AGGRENOX 200/25 mg Boehringer

Transcription

1 AGGRENOX 200/25 mg Boehringer modified release capsules Composition 1 modified release capsule contains: 2,6-bis (diethanolamino)-4,8-dipiperidino-pyrimido(5,4- d)-pyrimidine (= dipyridamole) 200 mg, and Acetylsalicylic acid 25 mg Excipients: lactose monohydrate, microcrystalline cellulose, maize starch, silica colloidal, aluminium stearate, purified water, sucrose, acacia, titanium dioxide, talc, tartaric acid, povidone, methyacrylic acid methylmethacrylate copolymer, hypromellose phthalate, hypromellose pharmacoat, dimeticone 350, stearic acid, solvents (isopropylalcohol, acetone, ethanol 96%),gelatine Pharmacological properties The antithrombotic action of the acetylsalicylic acid/ dipyridamole combination is based on the different biochemical mechanisms involved. Acetylsalicylic acid inactivates the enzyme cyclo-oxygenase in platelets thus preventing the production of thromboxane A2, a powerful inducer of platelet aggregation and vasoconstriction. 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 mcg/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). Acetylsalicylic acid inhibits collagen-induced platelet aggregation by the irreversible acetylation of the enzyme complex cyclooxygenase (COX). This enzyme is also found in platelets and endothelial cells and produces the precursors (endoperoxides) for prostaglandin and thromboxane biosynthesis. Mainly prostacyclin, a powerful vasodilator inhibitor of platelet aggregation, is produced from the endoperoxides in endothelial cells. Platelets, on the other hand, form large quantities of thromboxane A2 which causes aggregation and has a vasoconstrictor effect. The (indirect) inhibition of the formation of thromboxane by acetylsalicylic acid is therefore the cause of the inhibition of collagen induced platelet aggregation, which has been detected in vitro and ex vivo. The inhibition of cyclooxygenase in endothelial cells, unlike in platelets, is not permanent since a new enzyme is formed as a result of protein biosynthesis. However in (anuclear) platelets, which have a survival time of 8-10 days, virtually no protein synthesis takes place and the enzyme remains inhibited for the whole of the platelet s life. This is the reason for the cumulative inhibitory effect on platelet aggregation achieved by repeated doses of acetylsalicylic acid. Whereas acetylsalicylic acid inhibits only platelet aggregation, dipyridamole in addition inhibits platelet activation and adhesion. Therefore an additional benefit from combining both drugs can be expected. Pharmacokinetics There is no noteworthy pharmacokinetic interaction

2 between the extended release pellets of dipyridamole and acetylsalicylic acid. Therefore pharmacokinetics of AGGRENOX is reflected by the pharmacokinetics of the individual components. Dipyridamole (Most pharmacokinetic data refer to healthy volunteers.) With dipyridamole, there is dose linearity for all doses used in therapy. For long-term treatment dipyridamole modified release capsules, formulated as pellets were developed. The ph dependent solubility of dipyridamole which prevents dissolution in the lower parts of the gastrointestinal tract (where sustained release preparations must still release the active principle) was overcome by combination with tartaric acid. Retardation is achieved by a diffusion membrane, which is sprayed onto the pellets. Various kinetic studies at steady state showed, that all pharmacokinetic parameters which are appropriate to characterize 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. Absorption The absolute bioavailability is about 70%. As first pass removes approx. 1/3 of the dose administered, near to complete absorption of dipyridamole following administration of AGGRENOX modified release capsules can be assumed. Peak plasma concentrations of dipyridamole following a daily dose of 400 mg AGGRENOX (given as 200 mg b.i.d) are reached about 2-3 hours after administration. Mean peak concentrations at steady state conditions are 1.98 μg/ml (range μg/ml) and trough concentrations are 0.53 μg/ml (range 0.18 l.01 μg/ml). There is no relevant effect of food on the pharmacokinetics of dipyridamole in AGGRENOX modified release capsules. Distribution Owing to its high lipophilicity, log P 3.92 (n-octanol/0.1 n, NaOH), dipyridamole is distributed to many organs. In animals, dipyridamole is distributed preferentially to the liver, then to the lungs, kidneys, spleen and heart. The rapid distribution phase observed with i.v. administration cannot be discerned following oral administration. The apparent volume of distribution of the central compartment (Vc) is about 5 l (similar to plasma volume). The apparent volume of distribution at steady state is about 100 l, reflecting distribution to various compartments. The drug does not cross the blood-brain barrier to a significant extent. Placental transfer of dipyridamole is very low. In one woman approximately 1/17th of the plasma concentration was detectable 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 primarily 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 present as parent compound, and 20% of the total amount as monoglucuronide. The pharmacodynamic activity of dipyridamole glucuronides is considerably lower than of dipyridamole. Elimination The dominant half-life with oral administration is about 40 minutes as it is the case with i.v. administration. 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 and mean residence time is about 11 hours (resulting from an intrinsic MRT of about 6.4 h and a mean time of absorption of 4.6 h). As with i.v. administration a prolonged terminal elimination half-life of approximately 13 hours is observed. This terminal

