tract.
In single cases, obstructive symptoms have been described without known history of gastrointestinal disorders.
A false positive effect may be experienced when performing a barium contrast x-ray (e.g. filling defects interpreted as polyp).
For use in special populations see section 4.2.
4.5 Interaction with other medicinal products and other forms of interaction
Medicinal products that affect nifedipine
Nifedipine is metabolised via the cytochrome P450 3A4 system, located both in the intestinal mucosa and in the liver. Medicinal products 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.
The extent as well as the duration of interactions should be taken into account when administering nifedipine together with the following medicinal products:
Inducers of CYP3A4:
Rifampicin: Rifampicin strongly induces the cytochrome P450 3A4 system. Upon coadministration with rifampicin, the exposure of nifedipine was decreased approximately 97%. The use of nifedipine in combination with rifampicin is therefore contraindicated (see section 4.3).
Upon co-administration with the CYP3A4-inducers phenytoin, carbamazepine, phenobarbital or St John’s wort, 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 medicinal products, a reduction of the nifedipine dose should be considered when the treatment is discontinued.
Inhibitors of CYP3A4:
Upon co-administration of known inhibitors of the cytochrome P450 3A4 system, plasma concentrations of nifedipine may be strongly increased. If concomitant administration is deemed necessary, the blood pressure should be monitored and, if necessary, a reduction in the nifedipine dose considered (see section 4.2 and 4.4). The combination with potent CYP3A4-inhibitors (ketoconazole, itraconazole, voriconazole, pozaconazole, ritonavir, indinavir, saquinavir, atazanavir, nelfinavir, clarithromycin, telithromycin , nefazodone) should be avoided. Co-administration with moderate CYP3A4-inhibitors (fluconazole, erythromycin, diltiazem, verapamil, aprepitant) should be done with caution.
Macrolide antibiotics (e.g., erythromycin)
No interaction studies have been carried out between nifedipine and macrolide antibiotics. Certain macrolide antibiotics are known to inhibit the cytochrome P450 3A4 mediated metabolism of other medicinal products. Therefore the potential for an increase of nifedipine plasma concentrations upon co-administration of both medicinal products cannot be excluded (see section 4.4).
Azithromycin, although structurally related to the class of macrolide antibiotics is void of CYP3A4 inhibition.
Anti-HIV protease inhibitors (e.g. ritonavir)
A clinical study investigating the potential of a medicinal product interaction between nifedipine and certain anti-HIV protease inhibitors has not yet been performed. Medicinal products of this class are known to inhibit the cytochrome P450 3A4 system. In addition, medicinal products of this class have been shown to inhibit in vitro the cytochrome P450 3A4 mediated metabolism of nifedipine. When administered together with nifedipine, a substantial increase in plasma concentrations of nifedipine due to a decreased first pass metabolism and a decreased elimination cannot be excluded (see section 4.4).
Azole anti-mycotics (e.g., ketoconazole)
A formal interaction study investigating the potential of a medicinal product interaction between nifedipine and certain azole anti-mycotics has not yet been performed. Medicinal products of this class are known to inhibit the cytochrome P450 3A4 system. When administered orally together with nifedipine, a substantial increase in systemic bioavailability of nifedipine due to a decreased first pass metabolism cannot be excluded (see section 4.4).
Fluoxetine
A clinical study investigating the potential of a medicinal product interaction between nifedipine and fluoxetine has not yet been performed. Fluoxetine has been shown to inhibit in vitro the cytochrome P450 3A4 mediated metabolism of nifedipine. Therefore an increase of nifedipine plasma concentrations upon co-administration of both medicinal products cannot be excluded (see section 4.4).
Nefazodone
A clinical study investigating the potential of a medicinal product interaction between nifedipine and nefazodone has not yet been performed. Nefazodone is known to inhibit the cytochrome P450 3A4 mediated metabolism of other medicinal products.
Therefore an increase of nifedipine plasma concentrations upon co-administration of both medicinal products cannot be excluded (see section 4.4).
Quinupristin / Dalfopristin
Simultaneous administration of quinupristin / dalfopristin and nifedipine may lead to increased plasma concentrations of nifedipine (see section 4.4).
