felodipine - Plendil, INN - European Commission

1

Annex I

List of the names, pharmaceutical form, strength of the medicinal product, route of administration, Marketing Authorisation Holders in the Member

States

2

Member State EU/EEA

Marketing authorisation holder

(Invented) Name Strength Pharmaceutical form Route of administration

Austria AstraZeneca Österreich GmbH Schwarzenbergplatz 7 1037 Wien Austria

Plendil retard 2,5 mg - Filmtabletten

2,5 mg Prolonged release tablet Oral use

Austria AstraZeneca Österreich GmbH Schwarzenbergplatz 7 1037 Wien Austria

Plendil retard 5 mg - Filmtabletten

5 mg Prolonged release tablet Oral use

Belgium NV AstraZeneca SA Rue Egide van Ophemstraat 110, B-1180 Brussel Belgium

Plendil 5 mg Retard 5 mg Prolonged release tablet Oral use

Belgium NV AstraZeneca SA Rue Egide van Ophemstraat 110, B-1180 Brussel Belgium

Plendil 10 mg Retard 10 mg Prolonged release tablet Oral use

Bulgaria AstraZeneca AB S-151 85 Södertälje Sweden

Плендил (Plendil)

5 mg Prolonged-release tablet Oral use

Croatia AstraZeneca d.o.o. Radnička cesta 80 10 000 Zagreb Croatia

Plendil 5 mg tablete s produljenim oslobađanjem


3

Member State EU/EEA



Croatia AstraZeneca d.o.o. Radnička cesta 80 10 000 Zagreb Croatia

Plendil 10 mg tablete s produljenim oslobađanjem


Cyprus

AstraZeneca AB S-151 85 Södertälje Sweden

Plendil 2.5 mg Prolonged release tablets Oral use

Cyprus


Plendil 5 mg Prolonged-release tablet Oral use

Cyprus



Czech Republic

AstraZeneca UK Limited 2 Kingdom Street London W2 6BD United Kingdom

PLENDIL ER 5 mg 5 mg Prolonged-release tablet Oral use

Czech Republic

AstraZeneca UK Limited 2 Kingdom Street London W2 6BD United Kingdom

PLENDIL ER 10 mg 10 mg Prolonged-release tablet Oral use

Denmark

AstraZeneca A/S Arne Jacobsens Allé 13 2300 Köbenhavn S. Denmark

Plendil 2.5 mg Prolonged-release tablet Oral use

4

Member State EU/EEA



Denmark



Denmark



Estonia



Estonia



Estonia



Finland

AstraZeneca Oy Itsehallintokuja 4 02600 Espoo Finland


Finland



5

Member State EU/EEA



Finland



France

AstraZeneca 1 place Renault 92844 Rueil-Malmaison Cedex France

FLODIL 5 mg Prolonged-release tablet Oral use

Germany

AstraZeneca GmbH 22876 Wedel Germany

Modip 2,5 mg 2.5 mg Prolonged-release tablet Oral use

Germany


Modip 5 mg 5 mg Prolonged-release tablet Oral use

Germany


Modip 10 mg 10 mg Prolonged-release tablet Oral use

Greece

AstraZeneca S.A. Theotokopoulou & Astronafton str 151 25 Maroussi Greece


Greece



6

Member State EU/EEA



Greece



Hungary

AstraZeneca Kft. H-1113 Budapest Bocskai út 134-146 Hungary

Plendil 2,5 mg retard filmtabletta

2.5 mg Prolonged-release tablet Oral use

Hungary

AstraZeneca Kft. H-1113 Budapest Bocskai út 134-146 Hungary

Plendil 5 mg retard filmtabletta


Iceland



Iceland



Iceland



7

Member State EU/EEA



Ireland

AstraZeneca UK Ltd. 600 Capability Green Luton LU1 3LU United Kingdom

Plendil 2.5mg Prolonged-release, Film-coated Tablets

2.5 mg Prolonged-release tablet Oral use

Ireland


Plendil 5mg Prolonged-release, Film-coated Tablets


Ireland




Italy

AstraZeneca S.p.A Palazzo Volta Via F. Sforza 20080 Basiglio (MI) Italy

Plendil 5 mg compresse a rilascio prolungato


Italy


Plendil 10 mg compresse a rilascio prolungato


Italy


Feloday 5 mg compresse a rilascio prolungato


8

Member State EU/EEA



Italy


Feloday 10 mg compresse a rilascio prolungato


Italy

SIMESA S.p.A Palazzo Galileo Via F. Sforza 20080 Basiglio (MI) Italy

Prevex 5 mg compresse a rilascio prolungato


Italy

SIMESA S.p.A Palazzo Galileo Via F. Sforza 20080 Basiglio (MI) Italy

Prevex 10 mg compresse a rilascio prolungato


Latvia

AstraZeneca AB S-151 85, Södertälje Sweden

Plendil 5 mg ilgstošās darbības tabletes


Latvia


Plendil 10 mg ilgstošās darbības tabletes


Lithuania



Lithuania



9

Member State EU/EEA



Lithuania



Luxembourg

NV AstraZeneca SA Rue Egide van Ophemstraat B-1180 Brussel Belgium

PLENDIL 5 mg Retard 5 mg Prolonged-release tablet Oral use

Luxembourg

NV AstraZeneca SA Rue Egide van Ophemstraat B-1180 Brussel Belgium

PLENDIL 10 mg Retard 10 mg Prolonged-release tablet Oral use

Malta

Astra Zeneca AB Gartunavagen, S-151 85 Sodertalje, Sweden



Netherlands

AstraZeneca BV Louis Pasteurlaan 5 2719 EE Zoetermeer The Netherlands

Plendil 2.5 2.5 mg Prolonged-release tablet Oral use

Netherlands


Plendil 5 5 mg Prolonged-release tablet Oral use

Netherlands


Plendil 10 10 mg Prolonged-release tablet Oral use

10

Member State EU/EEA



Norway

AstraZeneca AS Postboks 6050, Etterstad 0601 Oslo Norway


Norway



Norway



Poland

AstraZeneca AB S-151 85 Sodertalje Sweden


Poland



Portugal

AstraZeneca Produtos Farmacêuticos, Lda. Rua Humberto Madeira, 7 Queluz de baixo 2730-097 Barcarena Portugal

Preslow 5 mg Prolonged-release tablet Oral use

11

Member State EU/EEA



Portugal

AstraZeneca Produtos Farmacêuticos, Lda. Rua Humberto Madeira, 7 Queluz de baixo 2730-097 Barcarena Portugal

