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OFCRAM PR 200MG PROLONGED RELEASE CAPSULES HARD

Active substance(s): DIPYRIDAMOLE / DIPYRIDAMOLE

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Ofcram PR 200mg Prolonged Release Capsules, Hard

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each modified release capsule contains dipyridamole 200 mg.
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Prolonged release capsules, hard.
Appearance:
Hard gelatin capsules consisting of a red cap and an orange body. Dimension 7,66
mm x 23,1 mm.
The capsule contains yellow coloured slow release pellets.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Secondary prevention of ischaemic stroke and transient ischaemia attacks either
alone or in conjunction with aspirin.
An adjunct to oral anti-coagulation for prophylaxis of thromboembolism associated
with prosthetic heart valves.

4.2

Posology and method of administration
For oral administration.
Dose
The recommended dose is one capsule twice daily, usually one in the morning and
one in the evening.
The capsules should be taken with food. The capsules should be swallowed whole
without chewing.

Paediatric population
Ofcram PR 200mg Prolonged Release Capsules, Hard is not recommended for
children, due to lack of data on safety and efficacy.
Elderly
No dosage adjustment is needed.
Patients with renal impairment
No dosage adjustment is needed.
Patients with hepatic impairment
No dosage adjustment is needed.

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 dipyridamole 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 adjustment of therapy may be necessary after
changes in dipyridamole dosage (see section 4.5, Interactions).
Dipyridamole should be used with caution in patients with coagulation disorders.
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.

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 anticoagulants 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.
Co-administration of alcohol may increase the rate of absorption of Ofcram
PR Prolonged Release Capsules. It is recommended that patients are advised
to avoid alcohol.

4.6

Fertility, pregnancy and lactation
Pregnancy
Ofcram PR 200mg Modified Release Capsules, Hard should only be administrated if
clearly needed. Data from the use of dipyridamole in pregnancy are inadequate.
Animal studies have shown no hazard of fetal harm. Nevertheless, medicines should
not be used in pregnancy, especially the first trimester unless the expected benefit is
thought to outweigh the possible risk to the fetus.
Lactation
Dipyridamole is excreted in breast milk (about 6% of plasma concentration), and
therefore there is a risk of affecting the breastfeeding infant. Dipyridamole should
only be used during lactation if considered essential by the physician.
Fertility
No studies on the effect on human fertility have been conducted with Ofcram PR 200
mg prolonged release capsules, hard. Non-clinical studies with dipyridamole did not
indicate direct or indirect harmful effects with respect to fertility (please refer to
section 5.3).

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 dipyridamole. If
patients experience dizziness they should avoid potentially hazardous tasks
such as driving or operating machinery.

4.8

Undesirable effects

Adverse reactions 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.
Adverse reactions are listed according to MedDRA system organ class and
frequency category. Frequency categories are defined using the following
convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon
(≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not
known (cannot be estimated from the available data).
Table 1
Blood and lymphatic system disorders
Not known
Thrombocytopenia
Immune system disorders
Not known
Hypersensitivity, angioedema
Nervous system disorders
Very common
Headache, dizziness
Cardiac disorders
Common
Angina pectoris
Not known
Tachycardia
Vascular disorders
Not known
Hypotension, hot flush
Respiratory, thoracic and mediastinal disorders
Not known
Bronchospasm
Gastrointestinal disorders
Very common
Diarrhoea, nausea
Common
Vomiting

Skin and subcutaneous tissue disorders
Common
Rash
Not known
Urticaria
Musculoskeletal, connective tissue and bone disorders
Common
Myalgia
Injury, poisoning and procedural complications
Not known
Post procedural haemorrhage, operative
haemorrhage

Dipyridamole has been shown to be incorporated into gallstones (please refer
to section 4.4 Special warnings and precautions for use).

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is
important. It allows continued monitoring of the benefit/risk balance of the medicinal
product. Healthcare professionals are asked to report any suspected adverse reactions
via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9

Overdose
Symptoms:
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 angina
complaints can be expected.
Therapy:
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 excluding heparin, ATC
code: B 01 AC 07
Dipyridamole inhibits the uptake of adenosine into erythrocytes, platelets and
endothelial cells in vitro and 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).

