Summary of medicine characteristics - DIPYRIDAMOLE 200 MG MODIFIED RELEASE CAPSULES HARD
1 NAME OF THE MEDICINAL PRODUCT
Dipyridamole 200 mg Modified Release Capsules, Hard
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each modified release capsule contains dipyridamole 200 mg.
Excipient with known effect: Each modified release capsule contains 0.05mg sunset yellow.
For a full list of excipients, see section 6.1
Modified release capsules, hard.
Hard gelatin capsules approximately 23.20 × 7.66 mm in size with red cap and orange body, imprinted with Glenmark Logo ‘G’ on Cap and ‘729’ on body with black ink, filled with light yellow to yellow colored pellets.
4.1 Therapeutic indications
Secondary prevention of ischaemic stroke and transient ischaemic attacks in conjunction with acetylsalicylic acid, or as monotherapy if acetylsalicylic acid is contra-indicated.
An adjunct to coumarin anticoagulants for prophylaxis of thromboembolism associated with prosthetic heart valves.
4.2 Posology and method of administration
Posology
Adults, including the elderly
Secondary prevention of stroke and TIA
The recommended dose is one capsule twice daily.
In patients with prosthetic heart valves
The recommended dose is one capsule twice daily. The anticoagulation regimen should be optimised even if dipyridamole is added to anticoagulants as an adjunct after prosthetic heart valve surgery. The study during which the addition of dipyridamole to the anticoagulation regimen led to reduced thromboembolic complications lasted up to one year after surgery.
Children
Dipyridamole capsules 200 mg 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 capsule should be swallowed whole with water, without chewing, usually one in the morning and one in the evening, preferably with meals.
4.3 Contraindications
Hypersensitivity to the dipyridamole 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 capsules 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 readjustment of therapy may be necessary after changes in dipyridamole dosage. (See Interactions).
Dipyridamole should be used with caution in patients with coagulation disorders.
A combination of anticoagulant therapy and antiplatelet therapy may increase the risk of bleeding.
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.
Excipients
Each modified release capsule contain the colour sunset yellow (E110), which may cause allergic reactions
4.5 Interaction with other medicinal products and other forms of interaction
Adenosine
Dipyridamole inhibits cellular adenosine reuptake, thereby increasing adenosine plasma concentrations. This potentiates the cardiovascular effects of adenosine increasing the risk of AV block, bradycardia and ventricular extrasystoles. Adjustment of the adenosine dose should be considered.
Anticoagulants and platelet inhibitors
When dipyridamole is used in combination with anticoagulants or platelet inhibitors, the statements on intolerance and risks for these preparations must be observed. Addition of dipyridamole to acetylsalicylic acid does not increase the incidence of bleeding events, but potentiates such events.
Antihypertensives
Dipyridamole may increase the hypotensive effect of blood pressure lowering drugs.
Cholinesterase inhibitors
Dipyridamole may counteract the anticholinesterase effect of cholinesterase inhibitors thereby potentially aggravating myasthenia gravis.
Indometacine
Dipyridamole in combination with indometacine may lead to fluid retention.
Enzyme-inducing medicinal products
Enzyme-inducing medicinal products, such as phenytoin, may increase dipyridamole clearance.
Other medicinal products with high protein binding
Protein binding of dipyridamole in humans is 98–99%: it binds with high affinity to alpha-1-acid glycoprotein, but also to other albumins. There is a theoretical risk of competition with other medicinal products with high protein binding, which could result in potential interactions. Although no formal pharmacokinetic interaction studies exist, the safety profile of dipyridamole after years of widespread global use has not revealed any evidence of competitive interactions.
4.6 Fertility, pregnancy and lactation
Pregnancy
There is inadequate evidence of safety in human pregnancy, but dipyridamole has been used for many years without apparent ill-consequence. Animal studies have shown no hazard. 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 foetus (please refer to section 5.3).
Lactation
Dipyridamole capsules 200 mg should only be used during lactation if considered essential by the physician.
Dipyridamole is excreted in breast milk.
Fertility
No studies on the effect on human fertility have been conducted with dipyridamole. 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 effects at therapeutic doses are usually mild and transient
The ESPS-2 trial with a total of 6602 patients, whereof 1654 patients were treated with dipyridamole modified release, as well as spontaneous reports on undesirable effects, were used to determine the safety profile.