Preslow 10 mg Prolonged-release tablet Oral use

Romania



Romania



Romania



Slovak Republic


Plendil 2.5 mg 2.5 mg Prolonged-release tablet Oral use

Slovak Republic


Plendil 5 mg 5 mg Prolonged-release tablet Oral use

Slovak Republic


Plendil 10 mg 10 mg Prolonged-release tablet Oral use

12

Member State EU/EEA



Spain

AstraZeneca Farmacéutica Spain, S.A. C/Serrano Galvache 56 Edificio Roble 28033 Madrid Spain

Plendil 5 mg comprimidos de liberación prolongada


Sweden



Sweden



Sweden



Sweden


Felodipin AstraZeneca 2.5 mg Prolonged-release tablet Oral use

Sweden


Felodipin AstraZeneca 5 mg Prolonged-release tablet Oral use

Sweden


Felodipin AstraZeneca 10 mg Prolonged-release tablet Oral use

13

Member State EU/EEA



United Kingdom AstraZeneca UK Ltd. 600 Capability Green Luton LU1 3LU United Kingdom






14

Annex II

Scientific conclusions and grounds for the variation to the terms of the Marketing Authorisation

15

Scientific conclusions Overall summary of the scientific evaluation of Plendil and associated names (see Annex I) Felodipine is a dihydropyridine-type calcium channel blocker (calcium antagonist) and is indicated for the control of hypertension and in many countries also for the treatment of stable angina pectoris.

Plendil was originally approved for marketing in Denmark on 16 March 1987, as an immediate release tablet. This formulation was available until 1994, though only launched in Australia. Today, Plendil is available worldwide for oral administration as a prolonged release tablet (except in Japan where another immediate release tablet is marketed). In Europe, the prolonged release tablet was first approved in December 1987 and was first launched in Denmark in 1988. The prolonged release tablet is available in three tablet strengths 2.5mg, 5mg and 10mg.

Plendil has been approved through national procedures in the following countries in the European Economic Area (EEA): Austria, Belgium, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, the Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Spain, Sweden and the United Kingdom.

Three European procedures have been completed leading to agreed wording in Plendil Summary of Product Characteristics (SmPCs):

− UK/W/002/pdWS/001 Article 45 Paediatric Workshare, finalised 15 October 2009.

− SK/H/PSUR/0006/001, PSUR (01 Jan 2007 to 31 Dec 2009), finalised 20 October 2011 with agreed Core Safety Profile (CSP).

− SK/H/PSUR/0006/002, PSUR (01 Jan 2010 to 31 Dec 2012), finalised 4 December 2013 and where no changes to the Product Information were proposed.

Due to the divergent national decisions taken by Member States (MS) concerning the authorisation of Plendil and its associated names, these products were included in the list of products for SmPC harmonisation, requested by the Coordination Group for Mutual Recognition and Decentralised Procedures - Human (CMDh). The European Commission notified the European Medicines Agency/ Committee for Medicinal Products for Human Use (EMA/CHMP) secretariat of an official referral under Article 30 of Directive 2001/83/EC in order to resolve divergences amongst the nationally authorised product information (PI) for the above-mentioned products and thus to harmonise them across the EU. A pre-referral meeting between the EMA and marketing authorisation holder (MAH) was held on 14 October 2013. The CHMP addressed a list of questions to the MAH, pointing out the sections of the products SmPC where divergences existed.

It is hereafter summarised the main points discussed for the harmonisation of the different sections of the SmPC.

Section 4.1 – Therapeutic Indications

Plendil is indicated for:

• hypertension;

• stable angina pectoris.

The wording for hypertension was divergent in all EU MSs. The CHMP endorsed the MAH proposal of having “Hypertension” as the wording for this indication.

http://www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/general/general_content_000094.jsp&mid=WC0b01ac0580028c79

16

For the indication “stable angina pectoris” there were several divergences. The different MSs had “stable angina pectoris and vasospastic angina (variant of Prinzmetal’s angina)”, “Prophylaxis of angina pectoris (stable and vasospastic forms)”, “Angina pectoris” and “Stable exertional angina pectoris; Plendil can be given as monotherapy or can be combined with a beta blocker. Plendil can also be used in the treatment of vasospastic (Prinzmetal’s) angina”. The MAH proposed not to include the indication vasospastic angina in the harmonised SmPC. The CHMP asked the MAH to further discuss the totality of available data on felodipine and dihydropyridine calcium channel blockers to support the indication of vasospastic angina, since currently calcium channel blockers are in prominent position for this indication. The results of the conducted studies on felodipine in vasospastic angina show an effect on the condition, as there are improvements in angina symptoms and reductions or disappearance of transient ST-segment elevations at hyperventilation or systemic ergonovine provocation. However, outside the referenced trials, no significant publication have been found, limiting the total reported material on felodipine use in vasospastic angina to around 30 patients. The total published experience of felodipine in vasospastic angina pectoris and the accumulated safety information is too limited to define a robust benefit risk ratio. Data on the efficacy and safety of specifically felodipine in this indication are very scarce and the MAH did not discuss the extrapolability of the results obtained with other dihydropyridines in this indication. Consequently, the CHMP agrees with the MAH that, although vasospastic angina indication is a condition where the current European Society of Cardiology clinical guidelines recommend calcium channel blockers like felodipine as the first-line treatment, an indication for vasospastic angina pectoris cannot be justified.

Section 4.2 – Posology and method of administration

The section 4.2 was divergent across MSs. The divergences were due to differences in the indication, recommendation in maximum daily dose and down titration. There were also discrepancies regarding recommendations for special population groups namely elderly and paediatric, renal and hepatic impairment, administration with/ without food.

The CHMP endorses the MAH proposal in adopting the CPS text as the harmonised text, deleting text that is not present in the referred document.

Section 4.3 – Contraindications

Divergences were found in section 4.3 of the SmPC.

The CHMP asked the MAH to comment on the following contraindications: stroke in the past 6 months, Hypertrophic cardiomyopathy, Atrioventricular block grade 2 and 3, Severe renal impairment (GFR <30 ml/min, creatinine > 1.8 mg/dl), Severe hepatic impairment/liver cirrhosis, Breast-feeding women/breast feeding infants and treatment with calcium channel blockers.

The CHMP accepted the proposal from the MAH to adopt the contraindications: pregnancy; Hypersensitivity to felodipine or ‘any of the excipients listed in section 6.1’; decompensated heart failure, instead of uncompensated heart failure as previously; acute myocardial infarction; unstable angina pectoris; haemodynamically significant cardiac valvular obstruction and dynamic cardiac outflow obstruction as the harmonised text.

