Medine.co.uk

Neozipine Xl 60 Mg Prolonged-Release Tablets

SUMMARY OF PRODUCT CHARACTERISTICS 1 NAME OF THE MEDICINAL PRODUCT

Neozipine XL 60 mg Prolonged-Release Tablets.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each prolonged release tablet contains 60 mg nifedipine.

Excipients:

Titanium dioxide (E172):    colouring aid

Red iron oxide (E172):    colouring aid

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Prolonged-release tablets.

Round, biconvex tablets with a pale red colour.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Symptomatic treatment of chronic stable angina pectoris as monotherapy or in combination with a beta-blocker.

For the treatment of all grades of hypertension.

4.2 Posology and method of administration

Method of administration

For oral administration.

The tablets should be swallowed whole and should not be bitten, chewed or crushed. The tablets should be taken at approximately 24-hour intervals, i.e., at the same time each day. Preferably the tablets are administered in the morning with a glass ofwater (no grapefruit juice; see also section 4.5).

The treating physician decides on the duration oftreatment.

Treatment should be titrated for optimal effect according to individual needs of the patient. Depending on the clinical symptoms, the standard dosage should be gradually increased.

Dosing Regimen

The following posology is recommended for adults:

For chronic stable angina pectoris (exertion-induced angina):

The recommended initial dose is one 30mg tablet once-daily. The dosage can be increased according to individual requirements up to a maximum of 90 mg once- daily.

For mild to moderate hypertension:

The recommended initial dose is one 20mg tablet once-daily. In severe hypertension, the recommended initial dose is one 30mg tablet once daily. If necessary the dosagecan be increased according to individual requirements up to a maximum of 90mg once-daily.

Patients switched from other calcium antagonists should initiate therapy at the recommended initial dose of 30mg Neozipine XL once-daily. Subsequent titration to a higher dose may be initiated as warranted clinically Co-administration with CYP 3A4 inhibitors or CYP3A4 inducers may result in

the recommendation to adapt the nifedipine dose or not to use nifedipine at all (see section 4.5)

Duration of treatment

Treatment may be continued indefinitely.

Additional information on special populations

Elderly (>65 years)

Based on pharmacokinetic data for Neozipine XL no dose adaptation in elderly people above 65 years in necessary

Hepatic impairment:

In patients with hepatic impairment careful monitoring is required and, in severe cases, a lowering of the dose may be necessary.

Renal impairment:

Patients with renal impairment should not require adjustment of dosage (see section 5.2).

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 should not be administered in the following situations:

In patients with a known hypersensitivity to nifedipine or other dihydropyridines because of the theoretical risk of cross-reactivity, or to any of the excipients (see Section 4.4 and 6.1).

During Pregnancy (See section 4.6).

In cases of cardiogenic shock, clinically significant aortic stenosis, unstable angina pectoris, or during or within one month of a myocardial infarction.

For the treatment of acute attacks of angina

Safety for use in malignant hypertension has not been established

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

The use of nifedipine concomitantly with rifampicin since effective plasma levels of nifedipine may not be achieved owing to enzyme induction (see 4.5).

In patients with a history of gastro-intestinal obstruction, oesophageal obstruction, or any degree of decreased lumen diameter of the gastro-intestinal tract

In patients with Kock pouch (ileostomy after proctocolectomy)

In patients with inflammatory bowel disease or Crohn’s disease

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.

In exceptional cases, the use of nifedipine can lead to severe complaints of angina pectoris, probably due to fast resorption and an overly abrupt decrease in blood pressure. Whenever this is the case, the treating physician should be notified immediately, and treatment with nifedipine should be ceased.

Nifedipine can aggravate an existing decompensatio cordis in:

-    patients with an obstruction of the out-flow tract, in which an increase of the gradient of the decompensation sometimes occurs (e.g. aorta stenosis) (See section 4.3);

-    patients with a right-sided decompensatio cordis, in which in some cases a decrease of cardiac output, accompanied with increased fluid retention, occurs.

Nifedipine should be used with caution in patients with (threatening) ischemia of fingers and/or toes, because this can be worsened due to decreased tissue perfusion as a result of a lower perfusion pressure.

In patients with diarrhoea, the residence time of the tablet in the gastrointestinal tract, and as a result thereof, the duration of action are decreased.

