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Bayer Limited

The Atrium, Blackthorn Road, Dublin 18,
Telephone: +353 1 2999 313
Fax: +353 1 2061 456


Summary of Product Characteristics last updated on medicines.ie: 04/11/2016
SPC Adalat 5mg Capsules


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1. NAME OF THE MEDICINAL PRODUCT

Adalat 5 mg soft capsules


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2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains 5 mg nifedipine.

Excipients: Sunset yellow (E110) 0.13 mg per capsule

For full list of excipients, see section 6.1.


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3. PHARMACEUTICAL FORM

Capsule, soft.

Orange, gelatin ovoid capsules containing a yellow viscous liquid.


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4. CLINICAL PARTICULARS

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4.1 Therapeutic indications

For the management of chronic stable angina pectoris, the treatment of Raynaud's syndrome and essential hypertension.

• For patients suffering from essential hypertension or chronic stable angina pectoris, and treated with fast release forms of nifedipine (Adalat 5 mg and 10 mg capsules), a dose dependent increase in the risk of cardiovascular complications (e.g., myocardial infarction) and mortality may occur.

• Due to this, Adalat 5 mg and 10 mg capsules should only be used for treatment of patients with essential hypertension or chronic stable angina pectoris if no other treatment is appropriate.


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4.2 Posology and method of administration

Method of administration

Oral Use

Dosage regimen

As far as possible the treatment must be tailored to the needs of the individual according to the severity of the disease and the patient's response.

Depending on the clinical picture in each case, the basic dose must be introduced gradually

Dose titration is recommended for hypertensives with severe cerebrovascular disease and for patients, who because of low body weight or multiple therapies with other antihypertensive drugs, are likely to have an excessive reaction to nifedipine. In addition, patients in whom side effects in response to the nifedipine treatment make a finer dose adjustment desirable should be individually stabilized with Adalat 5 mg capsule.

Unless otherwise prescribed, the following dosage guidelines are recommended for adults:

In coronary heart disease:

Chronic stable angina pectoris

(Angina of effort)

1 Adalat 5 mg capsule 3 times daily

(3 x 5 mg/day)

If the therapeutic result is inadequate after about 2 - 3 days of treatment with nifedipine 5 mg, the dose should be increased individually.

1 Adalat 10 mg capsule 3 times daily

(3 x 10 mg/day)

Starting dose should be nifedipine 5 mg preferably.

If higher dosages are necessary, the dose can be increased in stages up to maximum 60 mg daily.

In hypertension:

1 Adalat 5 mg capsule 3 times daily

(3 x 5 mg/day)

If the therapeutic result is inadequate after about 2 - 3 days of treatment with nifedipine 5 mg the dose should be increased individually.

1 Adalat 10 mg capsule 3 times daily

(3 x 10 mg/day)

Starting dose should be nifedipine 5 mg preferably.

If higher dosages are necessary, the dose can be increased in stages up to maximum 60 mg daily.

In Raynaud's syndrome

1 Adalat 5 mg capsule 3 times daily

(3 x 5 mg/day)

If the therapeutic result is inadequate after about 2 - 3 days of treatment with nifedipine 5 mg, the dose should be increased individually.

1 Adalat 10 mg capsule 3 times daily

(3 x 10 mg/day)

Starting dose should be nifedipine 5 mg preferably.

If higher dosages are necessary, the dose can be increased in stages up to maximum 60 mg daily.

Co-administration with CYP 3A4 inhibitors or CYP 3A4 inducers may result in the recommendation to adapt the nifedipine dose or not to use nifedipine at all (see “interaction with other medicinal products and other forms of interaction").

Duration of Treatment

The attending doctor will determine the duration of use.

Due to their pronounced antiischemic and antihypertensive action, Adalat capsules should be discontinued gradually, particularly when high doses are used.

Administration

As a rule Adalat capsules are swallowed whole with a little liquid, irrespective of meal times. Grapefruit juice is to be avoided (see “interaction with other medicinal products and other forms of interaction“).

Patients taking 20 mg unit doses of immediate release formulations such as Adalat 5 mg capsule or Adalat 10 mg capsule should allow an interval of at least 2 h between doses.

