JENAPRI PR 200 MG PROLONGED-RELEASE CAPSULES HARD
Active substance(s): DIPYRIDAMOLE
NAME OF THE MEDICINAL PRODUCT
Jenapri PR 200mg Prolonged-release capsules, hard
QUALITATIVE AND QUANTITATIVE COMPOSITION
Each prolonged-release capsule contains dipyridamole 200 mg. For the full list of
excipients, see section 6.1.
Prolonged-release capsule, 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.
Secondary prevention of ischaemic stroke and transient ischaemic attacks either alone
or in conjunction with aspirin.
An adjunct to oral anti-coagulation for prophylaxis of thromboembolism associated
with prosthetic heart valves.
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 Jenapri PR 200mg Prolonged-release
capsules, hard is not recommended for children, due to lack of data on safety and
Elderly No dosage adjustment is needed.
Patients with renal impairment No dosage adjustment is needed
Patients with hepatic impairment No dosage adjustment is needed
Hypersensitivity to the active substance or to any of the excipients listed in section
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.
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
Co-administration of alcohol may increase the rate of absorption of Jenapri PR
Prolonged-release capsules. It is recommended that patients are advised to avoid
Fertility, pregnancy and lactation
Jenapri PR 200mg Prolonged-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.
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.
No studies on the effect on human fertility have been conducted with Jenapri 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
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
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)
Blood and lymphatic system disorders
Immune system disorders
Nervous system disorders
Hypotension, hot flush
Respiratory, thoracic and mediastinal disorders
Skin and subcutaneous tissue disorders
Musculoskeletal, connective tissue and bone disorders
Injury, poisoning and procedural complications
Post procedural haemorrhage,
Dipyridamole has been shown to be incorporated into gallstones (please refer to
section 4.4 Special warnings and precautions for use).
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
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
Due to its wide distribution to tissues and its predominantly hepatic elimination,
dipyridamole is not likely to be accessible to enhanced removal procedures.
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
Dipyridamole reduces the thrombogenicity of subendothelial structures by increasing
the concentration of the protective mediator 13-HODE (13-hydroxyoctadecadienic
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
Jenapri 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 Jenapri 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
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
1¬acid glycoprotein and albumin.
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.
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).
Plasma concentrations (determined as AUC) in elderly subjects (> 65 years) were
about 50% higher for tablet treatment and about 30% higher with intake of Jenapri 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
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.
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.
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
List of excipients
Cetostearyl alcohol and Ethoxylate
Methacrylic acid - ethyl acrylate copolymer
Hypromellose phthalate P55
Titanium dioxide (E171)
Red and yellow iron oxides (E172)
Unopened: 30 months
In-use: Discard any capsules remaining 6 weeks after first opening.
Special precautions for storage
Do not store above 25°C.
Keep the container tightly closed in order to protect from moisture.
Nature and contents of container
HDPE bottle with polypropylene child resistant closures, containing 2 desiccants.
Packs contain 60 capsules.
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.
MARKETING AUTHORISATION HOLDER
Mercury Pharmaceuticals Ltd.
Capital House, 85 King William Street,
London, EC4N 7BL UK
MARKETING AUTHORISATION NUMBER(S)
DATE OF FIRST AUTHORISATION/RENEWAL OF THE
DATE OF REVISION OF THE TEXT