Diltiazem
Diltiazem increases the plasma concentrations of nifedipine with approximately 50%. Cimetidine
Concomitant administration of cimetidine increased the plasma concentrations of nifedipine with 100%. The combination should be used with caution and a reduction of the nifedipine dose might be necessary.
Valproic acid
No interaction studies have been conducted. Given that concomitant administration of the structurally similar calcium antagonist nimodipin and valproic acid resulted in a 50% increase in nifedipine plasma concentrations, an increased efficacy of nifedipine cannot be excluded.
Further studies:
Cisapride: Simultaneous administration of cisapride and nifedipine may lead to increased plasma concentrations of nifedipine.
Cytochrome P450 3A4 system inducing anti-epileptic medicinal products, such as phenytoin, carbamazepine and phenobarbitone.
Phenytoin induces the cytochrome P450 3A4 system. Upon co-administration with phenytoin, the bioavailability of nifedipine is reduced and thus its efficacy weakened. When both medicinal products are concomitantly administered, the clinical response to nifedipine should be monitored and, if necessary, an increase of the nifedipine dose considered. If the dose of nifedipine is increased during co-administration of both medicinal products, a reduction of the nifedipine dose should be considered when the treatment with phenytoin is discontinued.
No formal studies have been performed to investigate the potential interaction between nifedipine and carbamazepine or phenobarbitone. As both medicinal products have been shown to reduce the plasma concentrations of the structurally similar calcium channel blocker nimodipine due to enzyme induction, a decrease in nifedipine plasma concentrations and hence a decrease in efficacy cannot be excluded.
Effects of nifedipine on other medicinal products
Nifedipine may increase the blood pressure lowering effect of concomitant applied antihypertensives such as:
- Diuretics
- P-blockers
- ACE-inhibitors
- Angiotensin 1(AT1) receptor- antagonists
- other calcium antagonists
- a-adrenergic blocking agents
- PDE5 inhibitors
- a-methyldopa
When nifedipine is administered simultaneously with B-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 co-administration of both medicinal products, the tacrolimus plasma concentrations should be monitored and, if necessary, a reduction in the tacrolimus dose considered.
Medicinal product food interactions Grapefruit juice:
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 Fertility, pregnancy and lactation
Pregnancy
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 4.4).
There are no adequate 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 medicinal product effect.
The available information is inadequate to rule out adverse medicinal product effects on the unborn and newborn child. Therefore any use in pregnancy after week 20 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.
In animal studies, nifedipine has been shown to produce embryotoxicity, foetotoxicity and teratogenicity (see section 5.3 Preclinical safety data).
Fertility
In single cases of in vitro fertilisation 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 fertilisation, and where no other explanation can be found, calcium antagonists like nifedipine should be considered as possible causes.
Breast feeding
Nifedipine passes into the 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 medicinal product administration to decrease the nifedipine exposure to the infant (see section 4.4). As there is no experience of possible effects on infants, breastfeeding should first be stopped if nifedipine treatment becomes necessary during the breastfeeding period.
4.7 Effects on ability to drive and use machines
Reactions to the medicinal product, which vary in intensity from individual to individual, may impair the ability to drive or to operate machines. This applies particularly at the start of treatment, on changing the medication and in combination with alcohol.
4.8 Undesirable effects
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 known”.