Additional information on special populations

Paediatric population

The safety and efficacy of nifedipine in children below 18 years have not been established. Currently available data for the use of nifedipine in hypertension are described in section 5.1.

Elderly (>65)

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

Patients with hepatic impairment

In patients with mild, moderate or severe impaired liver function, careful monitoring and a dose reduction may be necessary. The pharmacokinetics of nifedipine has not been investigated in patients with severe hepatic impairment (see “Special warnings and precautions for use” and “Pharmacokinetic properties”).

Patients with renal impairment

Based on pharmacokinetic data no dosage adjustment is required in patients with renal impairment (see “Pharmacokinetic properties”).


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4.3 Contraindications

Adalat 5 mg must not be administered to patients with known hypersensitivity to nifedipine or to other dihydropyridines because of the theoretical risk of cross-reactivity, or to any of the excipients (see section 4.4, see section 6.1).

The safety of Adalat 5mg during pregnancy or in nursing mothers has not been established (see sections 4.4, 4.6 and 5.3).

Adalat 5 mg must not be used in cases of cardiogenic shock, clinically significant aortic stenosis, unstable angina pectoris, or during or within 4 weeks of an acute myocardial infarction.

Adalat 5 mg should not be used for the treatment of acute attacks of angina.

The safety of Adalat 5 mg in malignant hypertension has not been established.

Adalat 5 mg should not be used for secondary prevention of myocardial infarction.

Adalat 5 mg must not be administered concomitantly with rifampicin since effective plasma levels of nifedipine may not be achieved owing to enzyme induction (See Section 4.5).


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4.4 Special warnings and precautions for use

Adalat 5 mg is not a beta-blocker and therefore gives no protection against the dangers of abrupt beta-blocker withdrawal; any such withdrawal should be a gradual reduction of the dose of beta-blocker, preferably over 8-10 days.

Adalat 5 mg 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. Adalat 5 mg will not prevent possible rebound effects after cessation of other antihypertensive therapy.

Care must be exercised in patients with very low blood pressure (severe hypotension with systolic pressure less than 90 mm HG), in cases of manifest heart failure and in the case of severe aortic stenosis.

Treatment with short-acting nifedipine may induce an exaggerated fall in blood pressure and reflex tachycardia, which can cause cardiovascular complications such as myocardial and cerebrovascular ischaemia.

As with other vasoactive substances, angina pectoris may very rarely occur (data from spontaneous reports) with immediate release nifedipine, especially at the start of the treatment. Data from clinical studies confirm that the occurrence of angina pectoris attacks is uncommon.

In patients suffering from angina pectoris an increase in frequency, duration and severity of angina pectoris attacks may occur, especially at the start of the treatment.

The occurrence of myocardial infarction has been described in isolated cases, although it was not possible to distinguish this from the natural course of the underlying disease.

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).

Careful monitoring of blood pressure must be exercised, also when administered nifedipine with i.v. magnesium sulfate, owing to the possibility of an excessive fall in blood pressure which could harm both mother and fetus.

In patients with mild, moderate or severe impaired liver function, careful monitoring and a dose reduction may be necessary (see section 5.2). The pharmacokinetics of nifedipine has not been investigated in patients with severe hepatic impairment (see “Dosage and method of administration” and “Pharmacokinetic properties”). Therefore, nifedipine should be used with caution in patients with severe hepatic impairment.

Adalat 5 mg should be used with caution in patients whose cardiac reserve is poor. Deterioration of heart failure has occasionally been observed with nifedipine.

At doses higher than those recommended, there is some concern about increased mortality and morbidity in the treatment of ischaemic heart disease, in particular after myocardial infarction.

Ischaemic pain has been reported in a small proportion of patients within 30 to 60 minutes of the introduction of Adalat 5 mg therapy. Although a “steal” effect has not been demonstrated, patients experiencing this effect should discontinue Adalat 5 mg.

The use of Adalat 5 mg in diabetic patients 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 inhibitors of the cytochrome P450 3 A4 system, and which may therefore lead to increased plasma concentrations of nifedipine include, for example:

-macrolide antibiotics (e.g., erythromycin)

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

-azole antimycotics (e.g., ketoconazole)

-the antidepressants, nefazodone and fluoxetine

-quinupristin/dalfopristin

-valproic acid

-cimetidine

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

For use in special populations see section 4.2.