17

Section 4.4 – Special warnings and precautions for use

Divergences were found in section 4.4 of the SmPC. Some MSs were missing text from the CSP and some MSs had different text.

Considering that gingival enlargement is a known adverse reaction to treatment with felodipine and it is preventable by good oral hygiene, the CHMP endorsed the MAH proposal on including the warning “mild gingival enlargement has been reported in patients with pronounced gingivitis/periodontitis” in the section 4.4 of the harmonised EU SmPC for Plendil.

The use in combination with potent inhibitors or inducers of CYP3A4 is more appropriately addressed in sections 4.5 and 5.2 of the MAH proposal for a harmonised EU SmPC for Plendil. The CHMP therefore considers it necessary to include the following text in Section 4.4, including a reference to Section 4.5:

‘Concomitant administration of drugs that strongly induce or inhibit CYP3 A4 enzymes result in extensively decreased or increased plasma levels of felodipine, respectively. Therefore such combinations should be avoided (see section 4.5).’

Besides a warning that ‘The efficacy and safety of felodipine in the treatment of hypertensive emergencies has not been studied’ was also be included in view of the missing evidence with felodipine in hypertensive emergencies and to be in agreement with the product information of amlodipine the Rapporteurs see the need to include the warning as proposed in the LoOI.

Finally the CHMP requested the MAH to add a warning on castor oil. The information on castor oil is given under section 2 and section 6 of the proposed harmonised SmPC text and the MAH is of the opinion that castor oil is an excipient in Plendil tablets in an amount too small to have any effects, except for possibly hypersensitivity and hypersensitivity to any component of the product is a contraindication. The MAH agreed and included that ‘Plendil contains castor oil, which can cause stomach upset and diarrhoea’.

Section 4.5 – Interaction with other medicinal products and other forms of interaction

For the section 4.5, the MAH proposed to use the text from the CSP, with one addition and one deletion as per CDS. The wording was divergent for this section across EU SmPCs. The CHMP asked the MAH to insert statements regarding interactions leading increased plasma concentration of felodipine and interactions leading to decreased plasma concentration of felodipine. These changes were agreed accordingly.

Section 4.6 – Fertility, pregnancy and lactation

The wording in section 4.6 was divergent.

The MAH provided the CHMP with the justification of the reason why “Reproductive toxicity studies have demonstrated foetotoxicity effects” should not be in the harmonised EU SmPC for Plendil. The findings in the reproduction studies do not demonstrate evidence of direct fetotoxicity. The MAH considers that the fetodevelopmental findings in the rabbit, and the consequences of the prolonged parturition in the rat, are due to the pharmacological action of felodipine. The MAH agreed to include “In non-clinical reproductive toxicity studies there were a foetal developmental effects, which are considered to be due to the pharmacological action of felodipine.”

Pregnancy

Regarding the sentence “Pregnancy must be excluded before starting treatment with felodipine/ suitable contraceptive measure should be taken to prevent pregnancy”, the MAH safety surveillance for

18

Plendil has not identified adverse effects of fertility or pregnancy related nature to be excessive or increasing. Furthermore, during the initial weeks of pregnancy the embryo is nourished by the yolk sack, and, consequently, not exposed to felodipine taken by the mother to be. Subjective recognition of pregnancy usually occurs at the end of this period. It is expected that the patient has been informed to seek medical advice in that situation, and that all aspects of therapies are considered, included actions to be taken regarding discontinuation of felodipine treatment. The CHMP endorsed the MAH position not to include “Pregnancy must be excluded before starting treatment with felodipine/suitable contraceptive measure should be taken to prevent pregnancy” in section 4.6 of the harmonised EU SmPC for Plendil.

The final agreed wording is as follows: ‘Felodipine should not be given during pregnancy. In non-clinical reproductive toxicity studies there were foetal developmental effects, which are considered to be due to the pharmacological action of felodipine’.

Lactation

The initial proposal from the MAH for the EU harmonised wording on Breastfeeding was “Felodipine is detected in breast milk. When taken in therapeutic doses by the nursing mother it is, however, not likely to affect the infant”. The CHMP asked the MAH to further substantiate this sentence, or in case of data are not available, add that breastfeeding during treatment with felodipine is not recommended given the lack of data. The MAH reworded the text accordingly with CHMP requests “Felodipine has been detected in breast milk, and due to insufficient data on potential effect on the infant, treatment is not recommended during breastfeeding”.

Fertility

The following wording was agreed:

There are no data on the effects of felodipine on patient fertility. In a nonclinical reproductive study in the rat (see section 5.3), there were effects on fetal development but no effect on fertility at doses approximating to therapeutic.

Section 4.7 – Effects on ability to drive and use machines

The CHMP proposed an alternative text in line with amlodipine harmonised SmPC for this section: “Felodipine can have minor or moderate influence on the ability to drive and use machines. If patients taking felodipine suffer from headache, nausea, dizziness or fatigue the ability to react may be impaired. Caution is recommended especially at the start of treatment.” The MAH agreed with the above proposed wording.

Section 4.8 – Undesirable effects

The wording on section 4.8 was divergent. The proposal for the harmonised EU SmPC is based on the CPS from 2011 and CDS from October 2012. Modifications relate to deletion of unnecessary and outdated wording, table format and addition of Hypotension as an adverse drug reaction (ADR).

The MAH justified the deletion of ADRs using the Empirical Bayesian Data Mining techniques to compute disproportionality scores from the MAH’s global safety database. This method generates the Empirical Bayesian Geometric Mean (EBGM) with a 90% confidence interval (EB05 to EB95). The MAH considered an EB05 >1.8 a possible signal i.e. the event is reported disproportional often in association with that drug. Searches were also conducted in the FDA Adverse Event Reporting System (AERS) database and in the WHO Vigibase database. Overall, the statement of grounds for not including adverse events included in one or few national texts is considered acceptable by the CHMP.

19

Section 4.9 – Overdose

The CHMP endorsed the MAH proposal on a minor re-wording of section 4.9 of the CSP and to implement it as the harmonised text across EU MS. The CHMP requested the MAH to add information on when a gastric lavage should be performed.

Section 5.1 – Pharmacodynamic properties

The CHMP requested the MAH to shorten the text related to pharmacodynamic properties since it included parts of limited clinical relevance or not considered justified by clinical evidence. The MAH agreed to remove the parts suggested by the CHMP.

