Nivaten Retard Tablets 20mg

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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

NIVATEN RETARD TABLETS 20mg

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 20mg Nifedipine Ph.Eur.

3. PHARMACEUTICAL FORM

Pink film-coated modified-release tablets.

4. CLINICAL PARTICULARS

4.1. Therapeutic Indications

1) Prophylaxis of chronic stable angina pectoris and the treatment of Prinzmetal’s (variant) angina (under a cardiologist’s supervision).

2) Treatment of hypertension.

4.2 Posology and method of administration

Nifedipine should be taken with a little water.

The recommended starting dose of nifedipine is 10mg every 12 hours swallowed with water with subsequent titration of dosage according to response. The dose may be adjusted to 40mg every 12 hours.

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

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 must not be used in cases of known hypersensitivity to nifedipine, or to other dihydropyridines because of the theoretical risk of cross-reactivity, or to any of the excipients.

Nifedipine must not be used in cases of cardiovascular shock, 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.

Owing to the duration of action of the formulation, Nifedipine should not be administered to patients with hepatic impairment.

Nifedipine should not be administered to patients with a history of gastrointestinal obstruction, oesophageal obstruction, or any degree of decreased lumen diameter of the gastro-intestinal tract.

Nifedipine must not be used in patients with a Kock pouch (ileostomy after proctocolectomy).

Nifedipine is contra-indicated in patients with inflammatory bowel disease or Crohn's disease.

Nifedipine must not be used in combination with rifampicin because no efficient plasma levels of nifedipine may be obtained due to enzyme induction (see Section 4.5), potentially myelotoxic drugs or grapefruit juice.

4.4 Special Warnings and Precautions for Use

Nifedipine tablets must be swallowed whole; under no circumstances should they be bitten, chewed or broken up.

Caution should be exercised in patients with hypotension as there is a risk of further reduction in blood pressure and 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.

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 (see section 4.6).

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).

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

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.

Diabetic patients taking Nifedipine may require adjustment of their control.

In dialysis patients with malignant hypertension and hypovolaemia, a marked decrease in blood pressure can occur.

Nifedipine is metabolised via the cytochrome P450 3A4 system. Drugs that are known to either inhibit or to induce this enzyme system may therefore alter the first pass or the clearance of nifedipine (see section 4.5).

Drugs, which are knowninhibitors 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,

- 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.

For use in special populations see section 4.2.

As the outer membrane of the Nifedipine tablet is not digested, what appears to be the complete tablet may be seen in the toilet or associated with the patient's stools. As a result of this, care should be used when administering Nifedipine in patients with pre-existing severe gastrointestinal narrowing because obstructive symptoms may occur. Bezoars can occur in very rare cases and may require surgical intervention.

In single cases, obstructive symptoms have been described without known history of gastrointestinal disorders.

When doing a barium contrast x-ray nifedipine may cause false positive effects (e.g. filling defects interpreted as polyp). For use in special populations see Section 4.2.

Ischaemic pain has been reported in a small proportion of patients within one to four hours of the introduction of Nifedipine Retard therapy. Patients experiencing this effect should discontinue treatment.Since this medicinal product contains lactose, patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

For use in special populations see Section 4.2.

4.5 Interactions with other Medicaments 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.

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). 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.

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 antibiotic 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.

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.

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.

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 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 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 and 4.3).

Other forms of interaction:

Nifedipine may cause falsely increased spectrophotometric values of urinary vanillylmandelic acid. However, measurement with HPLC is unaffected.

Antidiabetics

Nifedipine may occasionally impair glucose tolerance.

Magnesium salts

Profound hypotension has been reported with concomitant use of nifedipine and intravenous magnesium sulphate in pre-eclampsia (see section 4.4).

Vincristine

Nifedipine possibly reduces the metabolism of vincristine.

4.6 Pregnancy and Lactation Pregnancy

Acute pulmonary oedema has been observed when calcium channel blockers, among others nifedipine, have been used as a tocolytic agent 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.

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.

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 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.

Effects on Ability to Drive and Use Machines

4.7

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 treatment, on changing the medication and in combination with alcohol.

4.8 Undesirable Effects

dverse 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 lymphatic system disorders				Agranulocytosis Leukopenia
Immune system disorders		Allergic reaction Allergic oedema / angioedema (incl. larynx oedema )	Pruritus Urticaria Rash	Anaphylactic/ anaphylactoid reactio
Psychiatric disorders		Anxiety reactions Sleep disorders
Metabolism and nutrition disorders				Hyperglycaemia
Nervous system disorders	Headache	Vertigo Migraine Dizziness Tremor	Par-/ Dysaesthesia	Hypoaesthesia Somnolence
Eye disorders		Visual disturbances		Eye pain
Cardiac disorders		Tachycardia Palpitations		Chest pain (Angina Pectoris)

System Organ Class (MedDRA)	Common	Uncommon	Rare	Not known
Vascular disorders	Oedema (incl. peripheral oedema) Vasodilatation	Hypotension Syncope
Respiratory, thoracic, and mediastinal disorders		Nosebleed Nasal congestion		Dyspnea, Pulmonary oedema**
Gastrointestinal disorders	Constipation	Gastrointestinal and abdominal pain Nausea Dyspepsia Flatulence Dry mouth	Gingival hyperplasia	Vomiting Gastrooesophageal sphincter insufficienc
Hepatobiliary disorders		Transient increase in liver enzymes		Jaundice
Skin and subcutaneous tissue disorders		Erythema		Toxic Epidermal Necrolysis Photosensitivity aller reaction Palpable purpura
Musculoskeletal and connective tissue disorders		Muscle cramps Joint swelling		Arthralgia Myalgia
Renal and urinary disorders		Polyuria Dysuria
Reproductive		Erectile

System Organ Class

(MedDRA)

Common

Uncommon

Rare

Not known

system and breast disorders

dysfunction

General disorders and administration site conditions

Feeling unwell

Unspecific pain Chills

* may result in life threatening outcome

** Cases have been reported when used as tocolytic during pregnancy (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

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.