Adalat 5mg capsules contain the excipient sunset yellow (E110) which may cause allergic reactions.


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4.5 Interaction with other medicinal products and other forms of interaction

Drugs that affect nifedipine

Nifedipine is metabolised via the cytochrome P450 3A4 system, located both in the intestinal mucosa and in the liver. Drugs that are known to either inhibit or to induce this enzyme system may therefore alter the first pass (after oral administration) or the clearance of nifedipine (See section 4.4, Special warnings and precautions for use).

The extent as well as the duration of interactions should be taken into account when administering nifedipine together with the following drugs:

Rifampicin

Rifampicin strongly induces the cytochrome P450 3A4 system. Upon co-administration with rifampicin, the bioavailability of nifedipine is distinctly reduced and thus its efficacy weakened. The use of nifedipine in combination with rifampicin is therefore contraindicated (See Section 4.3, Contraindications).

Upon co-administration of weak to moderate inhibitors of the cytochrome P450 3A4 system (listed immediately below), 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 antibiotics is void of CYP3A4 inhibition.

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

A clinical study investigating the potential of a drug interaction between nifedipine and certain anti-HIV protease inhibitors has not yet been performed. Drugs of this class are known to inhibit the cytochrome P450 3A4 system. In addition, drugs of this class have been shown to inhibit in vitro the cytochrome P450 3A4 mediated metabolism of nifedipine. When administered together with nifedipine, a substantial increase in plasma concentrations of nifedipine due to a decreased first pass metabolism and a decreased elimination cannot be excluded (See Section 4.4).

Azole anti-mycotics (e.g., ketoconazole):

A formal interaction study investigating the potential of a drug interaction between nifedipine and certain azole anti-mycotics has not yet been performed. Drugs of this class are known to inhibit the cytochrome P450 3A4 system. When administered orally together with nifedipine, a substantial increase in systemic bioavailability of nifedipine due to a decreased first pass metabolism cannot be excluded (See Section 4.4).

Fluoxetine:

A clinical study investigating the potential of a drug interaction between nifedipine and fluoxetine has not yet been performed. Fluoxetine has been shown to inhibit in vitro the cytochrome P450 3A4 mediated metabolism of nifedipine. Therefore an increase of nifedipine plasma concentrations upon co-administration 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 in nifedipine plasma concentrations upon co-administration of both drugs cannot be excluded (See Section 4.4).

Quinupristin/dalfopristin:

Simultaneous administration of quinupristin/dalfopristin and nifedipine, may lead to increased plasma concentrations of nifedipine (See Section 4.4).

Valproic acid:

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

Cimetidine:

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

Further studies

Cisapride

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

Cytochrome P450 3A4 system-inducing anti-epileptic drugs, such as phenytoin, carbamazepine and phenobarbital: 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 administered concomitantly, 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 phenobarbital. 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

-beta-blockers

-ACE-inhibitors

-Angiotensin II receptor-antagonists

-other calcium antagonists

-alpha-adrenergic blocking agents

-PDE5 inhibitors

-alpha-methyldopa

When nifedipine is administered simultaneously with beta-receptor blockers the patient should be carefully monitored, since deterioration of heart failure is also known to develop in isolated cases.

Digoxin:

The simultaneous administration of nifedipine and digoxin may lead to reduced digoxin clearance and, hence, an increase in the plasma digoxin level. 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 levels, or after discontinuation of nifedipine, a distinct increase in plasma concentrations of quinidine, have 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 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).

Drugs shown not to interact with nifedipine

The following drugs have been shown to have no effect on the pharmacokinetics of nifedipine when administered concomitantly: ajmaline, aspirin, benazepril, candesartan cilexetil, debrisoquine, doxazosin, irbesartan, omeprazole, orlistat, pantoprazole, ranitidine, rosiglitazone, talinolol and triamterene hydrochlorothiazide.

Other forms of interaction

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. Nifedipine should be reserved for women with severe hypertension who are unresponsive to standard therapy (see section 4.4).

Adalat 5 mg should not be used by women who intend to get pregnant in the near future.