Section 5.2 – Pharmacokinetic properties

The wording on section 5.2 was divergent across MSs. Some MSs were missing a text referring to absorption, distribution, metabolism and elimination. The CHMP endorsed the MAH opinion on adopting the CDS text with some modifications, since it covers the pharmacokinetic properties of felodipine.

Section 5.3 – Preclinical safety data

The MAH proposed the use of section 5.3 of the CDS for the preclinical section of the harmonised EU SmPC for felodipine, since the text is based on current non clinical nomenclature. The CHMP requested some additional wordings. The MAH included the information regarding the preclinical data, and subsequent text added to state that it cannot be stated with certainty that the pharmacological effects are not relevant for humans.

Grounds for the variation to the terms of the marketing authorisations

In conclusion, based on the assessment of the MAH proposal and responses and following the discussions of the Committee, the CHMP adopted harmonised sets of Product Information documents of Plendil and associated names.

Whereas

• the scope of the referral was the harmonisation of the Summary of Products Characteristics, labelling and package leaflet,

• the Summary of Products Characteristic, labelling and package leaflet proposed by the Marketing Authorisation Holders have been assessed based on the documentation submitted and the scientific discussion within the Committee,

the CHMP has recommended the variation to the terms of the marketing authorisations for which the summary of product characteristics, labelling and package leaflet are set out in Annex III for Plendil and associated names (see Annex I).

20

Annex III

Summary of product characteristics, labelling and package leaflet

21

Note: This Summary of Product Characteristics, labelling and package leaflet is the outcome of the referral procedure to which this Commission decision relates.

The product information may be subsequently updated by the Member State competent authorities, in liaison with the Reference Member State, as appropriate, in accordance with the procedures laid down in Chapter 4 of Title III of Directive 2001/83/EC.

SUMMARY OF PRODUCT CHARACTERISTICS

23

1. NAME OF THE MEDICINAL PRODUCT Plendil and associated names (see Annex I) 2.5 mg prolonged-release tablets Plendil and associated names (see Annex I) 5 mg prolonged-release tablets Plendil and associated names (see Annex I) 10 mg prolonged-release tablets [See Annex I – to be completed nationally] 5. 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each tablet contains 2.5 mg felodipine. Excipients with known effect: Each tablet contains 28 mg lactose and 2.5 mg polyoxyl 40 hydrogenated castor oil. Each tablet contains 5 mg felodipine. Excipients with known effect: Each tablet contains 28 mg lactose and 5 mg polyoxyl 40 hydrogenated castor oil. Each tablet contains 10 mg felodipine. Excipients with known effect: Each tablet contains 28 mg lactose and 10 mg polyoxyl 40 hydrogenated castor oil. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Prolonged-release tablet The tablet is yellow, circular, biconvex, engraved A/FL on one side and 2.5 on the other side, with a diameter of 8.5 mm. The tablet is pink, circular, biconvex, engraved A/Fm on one side and 5 on the other side, with a diameter of 9 mm. The tablet is reddish-brown, circular, biconvex, engraved A/FE on one side and 10 on the other side, with a diameter of 9 mm. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Hypertension Stable angina pectoris

24

4.2 Posology and method of administration Posology Hypertension The dose should be adjusted individually. Treatment can be started with 5 mg once daily. Depending on the patient’s response, the dosage can, where applicable, be decreased to 2.5 mg or increased to 10 mg daily. If necessary another antihypertensive agent may be added. The standard maintenance dose is 5 mg once daily. Angina pectoris The dose should be adjusted individually. Treatment should be initiated with 5 mg once daily and, if needed, increased to 10 mg once daily. Elderly population Initial treatment with lowest available dose should be considered. Renal impairment Dose adjustment is not needed in patients with impaired renal function. Hepatic impairment Patients with impaired hepatic function may have elevated plasma concentrations of felodipine and may respond to lower doses (see section 4.4). Paediatric population There is limited clinical trial experience of the use of felodipine in hypertensive paediatric patients (see sections 5.1 and 5.2). Method of administration The tablets should be taken in the morning and be swallowed with water. In order to keep the prolonged-release properties, the tablets must not be divided, crushed or chewed. The tablets can be administered without food or following a light meal not rich in fat or carbohydrate. 4.3 Contraindications • Pregnancy • Hypersensitivity to felodipine or any of the excipients listed in section 6.1 • Decompensated heart failure • Acute myocardial infarction • Unstable angina pectoris • Haemodynamically significant cardiac valvular obstruction • Dynamic cardiac outflow obstruction 4.4 Special warnings and precautions for use The efficacy and safety of felodipine in the treatment of hypertensive emergencies has not been studied. Felodipine may cause significant hypotension with subsequent tachycardia. This may lead to myocardial ischaemia in susceptible patients. Felodipine is cleared by the liver. Consequently higher therapeutic concentrations and response can be expected in patients with clearly reduced liver function (see section 4.2).

25

Concomitant administration of drugs that strongly induce or inhibit CYP3 A4 enzymes result in extensively decreased or increased plasma levels of felodipine, respectively. Therefore such combinations should be avoided. (see section 4.5). Plendil contains lactose. Patients with rare hereditary problems of galactose intolerance or glucose-galactose malabsorption should not take this medicinal product. Plendil contains castor oil, which may cause stomach upset and diarrhoea. Mild gingival enlargement has been reported in patients with pronounced gingivitis/peridontitis. The enlargement can be avoided or reversed by careful oral hygiene. 4.5 Interaction with other medicinal products and other forms of interaction Felodipine is metabolised in the liver by cytochrome P450 3A4 (CYP3A4). Concomitant administration of substances which interfere with CYP3A4 enzyme system may affect plasma concentrations of felodipine. Enzyme interactions

Enzyme inhibiting and enzyme inducing substances of cytochrome P450 isoenzyme 3A4 may exert an influence on the plasma level of felodipine. Interactions leading to increased plasma concentration of felodipine CYP3A4 enzyme inhibitors have been shown to cause an increase in felodipine plasma concentrations. Felodipine Cmax and AUC increased 8-fold and 6-fold, respectively, when felodipine was coadministered with the strong CYP3A4 inhibitor itraconazole. When felodipine and erythromycin were coadministered, the Cmax and AUC of felodipine were increased by about 2.5-fold. Cimetidine increased the felodipine Cmax and AUC by approximately 55%. The combination with strong CYP3A4 inhibitors should be avoided. In case of clinically significant adverse events due to elevated felodipine exposure when combined with strong CYP3A4 inhibitors, adjustment of felodipine dose and/or discontinuation of the CYP3A4 inhibitor should be considered. Examples: • Cimetidine • Erythromycin • Itraconazole • Ketoconazole • Anti HIV/protease inhibitors (e.g. ritonavir) • Certain flavonoids present in grapefruit juice Felodipine tablets should not be taken together with grapefruit juice. Interactions leading to decreased plasma concentration of felodipine Enzyme inducers of the cytochrome P450 3A4 system have been shown to cause a decrease in plasma concentrations of felodipine. When felodipine was coadministered with carbamazepine, phenytoin or phenobarbital, the Cmax and AUC of felodipine were decreased by 82% and 96% respectively. The combination with strong CYP3A4 inducers should be avoided. In case of lack of efficacy due to decreased felodipine exposure when combined with potent inducers of CYP3A4, adjustment of felodipine dose and/or discontinuation of the CYP3A4 inducer should be considered.

