4.2 Posology and method of administration

Additional information on special populations

Elderly (>65)Geriatric patients

4.3          Contraindications

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

Adalat LA must not be administered during pregnancy or to nursing mothers.

Adalat LA must not be used in cases of cardiogenic shock, clinically significant aortic stenosis, unstable angina pectoris, or during or within one month of a myocardial infarction.

4.4    Special warnings and precautions for use

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.

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).

There are no safety and efficacy data from well-controlled studies in pregnant women (See Section 4.6).

Animal studies have shown a variety of embryotoxic, placentotoxic and fetotoxic effects (see Section 5.3) when administered during and after the period of organogenesis.

Whilst nifedipine is contra-indicated in pregnancy, particular care must be exercised when administering nifedipine in combination with i.v. magnesium sulphate to pregnant women.

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

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.

4.5   Interaction with other medicinal products and other forms of interactions

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).

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, dDrugs 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 3 A4 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).

Effects of nifedipine on other drugs

Blood pressure lowering drugs

4.6          Fertility, pregnancy and lactation

Pregnancy

Adalat LA is contra-indicated during 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).

The safety of Adalat LA for use in human pregnancy has not been established.  Evaluation of experimental animal studies has shown reproductive toxicity consisting of embryotoxicity and teratogenic effects at maternally toxic doses.

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).

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.

Breast-feedingLactation

Adalat Retard 20mg is contra-indicated in breastfeeding. Nifedipine passes into the breast milk. As there is no experience of possible effects on infants, breastfeeding should first be stopped if nifedipine treatment becomes necessary during the breastfeeding period.

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).

In- vitro fertilisation

Fertility

4.8          Undesirable effects

                                        Oedema (incl. peripheral oedema)

                                       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 online reporting option (preferred method) accessible from the IMB homepage (www.imb.ie). A downloadable report form is also accessible from the IMB website, which may be completed manually and submitted to the IMB via ‘freepost’ (see details below). Alternatively, the traditional post-paid ‘yellow card’ option may also be used.

Ireland

IMB Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.imb.ie

e-mail: imbpharmacovigilance@imb.ie

10. Date of Revision of the Text

February 2014

June 2012To be inserted upon approval

• In section 6.1 (List of Ecxipients), Structure is updated to inclide; Osmotic Blend, Organic Coating, and Light Protective Coating; Macrogol 4000 is removed and replaced with Macrogol 3350, Iron oxide Red ( E172) is removed and replaced with Ferric oxide red (E172).
• In Section 10 ( Date of Revision of the Text); November 2008 is removed and replaced with May 2009.

Previously combined SPC changed to individual SPC

Section 5.3 Preclinical safety data

The sentence: “All of the doses associated with the teratogenic, embryotoxic effects in animals were maternally toxic and several times the recommended maximum dose for humans” was changed to “). 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.”.

Section 7, and section 8 have been changed to:

7. Marketing Authorisation Holder

Bayer Limited

The Atrium

Blackthorn Road

Dublin 18

8. Marketing Authorisation Number

Adalat LA 20mg Film-Coated Tablet                PA 1410/25/5

Adalat LA 30mg Film-Coated Tablet                PA 1410/25/6

Adalat LA 60mg Film-Coated Tablet                PA 1410/25/7

Section 4.9, paragraph on Clinical Effects/Symptoms has been re-written and the following deleted:

1.                   Cardiac effects may include heart block, AV dissociation and asystole

2.                   Other toxic effects include nausea, vomiting, drowsiness, dizziness, confusion, lethargy, flushing

The treatment section, ‘use Ipecacuanha should be given to children’ and ‘Activated charcoal should be given in 4-hourly doses of 25g for adults, 10g for children. Blood pressure, ECG, central arterial pressure, pulmonary wedge pressure, urea and electrolytes should be monitored’ has also been deleted.