Trolactin

Trolactin 200mg Prolonged-release Hard Capsules

Each prolonged-release capsule contains dipyridamole 200 mg.

For the full list of excipients, see section 6.1.

Prolonged-release capsule, hard.

Hard gelatin capsule, 23.5 mm, with a reddish-brown (orange) opaque body and cap.

Secondary prevention of ischaemic stroke and transient ischaemic attacks either alone or in conjunction with acetylsalicylic acid.

Posology

The recommended dose is one capsule twice daily, usually one in the morning and one in the evening, which can be taken with or without food.

Paediatric population

Trolactin 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 capsules should be swallowed whole without chewing.

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 Trolactin 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 readjustments of therapy may be necessary after changes in dipyridamole dosage (see section 4.5).

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.

Dipyridamole should be used with caution in patients with coagulation disorders.

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 anti-coagulants 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.

The effect of dipyridamole may be weakened by xanthines. This should especially be considered when administering intravenous theophylline (see section 4.9).

Pregnancy

There are no or limited amount of data from the use of dipyridamole in pregnant women.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity.

As a precautionary measure, it is preferable to avoid the use of Trolactin during pregnancy.

Breastfeeding

Dipyridamole is excreted in human milk. A risk to the newborns/infants cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Trolactin therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Fertility

No studies on the effect on human fertility have been conducted with Trolactin. Non-clinical studies with dipyridamole did not indicate direct or indirect harmful effects with respect to fertility.

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

Adverse effects 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.

The following frequency convention is being used: 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 (frequency cannot be estimated from the available data).

Injury, poisoning and procedural complications

post procedural haemorrhage* not known

operative haemorrhage* not known

*This side effect was reported post-marketing.

Dipyridamole has been shown to be incorporated into gallstones (see section 4.4).

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 national reporting system listed in Yellow Card Scheme

Website: 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 anginal complaints can be expected.

Management

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.

Pharmacotherapeutic group: Platelet aggregation inhibitors excl. heparin,

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 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 efficacy and safety

In the ESPS-2 (European Stroke Prevention Study 2) the fixed-dose combination of acetylsalicylic acid (ASA) and extended release dipyridamole (ERDP) was compared with ASA alone or ERDP 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 and ERDP and in 16 % on ASA alone.

Absorption

Peak plasma concentrations are observed 2-3 hours after administration. At steady-state following a daily dose of 400 mg (2x200 mg), an average peak concentration of 1.98 μg/mL and trough concentration of 0.53 μg/mL are seen. 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 two times daily oral administration of the modified release capsules containing 150 and 200 mg was demonstrated. Steady-state of exposure is reached within 2-3 days of continuous dosing.

Distribution

The volume of distribution at steady state (Vss) is about 100 L. The protein binding of dipyridamole is about 97-99 %and it is primarily bound to alpha₁-acid glycoprotein and albumin.

Due to its high lipophilicity, dipyridamole is distributed to many organs.

Non-clinical studies indicate that, dipyridamole does not cross the blood-brain barrier to a significant extent and shows a very low placental transfer.

Biotransformation

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, and 20 % of the total amount is monoglucuronide following oral administration.

Elimination

Dominant half-lives ranging from 2.2 to 3 hours have been calculated after the administration of dipyridamole. A terminal elimination half-life of approximately 15 hours is observed. This terminal elimination phase is of relatively minor importance as it represents a small part of the total AUC. 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 approximately 250 mL/min.

Elderly subjects

Plasma concentrations (determined as AUC) in elderly subjects (> 65 years) were 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.

Hepatic impairment

Patients with hepatic insufficiency show no change in plasma concentrations of dipyridamole, but an increase of (pharmacodynamically inactive) glucuronides. It is recommended 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. No pharmacokinetic changes were seen for dipyridamole or glucuronide metabolites in patients with creatinine clearance from 15 ml/min to > 100 ml/min, provided that results were corrected for age differences.

There are no preclinical data considered relevant to clinical safety beyond data included in other sections of the SmPC.

Capsule content

Tartaric acid

Hypromellose

Talc

Hydroxypropyl cellulose

Methacrylic acid – Methyl methacrylate copolymer (1:2)

Triethyl citrate

Capsule shell

Gelatin

Titanium dioxide (E171)

Red iron oxide (E172)

Not applicable.

Unopened: 3 years

In-use: 100 days after first opening

Store in the original package in order to protect from moisture. Keep the bottle tightly closed.

HDPE bottles closed with PP caps with integrated desiccant.

Pack sizes: 30 and 60 capsules, multipacks containing 100 (2 bottles of 50) capsules.

Not all pack sizes may be marketed.

No special requirements

Actavis Group PTC ehf.

Reykjavíkurvegi 76-78

220 Hafnarfjörður

Iceland

PL 30306/0647

19/10/2016

19/10/2016