26

Examples: • Phenytoin • Carbamazepine • Rifampicin • Barbiturates • Efavirenz • Nevirapine • Hypericum perforatum (Saint John’s wort)

Additional interactions

Tacrolimus: Felodipine may increase the concentration of tacrolimus. When used together, the tacrolimus serum concentration should be followed and the tacrolimus dose may need to be adjusted. Cyclosporin: Felodipine does not affect plasma concentrations of cyclosporin. 4.6 Fertility, pregnancy and lactation Pregnancy Felodipine should not be given during pregnancy. In non-clinical reproductive toxicity studies there were foetal developmental effects, which are considered to be due to the pharmacological action of felodipine. Breastfeeding Felodipine has been detected in breast milk, and due to insufficient data on potential effect on the infant, treatment is not recommended during breastfeeding. Fertility There are no data on the effects of felodipine on patient fertility. In a nonclinical reproductive study in the rat (see section 5.3), there were effects on fetal development but no effect on fertility at doses approximating to therapeutic. 4.7 Effects on ability to drive and use machines Felodipine has minor or moderate influence on the ability to drive and use machines. If patients taking felodipine suffer from headache, nausea, dizziness or fatigue and ability to react may be impaired. Caution is recommended especially at the start of treatment. 4.8 Undesirable effects Summary of the safety profile Felodipine can cause flushing, headache, palpitations, dizziness and fatigue. Most of these adverse reactions are dose-dependent and appear at the start of treatment or after a dose increase. Should such adverse reactions occur, they are usually transient and diminish with time. Dose-dependent ankle swelling can occur in patients treated with felodipine. This results from precapillary vasodilatation and is not related to any generalised fluid retention. Mild gingival enlargement has been reported in patients with pronounced gingivitis/periodontitis. The enlargement can be avoided or reversed by careful oral hygiene.

27

Tabulated list of adverse reactions The adverse reactions listed below have been identified from clinical trials and from post marketing surveillance. The following definitions of frequencies are used: 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 6. Table 1 Undesirable effects System organ class Frequency Adverse reaction Nervous system disorders Common

Uncommon Headache Dizziness, paraesthesia

Cardiac disorders Uncommon Tachycardia, palpitations Vascular disorders Common

Uncommon Rare

Flush Hypotension Syncope

Gastrointestinal disorders Uncommon Rare Very rare

Nausea, abdominal pain Vomiting Gingival hyperplasia, gingivitis

Hepatobiliary disorders Very rare Increased liver enzymes Skin and subcutaneous tissue disorders

Uncommon Rare Very rare

Rash, pruritus Urticaria Photosensitivity reactions, leucocytoclastic vasculitis

Musculoskeletal and connective tissue disorders

Rare Arthralgia, myalgia

Renal and urinary disorders Very rare Pollakisuria Reproductive system and breast disorders

Rare Impotence/sexual dysfunction

General disorders and administration site conditions

Very common Uncommon Very rare

Peripheral oedema Fatigue Hypersensitivity reactions, e.g. angio-oedema, fever

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 national reporting system listed in Appendix V. 4.9 Overdose Symptoms Overdosage may cause excessive peripheral vasodilatation with marked hypotension and sometimes bradycardia. Management If justified: activated charcoal, gastric lavage if performed within one hour after ingestion. If severe hypotension occurs, symptomatic treatment should be instituted.

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc

28

The patient should be placed supine with the legs elevated. In case of accompanying bradycardia, atropine 0.5-1 mg should be administered intravenously. If this is not sufficient, plasma volume should be increased by infusion of e.g., glucose, saline, or dextran. Sympathomimetic medicinal products with predominant effect on the α1-adrenoceptor may be given if the above-mentioned measures are insufficient. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: calcium channel blockers, dihydropyridine derivatives; ATC code: C08CA02 Mechanism of action Felodipine is a vascular selective calcium antagonist, which lowers arterial blood pressure by decreasing systemic vascular resistance. Due to the high degree of selectivity for smooth muscle in the arterioles, felodipine in therapeutic doses has no direct effect on cardiac contractility or conduction. Because there is no effect on venous smooth muscle or adrenergic vasomotor control, felodipine is not associated with orthostatic hypotension. Felodipine possesses a mild natriuretic/diuretic effect and fluid retention does not occur. Pharmacodynamic effects Felodipine is effective in all grades of hypertension. It can be used as monotherapy or in combination with other antihypertensive medicinal products, eg, ß-adrenoceptor blockers, diuretics or ACE-inhibitors, in order to achieve an increased antihypertensive effect. Felodipine reduces both systolic and diastolic blood pressure and can be used in isolated systolic hypertension. Felodipine has anti-anginal and anti-ischaemic effects due to improved myocardial oxygen supply/demand balance. Coronary vascular resistance is decreased and coronary blood flow and myocardial oxygen supply are increased by felodipine due to dilatation of both epicardial arteries and arterioles. The reduction in systemic blood pressure caused by felodipine leads to decreased left ventricular afterload and myocardial oxygen demand. Felodipine improves exercise tolerance and reduces anginal attacks in patients with stable effort-induced angina pectoris. Felodipine can be used as monotherapy or in combination with ß-adrenoceptor blockers in patients with stable angina pectoris. Haemodynamic effects The primary haemodynamic effect of felodipine is a reduction of total peripheral vascular resistance, which leads to a decrease in blood pressure. These effects are dose-dependent. Generally, a reduction in blood pressure is evident two hours after the first oral dose and lasts for at least 24 hours and the trough/peak ratio is usually well above 50%. Plasma concentrations of felodipine are positively correlated to the decrease in total peripheral resistance and blood pressure. Cardiac effects Felodipine in therapeutic doses has no effect on cardiac contractility or atrioventricular conduction or refractoriness.

