SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Adipine XL 60 mg Tablets Nimodrel XL 60 mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 60mg of nifedipine For the full list of excipients, see section 6.1

3. PHARMACEUTICAL FORM

Prolonged release tablet

Each pale red tablet is round and biconvex and embossed with " 60 " on one side.

4.    CLINICAL PARTICULARS

4.1    Therapeutic indications

The tablets are indicated for :

-    the treatment of all grades of hypertension

-    the prophylaxis of chronic stable angina pectoris, either as monotherapy or in combination with a beta-blocker

4.2 Posology and method of administration

Method of Administration For oral use

These tablets should be swallowed whole with a glass of water and not bitten, broken up or chewed.

Posology

It is recommended that each dose should be taken at approximately 24 hour intervals i.e. at the same time each day, preferably in the morning.

Adults: In mild to moderate hypertension, the recommended initial dose is one 20mg tablet once daily. In severe hypertension and the prophylaxis of angina pectoris, the recommended initial dose is one 30mg tablet once daily. The dose may be adjusted to a maximum of 90mg once daily.

Prophylactic anti-anginal efficacy is maintained when patients are switched from other calcium antagonists e.g. verapamil or diltiazem. When patients are switched, the recommended initial dose is 30mg nifedipine, once daily. Subsequent titration to a higher dosage should be according to clinical response.

OlderPeople: The pharmacokinetics of nifedipine may be altered in older people therefore, a lower maintenance dose may be necessary when treating older patients.

Patients With Renal Impairment: Dosage adjustments should not be required for patients with impaired renal function.

Patients With Hepatic Impairment: Nifedipine prolonged release tablets should not be administered to patients with impaired hepatic function.

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.

Nifedipine is not recommended for use in children.

Treatment with nifedipine may be continued long term.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Nifedipine XL Tablets are contraindicated:

-    in patients with a known hypersensitivity to the drug or other constituents of the tablets

-    in patients with a known hypersensitivity to other dihydropyridines calcium antagonists, because of the theoretical risk of cross-reactivity

-    in women who are or may become pregnant, are capable of child bearing or to nursing mothers

-    in patients with clinically significant aortic stenosis, in cardiogenic shock or unstable angina or for the treatment of acute attacks of angina

-    in patients with inflammatory bowel disease, Crohn’s disease or with a history of gastrointestinal obstruction, oesophageal obstruction or with decreased diameter of the gastrointestinal lumen

-    in patients with hepatic impairment

-    for secondary prevention of myocardial infarction or during or within one month of a myocardial infarction

Nifedipine XL Tablets 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).

The safety of nifedipine prolonged release tablets has not been established in patients with malignant hypertension.

4.4 Special warnings and precautions for use

Nifedipine should be used with caution in patients with hypotension, as there is a risk of blood pressure decreasing further and in patients whose cardiac reserve is poor. Deterioration of heart failure has occasionally been observed with nifedipine.

Cardiac ischaemic pain has been reported to occur in a small proportion of patients following the introduction of nifedipine therapy. In such cases, treatment with nifedipine should be discontinued.

Caution should be exercised when nifedipine tablets are given to diabetic patients as they may require adjustment of their diabetic therapy.

In patients with malignant hypertension and hypovolaemia and who are on dialysis, a significant decrease in blood pressure can occur.

Nifedipine may be used in combined therapy with other antihypertensive agents including beta-blocker drugs, but the possibility of an additive effect resulting in postural hypotension should be borne in mind. Withdrawal of any previous antihypertensive agents should be gradual, as nifedipine will not prevent any possible rebound effects.

Nifedipine is contra-indicated in pregnancy. However, caution must be exercised when nifedipine with intravenous magnesium sulfate is given to pregnant women.

Nifedipine XL Tablets must not be administered to patients with Kock pouch (ileostomy after proctocolectomy).

A false positive effect may be obtained when carrying out a barium contrast X-ray.

Nifedipine XL Tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance e.g. galactosaemia, the Lapp lactase deficiency or glucose-galactose malabsorption, should be advised not to take these tablets.

4.5 Interaction with other medicinal products and other forms of interaction

Known Interactions

Nifedipine should not be taken with grapefruit juice because bioavailability is increased.

Cimetidine may potentiate the antihypertensive effect of nifedipine tablets if it is administered simultaneously.

It is reported that serum quinidine levels have been reduced when it is used in combination with nifedipine, irrespective of the quinidine dose taken.

The administration of nifedipine and digoxin concurrently may lead to reduced digoxin clearance and therefore, bring about an increase in the plasma digoxin level. Close monitoring of plasma digoxin levels should take place and, if necessary, a reduction in the dosage of digoxin.