Since symptoms of obstruction can occur in patients with pre-existing severe gastrointestinal narrowing, Neozipine XL should not be administered to those patients. Symptoms of obstruction have also been seen in patients in which no gastrointestinal narrowing was diagnosed. Neozipine XL should neither be prescribed to patients with Kock pouch (ileostomy after proctocolectomy).

Special care is needed in case of very low blood pressure (severe hypotension with systolic pressure below 90 mmHg).

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

The possibility of an additive effect resulting in postural hypotension should be borne in mind when Neozipine XL is used in combination with other beta-blocking medicinal products and antihypertensive agents. Neozipine XL will not prevent possible rebound effects after cessation of other antihypertensive therapy.

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

Neozipine XL should not be used for secondary prevention of myocardial infarction. It should not be used for acute attacks of angina.

Safety in malignant hypertension is not established.

Diabetic patients taking Neozipine XL may require adjustment of their control. In patients with possible hyperglycaemia, nifedipine should be given with caution.

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 Sectio 4.5)

Drugs, which are known inhibitors of the cytochrome P450 3A4 system, and which may therefore lead to increased plasma concentations 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/dalfosristin

Valproic acid

Cimetidine

Upon co-aministration with these drugs, the blood pressure should be monitored and, if necessary, a reduction of the nifedipine dose should be considered.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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

Neozipine XL should not be used during pregnancy unless the clinical condition of the woman requires treatment with nifedipine. It should be reserved for women with severe hypertension who are unresponsive to standard therapy (see Section 4.6)

Neozipine XL is not recommended for use during breastfeeding because nifedipine has been reported to be excreted in human milk and the effects of nifedipine exposure to the infant are not known (see Section 4.6)

As the outer membrane of the Neozipine XL tablet is not digested, what appears to be the complete tablet may be seen in the toilet or associated with the patient's stools. Also, as a result of this, care should be exercised when administering Neozipine XL to patients, as obstructive symptoms may occur. Bezoars can occur in very rare cases and may require surgical intervention.

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

A false positive effect may be experienced when performing a barium contrast x-ray. For use in special populations see Section 4.2 In-vitro fertilisation

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.

4.5 Interaction with other medicinal products and other forms of interaction

Nifedipine is metabolised via the cytochrome P450 3A4 system (CYP3A4), which is present in the intestinal mucosa and the liver. Medicines that are known to either inhibit or induce this enzyme can therefore alter the absorption (after oral administration) or elimination 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:

Drugs increasing nifedipine exposure:

-    Macrolide antibiotics (e.g. erythromycin)

-    Anti-HIV protease inhibitors (e.g. ritonavir)

-    Azole antimycotics (e.g., ketoconazole)

-    Nefazodone

-    Fluoxetine

-    Quinupristin/dalfosristin

-    Valproic acid

-    Cimetidine

-    Cisapride

-    Diltizaem

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 the co-administration ofboth drugs, a reduction of the nifedipine dose should be considered when the treatment is discontinued.

Substances that induce CYP3A4 (decrease nifedipine exposure)

Rifampicin

Rifampicin strongly induces the CYP3A4 system. Upon co-administration with rifampicin, the bioavailability of nifedipine is markedly reduced (95% decrease of AUC) and thus its efficacy weakened. Co-administration of nifedipine with rifampicin is therefore contra- indicated (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 Section 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.

Phenytoin

Phenytoin induces the CYP3A4 system. Upon co-administration with phenytoin, the bioavailability of nifedipine is reduced (70% decrease of AUC) and thus its efficacy weakened. When both medicines 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 medicines, a reduction of the nifedipine dose should be considered when the treatment with phenytoin is discontinued.

Carbamazepine, phenobarbitone and valproic acid

Some substances have been shown to influence the plasma concentration of the structurally related calcium antagonist nimodipine, either by enzyme induction (carbamazepine, phenobarbitone) or enzyme inhibition (valproic acid). Therefore, a decrease or an increase in nifedipine plasma concentrations and hence an alteration in efficacy cannot be excluded.

Substances that inhibit CYP3A4

Grapefruit juice

Grapefruit juice inhibits the CYP3A4 system. Co-administration of grapefruit juice with nifedipine causes elevated plasma concentrations of nifedipine, due to a decreased first pass metabolism. 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. The intake of grapefruit juice during treatment with nifedipine should be avoided (see also section 5.2).

Cimetidine

Due to inhibition of the CYP3A4 system, cimetidine increases the plasma concentration of nifedipine, and therefore the antihypertensive effect of nifedipine may be potentiated. This should be considered during treatment ofhypertension.