29

Antihypertensive treatment with felodipine is associated with significant regression of pre-existing left ventricular hypertrophy. Renal effects Felodipine has a natriuretic and diuretic effect due to reduced tubular reabsorption of filtered sodium. Felodipine does not affect daily potassium excretion. The renal vascular resistance is decreased by felodipine. Felodipine does not influence urinary albumin excretion. In cyclosporin-treated renal transplant recipients, felodipine reduces blood pressure and improves both the renal blood flow and the glomerular filtration rate. Felodipine may also improve early renal graft function. Clinical efficacy In the HOT (Hypertension Optimal Treatment) study, the effect on major cardiovascular events (ie, acute myocardial infarction, stroke and cardiovascular death) was studied in relation to diastolic blood pressure targets < 90 mmHg, < 85 mmHg and < 80 mmHg and achieved blood pressure, with felodipine as baseline therapy. A total of 18,790 hypertensive patients (DBP 100-115 mmHg), aged 50-80 years were followed for a mean period of 3.8 years (range 3.3-4.9). Felodipine was given as monotherapy or in combination with a betablocker, and/or an ACE-inhibitor and/or a diuretic. The study showed benefits of lowering SBP and DBP down to 139 and 83 mmHg, respectively. According to the STOP-2 (Swedish Trial in Old Patients with Hypertension-2 study), performed in 6614 patients, aged 70-84 years, dihydropyridine calcium antagonists (felodipine and isradipine) have shown the same preventive effect on cardiovascular mortality and morbidity as other commonly used classes of antihypertensive medicinal products – ACE inhibitors, beta-blockers and diuretics. 7. Paediatric population

There is limited clinical trial experience of the use of felodipine in hypertensive paediatric patients. In a randomised, double-blind, 3-week, parallel group study in children aged 6-16 years with primary hypertension, the antihypertensive effects of once daily felodipine 2.5 mg (n=33), 5 mg (n=33) and 10 mg (n=31) were compared with placebo (n=35). The study failed to demonstrate the efficacy of felodipine in lowering blood pressure in children aged 6-16 years (see section 4.2)

The long-term effects of felodipine on growth, puberty and general development have not been studied. The long-term efficacy of antihypertensive therapy as therapy in childhood to reduce cardiovascular morbidity and mortality in adulthood has also not been established.

5.2 Pharmacokinetic properties

Absorption Felodipine is administered as extended-release tablets, from which it is completely absorbed in the gastrointestinal tract. The systemic availability of felodipine is approximately 15% and is independent of dose in the therapeutic dose range. The extended-release tablets produce a prolonged absorption phase of felodipine. This results in even felodipine plasma concentrations within the therapeutic range for 24 hours. Maximum blood plasma levels (tmax) are achieved with the prolonged-release form after 3 to 5 hours. The rate but not the extent of absorption of felodipine is increased when taken simultaneously with food with a high fat content.

30

Distribution The plasma protein binding of felodipine is approximately 99%. It is bound pre-dominantly to the albumin fraction. Volume of distribution at steady state is 10 L/kg. Biotransformation Felodipine is extensively metabolised in the liver by cytochrome P450 3A4 (CYP3A4) and all identified metabolites are inactive. Felodipine is a high clearance medicinal product with an average blood clearance of 1200 ml/min. There is no significant accumulation during long-term treatment. Elderly patients and patients with reduced liver function have on average higher plasma concentrations of felodipine than younger patients. The pharmacokinetics of felodipine is not changed in patients with renal impairment, including those treated with haemodialysis. Elimination The half-life of felodipine in the elimination phase is approximately 25 hours and steady state is reached after 5 days. There is no risk of accumulation during long-term treatment. About 70% of a given dose is excreted as metabolites in the urine; the remaining fraction is excreted in the faeces. Less than 0.5% of a dose is recovered unchanged in urine. Linearity/non-linearity Plasma concentrations are directly proportional to dose within the therapeutic dose range 2.5 – 10 mg. Paediatric population In a single dose (felodipine prolonged-release 5 mg) pharmacokinetic study with a limited number of children aged between 6 and 16 years (n=12) there was no apparent relationship between the age and AUC, Cmax or half-life of felodipine. 5.3 Preclinical safety data Reproduction toxicity In a study on fertility and general reproductive performance in rats treated with felodipine, a prolongation of parturition resulting in difficult labour/increased foetal deaths and early postnatal deaths was observed in the medium and high dose groups. These effects were attributed to the inhibitory effect of felodipine in high doses on uterine contractility. No disturbances of fertility were observed when doses within the therapeutic range were given to rats. Reproduction studies in rabbits have shown a dose-related reversible enlargement of the mammary glands of the parent animals and dose-related digital anomalies in the foetuse. The anomalies in the foetuses were induced when felodipine was administered during early foetal development (before day 15 of pregnancy). In a reproduction study in monkeys, an abnormal position of the distal phalange(s) was noticed. There were no other pre clinical findings considered to be of concern and the reproductive findings are considered to be related to the pharmacological action of felodipine, when given to normotensive animals. The relevance of these findings for patients receiving felopidine is unknown. However, there have been no reported clinical incidences of phalangeal changes in foetus/neonate exposed to felodipine in-utero, from the information maintained within the internal patient safety databases. 8.

31

6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Tablet core Hydroxypropylcellulose Hypromellose 50 mPa·s Hypromellose 10000 mPa·s Lactose anhydrous Microcrystalline cellulose Polyoxyl 40 hydrogenated castor oil Propyl gallate Sodium aluminium silicate Sodium stearyl fumarate Coating Carnauba wax Iron oxide yellow (E172) Hypromellose 6 mPa·s Macrogol 6000 Titanium dioxide (E 171) [Plendil 5 mg and 10 mg] Carnauba wax Iron oxide reddish-brown (E172) Iron oxide yellow (E172) Hypromellose 6 mPa·s Macrogol 6000 Titanium dioxide (E 171) 6.2 Incompatibilities Not applicable. 6.3 Shelf life [To be completed nationally] 6.4 Special precautions for storage [To be completed nationally] 6.5 Nature and contents of container High-density polyethylene bottle with a cap of polypropylene PVC/PVDC blister and Aluminum blister Pack Size Carton (pack) contents 20 tablets 2 blisters of 10 tablets 28 tablets 4 blisters of 7 tablets 30 tablets 3 blisters of 10 tablets