|
System Organ Class (MedDRA) |
Common |
Uncommon |
Rare |
Not Known |
|
Blood and |
Agranulocytosis | |||
|
Lymphatic System Disorders |
Leucopenia | |||
|
Immune System |
Allergic reaction |
Pruritus |
Anaphylactic/ | |
|
Disorders |
Allergic oedema/angioedema |
Urticaria |
anaphylactoid reaction | |
|
(incl. larynx oedema) |
Rash | |||
|
Psychiatric |
Anxiety reactions | |||
|
Disorders |
Sleep disorders | |||
|
Metabolism and Nutrition Disorders |
Hyperglycaemia | |||
|
Nervous System |
Headache |
Vertigo |
Par- |
Hypoaesthesia |
|
Disorders |
Migraine |
/Dysaesthesia |
Somnolence | |
|
Dizziness | ||||
|
Tremor | ||||
|
Eye Disorders |
Visual disturbances |
Eye pain | ||
|
Cardiac |
Tachycardia |
Chest pain | ||
|
Disorders |
Palpitations |
(Angina pectoris) | ||
|
Vascular |
Oedema (incl. |
Hypotension | ||
|
Disorders |
peripheral oedema) |
Syncope | ||
|
Vasodilatation | ||||
|
Respiratory, |
Nosebleed |
Dyspnoea | ||
|
Thoracic, and Mediastinal Disorders |
Nasal congestion | |||
|
Gastrointestinal |
Constipation |
Gastrointestinal and |
Gingival |
Bezoar |
|
Disorders |
hyperplasia |
|
System Organ Class (MedDRA) |
Common |
Uncommon |
Rare |
Not Known |
|
abdominal pain |
Dysphagia | |||
|
Nausea |
Intestinal obstruction | |||
|
Dyspepsia |
Intestinal ulcer | |||
|
Flatulence |
Vomiting | |||
|
Dry mouth |
Gastroesophageal sphincter insufficiency | |||
|
Hepatobiliary |
Transient increase |
Jaundice | ||
|
Disorders |
in liver enzymes | |||
|
Skin and |
Erythema |
Toxic Epidermal | ||
|
Subcutaneous Tissue |
Necrolysis | |||
|
Disorders |
Photosensitivity allergic reaction | |||
|
Palpable purpura | ||||
|
Musculoskeletal |
Muscle cramps |
Arthralgia | ||
|
and Connective Tissue Disorders |
Joint swelling |
Myalgia | ||
|
Renal and |
Polyuria | |||
|
Urinary Disorders |
Dysuria | |||
|
Reproductive System and Breast Disorders |
Erectile dysfunction | |||
|
General Disorders and |
Feeling unwell |
Unspecific pain | ||
|
Administration Site Conditions |
Chills |
= may result in life-threatening outcome
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.
4.9 Overdose
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. After oral ingestion thorough gastric lavage is indicated, if necessary in combination with irrigation of the small intestine.
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 12 hours after ingestion.
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). As a result, the serum calcium can reach the upper normal range to slightly elevated levels. 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 medicinal products 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.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Calcium antagonist (1, 4-Dihydropyridine derivatives); ATC code: C08 CA05
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 nifedipine is to relax arterial smooth muscle, both in the coronary and peripheral circulation. ENFED XL prolonged release tablets tablet is formulated to achieve controlled delivery of nifedipine in a release profile sufficient to enable once-daily administration to be effective in clinical use.
In hypertension, the main action of nifedipine is to cause peripheral vasodilatation and thus reduce peripheral resistance. Nifedipine administered once-daily provides 24-hour control of raised blood pressure. Nifedipine causes reduction in blood pressure such that the percentage lowering is proportional to its initial level. In normotensive individuals, nifedipine has little or no effect on blood pressure.
In angina, ENFED XL prolonged release tablets reduces peripheral and coronary vascular resistance, leading to an increase in coronary blood flow, cardiac output and stroke volume, whilst decreasing after-load. Additionally, nifedipine dilates submaximally both clear and atherosclerotic coronary arteries, thus protecting the heart against coronary artery spasm and improving perfusion to the ischaemic myocardium. Nifedipine reduces the frequency of painful attacks and the ischaemic ECG changes irrespective of the relative contribution from coronary artery spasm or atherosclerosis.
In a multicenter, randomized, placebo-controlled, double-blind study (ACTION study) involving 7665 patients with stable angina pectoris who received the best possible standard of care, the effects of nifedipine were studied versus placebo on clinical outcomes. The nifedipine group included 3825 patients and 3840 placebo patients. The following parameters were used as the primary efficacy endpoint: combined incidence of death from any cause, acute myocardial infarction, refractory angina, newly-diagnosed heart failure, debilitating stroke and peripheral revascularisation. No differences in the frequency of the primary endpoint for efficacy were observed between the two treatment groups (P = .54).
In a predefined analysis of a subgroup of 3997 angina pectoris patients who had a high blood pressure prior to the study, it was shown that treatment with nifedipine resulted in a significant reduction (13%) in the primary endpoint of efficacy.
The primary endpoint for safety (combined incidence of death from any cause, acute myocardial infarction, stroke with debility) was the same in both the treatment groups (P = .86).