Erythromycin, fluoxetine, protease-inhibitors and azole-derivatives

No clinical interaction studies have been performed between nifedipine and active substances that inhibit the CYP3A4 system, like erythromycin, fluoxetine, protease-inhibitors (amprenavir, indinavir, nelfinavir, ritonavir, saquinavir) and azole-derivatives (ketoconazole, itraconazole and fluconazole). Some of these substances, like fluoxetine, indinavir and ritonavir, have been demonstrated to inhibit the CYP3A4 mediated metabolism of nifedipine in vitro. Co-administered of the mentioned medicines with nifedipine can be expected to lead to a substantial increase in bioavailability of nifedipine, due to a decreased first pass metabolism and decreased elimination. In case of concomitant use, blood pressure should be monitored and, if necessary, a reduction in the nifedipine dose considered.

Other interactions with nifedipine Antihypertensive medicines

The blood pressure lowering effect of nifedipine can be induced in case of co-administration with other antihypertensive medicines.

In case of co-administration of nifedipine with P-blocking medicines, the patient should be carefully monitored, since severe hypotension can occur. Furthermore, a deterioration of heart failure can occur.

Quinupristin/Dalfopristin

Simultaneous administration of quinupristin/dalfopristin and nifedipine may lead to increased plasma concentrations of nifedipine (Cmax increase of 33% compared to placebo). In case of concomitant use of both medicines, blood pressure should be monitored and, if necessary, a reduction in the nifedipine dose considered.

Diltiazem

Diltiazem decreases the clearance of nifedipine. Caution should be taken when both medicines are used in combination. A reduction of the nifedipine dose can be considered.

Cisapride

Simultaneous administration of cisapride and nifedipine may lead to increased plasma concentrations of nifedipine. In case of concomitant use of both medicines, blood pressure should be monitored and, if necessary, a reduction in the nifedipine dose considered.

Digoxin

The simultaneous administration of nifedipine and digoxin may lead to reduced digoxin clearance and, hence, an increase in the plasma digoxin level. As a precaution, the patient should be examined for symptoms of digoxin overdose and, if necessary, a reduction of the glycoside-dosage should be considered, taking into account the plasma concentration of digoxin.

Quinidine

In individual cases, when used in combination with nifedipine, serum quinidine levels have been shown to be suppressed or, after cessation of nifedipine treatment, increased. Therefore, monitoring of quinidine plasma levels is recommended. If necessary, adjustment of the quinidine dosage is recommended when treatment with nifedipine is started or ceased during treatment with quinidine (see also subsection ‘Interactions of other medicines with Neozipine XL’). Blood pressure should be carefully monitored and, if necessary, the dose of nifedipine should be decreased.

Diuretics

When nifedipine is added to therapy with a diuretic, a temporary induced saluretic effect can occur, and a pre-existing hypokalaemia can be induced.

Intravenous magnesium sulphate

Caution should be exercised when nifedipine is co-administered with intravenous magnesium sulphate. In individual cases of concomitant use, neuromuscular block has been observed.

Tacrolimus

Tacrolimus has been shown to be metabolised via the cytochrome P450 3A4 system. Published data show that in individual cases the tacrolimus dose can be reduced when coadministered with nifedipine. Upon co-administration of both medicines, the tacrolimus plasma concentrations should be monitored and, if necessary, a reduction in the tacrolimus dose considered.

Medicines that do not influence Neozipine XL or are not influenced by Neozipine XL.

Co-administration of nifedipine with 100 mg acetylsalicylic acid, benazepril, candesartan cilexetil, doxasozin, omeprazole, orlistat, pantoprazole, ranitidine, rosiglitazone or triamterene/hydrochlorothiazide does not affect the pharmacokinetics of nifedipine.

Co-administration of nifedipine with 100 mg acetylsalicylic acid does not alter the effect of acetylsalicylic acid on platelet aggregation or bleeding time.

When used concomitantly, nifedipine does not affect the pharmacokinetics of candesartan cilexetil, cerivastatin orirbesartan.

Other types ofinteractions

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

4.6 Fertility, pregnancy and lactation

Pregnancy

Nifedipine should not be used during pregnancy unless the clinical condition of the woman requires treatment with nifedipine (see Section 4.4).

There is no adequate data from the use of nifedipine in pregnant women. Studies in animals have shown reproductive toxicity, consisting of embryotoxicity, foetotoxicity and teratogenic effects at maternally toxic doses (see Section 5.3).

