Nifedipine 10mg Capsules

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SUMMARY OF PRODUCT CHARACTERISTICS 1 NAME OF THE MEDICINAL PRODUCT

Nifedipine 10-mg Capsules.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains 10 mg nifedipine

Excipient(s) with known effect

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Capsule

Opaque, oblong, soft gelatin capsules containing an orange liquid. Overprinted 2L4 in white.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Nifedipine is indicated for the prevention of chronic stable angina pectoris and for the treatment of Raynaud’s phenomenon and hypertension.

4.2 Posology and method of administration

Posology

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

Elderly (>65 years)

The pharmacokinetics of nifedipine are altered in the elderly so that lower maintenance doses of nifedipine may be required.

Nifedipine is metabolised primarily by the liver and therefore patients with liver dysfunction should be carefully monitored. Patients with renal impairment should not require adjustment of dosage. Nifedipine is not recommended for use in children.

Treatment may be continued indefinitely.

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

For oral administration.

The capsules should be taken with a little water.

4.3 Contraindications

Nifedipine must not be administered to patients with known hypersensitivity to the active substance(s), or to other dihydropyridines because of the theoretical risk of cross-reactivity, or to any of the excipients listed in section 6.1.

Nifedipine is contraindicated in pregnancy before week 20 and during breastfeeding

(see Sections 4.4, 4.6 and 5.3).

Nifedipine should not be used in cases of cardiovascular shock, clinically significant aortic stenosis.

Immediate release nifedipine is contraindicated in unstable angina pectoris, or after acute myocardial infarction within the first 4 weeks.

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 must not be used in combination with rifampicin because no efficient plasma levels of nifedipine may be obtained due to enzyme induction (please 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 a 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.

Care must be exercised in patients with very low blood pressure (severe hypotension with systolic pressure less than 90 mm Hg), in cases of manifest heart failure and in 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. 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, (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 amount of nifedipine are not known (see section 4.6)

Treatment with immediate release nifedipine may induce an exaggerated fall in blood pressure with reflex tachycardia, which could result in cardiovascular complications .

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.

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

Nifedipine should be used with caution in patients whose cardiac reserve is poor and less frequently deterioration of heart failure has been observed.

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 nifedipine in diabetic patients may require adjustment of their control.

In dialysis patients with malignant hypertension and hypovolaemia, a decrease in blood pressure may be observed.

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 which are inhibitors of the cytochrome P450 3A4 system and therefore may lead to increased plasma concentrations of nifedipine are, for e.g.:

• macrolide antibiotics (e.g., erythromycin)

• anti-HIV protease inhibitors (e.g., ritonavir)

• azole antimycotics (e.g., ketoconazole)

• 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.

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.

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 coadministration 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 the following weak to moderate 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).

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 drugs. Therefore the potential for an increase of nifedipine plasma concentrations upon co-administration of both drugs 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 drug interaction between nifedipine and certain anti-HIV protease inhibitors has not yet been performed. Drugs of this class are known to inhibit the cytochrome P450 3A4 system. In addition, drugs 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 drug interaction between nifedipine and certain azole anti-mycotics has not yet been performed. Drugs 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 drug 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 coadministration of both drugs cannot be excluded (see section 4.4).

Nefazodone

A clinical study investigating the potential of a drug interaction between nifedipine and nefazodone has not yet been performed. Nefazodone is known to inhibit the cytochrome P450 3A4 mediated metabolism of other drugs.

Therefore an increase of nifedipine plasma concentrations upon coadministration of both drugs 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).

Valproic acid

No formal studies have been performed to investigate the potential interaction between nifedipine and valproic acid. As valproic acid has been shown to increase the plasma concentrations of the structurally similar calcium channel blocker nimodipine due to enzyme inhibition, an increase in nifedipine plasma concentrations and hence an increase in efficacy cannot be excluded (see section 4.4).

Cimetidine

Due to its inhibition of cytochrome P450 3A4, cimetidine elevates the plasma concentrations of nifedipine and may potentiate the antihypertensive effect (see section 4.4).

Further studies

Cisapride

Simultaneous administration of cisapride and nifedipine may lead to increased plasma concentrations of nifedipine.

