Dipyridamole 200 mg Prolonged Release Capsules, Hard

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.

Posology

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

The capsules should be taken with or independently of food. The capsules should be swallowed whole without chewing.

Paediatric population

Dipyridamole 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.

Method of administration

For oral administration.

Alternative dosage in case of intolerable headache

In case of intolerable headache at the start of treatment, 1 capsule can be provisionally dosed at bedtime and a low dose of acetylsalicylic acid in the morning.

As there are insufficient efficacy data on this alternative dosing and headache usually resolves with regular dosing, the patient should return to the normal dosing promptly (within one week).

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

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.

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

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.

It is possible that dipyridamole may enhance the effects of oral anti-coagulants.

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 Dipyridamole 200mg Prolonged Release Capsules. It is recommended that patients are advised to avoid alcohol.

Theophylline and other xanthines

Xanthines may reduce the effect of dipyridamole. This should be taken into account in particular with intravenous administration of theophylline.

Pregnancy

There is inadequate evidence of safety in human pregnancy, but Dipyridamole 200mg Prolonged Release Capsules has been used for many years without apparent ill-consequence. Dipyridamole 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 foetus (see section 5.3).

Breast-feeding

Dipyridamole is excreted in breast milk (at levels about 6% of plasma concentration), and therefore there is a risk of affecting the breast-feeding infant. Dipyridamole should only be used during breast-feeding if considered essential by the physician.

Fertility

No studies on the effect on human fertility have been conducted with Dipyridamole 200 mg prolonged‑release capsules, hard. Non-clinical studies with dipyridamole did not indicate direct or indirect harmful effects with respect to fertility (see section 5.3).

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.

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

* This side effect has been seen after marketing. There is a 95% probability that the frequency does not exceed "not common" and it may be lower. It is not possible to determine the exact frequency as this side effect was not seen in a clinical trial database of 1654 patients.

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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

Symptoms:

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

Toxicity

The toxicity is likely to be low. 37.5 mg in 2-year-olds caused mild intoxication, while 75-150 mg in 1- to 3-year-olds after administration of charcoal caused no symptoms. 1 g as a single dose and 2.8 g per 24 hours in adults did not cause any pronounced symptoms. However, 1.75 g in adults caused severe intoxication, and 5 g in adults may promote heart attacks.

Symptoms

Symptoms such as feeling warm, redness, flushes, sweating, restlessness, feeling of weakness, dizziness, headache and angina complaints can be expected. A drop in blood pressure and tachycardia might be observed.

Tachypnoea, tachycardia, angina pectoris, coma, bronchospasm, respiratory depression, gastrointestinal discomfort, prolonged bleeding time and yellowing of the skin.

Therapy:

Symptomatic therapy is recommended.

Ventricular emptying must 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.

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).

Clinical trials

The ESPS-2 study showed that asasantin retard twice daily reduced the risk of ischemic stroke by 23.1% compared to acetylsalicylic acid (ASA) 25 mg twice daily, by 24.7% compared to Persantin Retard twice daily, and by 37% compared to placebo. Asasantin XR is a combination preparation similar to Persantin XR with 25 mg of acetylsalicylic acid added.

The results from the ESPS-2 trial are supported by the results from the ESPRIT trial, where there was a combined cardiovascular endpoint which, in addition to stroke and death, also included myocardial infarction and severe bleeding. In this study, a 20% risk reduction was seen with the combination of dipyridamole 400 mg and ASA 30-325 mg compared to treatment with ASA alone.

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 Dipyridamole 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 Dipyridamole 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 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. 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 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. 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.

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

Dipyridamole has very low acute toxicity. Intravenous toxicity in dogs and rats is markedly higher, suggesting poor absorption following oral administration of high doses. The cause of death was considered to be cardiovascular failure.

In repeated dose toxicity studies, dipyridamole was well tolerated in all animal species studied. The NOEL following oral administration was 10 mg/kg/day in dogs, 50 mg/kg/day in rats and 60 mg/kg/day in baboons. In rats, doses up to 600 mg/kg did not cause serious toxic effects after 18 months of daily administration. In the experiments with baboons, the toxic dose was not reached.

In studies in dogs, dose-dependent toxic effects on the heart, blood vessels and kidneys were observed at doses of 20 mg/kg/day and above. These changes have been described with the use of phosphodiesterase inhibitors and vasodilators and are considered to reflect a particular sensitivity in dogs. No similar effects are expected in humans. The renal toxicity is thought to be secondary to changes in the haemodynamic parameters.

There is no embryotoxicity/foetotoxicity in the organogenesis or peri- or postnatal phase. The NOEL for embryotoxicity/foetotoxicity was 40 mg/kg/day in rabbits, 125 mg/kg/day in mice and 1,000 mg/kg/day in rats. In the peri-/postnatal studies in rats at doses greater than 100 mg/kg/day, increased perinatal mortality and reduced body weight were observed in the offspring. Fertility in rats was not affected by doses up to 1,250 mg/kg/day. It is estimated that approximately 0.032% of a 25 mg dose of dipyridamole is excreted in rabbit milk.

Genotoxicity studies in vivo and in vitro showed no mutagenic or clastogenic effects up to the maximum possible concentration. In carcinogenicity studies at doses up to 75 mg/kg/day in rats and mice, no tumourigenic potential was observed.

Tartaric acid pellets [Tartaric acid, Sucrose and Povidone]

Hypromellose

Talc

Acacia, spray-dried

Triacetin

Povidone

Simeticone Emulsion (30 % W/V) [Simethicone, Cetostearyl alcohol and Ethoxylate Sodium benzoate]

Methacrylic acid - ethyl acrylate copolymer

Hypromellose phthalate P55

Capsule shells

Gelatin

Titanium dioxide (E171)

Red and yellow iron oxides (E172)

Not applicable

Unopened: 30 months

In-use: Discard any capsules remaining 6 weeks after first opening.

Do not store above 25°C.

Keep the container tightly closed in order to protect from moisture.

HDPE bottle with polypropylene child resistant closure, containing desiccant in a canister.

Packs contain 60 capsules.

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