Phenytoin induces the cytochrome P450 3A4 system. When nifedipine is coadministered with phenytoin, nifedipine’s bioavailability is reduced and consequently, its efficacy is weakened. In such cases, the clinical response to nifedipine should be monitored following concomitant administration and, if necessary, consideration should be given to increasing the nifedipine dose. If the nifedipine dose is increased during the co-administration of both drugs, consideration should be given to reducing the nifedipine dose when phenytoin therapy is discontinued.

Diltiazem decreases the clearance of nifedipine and hence increases plasma nifedipine levels. Caution should be exercised when both drugs are given simultaneously. A reduction of nifedipine dose may be required when the two are used together.

Nifedipine may falsely increase the spectrophotometric values of urinary vanillylmandelic acid. HPLC measurements are not affected.

Nifedipine should not be administered concomitantly with rifampicin, as effective plasma levels of nifedipine may not be achieved as a result of enzyme induction.

Simultaneous administration of cisapride and nifedipine or quinupristin/dalfopristin and nifedipine may lead to increased plasma concentration of nifedipine. Hence, the blood pressure may need to be monitored and a reduction in the nifedipine dose may be necessary.

Nifedipine enhances the effect of non-polarising muscle relaxants.

Theoretical Interactions

Nifedipine is metabolised via the cytochrome P450 3A4 system. Therefore, there are theoretical interactions with drugs such as erythromycin, ketoconazole, itraconazole, fluconazole, fluoxetine, indinavir, nelfinavir, ritonavir and saquinavir that are known to inhibit this enzyme system. Although no in vivo interaction studies with these drugs have been carried out, their co-administration with nifedipine in vitro, have shown increases in nifedipine plasma concentrations. Therefore, the blood pressure should be monitored and, if necessary, a reduction in the nifedipine dose should be considered.

Similarly, the potential interaction between nifedipine and nefazodone has not been clinically investigated. Nefazodone is known to inhibit the cytochrome P450 3A4 mediated metabolism of other drugs and therefore, co-administration with nifedipine may increase the plasma concentrations of nifedipine. Again, monitoring of the blood pressure is advised when both drugs are simultaneously administrated with, if necessary, a reduction in the nifedipine dose.

Tacrolimus is metabolised via the cytochrome P450 3A4 system. Upon coadministration with nifedipine, the plasma levels of tacrolimus should be monitored and, if necessary, consideration should be given to reducing the tacrolimus dose.

Carbamazepine, phenobarbital or valproic acid have been shown to alter the plasma levels of a structurally similar calcium channel blocker, however, no interactive studies have been carried out with these drugs and nifedipine. A decrease (with carbamazepine or phenobarbital) or an increase (with valproic acid) in nifedipine plasma concentrations, leading to a change in efficacy, can therefore not be ruled out.

Drugs Shown Not to Interact With Nifedipine

Aspirin, benazepril, candesartan cilexetil, debrisoquine, doxazosin, irbesartan, omeprazole, orlistat, pantoprazole, ranitidine, rosiglitazone and triamterene hydrochlorothiazide are drugs known not to affect the pharmacokinetics of nifedipine when they are administered concomitantly with nifedipine.

4.6 Fertility, pregnancy and lactation

Nifedipine is contraindicated in woman capable of child-bearing.

Safe use of nifedipine during human pregnancy has not been established. Animal studies have shown reproductive toxicity (embryotoxic and teratogenic effects) at maternally toxic doses.

Nifedipine may be present in breast milk and therefore, Nifedipine XL Tablets are contraindicated for use in nursing mothers.

In single reports of in vitro fertilisation, calcium antagonists like nifedipine have been associated with biochemical alterations in the head of the spermatozoa that may impair sperm function. Calcium antagonists like nifedipine should be considered as possible causes in those men who are repeatedly unsuccessful in fathering a child by in vitro fertilisation and where no other explanation can be found.

4.7 Effects on ability to drive and use machines

Reactions to nifedipine may vary in intensity in patients, especially at the onset of therapy, on changing medication or when combined with alcohol. Therefore, the patient should be warned of the possible effects and advised not to drive or operate machinery, if affected.

4.8 Undesirable effects

Most undesirable effects are due to vasodilatory action of nifedipine and usually regress upon withdrawal of treatment.

Those commonly reported (at an incidence of > 1 % < 10 %) in clinical studies include headache, palpitations, vasodilatation (especially at the start of therapy), lethargy, constipation, dizziness and oedema particularly peripheral oedema not connected with weight gain or heart failure.

