Dipyridamol Actavis 200 mg Depotkapsel, hård

Sverige - svenska - Läkemedelsverket (Medical Products Agency)

Bipacksedel Bipacksedel (PIL)

12-03-2019

Produktens egenskaper Produktens egenskaper (SPC)

12-03-2019

Aktiva substanser:
dipyridamol
Tillgänglig från:
Actavis Group PTC ehf.
ATC-kod:
B01AC07
INN (International namn):
dipyridamole
Dos:
200 mg
Läkemedelsform:
Depotkapsel, hård
Sammansättning:
dipyridamol 200 mg Aktiv substans
Receptbelagda typ:
Receptbelagt
Produktsammanfattning:
Förpacknings: Burk, 30 kapslar; Burk, 60 kapslar; Burk, 100 (2 x 50) kapslar
Bemyndigande status:
Godkänd
Godkännandenummer:
52197
Tillstånd datum:
2017-01-19

Dokument på andra språk

Bipacksedel Bipacksedel - engelska

25-10-2017

Produktens egenskaper Produktens egenskaper - engelska

21-09-2016

Offentlig bedömningsrapport Offentlig bedömningsrapport - engelska

02-11-2016

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Package leaflet: Information for the user

Dipyridamol Actavis 200 mg prolonged-release capsules, hard

dipyridamole

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 or pharmacist.

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 or pharmacist. This includes any possible side

effects not listed in this leaflet. See section 4.

What is in this leaflet

What Dipyridamol Actavis is and what it is used for

What you need to know before you take Dipyridamol Actavis

How to take Dipyridamol Actavis

Possible side effects

How to store Dipyridamol Actavis

Contents of the pack and other information

1.

What Dipyridamol Actavis is and what it is used for

Dipyridamol Actavis contains the active substance dipyridamole. This belongs to a group of

medicines called ‘anti-thrombotic agents’, which are used to stop blood clots forming.

Dipyridamol Actavis is used:

To reduce the risk of having another stroke in people who have had a stroke caused by a blood

clot in the brain.

2.

What you need to know before you take Dipyridamol Actavis

Do not take Dipyridamol Actavis:

if you are allergic to dipyridamole or any of the other ingredients of this medicine (listed in

section 6).

Warnings and precautions

Talk to your doctor or pharmacist before taking Dipyridamol Actavis:

If you have angina or other heart diseases or have had a recent heart attack

If you have myasthenia gravis (muscle weakness)

If you have any bleeding problems

If you are having heart tests

Dipyridamol Actavis contains dipyridamole. Dipyridamole is also sometimes given as an injection

during tests to see if the heart is working properly (also called ‘myocardial imaging’). This means that

the test and your medicine may contain the same substance. If you are going to have an injection of

dipyridamole, tell the doctor that you are taking Dipyridamol Actavis.

Children and adolescents

Dipyridamol Actavis should not be given to children since the safety and efficacy has not been

established.

Other medicines and Dipyridamol Actavis

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other

medicines. This includes herbal medicines. This is because Dipyridamol Actavis can affect the way

some other medicines work. Also some other medicines can affect the way Dipyridamol Actavis

works.

In particular, tell your doctor or pharmacist if you are taking any of the following medicines:

Medicines for high blood pressure

Medicines for muscle weakness (myasthenia gravis), called a ‘cholinesterase inhibitor’

Adenosine, used for heart problems or tests on the heart

Warfarin, acetylsalicylic acid or other medicines to stop blood clots forming

Theophylline (a medicine for respiratory problems)

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask

your doctor for advice before taking this medicine.

Dipyridamol Actavis should generally not be used in pregnancy.

Dipyridamol Actavis should only be used during breast-feeding if your doctor considers it essential,

since dipyridamole is excreted in breastmilk.

Driving and using machines

You may feel dizzy while taking Dipyridamol Actavis. If this happens do not drive or use any tools or

machines.

3.

How to take Dipyridamol Actavis

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist

if you are not sure.

The recommended dose is one capsule twice a day, usually one in the morning and one in the evening.

The capsules may be taken with or without food.

Swallow the capsule whole. Do not crush or chew it.

If you take more Dipyridamol Actavis than you should

If you take more of this medicine than you should, talk to a doctor or go to a hospital straight away.

Take the medicine pack with you, even if there are no capsules left.

Symptoms such as feeling warm, flushes, sweating, faster pulse, restlessness, feeling of weakness,

dizziness, drop in blood pressure and chest pain can be expected.

If you forget to take Dipyridamol Actavis

If you forget a dose, take it as soon as you remember it. However, if it is time for the next dose, skip

the missed dose.

Do not take a double dose to make up for a forgotten dose.

If you stop taking Dipyridamol Actavis

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4.

Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Allergic reactions

If you have an allergic reaction, stop taking your medicine and see a doctor straight away. The signs

may include feeling breathless, runny nose, severe rash with itching, swelling and swelling around the

eyes.

Other side effects that have been reported for Dipyridamol Actavis are described below.

Very common (may affect more than 1 in 10 people)

Headache

Feeling dizzy

Feeling sick (nausea)

Diarrhoea

Common (may affect up to 1 in 10 people)

Muscle pain

Being sick (vomiting)

Rash

Worsening of the symptoms of heart disease such as chest pain and shortness of breath

Not known (frequency cannot be estimated from the available data)

Hot flushes

Lowering of blood pressure or increased heart rate

A blood problem called ‘thrombo-cytopenia’ which can cause bruising and prolonged bleeding

from wounds, including during or after surgery

In people who have gallstones, the dipyridamole in this medicine can be absorbed into the gallstones.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. 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 Dipyridamol Actavis

Keep this medicine out of the sight and reach of children.

Store in the original package in order to protect from moisture. Keep the bottle tightly closed.

Do not use this medicine after the expiry date which is stated on the label and carton after EXP. The

expiry date refers to the last day of that month.

Shelf life after first opening: 100 days

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.

6.

Contents of the pack and other information

What Dipyridamol Actavis contains

The active substance is dipyridamole. Each prolonged release capsule contains dipyridamole

200 mg. Dipyridamol Actavis is a prolonged release capsule which releases the active

substance slowly in your body over a number of hours.

The other ingredients are: Capsule content: Tartaric acid, hypromellose, talc, hydroxypropyl

cellulose, methacrylic acid – methyl methacrylate copolymer (1:2), triethyl citrate.

Capsule shell: Gelatin, titanium dioxide (E171) and red iron oxide (E172).

What Dipyridamol Actavis looks like and contents of the pack

Dipyridamol Actavis 200 mg capsules are reddish-brown (orange) hard capsules, 23.5 mm.

Dipyridamol Actavis is available in packs of 30 and 60 capsules and in multipacks comprising 2

bottles, each containing 50 capsules.

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

<[To be completed nationally]>

{Name and address}

<{tel}>

<{fax}>

<{e-mail}>

<This medicinal product is authorised in the Member States of the EEA under the following

names:>

<{Name of the Member State}> <{Name of the medicinal product}>

<{Name of the Member State}> <{Name of the medicinal product}>

This leaflet was last revised in 2017-10-25

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SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT

Dipyridamol Actavis 200 mg prolonged-release capsules, hard.

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each prolonged-release capsule contains dipyridamole 200 mg.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Prolonged-release capsule, hard.

Hard gelatin capsule, 23.5 mm, with a reddish-brown (orange) opaque body and cap.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Secondary prevention of ischaemic stroke and transient ischaemic attacks either alone or in

conjunction with acetylsalicylic acid.

4.2

Posology and method of administration

Posology

The recommended dose is one capsule twice daily, usually one in the morning and one in the evening,

which can be taken with or without food.

Paediatric population

Dipyridamol Actavis is not recommended for children since the safety and efficacy of dipyridamole in

children has not yet been established.

Method of administration

For oral administration.

The capsules should be swallowed whole without chewing.

4.3

Contraindications

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

4.4

Special warnings and precautions for use

Among other properties, dipyridamole acts as a potent vasodilator. It should therefore be used with

caution in patients with severe coronary artery disease including unstable angina and/or recent

myocardial infarction, left ventricular outflow obstruction or haemodynamic instability (e.g.

decompensated heart failure).

Patients being treated with regular oral doses of Dipyridamol Actavis should not receive additional

intravenous dipyridamole. Clinical experience suggests that patients being treated with oral

dipyridamole who also require pharmacological stress testing with intravenous dipyridamole should

discontinue drugs containing oral dipyridamole for twenty-four hours prior to stress testing.

In patients with myasthenia gravis readjustments of therapy may be necessary after changes in

dipyridamole dosage (see section 4.5).

A small number of cases have been reported in which unconjugated dipyridamole was shown to be

incorporated into gallstones to a variable extent (up to 70 % by dry weight of stone). These patients

were all elderly, had evidence of ascending cholangitis and had been treated with oral dipyridamole

for a number of years. There is no evidence that dipyridamole was the initiating factor in causing

gallstones to form in these patients. It is possible that bacterial deglucuronidation of conjugated

dipyridamole in the bile may be the mechanism responsible for the presence of dipyridamole in

gallstones.

Dipyridamole should be used with caution in patients with coagulation disorders.

4.5

Interaction with other medicinal products and other forms of interaction

Dipyridamole increases the plasma levels and cardiovascular effects of adenosine. Adjustment of

adenosine dosage should therefore be considered if use with dipyridamole is unavoidable.

