POM: Prescription only medicine
This information is intended for use by health professionals
Adults, including the elderlyThe recommended dose is one capsule twice daily, usually one in the morning and one in the evening preferably with meals.The capsules should be swallowed whole without chewing.
ChildrenPERSANTIN Retard 200 mg is not recommended for children.
PregnancyThere 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).
LactationPERSANTIN Retard 200 mg should only be used during lactation if considered essential by the physician.
FertilityNo studies on the effect on human fertility have been conducted with PERSANTIN. Non-clinical studies with dipyridamole did not indicate direct or indirect harmful effects with respect to fertility (please refer to section 5.3).
|Very common||≥ 1/10|
|Common||≥ 1/100 < 1/10|
|Uncommon||≥ 1/1,000< 1/100|
|Rare||≥ 1/10,000 < 1/1,000|
|Very rare||< 1/10,000|
|Blood and lymphatic system disorders|
|Immune system disorders|
|Nervous system disorders|
|Hot flush||not known|
|Respiratory, thoracic and mediastinal disorders|
|Skin and subcutaneous tissue disorders|
|Musculoskeletal, connective tissue and bone disorders|
|Injury, poisoning and procedural complications|
|post procedural haemorrhage||not known|
|operative haemorrhage||not known|
SymptomsDue 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.
TherapySymptomatic 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.
AbsorptionPERSANTIN modified release capsulesPeak 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 - l.01 μg/mL). There is no clinically relevant effect of food on the pharmacokinetics of PERSANTIN 200 mg modified release capsules. The absolute bioavailability is about 70%. The dose linearity of dipyridamole after oral b.i.d. administration of the modified 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 PERSANTIN® modified 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
DistributionOwing 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.MetabolismMetabolism 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.EliminationDominant half-lives ranging from 2.2 to 3 hours have been calculated after the administration of PERSANTIN. 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 subjectsPlasma concentrations (determined as AUC) in elderly subjects (> 65 years) were about 50% higher for tablet treatment and about 30% higher with intake of PERSANTIN 200 mg modified 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 impairmentPatients 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 impairmentSince 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.