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

Particularly in cases of intoxication with slow release nifedipine formulations, elimination must be as complete as possible, including the small intestine, to prevent the otherwise inevitable subsequent absorption of the active substance.

The benefit of gastric decontamination is uncertain.

1. Consider activated charcoal (50 g for adults, 1 g/kg for children) if the patient presents within 1 hour of ingestion of a potentially toxic amount.

Although it may seem reasonable to assume that late administration of activated charcoal may be beneficial for sustained release (SR, MR) preparations there is no evidence to support this.

2. Alternatively consider gastric lavage in adults within 1 hour of a potentially life-threatening overdose

3. Consider further doses of activated charcoal every 4 hours if a clinically significant amount of a sustained release preparation has been ingested with a single dose of an osmotic laxative (e.g. sorbitol, lactulose or magnesium sulphate).

4. Asymptomatic patients should be observed for at least 4 hours after ingestion and for 12 hours if a sustained release preparation has been taken.

Haemodialysis serves no purpose as nifedipine is not dialysable, but plasmapheresis is advisable (high plasma protein binding, relatively low volume of distribution).

Hypotension as a result of cardiogenic shock and arterial vasodilatation can be treated with calcium (10- 20 ml of a 10 % calcium gluconate solution administered slowly i.v. and repeated if necessary). 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 (norepinephrine) are additionally administered. The dosage of these drugs should be determined by the effect obtained.

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

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: 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. The Nifedipine 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, Nifedipine 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 multi-national, randomised, double-blind, prospective study involving 6321 hypertensive patients with at least one additional risk factor followed over 3 to 4.8 years, Nifedipine 30 and 60 (nifedipine GITS) were shown to reduce blood pressure to a comparable degree as a standard diuretic combination.

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

General characteristics:

Nifedipine tablets are formulated to provide nifedipine at an approximately constant rate over 24 hours. Nifedipine is released from the tablet at a zero-order rate by a membrane-controlled, osmotic push-pull process. The pharmacokinetic profile of this formulation is characterized by low peak-trough fluctuation.

0-24 hour plasma concentration versus time profiles at steady state are plateau-like, rendering the Nifedipine tablet 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 Nifedipine tablets ranges from 68- 86% relative to Nifedipine capsules. Administration in the presence of food slightly alters the early rate of absorption but does not influence the extent of drug availability.

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. These 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 Nifedipine 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 finally declines with an elimination halflife as seen in 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, Nifedipine 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. Following acute oral and intravenous administration of nifedipine in various animal species, the following LD50 (mg/kg) values were obtained:

Mouse:	Oral: 494 (421-572)*;	i.v.: 4.2 (3.8-4.6)*.
Rat:	Oral: 1022 (9501087)*;	i.v.: 15.5 (13.7-17.5)*.
Rabbit	Oral: 250-500;	i.v.: 2-3.
Cat:	Oral: ~ 100;	i.v.: 0.5-8.
Dog:	Oral: > 250;	i.v.: 2-3.
* 95% confidence interval.

In subacute and subchronic toxicity studies in rats and dogs, nifedipine was tolerated without damage at doses of up to 50 mg/kg (rats) and 100 mg/kg (dogs) p.o. over periods of thirteen and four weeks, respectively. Following intravenous administration, dogs tolerated up to 0.1 mg/kg nifedipine for six days without damage. Rats tolerated daily intravenous administration of 2.5 mg/kg nifedipine over a period of three weeks without damage.

In chronic toxicity studies in dogs with treatment lasting up to one year, nifedipine was tolerated without damage at doses up to and including 100 mg/kg p.o. In rats, toxic effects occurred at concentrations above 100 ppm in the feed (approximately 57 mg/kg bodyweight).

In a carcinogenicity study in rats (two years), there was no evidence of a carcinogenic effect of nifedipine.

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.

In a carcinogenicity study in rats (two years), there was no evidence of a carcinogenic effect of nifedipine.

6. PHARMACEUTICAL PARTICULARS

6.1. List of Excipients

Also contains: colloidal silica, lactose, magnesium stearate, maize starch, polysorbate 80, propylene glycol, E171, E172, E460, E463, E464, E553.

6.2. Incompatibilities

None known.

6.3. Shelf-Life

PVC blister packs: 36 months from the date of manufacture. Polypropylene containers: 24 months from the date of manufacture.

6.4. Special Precautions for Storage

Store in a dry place.

Protect from light.

6.5.

Nature and Contents of Container

The product containers are rigid injection moulded polypropylene containers with polyfoam wad or polyethylene ullage filler and snap-on polyethylene lids.

The product may also be supplied in blister packs in cartons:

a) Carton: Printed carton manufactured from white folding box board.

b) Blister pack: (i) 250pm red or white rigid PVC. (ii) Surface printed 20pm hard temper aluminium foil with red or white 5-7g/M² PVC and PVdC compatible heat seal lacquer on the reverse side.

Pack sizes: 56, 60, 100, 112, 120, 168, 180, 1000, 5000.

6.6. Instructions for Use, Handling and Disposal

Not applicable.

7 MARKETING AUTHORISATION HOLDER

Actavis UK Limited (Trading style: Actavis) Whiddon Valley BARNSTAPLE N Devon EX32 8NS

8. MARKETING AUTHORISATION NUMBER(S)

PL 0142/0409

9. DATE OF FIRST AUTHORISATION / RENEWAL OF

AUTHORISATION

20 December 1996

10 DATE OF REVISION OF THE TEXT

10/08/2016