There is evidence that the effects of acetylsalicylic acid and dipyridamole on platelet behaviour are

additive.

When dipyridamole is used in combination with any substances impacting coagulation such as

anti-coagulants and antiplatelets, the safety profile for these medications must be observed. Addition

of dipyridamole to acetylsalicylic acid does not increase the incidence of bleeding events. When

dipyridamole was administered concomitantly with warfarin, bleeding was no greater in frequency or

severity than that observed when warfarin was administered alone.

Dipyridamole may increase the hypotensive effect of blood pressure lowering drugs and may

counteract the anticholinesterase effect of cholinesterase inhibitors thereby potentially aggravating

myasthenia gravis.

The effect of dipyridamole may be weakened by xanthines. This should especially be considered

when administering intravenous theophylline (see section 4.9).

4.6

Fertility, pregnancy and lactation

Pregnancy

There are no or limited amount of data from the use of dipyridamole in pregnant women.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity.

As a precautionary measure, it is preferable to avoid the use of Dipyridamol Actavis during

pregnancy.

Breastfeeding

Dipyridamole is excreted in human milk. A risk to the newborns/infants cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from

Dipyridamol Actavis therapy taking into account the benefit of breast feeding for the child and the

benefit of therapy for the woman.

Fertility

No studies on the effect on human fertility have been conducted with Dipyridamol Actavis.

Non-clinical studies with dipyridamole did not indicate direct or indirect harmful effects with respect

to fertility.

4.7

Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed.

However, patients should be advised that they may experience undesirable effects such as dizziness

during treatment with Dipyridamol Actavis. If patients experience dizziness they should avoid

potentially hazardous tasks such as driving or operating machinery.

4.8

Undesirable effects

Adverse effects at therapeutic doses are usually mild and transient.

The following side effects have been reported, frequencies have been assigned based on a clinical trial

(ESPS-2) in which 1654 patients received dipyridamole alone.

The following frequency convention is being 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),

not known (frequency cannot be estimated from the available data).

Blood and lymphatic system disorders

Thrombocytopenia*

not known

Immune system disorders

Hypersensitivity*

not known

Angioedema*

not known

Nervous system disorders

Headache

very common

Dizziness

very common

Cardiac disorders

Angina pectoris

common

Tachycardia*

not known

Vascular disorders

Hypotension*

not known

Hot flush*

not known

Respiratory, thoracic and mediastinal disorders

Bronchospasm*

not known

Gastrointestinal disorders

Diarrhoea

very common

Nausea

very common

Vomiting

common

Skin and subcutaneous tissue disorders

Rash

common

Urticaria*

not known

Musculoskeletal and connective tissue disorders

Myalgia

common

Injury, poisoning and procedural complications

post procedural haemorrhage*

not known

operative haemorrhage*

not known

*This side effect was reported post-marketing.

Dipyridamole has been shown to be incorporated into gallstones (see section 4.4).

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

Due to the low number of observations, experience with dipyridamole overdose is limited. Symptoms

such as feeling warm, flushes, sweating, accelerated pulse, restlessness, feeling of weakness,

dizziness, drop in blood pressure and anginal complaints can be expected.

Management

Symptomatic therapy is recommended. Administration of xanthine derivatives (e.g. aminophylline)

may reverse the haemodynamic effects of dipyridamole overdose. ECG monitoring is advised in such

a situation. Due to its wide distribution to tissues and its predominantly hepatic elimination,

dipyridamole is not likely to be accessible to enhanced removal procedures.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Platelet aggregation inhibitors excl. heparin, ATC code: B01AC07.

Mechanism of action

Dipyridamole inhibits the uptake of adenosine into erythrocytes, platelets and endothelial cells

in

vitro

in vivo

; the inhibition amounts to 80 % at its maximum and occurs dose-dependently at

therapeutic concentrations (0.5-2 µg/mL). Consequently, there is an increased concentration of

adenosine locally to act on the platelet A2-receptor, stimulating platelet adenylate cyclase, thereby

increasing platelet cAMP levels. Thus, platelet aggregation in response to various stimuli such as

PAF, collagen and ADP is inhibited. Reduced platelet aggregation reduces platelet consumption

towards normal levels. In addition, adenosine has a vasodilator effect and this is one of the

mechanisms by which dipyridamole produces vasodilation.

Dipyridamole inhibits phosphodiesterase (PDE) in various tissues. Whilst the inhibition of

cAMP-PDE is weak, therapeutic levels inhibit cGMP-PDE, thereby augmenting the increase in cGMP

produced by EDRF (endothelium-derived relaxing factor, identified as NO).

Dipyridamole also stimulates the biosynthesis and release of prostacyclin by the endothelium.

Dipyridamole reduces the thrombogenicity of subendothelial structures by increasing the

concentration of the protective mediator 13 -HODE (13-hydroxyoctadecadienic acid).