1 bottle of 30 tablets 98 tablets 7 blisters of 14 tablets

32

100 tablets 10 blisters of 10 tablets

14 tablets 1 blister of 14 tablets 20 tablets 2 blisters of 10 tablets 28 tablets 1 blister of 28 tablets

2 blisters of 14 tablets 4 blisters of 7 tablets

30 tablets 3 blisters of 10 tablets 1 bottle of 30 tablets

90 tablets 3 blisters of 30 tablets 98 tablets 7 blisters of 14 tablets 100 tablets 1 bottle of 100 tablets

10 blisters of 10 tablets

14 tablets 1 blister of 14 tablets 20 tablets 2 blisters of 10 tablets 28 tablets 1 blister of 28 tablets

2 blisters of 14 tablets 4 blisters of 7 tablets

30 tablets 1 bottle of 30 tablets 3 blisters of 10 tablets

98 tablets 7 blisters of 14 tablets 100 tablets 1 bottle of 100 tablets

10 blisters of 10 tablets Not all pack sizes may be marketed. 6.6 Special precautions for disposal Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER [See Annex I - To be completed nationally] {Name and address} <{tel}> <{fax}> <{e-mail}> 8. MARKETING AUTHORISATION NUMBER(S) [To be completed nationally] 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION <Date of first authorisation: {DD month YYYY}> <Date of latest renewal: {DD month YYYY}>

33

<[To be completed nationally]> 10. DATE OF REVISION OF THE TEXT <{MM/YYYY}> <{DD/MM/YYYY}> <{DD month YYYY}> [To be completed nationally] Detailed information on this medicinal product is available on the website of {name of MS/Agency}

34

LABELLING

35

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE PACKAGING CARTON 1. NAME OF THE MEDICINAL PRODUCT Plendil and associated names (see Annex I) 2.5 mg prolonged-release tablets Plendil and associated names (see Annex I) 5 mg prolonged-release tablets Plendil and associated names (see Annex I) 10 mg prolonged-release tablets [See Annex I - To be completed nationally] felodipine 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each tablet contains 2.5 mg (or 5 mg, or 10 mg) felodipine 3. LIST OF EXCIPIENTS Contains lactose and polyoxyl 40 hydrogenated castor oil. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS 9. 2.5 mg tablet 20 tablets 28 tablets 30 tablets 98 tablets 100 tablets 10. 5 mg tablet 14 tablets 20 tablets 28 tablets 30 tablets 90 tablets 98 tablets 100 tablets 11. 10 mg tablet 14 tablets 20 tablets 28 tablets 30 tablets 98 tablets 100 tablets [To be completed nationally] 5. METHOD AND ROUTE(S) OF ADMINISTRATION

36

Read the package leaflet before use. Oral use 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF

THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS [To be completed nationally] 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER [See Annex I - To be completed nationally] {Name and Address} {tel} {fax} {e-mail} 12. MARKETING AUTHORISATION NUMBER(S) [To be completed nationally] 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY [To be completed nationally]

37

15. INSTRUCTIONS ON USE [To be completed nationally] 16. INFORMATION IN BRAILLE <Justification for not including Braille accepted> [To be completed nationally]

38

12. MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS BLISTERS 1. NAME OF THE MEDICINAL PRODUCT Plendil and associated names (see Annex I) 2.5 mg prolonged-release tablets Plendil and associated names (see Annex I) 5 mg prolonged-release tablets Plendil and associated names (see Annex I) 10 mg prolonged-release tablets [See Annex I - To be completed nationally] felodipine 2. NAME OF THE MARKETING AUTHORISATION HOLDER [See Annex I - To be completed nationally] {Name} 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. OTHER

39

PACKAGE LEAFLET

40

Package leaflet: Information for the patient

Plendil and associated names (see Annex I) 2.5 mg [5 mg or, 10 mg] prolonged-release tablets [See Annex I - To be completed nationally]

felodipine

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor. - This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even

if their signs of illness are the same as yours. - If you get any side effects, talk to your doctor. This includes any possible side effects not listed in

this leaflet. See section 4. What is in this leaflet 1. What Plendil is and what it is used for 2. What you need to know before you take Plendil 3. How to take Plendil 4. Possible side effects 13. How to store Plendil 6. Contents of the pack and other information 1. What Plendil is and what it is used for Plendil contains the active substance felodipine. This belongs to a group of medicinces called calcium antagonists. It lowers blood pressure by dilating small blood vessels. It does not negatively affect the heart function. Plendil is used in the treatment of high blood pressure (hypertension) and heart and chest pain brought on by for example exercise or stress (angina pectoris). 2. What you need to know before you take Plendil Do not take Plendil - if you are pregnant. You should tell your doctor as soon as possible if you become pregnant while

using this medicine. - if you are allergic to felodipine or any of the other ingredients of this medicine (listed in section 6). - if you suffer from uncompensated heart failure. - if you have acute myocardial infarction (heart attack). - if you have chest pain of recent onset, or angina pectoris that is lasting for more than 15 minutes or

longer or is more severe than usual. - if you have disease of a heart valve or heart muscle, until you have talked to your doctor. Warnings and precautions Plendil, like other blood-pressure lowering medicinal products, may in rare cases lead to pronounced low blood pressure which in some patients may result in an inadequate supply of blood to the heart. Symptoms of excessive low blood pressure and inadequate blood supply to the heart itself, frequently include dizziness and chest pain. If you experience these symptoms, seek emergency care immediately. Talk to your doctor before taking Plendil, especially if you have problems with your liver.