Other side effects associated with nifedipine therapy are named below:

Cardiovascular	hypotension, postural hypotension, syncope, tachycardia	cardiovascular disorder
Digestive	diarrhoea, dry mouth, dyspepsia, flatulence, nausea	anorexia, eructation, gastrointestinal disorder, gingivitis, gingival hyperplasia, vomiting	bezoar, dysphagia, oesophagitis, gum disorder, intestinal obstruction, intestinal ulcer
Haematological			leucopenia, hyperglycaemia
Hepatic		liver function test abnormalities, increase in GGT	increase in ALT, jaundice
Musculoskeleta l	leg cramps	arthralgia, joint disorder, myalgia	muscle cramps
Neurological	insomnia, nervousness, paraesthesia, somnolence, vertigo	hyperaesthesia, sleep disorder, tremor, mood changes
Respiratory	dyspnoea	epistaxis
Dermatological	pruritus, rash	angioedema, maculopapular, pustular and vesiculobullous rash, sweating, urticaria	purpura, exfoliative dermatitis, photosensitive dermatitis
Special Senses		abnormal vision, eye disorder, eye pain	blurred vision
	nocturia, polyuria	dysuria, impotence

Urogenital

There have also been reports of gynaecomastia in older men on long-term therapy, but this usually regresses when treatment is withdrawn.

Exacerbation of angina pectoris has been observed at the start of treatment with modified-release preparations of dihydropyridines, including nifedipine. Myocardial infarction is also known to occur although it is not possible to distinguish it from the natural course of ischaemic heart disease.

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

There are few reports of nifedipine overdose and the symptoms are not necessarily dose-related. The most likely manifestations of overdose are severe hypotension due to vasodilatation, tachycardia or bradycardia.

The metabolic disturbances may include hyperglycaemia, metabolic acidosis and hypo- or hyperkalaemia. The cardiac effects, which may occur, include heart block, AV dissociation and asystole and cardiogenic shock with pulmonary oedema.

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

Management

In the treatment of overdose it is important to restore stable cardiovascular conditions as soon as possible and achieve total elimination of nifedipine.

Gastric lavage and charcoal instillation may be of assistance if the patient is found early after the overdose. Gastric lavage may be necessary in combination with irrigation of the small intestine. Ipecacuanha should be given to children.

To prevent the subsequent absorption of nifedipine, elimination must be complete, including from the small intestine.

Activated charcoal should be given in 4 hourly doses of 25g for adults and 10g for children. The blood pressure, central arterial pressure, ECG, electrolytes, pulmonary wedge pressure and urea should be carefully monitored.

Placing the patient in the supine position with the feet raised and the use of plasma expanders, as appropriate, should treat the hypotension resulting from cardiogenic shock and arterial vasodilatation. If these measures are ineffective, hypotension may be treated with 10ml to 20ml of 10% calcium gluconate, administered intravenously over a period of 5 to 10 minutes. If ineffective, the therapy can be continued, with ECG monitoring.

Also, beta-sympathomimetics may be given eg., 0.2mg of isoprenaline by slow intravenous or    5 ^g per minute as a continuous infusion. If the blood

pressure response    is inadequate with calcium and isoprenaline,

vasoconstricting sympathomimetics such as dopamine or noradrenaline should

be administered. The patient’s response should determine the dosage of these drugs.

Bradycardia may be treated with atropine, beta-sympathomimetics or a temporary cardiac pacemaker.

Additional fluid should be administered with caution to avoid cardiac overload.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Anatomical Therapeutic Chemical (ATC) code: C08C A05

Selective calcium channel blocker (dihydropyridine derivative), with mainly vascular effects

Nifedipine is a dihydropyridine and is a specific and potent antagonist of calcium influx through the slow channel of the cell membrane of cardiac and smooth muscle cells, both in coronary and peripheral circulation.

The antihypertensive effects of nifedipine are achieved by causing peripheral vasodilatation resulting in a reduction in peripheral resistance. Nifedipine administered once daily provides twenty-four hours control of elevated blood pressure. Nifedipine reduces blood pressure such that the percentage lowering is proportional to its initial level. In normotensive individuals, nifedipine has little or no effect.

Nifedipine produces its effects in the treatment of angina by reducing peripheral and coronary vascular resistance, leading to an increase in coronary blood flow, cardiac output and stroke volume and causing a decrease in after-load. Also, nifedipine submaximally dilates clear and atherosclerosis coronary arteries to protect the heart against coronary artery spasm and improve perfusion to the ischaemic myocardium. Nifedipine decreases the frequency of painful attacks and the ischaemic ECG changes regardless of the relative contribution from coronary artery spasm or atheroschlerosis.