Nifedipine showed positive effects in 2 of 3 predefined secondary endpoints. The combined incidence of death, major cardiovascular events, revascularizations and coronary angiograms were reduced by 11% (P = 0.0012), mainly due to a significant reduction of coronary angiograms in the nifedipine group (150 fewer coronary angiograms as first event in nifedipine than in placebo). The total number of vascular events was reduced by 9% (P = 0.027), mainly as a result of reduced need for invasive percutaneous coronary interventions and bypass surgery (in total, 89 fewer procedures as first event in nifedipine than in placebo). In the third of the secondary endpoints (major cardiovascular events) no differences were detected between the two treatment groups (P = .26).
In a multi-national, randomised, double-blind, prospective INSIGHT study involving 6,321 hypertensive patients with at least one additional cardiovascular risk factor followed over 3 to 4.8 years, the effect of nifedipine on cardiovascular and cerebrovascular events morbidity and mortality versus hydrochlorothiazide with amiloride diuretic combination was investigated. A comparable effect on the primary endpoint of stoke, MI or cardiovascular mortality was demonstrated with a comparable blood pressure reduction.
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. Pediatric dosing forms are lacking.
5.2 Pharmacokinetic properties
General characteristics:
ENFED XL prolonged release tablets are formulated to provide nifedipine at an approximately constant rate over 24 hours. ENFED XL prolonged release tablets are appropriate for once-a-day administration.
The delivery rate is independent of gastrointestinal pH or motility. Upon swallowing, the biologically inert components of the tablet remain intact during gastrointestinal transit and are eliminated in the faeces as an insoluble shell.
Absorption
Orally administered nifedipine is almost completely absorbed in the gastro-intestinal tract. The systemic availability of orally administered nifedipine immediate release formulations (nifedipine capsules) is 45-56% owing to a first pass effect. At steady-state, the bioavailability of ENFED XL prolonged release tablets tablets ranges from 68-86% relative to nifedipine capsules. Administration in the presence of food slightly alters the rate of absorption but does not influence the extent of 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 metabolised in the gut wall and in the liver, primarily by oxidative processes. The metabolites show no pharmacodynamic activity. Nifedipine is eliminated in the form of its metabolites, predominantly via the kidneys, with approximately 5-15% being excreted via the bile in the faeces. Non-metabolised nifedipine can be detected only in traces (below 0.1%) in the urine.
Elimination
The terminal elimination half-life is 1.7 to 3.4 h in conventional formulations (nifedipine capsules). The terminal half-life following ENFED XL prolonged release tablets administration does not represent a meaningful parameter as a plateau-like plasma concentration is maintained during release from the tablets and absorption. After release and absorption of the last dose the plasma concentration declines with an elimination half-life as seen after conventional formulations.
Characteristics in patients:
There are no significant differences in the pharmacokinetics of nifedipine between healthy subjects and subjects with renal impairment. Therefore, dosage adjustment is not needed in these patients.
In patients with hepatic impairment, the elimination half-life is distinctly prolonged and the total clearance is reduced. Owing to the duration of action of the formulation, ENFED XL prolonged release tablets should not be administered in these patients.
5.3 Preclinical safety data
Preclinical data reveal no special hazards for humans based on conventional studies of single and repeated dose toxicity, genotoxicity and carcinogenic potential.
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.
In in vitro and in vivo tests, nifedipine has not been associated with mutagenic properties.
6.1 List of excipients Core
Polyethylene Oxide Hypromellose (E464)
Sodium chloride Magnesium Stearate Iron oxide (E172)
Seal coating
Hypromellose (E464)
Cellulose Acetate coating
Cellulose acetate Macrogol (PEG-4000)
Film coating
Hydroxypropylcellulose (E463) Hypromellose (E464)
Titanium dioxide (E171)
Talc (E553b)
Iron oxide red (E172)
6.2 Incompatibilities
Not Applicable.
6.3 Shelf life
2 years.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
PVC/PE/PVDC, aluminium blister. Blister pack of 28’s, 30’s, 90’s, and 98’s
tablets
6.6 Special precautions for disposal
No special requirements.
7 MARKETING AUTHORISATION HOLDER
Cipla (EU) Limited, Hillbrow House, Hillbrow Road, Esher, Surrey, KT10 9NW, United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 36390/0081
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
10/06/2014
10 DATE OF REVISION OF THE TEXT
10/06/2014