The safety of Adalat 5 mg for use in human pregnancy has not been established.

There are no adequate and well controlled studies in pregnant women.

The available information is inadequate to rule out adverse drug effects on the unborn and newborn child.

In animal studies nifedipine has been shown to produce embryotoxicity, fetotoxicity and teratogenicity (see section 5.3).

Evaluation of experimental animal studies has shown reproductive toxicity consisting of embryotoxicity and teratogenic effects at maternally toxic doses.

From the clinical evidence available a specific prenatal risk has not been identified. Although an increase in perinatal asphyxia, caesarean delivery as well as prematurity and intrauterine growth retardation has been reported. It is unclear whether these reports are due to the underlying hypertension, its treatment or to a specific drug effect.

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.

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.


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4.7 Effects on ability to drive and use machines

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


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4.8 Undesirable effects

Adverse drug reactions (ADRs) based on placebo-controlled studies with nifedipine sorted by CIOMS III categories of frequency (clinical trial data base: nifedipine n=2,661; placebo n=1,486; status: 22 Feb 2006 and the ACTION study: nifedipine n=3,825; placebo n=3,840) are listed below: ADRs listed under “common” were observed with a frequency below 3% with the exception of oedema (9.9%) and headache (3.9%).

The frequencies of ADRs reported with nifedipine 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 1)

Pruritus

Urticaria

Rash

Anaphylactic/ anaphylactoid reaction

Psychiatric disorders

Anxiety reactions

Sleep disorders

Metabolism and nutrition disorders

Hyperglycaemia

Nervous system disorders

Headache

Vertigo

Migraine

Dizziness

Tremor

Par-/ Dysaesthesia

Hypoaesthesia

Somnolence

Eye disorders

Visual disturbances

Eye Pain

Cardiac disorders

Tachycardia

Palpitations

Chest Pain (Angina Pectoris)

Vascular disorders

Oedema (incl. peripheral oedema)

Vasodilatation

Hypotension

Syncope

Respiratory, thoracic, and mediastinal disorders

Nosebleed

Nasal congestion

Dyspnea

Pulmonary oedema*

Gastrointestinal disorders

Constipation

Gastrointestinal and abdominal pain

Nausea

Dyspepsia

Flatulence

Dry mouth

Gingival hyperplasia

Vomiting

Gastrooesophageal sphincter insufficiency

Hepatobiliary disorders

Transient increase in liver enzymes

Jaundice

Skin and subcutaneous tissue disorders

Erythema

Toxic Epidermal Necrolysis

Photosensitivity allergic reaction

Palpable purpura

Musculoskeletal and connective tissue disorders

Muscle cramps

Joint swelling

Arthralgia

Myalgia

Renal and urinary disorders

Polyuria

Dysuria

Reproductive system and breast disorders

Erectile dysfunction

General disorders and administration site conditions

Feeling unwell

Unspecific pain

Chills

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

[1] = 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 HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.


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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. In case of intoxication with nifedipine, elimination must be as complete as possible, including the small intestine, to prevent the otherwise inevitable subsequent absorption of the active substance.

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 an insufficient increase in blood pressure is achieved with calcium, vasoconstricting sympathomimetics such as dopamine or noradrenaline should be administered. The dosage of these drugs should be determined by the patient's response.

Symptomatic bradycardia may be treated with 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.


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5. PHARMACOLOGICAL PROPERTIES

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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 Adalat 5 mg is to relax arterial smooth muscle both in the coronary and peripheral circulation.

In angina pectoris, Adalat 5 mg relaxes peripheral arteries so reducing the load on the left ventricle. Additionally, Adalat 5 mg dilates submaximally both clear and pre-stenotic coronary arteries, and stenotic and post-stenotic coronary arteries, thus protecting the heart against coronary artery spasm and improving perfusion to the ischaemic myocardium.

Adalat 5 mg reduces the frequency of painful attacks and the ischaemic ECG changes irrespective of the relative contribution from coronary artery spasm or atherosclerosis.

Adalat 5 mg causes a reduction in blood pressure such that the percentage lowering is directly related to its initial level. In normotensive individuals, Adalat 5mg has little or no effect on blood pressure.