Frequencies
Very common: may affect more than 1 in 10 people
Common: may affect up to 1 in 10 people
Uncommon: may affect up to 1 in 100 people
Rare: may affect up to 1 in 1,000 people
Very rare: may affect up to 1 in 10,000 people
Not known (cannot be estimated from the available data)
Blood and lymphatic system disorders
Thrombocytopenia uncommon
Immune system disorders
Hypersensitivity uncommon
Angioedema uncommon
Anaphylactic reactions uncommon
Nervous system disorders Headache
very common
Dizziness
very common
Cardiac disorders
Angina pectoris
Tachycardia
Vascular disorders
Hypotension
Hot flush
common
uncommon
uncommon
uncommon
Respiratory, thoracic and mediastinal disorders Bronchospasm uncommon
Laryngospasm
Gastrointestinal disorders
Diarrhoea
Nausea
Vomiting
uncommon
very common very common common
Skin and subcutaneous tissue disorders
Rash
Urticaria
common
uncommon
Musculoskeletal, connective tissue and bone disorders
Myalgia
common
Injury, poisoning and procedural complications
Post procedural haemorrhage uncommon
Operative haemorrhage uncommon
Hepatobiliary disorders
Incorporation of Dipyridamole into gallstones (please refer to section 4.4): uncommon
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.co.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 Overdose
4.9 OverdoseSymptoms
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.
Therapy
Symptomatic therapy is recommended. Because of the enterohepatic cycle repeated administration of activated charcoal, if necessary in combination with a laxative, can be considered. 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: Anti-thrombotic Agent, ATC code: B01AC07
Mechanism of action
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 ^g/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) 25 mg and extended release dipyridamole (ERDP) 200 mg was compared with ASA 25 mg alone or ERDP 200 mg 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 30–325 mg daily and ERDP 400 mg daily and in 16 % on ASA alone.
A meta-analysis from 1995 of six clinical trials published in 1971–1982 has shown that addition of dipyridamole to coumarin anticoagulant regimens of different dosages (no INR-adjusted warfarin therapy has been investigated) has reduced the frequency of embolization after valve replacement with a mechanical prosthesis.
5.2 Pharmacokinetic properties
For long-term treatments Dipyridamole modified release capsules, formulated as pellets have been developed. The pH dependent solubility of Dipyridamole capsules which prevents dissolution in the lower parts of the gastrointestinal tract is overcome by means of a formula containing tartaric acid. Retardation of release is achieved by a diffusion membrane which is sprayed onto the pellets.
Absorption
Peak plasma concentrations are reached about 2 – 3 hours after administration. The mean peak concentrations at steady state conditions with a daily dose of 300 mg (150 mg twice daily) is 1Dg/mL, the trough concentration is 0.35 Dg/mL. With a daily dose of 400 mg (200 mg twice daily), the corresponding peak concentration is 2
□g/mL, the trough concentration is 0.53 Dg/mL.
Near to complete absorption of Dipyridamole modified release capsules can be assumed. The absolute bioavailability is about 70%; 1/3 of the dose being removed via first-pass metabolism.
There is no clinically relevant effect of food on the pharmacokinetics of Dipyridamole 200 mg modified release capsules. The dose linearity of dipyridamole after oral b.i.d. administration of the modified release capsules containing 150 and 200 mg was demonstrated.
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 1-acid 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 capsules. 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).
Other special populations
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 dipyridamole 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
5.3 Preclinical safety dataDipyridamole has been extensively investigated in animal models and no clinically significant findings have been observed at doses equivalent to therapeutic doses in humans.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Tartaric acid
Hypromellose
Talc
Acacia
Povidone
Hypromellose phthalate
Methylacrylic acid – methyl methacrylate copolymer (1:2)
Triacetin
Capsule shell:
Titanium dioxide (E171)
Iron oxide red (E172)
Sunset yellow (E110)
Gelatin
Printing ink (TekPrint™ SW-9008 Black Ink):
Shellac
Iron oxide black (E172)
Potassium hydroxide
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
Store in the original package with desiccant in order to protect from moisture.
Keep the bottle tightly closed.
6.5 Nature and contents of container
HDPE bottles with polypropylene cap and heat seal liner (composed of Alu/Adhesive/PET/HS (Product contact layer)). The bottles contain 5g molecular sieve pouch and 5g silica gel pouch as desiccant.
Pack sizes: 50, 60 or multi pack containing 100 (2 cartons of 50) capsules.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
6.6 Special precautions for disposalNo special requirements
Glenmark Pharmaceuticals Europe Limited
Laxmi House, 2B Draycott Avenue, Kenton, Middlesex
HA3 0BU
United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 25258/0284
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
08/02/2019