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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Nifedipine Capsules 10mg.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains nifedipine USP 10mg.

3.    PHARMACEUTICAL FORM

Soft gelatin capsule

Nifedipine Capsules 10 mg are shiny, oval, dark maroon soft gelatine capsules.

Plain practically odourless.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Used in the prophylaxis of chronic stable angina pectoris and in the treatment of hypertension and Raynaud’s phenomenon.

Nifedipine is a potent antagonist of calcium influx through the slow channel of the cell membrane of cardiac and smooth muscle cells. It is known to be an effective and relatively well tolerated prophylaxis for chronic stable angina and mild to severe hypertension. The antihypertensive effects of nifedipine are achieved by causing peripheral vasodilatation resulting in a reduction in peripheral resistance.

Nifedipine reduces blood pressure in hypertension but has little or no effect in normotensive individuals. It has no therapeutic antiarrhythmic effect.

4.2 Posology and method of administration

Adults:

The recommended starting dose is 5mg, every 8 hours, swallowed with water, with subsequent titration of dosage according to response. The dosage may be adjusted to 20mg, every 8 hours.

Patients on concomitant therapy and patients with liver dysfunction should be carefully monitored. Nifedipine is metabolised primarily by the liver.

Dosage adjustments should not be required for patients with renal impairment.

Elderly:

The pharmacokinetics of nifedipine are altered in the elderly so that lower maintenance doses 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

Method of administration: oral

4.3    Contraindications

Nifedipine capsules are contraindicated in pregnancy before week 20 and during breastfeeding (see Sections 4.4, 4.6 and 5.3).

•    Patients with cardiogenic shock

•    Hypersensitivity to nifedipine or other dihydropyridines of the theoretical risk of cross reactivity, or to any of the excipients.

•    Nifedipine should not be used in clinically significant aortic stenosis, unstable angina, or during or within 1 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 special precautions for use

Nifedipine 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.

Nifedipine 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. Nifedipine 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).

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.

Careful monitoring of blood pressure must be exercised when administering nifedipine with I.V. 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.

In patients with impaired liver function, careful monitoring, and in severe cases, a dose reduction may be necessary.

Nifedipine capsules should be used with caution in patients whose cardiac reserve is poor. Deterioration of heart failure has occasionally been observed with nifedipine.

In some patients, treatment with short-acting nifedipine induces an exaggerated fall in blood pressure with reflex tachycardia which can cause cardiovascular complications such as myocardial and cerebrovascular ischaemia.

Caution should be exercised when nifedipine is given to diabetic patients as such treatment may require adjustment of their diabetic therapy

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.

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 (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).

For use in special populations see Section 4.2.

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..

Other forms of interaction

Nifedipine may increase the spectrophotometric values of urinary vanillylmandelic acid falsely. However, HPLC measurements are unaffected.

Other interactions reported include increased plasma levels of theophylline and phenytoin when used in combination with nifedipine and the enhanced effect of non-polarising relaxants such as tubocurarine

4.6 Fertility, Pregnancy and lactation

Nifedipine capsules are contra-indicated in pregnancy before week 20 (see Section 4.3).

In animal studies, nifedipine has been shown to produce embryotoxicity, foetotoxicity and teratogenicity (see Section 5.3 Preclinical safety data).

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 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 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.

Nifedipine passes into the breast milk. 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

Patients should be warned of the possible side effects if they are to drive or to operate machinery. 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

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%). 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”.

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
Disorders		reactions
		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	Hypotension
Disorders	Vasodilatation	Syncope
Respiratory,		Nasal congestion		Dyspnoea
Thoracic, and Mediastinal Disorders		Nosebleed
Gastrointestinal	Constipation	Gastrointestinal	Gingival	Vomiting
Disorders		and abdominal pain	hyperplasia	Gastroesophageal sphincter
		Nausea		insufficiency

		Dyspepsia Flatulence Dry mouth
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	Gynaecomastia	Erectile dysfunction
General Disorders and Administration Site Conditions	Feeling unwell lethargy	Unspecific pain 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.

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.

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.

5 PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

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 Nifedipine capsules 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 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.

Nifedipine capsules reduce the frequency of painful attacks and ischaemic ECG changes, irrespective of the relative contribution from coronary artery spasm or atherosclerosis.

Nifedipine capsules cause a reduction in blood pressure such that the percentage lowering is directly related to its initial level. In normotensive individuals, Nifedipine 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. Pediatric 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 formulation (Nifedipine 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 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 recommended maximum dose for humans.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Povidone, polysorbate 80, saccharin sodium, menthol, tetrahydrofurfuryl alcohol-polyethyleneglycol ether, gelatin, glycerol 85%, titanium dioxide (E171), iron oxide black (E172), ponceau 4R 70% (E124) and purified water.

6.2 Incompatibilities

None known.

6.3 Shelf life

36 months.

6.4    Special precautions for storage

Store below 25°C in a dry place. Protect from light.

6.5    Nature and contents of container

Red transparent PVdC/PVC/aluminium foil blister strips.

Pack sizes: 28, 30, 56, 60, 84, 90, 100, 112 and 120.

6.6    Special precautions for disposal

Not applicable.

7    MARKETING AUTHORISATION HOLDER

Ennogen Pharma Limited

Unit G4 Riverside Industrial Estate

Riverside Way

Dartford