41

Taking Plendil may cause your gums to become swollen. Practice good oral hygiene to help avoid your gums from swelling (see section 4). Children The use of Plendil is not recommended in children. Other medicines and Plendil Tell your doctor if you are taking, have recently taken or might take any other medicines. Some medicines/herbal remedies can affect treatment with Plendil. Examples are: • cimetidine (medicine to treat gastric ulcers) • erythromycin (medicine to treat infections) • itraconazole (medicine to treat fungi) • ketoconazole (medicine to treat fungi) • medicines to treat HIV protease inhibitors (such as ritonavir) • medicines to treat HIV infection (such as efavirenz, nevirapine) • phenytoin (medicine to treat epilepsy) • carbamazepine (medicine to treat epilepsy) • rifampicin (medicine to treat infections) • barbiturates (medicine to treat anxiety, sleeping problems and epilepsy) • tacrolimus (medicine used in organ transplantations) Medicines containing St John’s wort (Hypericum perforatum) (herbal product used to treat depression) may reduce the effect of Plendil and should therefore be avoided. 14. Plendil with food and drink Do not drink grapefruit juice if you are treated with Plendil, as this may increase the effect of Plendil and the risk of side effects. Pregnancy and breast-feeding Pregnancy Do not use Plendil if you are pregnant. 15. Breast-feeding Tell your doctor if you are breast-feeding or about to start breast-feeding. Plendil is not recommended for mothers who are breast-feeding, and your doctor may choose another treatment for you if you wish to breast-feed. Driving and using machines Plendil can have minor or moderate influence on your ability to drive and use machines. If you experience headache, nausea, dizziness or fatigue your ability to react may be impaired. Caution is recommended especially at the start of treatment. Plendil contains lactose and castor oil Plendil contains lactose that is a type of sugar. If you have been told by your doctor that you have intolerance to some sugars, contact your doctor before taking this medicine. Plendil contains castor oil, which may cause stomach upset and diarrhoea. 3. How to take Plendil Always take this medicine exactly as your doctor has told you. Check with your doctor if you are not sure.

42

Plendil extended release tablets should be taken in the morning and be swallowed with water. The tablet must not be divided, crushed or chewed. This medicine can be taken without food or following a light meal not high in fat or carbohydrates. 16. Hypertension Treatment should be started with 5 mg once a day. If necessary, your doctor may increase the dose or add another blood-pressure lowering medicine. The usual dose when treating this disease for a long time is 5-10 mg once a day. In elderly patients, a starting dose of 2.5 mg daily may be considered. 17. Stable angina pectoris Treatment should be started with 5 mg once a day and if needed, your doctor may increase the dose to 10 mg once a day. 18. If you have liver problems The level of felodipine in your blood may be increased. Your doctor may lower the dose. 19. Elderly people Your doctor may initiate treatment with the lowest available dose. If you take more Plendil than you should If you take more than the recommended number of doses of Plendil, you may suffer from very low blood pressure and sometimes palpitations, high or, rarely, slow heart rate. Therefore, it is very important that you take the number of doses prescribed by your doctor. If you experience symptoms such as feeling faint, light-headedness or dizziness, contact your doctor immediately. If you forget to take Plendil If you forget to take a tablet, leave out that dose completely. Take your next dose at the right time. Do not take a double dose to make up for a forgotten dose. If you stop taking Plendil If you stop taking this medicine your condition may return. Please consult your doctor and seek advice before you stop taking Plendil. Your doctor will advise you how long to take your medicine. If you have any further questions on the use of this medicine, ask your doctor. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. If any of the following happen to you, stop taking Plendil and tell a doctor straight away: • Hypersensitivity and allergic reactions: The signs may include raised lumps on your skin (weals) or

swelling of your face, lips, mouth, tongue or throat. The following undesirable effects have been identified. Most of these reactions appear at start of treatment or after a dose increase. Should such reactions occur, they are usually brief and diminish in intensity with time. If you experience any of the following symptoms and they persist, please tell your doctor. Mild enlargement of the gums has been reported in patients with an inflammation in the mouth (gingivitis/periodontitis). The enlargement can be avoided or reversed by careful oral hygiene. Very common: may affect more than 1 in 10 people • Ankle swelling

43

Common: may affect up to 1 in 10 people • Headache • Flushing Uncommon: may affect up to 1 in 100 people • Abnormally rapid heart rate • Palpitations • Too low blood pressure (hypotension) • Nausea • Abdominal pain • Burning/prickling/numbness • Rash or itching • Fatigue • Dizziness Rare: may affect up to 1 in 1,000 people • Fainting • Vomiting • Nettle rash • Pain in joints • Muscular pain • Impotence/sexual dysfunction Very rare: may affect up to 1 in 10,000 people • Gingivitis (swollen gums) • Increased liver enzymes • Skin reactions due to increased sensitivity to sunlight • Inflammation of small blood vessels of the skin • A need to pass water frequently • Hypersensitivity reactions such as fever or swelling of the lips and tongue Other undesirable effects may occur. If you have any bothersome or unusual reaction while taking Plendil, check with your doctor right away. Reporting of side effects If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine. 5. How to store Plendil [To be completed nationally] Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the carton, blister and bottle after ‘EXP’. The expiry date refers to the last day of that month. Do not use this medicine if you notice the packaging is torn or damaged. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc

44

6. Contents of the pack and other information What Plendil contains

- The active substance felodipine. Each tablet contains 2.5 mg 5 mg or 10 mg of felodipine.

- The other ingredients are: Tablet core: Hydroxypropylcellulose Hypromellose 50 mPa·s Hypromellose 10000 mPa·s Lactose anhydrous Microcrystalline cellulose Polyoxyl 40 hydrogenated castor oil Propyl gallate Sodium aluminium silicate Sodium stearyl fumarate Tablet coating: Carnauba wax Iron oxide reddish-brown (E172) (Only used for Plendil 5 mg and 10 mg) Iron oxide yellow (E172) Hypromellose 6 mPa·s Macrogol 6000 Titanium dioxide (E 171)

What Plendil looks like and contents of the pack Plendil 2.5 mg prolonged-release tablet is yellow, circular, biconvex, engraved A/FL on one side and 2.5 on the other side, with a diameter of 8.5 mm. Plendil 5 mg prolonged-release tablet is pink, circular, biconvex, engraved A/Fm on one side and 5 on the other side, with a diameter of 9 mm. Plendil 10 mg prolonged-release tablet is reddish-brown, circular, biconvex, engraved A/FE on one side and 10 on the other side, with a diameter of 9. Pack sizes of 20, 28, 30, 98 and 100 tablets Pack sizes of 14, 20, 28, 30, 90, 98 and 100 tablets Pack sizes of 14, 20, 28, 30, 98 and 100 tablets Marketing Authorisation Holder and Manufacturer [To be completed nationally] [See Annex I - To be completed nationally] {Name and address} <{tel}> <{fax}> <{e-mail}>

45

This medicinal product is authorised in the Member States of the EEA under the following names: Austria, Belgium, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Spain, Sweden, United Kingdom: Plendil France: Flodil Germany: Modip Italy: Feloday, Prevex Portugal: Preslow Sweden: Felodipin AstraZeneca [See Annex I - To be completed nationally] This leaflet was last revised in {MM/YYYY} {month YYYY} [To be completed nationally] Detailed information on this medicine is available on the website of {MS/Agency}

felodipine - Plendil, INN - European Commission

Documents

Transcript of felodipine - Plendil, INN - European Commission