Cytochrome P450 3A4 system inducing anti-epileptic drugs, 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 drugs 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 drugs, 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 drugs 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.

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

• itraconazole

• fluconazole

• indinavir

• nelfinavir

• saquinavir

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

• Blood Pressure lowering Drugs

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 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 plasma concentrations of digoxin. The patient should therefore be checked for symptoms of digoxin overdosage as a precaution and, if necessary, the glycoside dose should be reduced taking account of the plasma concentration of digoxin.

Quinidine

When nifedipine and quinidine have been administered simultaneously, lowered quinidine or,after discontinuation of nifedipine, a distinct increase in plasma concentrations of quinidine has been observed in individual cases. For this reason,, when nifedipine is either additionally administered or discontinued, monitoring of the quinidine plasma concentration, and if necessary, adjustment of the quinidine dose are recommended. Some authors reported increased plasma concentrations of nifedipine upon co-administration of both drugs, while others did not observe an alteration in the pharmacokinetics of nifedipine.

Therefore, the blood pressure should be carefully monitored, if quinidine is added to an existing therapy with nifedipine. If necessary, the dose of nifedipine should be decreased.

Tacrolimus

Tacrolimus has been shown to be metabolised via the cytochrome P450 3A4 system. Data recently published indicate that the dose of tacrolimus administered simultaneously with nifedipine may be reduced in individual cases. Upon co-administration 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

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 cause falsely increased spectrophotometric values of urinary vanillyl-mandelic acid. However, measurement with HPLC is unaffected.

Drugs shown not to interact with nifedipine

The following drugs have been shown to have no effect on the pharmacokinetics of nifedipine when administered concomitantly: ajmaline, aspirin, benazepril, candesartan, cilexetil, debrisoquine, doxazosin, irbesartan,

omeprazole, orlistat, pantoprazole, ranitidine, rosiglitazone, talinolol and triamterene hydrochlorothiazide.

4.6 Fertility, pregnancy and lactation

Pregnancy

Nifedipine is contraindicated in pregnancy before week 20 (see Sections 4.3).

The safety of nifedipine for use in human pregnancy has not been established.

In animal studies nifedipine has been shown to produce embryotoxicity, fetotoxicity 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 has 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.

Acute pulmonary oedema has been observed when nifedipine has been used as tocolytic during pregnancy (see section 4.8), especially in cases of multiple pregnancy (twins or more), with the intravenous route and/or concomitant use of beta-2 agonists. Nifedipine should not be used in multiple pregnancies or in pregnant women with compromised cardio-vascular condition, except if there is no other acceptable alternative.

Breast-feeding

Nifedipine is excreted in 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 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.

Nifedipine is contra-indicated in nursing mothers, as nifedipine may be present in breast milk.

4.7 Effects on ability to drive and use machines

Reactions to the drug, which vary in intensity from individual to individual, can impair the ability to drive or to operate machinery ( see section 4.8). This applies particularly at the start of the treatment, on changing the medication and in combination with alcohol.

4.8 Undesirable effects

Most undesirable effects are consequences of the vasodilatory effects of nifedipine and usually regress upon withdrawal of treatment.

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%).

Tabulated list of adverse reactions

The frequencies of ADRs reported with nifedipine-containing products are summarized 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 post marketing 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 Lymphatic

Agranulocytosis,

Leucopenia

System Disorders
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, Agitation, nervousness	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,	Gingival hyperplasia	Vomiting, Gastroesophageal sphincter insufficiency

		Nausea, Dyspepsia, Flatulence, Dry mouth, diarrhoea
Hepatobiliary Disorders		Transient increase in liver enzymes	Jaundice
Skin and Subcutaneous Tissue Disorders		Erythema, sweating	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, lethargy

• * may result in life-threatening outcome

• ** cases have been reported when used as tocolytic during pregnancy (see section 4.6)

In dialysis patients with malignant hypertension and hypovolaemia a distinct fall in blood pressure can occur as a result of vasodilation..