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 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.

Breastfeeding

Nifedipine is excreted into breast milk in small amounts. The nifedipine concentration in the milk is almost comparable with mother serum concentration. It is not known if a pharmacological effect in the infant can occur because of this; however, it is recommended to cease breast feeding as a precautionary measure.

Fertility

Nifedipine should not be used by women who intend to get pregnant in the near future (see section 4.4).

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.

4.7 Effects on ability to drive and use machines

In patients that experience dizziness, headache, fatigue or nausea, impaired reaction time may effect ability to drive or to operate machinery (see Section 4.8). This occurs especially

at the beginning of treatment, in case of a change in medication or in case of concomitant use ofalcohol.

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: 22Feb 2006 and the ACTION study: nifedipine n=3,825; placebo n=3,840) are listed below.

Frequency of undesirable effects is classified as:

Very common ( 1/10), Common (    1/100 to <1/10), Uncommon (    1/1,000 to <1/100), Rare

( 1/10,000 to <1/1,000), Very rare (<1/10,000), not known (cannot be estimated from the available data)

ADRs listed under “common” were observed with a frequency below 3% with the exception of oedema (9.9%) and headache (3.9%)

Adverse reactions are often dose related and occur most frequently in the first couple of weeks after initiation of therapy.

e

Very

Common

Common

Uncommon

Rare

Very Rare

Not Known

Blood

and

lymphati c system disorders

Aplastic anaemia, increase in serum potassiu m when nifedipin e is

combined

with

propranol

Agranulocyt os is,

leucopenia

Immune

System

Disorder

s

Allergic

reaction,

Allergic

oedema/ang

io edema

(incl. larynx

oedema*)

Anaphylacti

c/

anaphylacto id reaction

Psvchiatri

c

Disorders

Anxiety

reactions,

sleep

disorders

Depression

Metabolism

and

Nutrition

Hyperglycae m ia

Nervou

s

system

disorder

s

Heachache

giddiness,

light

headedness

Paresthesia of the extremities (arms and legs), finger twitching, vertigo, migraine, tremor

Dysaesth e sia

Hypoaesthes

i,

somnolence

e

Very

Common

Common

Uncommon

Rare

Very Rare

Not Known

Eye disorders:

Eye

reactions such as eye pain,

temporary

visual

disturbances

Cardiac

disorder

s

Angina upon abrupt withdrawa l of

nifedipine,

increased

frequencv

or

worsening of angina, aggravatio n of

mvocardia l ischemia including mvocardia l

infarction,

palpitation

s

(tachvcard

ia

accelerate d pulse rate),

congestive

heart

failure

Ventricular

arrhythmia,

conduction

disturbances,

exacerbation

of

supraventricula r arrhythmias,

heart block

Chest

pain

(Angina

pectoris)

Vascula

r

Disorder

s

Peripheral

oedema,

flushing

(facial

reddening).

Hvpotensio

orthostatic

hypotension

Digital blood flow

reduction in patients with Raynaud’s syndrome

syncope

Respiratory , thoracic and

mediastinal

Nosebleed , nasal congestion

Pulmonar y oedema

Dyspnoea

Gastrointesti

nal

disorders:

Constipatio

n

, nausea.

Oesophageal

reflux in

patients with

systemic

sclerosis,

Increased

portal

pressure in

patients with

alcoholic

cirrhosis,

Gastrointestin

al and

abdominal

pain,

Dyspepsia, Flatulence, Dry mouth

Bezoars, gingival hyperplas ia after longterm

treatment which recedes complete ly at

discontin ua tion of nifedipin e.

Dysphagia,

Intestinal

obstruction,

Intestinal

ulcer,

Vomiting,

Gastroesoph

ag eal

sphincter

insufficiency

Hepatobiliar v Disorders

Allergic

hepatitis,

Transien

t

Increase in liver enzymes

Jaundice

Skin and subcutaneou s tissue disorders:

Erythema

Skin

rash.

Pruritus

exfoliativ

e

dermatitis , Steven-Johnsons syndrom

e,

erythema

Toxic

epiderma

l

necrolysi

s,

palpable

purpura

e

Very

Commo

Common

Uncommon

Rare

Very Rare

Not Known

multiforme

urticaria,

fixed

drug

eruption,

pemphigu

s

phototoxic i ty

(photosen si tivity allergic reaction)

Musculosk e letal and connective tissue disorders

Joint

swelling.