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 XL Tablets are formulated as prolonged release products. They are designed to control the release of nifedipine over twenty-four hours so that a clinical effect is achieved when the tablets are swallowed, once a day.

The pharmacokinetic profile is characterised by low peak-trough fluctuation. Over twenty-four hours plasma concentration versus time profiles at steady state are plateau-like, rendering the Nifedipine XL Tablets suitable for once daily administration.

Absorption

Nifedipine is rapidly and almost completely absorbed from the gastrointestinal tract after oral administration. However due to extensive hepatic first pass metabolism in the liver, the resultant bioavailability lies between 45 % and 68 %. The absorption rate is slightly changed when the tablets are taken after ingesting food but the extent of drug availability is not affected.

Distribution

Nifedipine is about 95 % bound to plasma proteins. Metabolism

Nifedipine is almost completely metabolised in the liver by oxidative and hydrolytic processes.

Elimination

The elimination half-life is 2 to 5 hours. About 70 % to 80 % of the administered dose of nifedipine is excreted via the kidneys, mostly as its active metabolites. The rest ( 5 % to 15 % ) is excreted via the bile in the faeces. The non-metabolised drug substance is only found in traces ( less than 1.0 % ) in the urine.

Characteristics in Patients Patients With Renal Impairment

There are no significant differences in the pharmacokinetics of nifedipine in patients with renal impairment and in healthy subjects. Therefore, dosage adjustments should not be required for patients with impaired renal function.

Patients With Hepatic Impairment

Nifedipine is primarily metabolised in the liver. The elimination half-life is markedly prolonged and there is a reduction in total clearance. Therefore, owing to the duration of action, nifedipine should not be administered to patients with reduced hepatic function.

5.3 Preclinical safety data

The LD₅₀ values ( in mg per Kg ) determined when nifedipine was given orally and intravenously to different animal species, are reported below :

*95 % confidence interval

Subacute & Subchronic Toxicity Studies (in Rats and Dogs )

Nifedipine doses of up to 50 mg per Kg in rats and 100 mg per Kg in dogs p.o were tolerated without any damage when administered orally over periods of thirteen and four weeks, respectively.

Nifedipine doses of 2.5 mg per Kg in rats and 0.1 mg per Kg in dogs were tolerated without any damage when administered intravenously over periods of three weeks and six days, respectively.

Chronic Toxicity Studies (in Rats and Dogs )

Nifedipine doses of up to and including 100 mg per Kg in dogs p.o were tolerated without any damage when administered orally up to one year.

In rats, toxic effect occurred at nifedipine concentrations above 100 ppm in the feed ( about 5 mg to 7 mg per Kg body weight ).

Carcinogenic Studies ( in Rats )

Studies in rats over two years produced no evidence of carcinogenic effects caused by nifedipine.

Reproductive Studies ( in Rats, Mice & Rabbits )

Studies in rats, mice and rabbits maternally toxic doses of nifedipine induced some teratogenic and embryotoxic effects.

Mutagenic Studies

In vivo and in vitro studies showed that nifedipine has no mutagenic properties.

PHARMACEUTICAL PARTICULARS

6.1 List of excipients

In Tablet Core

Povidone K30 Lactose monohydrate Carbomer 974P Silica, colloidal anhydrous

In Tablet Core & Coat

Talc

Hypromellose ( E. 464 )

Magnesium stearate

In Tablet Coat

Dimethylaminoethyl methacrylate-Butyl methacrylate-Methyl methacrylate

copolymer

Macrogol 4000

Red iron oxide ( E. 172 )

Titanium dioxide ( E. 171 )

6.2 Incompatibilities

Not applicable

6.3 Shelf life

Shelf Life of the Medicinal Product as Packaged for Sale 24 months

Shelf Life After Dilution or Reconstitution Not applicable

Shelf Life After First Opening the Container Not applicable

6.4 Special precautions for storage

Do not store above 25 °C. Keep blister in the outer carton.

6.5 Nature and contents of container

The tablets are enclosed in blisters composed of 25 pm aluminium foil coated with 20g.m^-2 PVDC film / 250 pm PVC foil coated with 40g.m^-2 PVDC film

The blisters are boxed in cardboard cartons containing 28 tablets and a patient information leaflet.

6.6 Special precautions for disposal and other handling

Not applicable

7.    MARKETING AUTHORISATION HOLDER

Chiesi Limited

Cheadle Royal Business Park

Highfield

Cheadle

SK83GY

United Kingdom

8.    MARKETING AUTHORISATION NUMBER(S)

PL08829/0148

9. DATE OF FIRST AUTHORISATION / RENEWAL OF AUTHORISATION

28^th October 2004

10 DATE OF REVISION OF THE TEXT

29/04/2015