For spontaneous reports the following undesirable effects were reported very rarely worldwide (<0.01%): Hypotension which may lead to prolonged QT interval and ventricullar fibrillation, liver function test abnormalities, agranulocytosis, purpura, hyperglycaemia, exfoliative dermatitis, photosensitive dermatitis and blurred vision. There have also been reports of

gynaecomastia in older men on long-term therapy, but this usually regresses upon withdrawal of therapy.

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, tachycardiac/bradycardiac heart rhythm disturbances, hyperglycaemia, metabolic acidosis, hypoxia, cardiogenic shock with pulmonary oedema.

Reports of nifedipine overdosage are limited and symptoms are not necessarily dose-related. Severe hypotension due to vasodilatation, and tachycardia or bradycardia are the most likely manifestations of overdose.

Metabolic disturbances include hyperglycaemia, metabolic acidosis and hypo- or hyperkalaemia.

Cardiac effects may include heart block, AV dissociation and asystole, and cardiogenic shock with pulmonary oedema.

Other toxic effects include nausea, vomiting, drowsiness, dizziness, confusion, lethargy, flushing, hypoxia and unconsciousness to the point of coma.

Management of overdose

As far as treatment is concerned, elimination of the active substance and the restoration of stable cardiovascular conditions have priority.

After oral ingestion thorough gastric lavage is indicated, if necessary in combination with irrigation of the small intestine.

In case of intoxication with nifedipine elimination must be as complete as possible, including the small intestine, to prevent 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).

Bradycardiac heart rhythm disturbances may be treated symptomatically with B-sympathomimetics, and in life-threatening bradycardiac disturbances of heart rhythm temporary pacemaker therapy can be advisable.

Hypotension as a result of cardiogenic shock and arterial vasodilation can be treated with calcium (10 - 20 ml of a 10 % calcium gluconate solution administered slowly i.v. and repeated if necessary) As a result, the serum calcium can reach the upper normal range to slightly elevated levels. If an insufficient increase in blood pressure is achieved with calcium, vasoconstricting sympathomimetics such as dopamine or noradrenaline are additionally administered. The dosage of these drugs is determined solely by the effect obtained..

Additional liquid or volume must be administered with caution because of the danger of overloading the heart.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

ATC Code: CO8C A05

Selective calcium channel blocker (Dihydropyridine derivative) with mainly vascular effects.

As a specific and potent calcium antagonist, the main action of nifedipine 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 level. 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

Greater than 90% of a single oral or sub-lingual dose of nifedipine is absorbed. Radioactivity is detected in the serum 20 minutes after an oral dose and 10 minutes after a sub-lingual dose. Maximal equivalent serum concentrations are achieved 1-2 hours after enteral administration and these correspond to the equivalent concentrations over the same time period after intravenous administration (the drug is almost completely absorbed).

After enteral or intravenous doses, 70-80% of activity is eliminated (primarily as metabolites) via the urine. Remaining excretion is via the faeces.

After 24 hours, 90% of the administered dose is eliminated.

Protein binding of nifedipine exceeds 90% in human serum.

5.3 Preclinical safety data

Preclinical information has not been included because the safety profile of nifedipine has been established after many years of clinical use. Please refer to section 4.

PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Capsule contents: Polyethylene glycol 400 Glycerol (E422) Peppermint oil Sodium saccharin (E954)

Capsule shell:

Gelatin

Glycerol (E422)

Titanium dioxide (E171) Sunset Yellow (El10) Erythrosine (E127)

Printing ink:

Propylene glycol Titanium dioxide (E171) Polyvinyl acetate phthalate Polyethylene glycol

6.2 Incompatibilities

Not applicable.

6.3. Shelf life

24 months.

6.4 Special precautions for storage

Store in a cool dry place. Store in the original package.

Blister strips in packs of 7, 10, 14, 21, 28, 30, 56, 60, 84, 90, 100, 110, 112, 120, 150, l60 and 168.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Not applicable.

7 MARKETING AUTHORISATION HOLDER

Teva UK Limited Brampton Road Hampden Park Eastbourne East Sussex BN22 9AG

8 MARKETING AUTHORISATION NUMBER(S)

PL 00289/0746

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

24 February 1999

10 DATE OF REVISION OF THE TEXT

25/08/2016