In Raynaud's syndrome nifedipine can prevent or reduce the occuring digital vasospasm.

Paediatric populations

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.


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5.2 Pharmacokinetic properties

Absorption

After oral administration nifedipine is immediately and almost completely absorbed. The systemic availability of orally administered nifedipine immediate release formulations (Adalat capsules) is 45 - 56% owing to a first pass effect. Maximum plasma and serum concentrations are reached at 30 to 60 minutes. Simultaneous food intake leads to delayed, but not reduced absorption.

Distribution

Nifedipine is about 95% bound to plasma protein (albumin). The distribution half-life after intravenous administration has been determined to be 5 to 6 minutes.

Biotransformation

After oral administration nifedipine is metabolised in the gut wall and in the liver, primarily by oxidative processes. These metabolites show no pharmacodynamic activity. Nifedipine is excreted in the form of its metabolites predominantly via the kidneys and about 5 - 15% via the bile in the faeces. The unchanged substance is recovered only in traces (below 0.1%) in the urine.

Elimination

The terminal elimination half-life is 1.7 to 3.4 hours. No accumulation of the substance after the usual dose was reported during long-term treatment. In cases of impaired kidney function no substantial changes have been detected in comparison with healthy volunteers. In a non-blinded study among white subjects only (69% male), which compared the pharmacokinetics of single dose controlled-release nifedipine in patients with mild (Child Pugh A, n=8) or moderate (Child Pugh B, n=8) hepatic impairment with those in patients with normal liver function (n=8+8), oral clearance of nifedipine was reduced by on average 48% (Child Pugh A) and 72% (Child Pugh B). As a result AUC and Cmax of nifedipine increased on average by 93% (with 90% confidence interval 20.2%~ 209%) and 64% (with 90% confidence interval 14.3%~ 136%) for Child Pugh A, and by 253% (with 90% confidence interval 120%~ 466%) and 171% (with 90% confidence interval 88.7%~ 289%) for Child Pugh B, respectively, compared to patients with normal hepatic function. The pharmacokinetics of nifedipine has not been investigated in patients with severe hepatic impairment (see “Special warnings and precautions for use”).


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5.3 Preclinical safety data

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

Reproduction toxicology

Nifedipine has been shown to produce teratogenic findings in rats, mice and rabbits, including digital anomalies, malformation of the extremities, cleft palates, cleft sternum, and malformation of the ribs. Digital anomalies and malformation of the extremities are possibly a result of compromised uterine blood flow, but have also been observed in animals treated with nifedipine solely after the end of the organogenesis period.

Nifedipine administration was associated with a variety of embryotoxic, placentotoxic and fetotoxic effects, including stunted fetuses (rats, mice, rabbits), small placentas and underdeveloped chorionic villi (monkeys), embryonic and fetal deaths (rats, mice, rabbits) and prolonged pregnancy/decreased neonatal survival (rats; not evaluated in other species). All of the doses associated with the teratogenic, embryotoxic or fetotoxic effects in animals were maternally toxic and several times the recommended maximum dose for humans (See Section 4.6, Pregnancy and lactation).


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6. PHARMACEUTICAL PARTICULARS

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6.1 List of excipient(s)

Glycerol

Purified water

Saccharin sodium

Peppermint oil

Macrogol 400

The capsule shell contains:

Gelatin

Glycerol (85 per cent)

Titanium dioxide (E171)

Sunset yellow (E110)


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6.2 Incompatibilities

Not applicable.


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6.3 Shelf life

3 years.


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6.4 Special precautions for storage

Store in the original package. Keep blister in the outer carton.

Do not store above 30°C.


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6.5 Nature and contents of container

Blister strips of polypropylene foil backed with aluminium foil: 90 capsules.


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6.6 Special precautions for disposal and other handling

No special requirements.


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7. MARKETING AUTHORISATION HOLDER

Bayer Limited

The Atrium

Blackthorn Road

Dublin 18


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8. MARKETING AUTHORISATION NUMBER(S)

PA1410/025/001


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9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 26 February 1982

Date of last renewal: 26 February 2007


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10. DATE OF REVISION OF THE TEXT

September 2016



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Active Ingredients

 
   Nifedipine