Clinical efficacy and safety

In the ESPS-2 (European Stroke Prevention Study 2) the fixed-dose combination of acetylsalicylic

acid (ASA) and extended release dipyridamole (ERDP) was compared with ASA alone or ERDP

alone. Treatment in all groups was administered twice daily and a total of 6602 patients with stroke or

prior TIA were followed up for 24 months. Stroke risk in comparison to placebo was reduced by 18 %

with ASA alone; 16 % with ERDP alone and 37 % with the combination therapy. The risk reduction

for the combination in preventing TIA was 36 % in comparison with placebo.

Results of the ESPRIT trial support the results from ESPS-2. In ESPRIT the primary outcome event

was the composite of death from all vascular causes, non-fatal stroke, non-fatal myocardial infarction

or major bleeding complication, whichever happened first. Primary outcome events arose in 13 % of

patients on ASA and ERDP and in 16 % on ASA alone.

5.2

Pharmacokinetic properties

Absorption

Peak plasma concentrations are observed 2-3 hours after administration. At steady-state following a

daily dose of 400 mg (2x200 mg), an average peak concentration of 1.98 μg/mL and trough

concentration of 0.53 μg/mL are seen. There is no clinically relevant effect of food on the

pharmacokinetics of dipyridamole 200 mg prolonged-release capsules. The absolute bioavailability is

about 70 %. The dose linearity of dipyridamole after two times daily oral administration of the

modified release capsules containing 150 and 200 mg was demonstrated. Steady-state of exposure is

reached within 2-3 days of continuous dosing.

Distribution

The volume of distribution at steady state (Vss) is about 100 L. The protein binding of dipyridamole

is about 97-99 %and it is primarily bound to alpha

-acid glycoprotein and albumin.

Due to its high lipophilicity, dipyridamole is distributed to many organs.

Non-clinical studies indicate that, dipyridamole does not cross the blood-brain barrier to a significant

extent and shows a very low placental transfer.

Biotransformation

Metabolism of dipyridamole occurs in the liver. Dipyridamole is metabolized by conjugation with

glucuronic acid to form mainly a monoglucuronide and only small amounts of diglucuronide. In

plasma about 80 % of the total amount is parent compound, and 20 % of the total amount is

monoglucuronide following oral administration.

Elimination

Dominant half-lives ranging from 2.2 to 3 hours have been calculated after the administration of

dipyridamole. A terminal elimination half-life of approximately 15 hours is observed. This terminal

elimination phase is of relatively minor importance as it represents a small part of the total AUC.

Renal excretion of parent compound is negligible (< 0.5 %). Urinary excretion of the glucuronide

metabolite is low (5 %), the metabolites are mostly (about 95 %) excreted via the bile into the faeces,

with some evidence of entero-hepatic recirculation. Total clearance is approximately 250 mL/min.

Elderly subjects

Plasma concentrations (determined as AUC) in elderly subjects (> 65 years) were about 30 % higher

with intake of dipyridamole 200 mg prolonged-release capsules than in young (<55 years) subjects.

The difference is caused mainly by reduced clearance; absorption appears to be similar.

Hepatic impairment

Patients with hepatic insufficiency show no change in plasma concentrations of dipyridamole, but an

increase of (pharmacodynamically inactive) glucuronides. It is recommended to dose dipyridamole

without restriction as long as there is no clinical evidence of liver failure.

Renal impairment

Since renal excretion is very low (5 %), no change in pharmacokinetics is to be expected in cases of

renal insufficiency. No pharmacokinetic changes were seen for dipyridamole or glucuronide

metabolites in patients with creatinine clearance from 15 ml/min to > 100 ml/min, provided that

results were corrected for age differences.

5.3

Preclinical safety data

There are no preclinical data considered relevant to clinical safety beyond data included in other

sections of the SmPC.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Capsule content

Tartaric acid

Hypromellose

Talc

Hydroxypropyl cellulose

Methacrylic acid – Methyl methacrylate copolymer (1:2)

Triethyl citrate

Capsule shell

Gelatin

Titanium dioxide (E171)

Red iron oxide (E172)

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

Unopened: 3 years

In-use: 100 days after first opening

6.4

Special precautions for storage

Store in the original package in order to protect from moisture. Keep the bottle tightly closed.

6.5

Nature and contents of container

HDPE bottles closed with PP caps with integrated desiccant.

Pack sizes: 30 and 60 capsules, multipacks containing 100 (2 bottles of 50) capsules.

Not all pack sizes may be marketed.

6.6

Special precautions for disposal and other handling

No special requirements

7.

MARKETING AUTHORISATION HOLDER

<[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}>

<[To be completed nationally]>

10.

DATE OF REVISION OF THE TEXT

2016-09-21

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