Muscle

cramps

Arythralgi a, Myalgia

Renal

and

Urinary

Disorder

s

Polyuri

a,

Dysuria

Nocturnal

enuresis,

acute,

reversible

deteriorati

on in

renal

function

in patients

with

chronic

renal

insufficie

n cy

Endocrin

e

disorders:

Gynaeco m astia in men over 50 years; reversible at

discontinu ation of treatment.

Reproductiv e system and breast disorders:

Atrophic endometriu m Erectile dysfunction

Ear and labyrint h

Periorbita l oedema, tinnitus

General

disorders

and

administratio n site

conditions:

Feeling

of

pressure in the head,

Feeling

unwell,

Dizziness

tiredness

?

Fever in the first few days after initiating therapy, 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

Clinical effects

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, headache, red spots on the face, and unconsciousness to the point of coma

Treatment

Elimination of the active substance and the restoration of stable cardiovascular conditions have priority. After oral ingestion, gastric lavage is indicated, if necessary in combination with irrigation of the small intestine.

Especially for prolonged-release products (Neozipine XL) 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)    Activated charcoal should be given in 4-hourly doses of 25g for adults, 10g for

children if nifedipine has been digested accidentally or 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 is not useful, since nifedipine cannot be dialysed. However, plasmaferesis can be recommended (high plasma protein-binding, relatively small volume of distribution).

Blood pressure, ECG, central arterial pressure, pulmonary wedge pressure, urea and electrolytes should be monitored.

Bradycardia can be treated symptomatically with atropine or with P-sympathomimetics, like isoprenaline. In case of life-threatening bradycardia, a temporary cardiac pacemaker can be used.

Hypotension as a result of cardiogenic shock and arterial vasodilatation should be treated with calcium (10-20 ml of calcium gluconate 10% slowly i.v., to be repeated if necessary). As a result of this treatment, the serum calcium levels can reach or exceed the upper limit of normal levels. If the effects are inadequate, the treatment can be continued, with ECG monitoring. In addition, P-sympathomimetics may be given, e.g. 0.2 mg isoprenaline slowly i.v. or as a continuous infusion of 5 mg/min. If an insufficient increase in blood pressure is achieved with calcium and isoprenaline, vasoconstricting sympathomimetics such as dopamine or noradrenaline should be administered. The dosage of these medicines should be determined by the patient’s response.

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

5.1 Pharmacodynamic properties

ATC code: C08CA05

Pharmacotherapeutic group: Calcium antagonists.

Mechanism of action:

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 specific and potent calcium antagonist.nifedipine has a spasmolytic effect on the cells of the myocardium, vascular wall of mainly coronary arteries and the peripheral resistance vessels. As a result of the relaxation of arterial muscle, nifedipine reduces peripheral resistance, leading to an improvement of peripheral blood flow whilst decreasing after-load. Therefore, Neozipine XL is effective in angina pectoris and hypertension.

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 afterload. 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.

Pharmacodynamic effects:

In a clinical study, the effect of Nifedipine retard prolonged-release tablets on cardiovascular and cerebrovascular morbidity was studied. The primary end-point was the combination of stroke, MI (including sudden death), heart failure or death from any other cardiovascular cause (composite end-point). This randomised, double blind, prospective study was carried out on an average population of patients with hypertension that, besides a blood pressure of 150/95 mm Hg or higher or a systolic blood pressure of >160 mm Hg, presented with at least one other cardiovascular risk factor. A total of 6321 patients (55-80 years) were treated during 3 to 4.8 years with Nifedipine Retard or a standard combination of diuretics (hydrochlorothiazide 25 mg

+ amiloride 5 mg). The results show that Nifedipine Retard demonstrates both a comparable antihypertensive effect and a comparable effect on the above-mentioned composite end-point.

Clinical efficacy and safety:

Separate analysis of the individual end-points show little differences in incidence between the groups treated with nifedipine or diuretics of stroke (2.0% versus 2.3%), MI (2.9% versus 2.7%) and death caused by any other cardiovascular disease (0.4% versus 0.4%). The incidence of heart failure shows a difference between both treatments (0.9% versus 0.3%). Considering the design of the study, no conclusions can be drawn from the results of the separate analysis.

Moreover, the number of reported symptomatic adverse events was higher in the group treated with nifedipine than in the control group. This could mainly be attributed to the increased incidence of peripheral oedema. The number of severe adverse events, as well as the number of reported metabolism-related adverse events such as hypokalaemia, hyponatraemia and hyperuremia, was lower in the group treated with nifedipine.