5.2

Pharmacokinetic properties
Absorption
Peak plasma concentrations are reached about 2 - 3 hours after administration. Mean
peak concentrations at steady state conditions with 150 mg b.d. are 1.43 μg/mL
(range 0.705 - 2.75 μg/mL), trough levels are 0.351 μg/mL (range 0.200 - 0.741
μg/mL). With a daily dose of 400 mg, the corresponding peak concentrations are 1.98
μg/mL (range 1.01 - 3.99 μg/mL), trough concentrations are 0.53 μg/mL (range 0.18 1.01 μg/mL). There is no clinically relevant effect of food on the pharmacokinetics of
Ofcram PR 200 mg Prolonged Release Capsules. The absolute bioavailability is about
70% . The dose linearity of dipyridamole after oral b.i.d. administration of the
prolonged release capsules containing 150 and 200 mg was demonstrated .
As first pass removes approx. 1/3 of the dose administered, near to complete
absorption of Ofcram PR 200 mg Prolonged Release Capsules can be assumed.
Various kinetic studies at steady state showed, that all pharmacokinetic parameters
which are appropriate to characterise the pharmacokinetic properties of modified
release preparations are either equivalent or somewhat improved with dipyridamole
modified release capsules given b.i.d. compared to dipyridamole tablets administered
t.d.s./q.d.s.: Bioavailability is slightly greater, peak concentrations are similar, trough
concentrations are considerably higher and peak trough fluctuation is reduced
Distribution
Owing to its high lipophilicity, log P 3.92 (n-octanol/0.1 N, NaOH), dipyridamole
distributes to many organs.
Non-clinical studies indicate that, dipyridamole is distributed preferentially to the
liver, then to the lungs, kidneys, spleen and heart, it does not cross the blood-brain

barrier to a significant extent and shows a very low placental transfer. Non-clinical
data have also shown that dipyridamole can be excreted in breast milk.
Protein binding of dipyridamole is about 97 - 99%, primarily it is bound to alpha 1acid glycoprotein and albumin.
Metabolism
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, 20% of the total amount is monoglucuronide with oral administration.
Elimination
Dominant half-lives ranging from 2.2 to 3 hours have been calculated after the
administration of dipyridamole. A prolonged terminal elimination half-life of
approximately 15 h is observed. This terminal elimination phase is of relatively minor
importance in that it represents a small proportion of the total AUC, as evidenced by
the fact that steady-state is achieved within 2 days with both t.d.s. and q.d.s.,
regimens. There is no significant accumulation of the drug with repeated dosing.
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 approx. 250 mL/min and mean residence time is approx. 8 h (resulting
from an intrinsic MRT of approx. 6.4 h and a mean time of absorption of 1.4 h).
Elderly subjects
Plasma concentrations (determined as AUC) in elderly subjects (> 65 years) were
about 50% higher for tablet treatment and about 30% higher with intake of Ofcram
PR 200 mg Prolonged Release Capsules than in young (<55 years) subjects. The
difference is caused mainly by reduced clearance; absorption appears to be similar. A
similar increase in plasma concentrations in elderly patients was observed in the
ESPS2 study.
Hepatic impairment
Patients with hepatic insufficiency show no change in plasma concentrations of
dipyridamole, but an increase of (pharmacodynamically inactive) glucuronides. It is
suggested 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. In the ESPS2 trial, in patients with creatinine
clearances ranging from about 15 mL/min to >100 mL/min, no changes were
observed in the pharmacokinetics of dipyridamole or its glucuronide metabolite if
data were corrected for differences in age.

5.3

Preclinical safety data
Dipyridamole has been extensively investigated in animal models and no clinically
significant findings have been observed at doses equivalent to therapeutic doses in
humans.

PHARMACEUTICAL PARTICULARS
6.1

List of excipients
Tartaric acid pellets
Hypromellose
Talc
Acacia, spray-dried
Triacetin
Povidone
Simeticone Emulsion (30 % W/V)
Methacrylic acid - ethyl acrylate copolymer
Hypromellose phthalate P55
Capsule shells
Gelatin
Titanium dioxide (E171)
Red and yellow iron oxides (E172)

6.2

Incompatibilities
Not applicable

6.3

Shelf life
Unopened: 30 months
In-use: Discard any capsules remaining 6 weeks after first opening.

6.4

Special precautions for storage
Do not store above 25°C.
Keep the container tightly closed in order to protect from moisture.

6.5

Nature and contents of container
HDPE bottle with polypropylene child resistant closure, containing a desiccant in a
pillow pouch.
Packs contain 60 capsules.

6.6

Special precautions for disposal
No special requirements for disposal.

Any unused medicinal product or waste material should be disposed of in accordance
with local requirements.

7

MARKETING AUTHORISATION HOLDER
Focus Pharmaceuticals Ltd
Capital House, 1st Floor,
85 King William Street,
London EC4N 7BL,
United Kingdom.

8

MARKETING AUTHORISATION NUMBER(S)
PL 20046/ 0270

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
18/10/2013

10

DATE OF REVISION OF THE TEXT
10/11/2016

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Source: Medicines and Healthcare Products Regulatory Agency

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