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

Nifedipine is rapidly and almost completely absorbed (>90%) in the gastro-intestinal tract. Bioavailability is approximately 40-60%. Neozipine XL is formulated in such way that it releases the active substance in the intestine with a practically constant rate over a 16 to 18 hour time period. Therefore, the tablets are appropriate for once-daily administration. An almost constant release rate provides a relatively constant concentration of active substance in plasma, without major differences between maximal and minimal levels. It takes some time (lagtime of 2-4 hours) before the active substance escapes from Neozipine XL tablets. Moreover, as is the case for all oral administrations, the active substance undergoes a first pass effect. Steady- state concentrations are already reached after administration of the second Neozipine XL tablet. At steady-state, the bioavailability of Neozipine XL tablets ranges from 68-86% relative to Neozipine capsules. Administration in the presence of food slightly alters the early rate of absorption but does not influence the extent of drug availability.

The delivery rate is independent of gastrointestinal pH or motility. Upon swallowing, the biological inert components of the tablet remain intact during gastrointestinal transit and are eliminated in the faeces as an insoluble shell.

Co-administration of grapefruit juice reduces the first pass effect on nifedipine (see section 4.5).

The pharmacokinetic properties of nifedipine in the Neozipine XL tablet are linear in a dose range of 30-180 mg. Based on the results of the bioequivalence studies, Neozipine XL tablets 30 mg and 60 mg can be considered to be bioequivalent to the reference product Adalat LA under fasting and fed conditions. Since it has been demonstrated that Neozipine XL tablets are bioequivalent with the nifedipine containing product Adalat LA tablets, the Neozipine XL tablets are interchangeable with Adalat LA tablets at all times.

Distribution

Both nifedipine and its metabolites are mainly bound to plasma protein (92-98%). The distribution half-life after intravenous administration has been determined to be 5 to 6 minutes.

Biotransformatin

Nifedipine undergoes a first pass metabolism in the liver of 30-40% and in the gut wall. Nifedipine is almost entirely metabolised (> 90%); approximately 70-80% is excreted in urine 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. The two main metabolites are the pyridine-3-carbonic acid metabolite and a 2- hydroxymethyl-pyridine-3- carbonic acid metabolite or, depending on the pH, its lacton form. The metabolites are pharmacologically inactive and non-toxic.

Elimination

Nifedipine has a short half-life of approximately 2 - 4 hours. The terminal half-life following Neozipine XL 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 final dose the plasma concentration decreases, showing the same half-life values that were observed with oral formulations. 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, Neozipine XL should not be administered in these patients. In severe cases, a lowering of the dose can be necessary.

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.

5.3 Preclinical safety data

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.

In studies in mice, rats and rabbits, a dose which was maternally toxic induced teratogenic effects in some cases and embryotoxicity.

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 (950-1087)*;

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 5-7 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.

Nifedipine administration was associated with a variety of embryotoxic, placentotoxic and foetotoxic effects, including stunted foetuses (rats, mice, rabbits), small placentas and underdeveloped chorionic villi (monkeys), embryonic and foetal deaths (rats, mice, rabbits) and prolonged pregnancy/decreased neonatal survival (rats; not evaluated in other species). The

risk to humans cannot be ruled out if a sufficiently high systemic exposure is achieved, however, all of the doses associated with the teratogenic, embryotoxic or foetotoxic effects in animals were maternally toxic and were several times the recommended maximum dose for humans.

In in vitro and in vivo tests, nifedipine has not been associated with mutagenic properties.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Carbomer

Colloidal silicon dioxide (E551)

Hypromellose (E464)

Lactose monohydrate Magnesium stearate (E572)

Methacrylic acid copolymer

Macrogol

Povidone (E1201)

Red iron oxide (E172)

Talc (E533b)

Titanium dioxide (E171)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Store in the original package.

6.5 Nature and contents of container

Carton box with blister strips made of PVC/PVDC and aluminium foil.

Neozipine XL 60 mg tablets are available as prolonged-release tablets in a calendar packaging of 28 tablets (2 blisters of 14 tablets).

6.6 Special precautions for disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

PL 20417/0090

8    MARKETING AUTHORISATION NUMBER(S)

Fannin (UK) Limited 42-46 Booth Drive Park Farm South Wellingborough Northamptonshire NN8 6GT UK

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

27/07/2006

10 DATE OF REVISION OF THE TEXT

05/05/2016