3 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 b.i.d. regimens of modified release capsules. There is no significant accumulation of the drug with repeated dosing. Kinetics in elderly Dipyridamole plasma concentrations (determined as AUC) in elderly subjects (> 65 years) were about 50% higher for tablet treatment and about 30% higher with intake of AGGRENOX modified release than in young (<55 years) subjects. The difference with the modified release pellets is caused mainly by reduced clearance; absorption appears to be similar. Similar increases in plasma concentrations in elderly patients were observed in the ESPS2 study for PERSANTIN modified release as well as for AGGRENOX. Kinetics in patients with 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. Kinetics in patients with hepatic impairment Patients with hepatic insufficiency show no change in plasma concentrations of dipyridamole, but an increase of (pharmacodynamically low active) glucuronides. It is suggested to give dipyridamole without restriction as long as there is no clinical evidence of liver failure. Acetylsalicylic acid Absorption Acetylsalicylic acid is rapidly and completely absorbed. Maximum plasma concentrations after a daily dose of 50 mg acetylsalicylic acid from AGGRENOX (given as 25 mg b.i.d.) are attained after 30 minutes, and peak plasma concentration at steady state amounted 319 ng/ml (range ). Maximum plasma concentrations of salicylic acid are achieved after minutes % of the dose of acetylsalicylic acid is subject to first-pass metabolism, with cleavage to salicylic acid being the chief pathway. There is no relevant effect of food on the pharmacodynamics of acetylsalicylic acid in AGGRENOX. Distribution Aspirin is poorly bound to plasma proteins and its apparent volume of distribution is low (10 L). Its metabolite, salicylic acid, is highly bound to plasma proteins, but its binding is concentration-dependent (nonlinear). At low concentrations (<100 µg/ml), approximately 90% of salicylic acid is bound to albumin. Salicylic acid is widely distributed to all tissues and fluids in the body, including the central nervous system, breast milk, and fetal tissues. Metabolism Acetylsalicylic acid is metabolised rapidly by nonspecific esterases in the liver and, to a lesser extent, in the stomach to salicylic acid and subsequently to hydroxyhippuric acid via reaction with glycine. Elimination Acetylsalicylic acid has a half-life of elimination of minutes; the chief metabolite, salicylic acid, has a half-life of elimination of 2-3 hours, which may rise to 5-18 hours at high doses (> 3 g) because of enzyme saturation. About 90% of acetylsalicylic acid is excreted as metabolites via the kidneys. Kinetics in patients with renal impairment Renal dysfunction: acetylsalicylic acid is to be avoided in patients with severe renal failure (glomerular filtration rate less than 10 ml/min). A prolongation of the half-life by a factor of 2-3 in patients with kidney disease has been reported. Kinetics in patients with hepatic impairment Hepatic dysfunction: acetylsalicylic acid is to be avoided in patients with severe hepatic insufficiency. Clinical efficacy The clinical efficacy of the combination was tested in the European Stroke Prevention Study2 (ESPS2). A total of 6,602 patients were included in this large,

4 multi-centered (59 centers in13 European countries), double-blind, placebo-controlled study. The test substances were 200 mg sustained-release dipyridamole administered twice a day, 25 mg ASA administered twice a day, and a combination of the two, also administered twice a day. The study lasted for a total of two years. The main criterion for inclusion was an ischaemic stroke or a transient ischaemic attack (TIA) suffered in the preceding 3 months. The study looked at the relative reduction in risk of a second cerebrovascular event (secondary prevention). The primary question investigated was whether, in addition to the effect of the individual substances, dipyridamole and ASS, there was an additive effect from a combination of these two substances and what role this effect played in the secondary prevention of a cerebrovascular event. The special design of the study made it possible to answer this question. There were four groups: - Dipyridamole (DP) 200 mg + ASA 25 mg, twice a day - Dipyridamole (DP) 200 mg, twice a day - ASA 25 mg, twice a day - Placebo, twice a day The primary target parameters were: - Fatal or non-fatal stroke - Overall mortality - Stroke and/or death from any cause Furthermore, a number of secondary parameters were investigated, e.g. myocardial infarction, transient ischaemic attacks (TIA) and others. The main results can be seen in the following Table. Shown here is the relative reduction in risk for the primary target parameter stroke for the four treatment groups: treatment comparison risk reduction significance with DP/ASA Placebo 36.8 p<0.001 DP Placebo 16.5 p=0.039 ASA Placebo 18.9 p=0.013 DP ASA - p=0.677 DP/ASA ASA 22.1 p=0.006 DP/ASA DP 24.4 p=0.002 The two single agents, dipyridamole (DP) and ASA, were found to be highly significantly effective in the secondary prevention of a second stroke; the efficacy of the two agents was more or less equal; the reduction in the risk compared with placebo was 16.5% for dipyridamole and 18.9% for ASA. Highly significant results were also obtained with respect to the main issue, namely of whether a combination of dipyridamole and ASA produced an additional additive effect. The relative reduction in risk achieved by the combination product compared with placebo is 36.8%. If the efficacy of the combination product is compared with that of the two single agents, which the design of the study made possible for the first time, the reduction in risk is 24.4% compared with dipyridamole and 22.1% compared with ASA. From these results it can be concluded that neither single agent affects the activity of the other, and that the two modes of action are independent of one another and mutually complementary and thus produce additive effects when combined. There was no significant effect on overall mortality in any of the four groups. This result is consistent with other clinical studies of aggregation inhibitors. Tolerance The number of patients who reported at least one adverse event was virtually the same in all four treatment groups. However, there were differences in the individual groups with regard to the distribution of the most common adverse events: In the groups that received ASA, alone or in combination, there were almost twice as many haemorrhages as in the other two groups which received no ASA. On the other hand, headaches were more common in the two groups receiving dipyridamole, whether alone or in combination. In particular, headaches were much more common during the first month of treatment. Indications AGGRENOX is indicated to reduce the risk of stroke in patients who have had transient ischemia of the brain or completed ischemic stroke due to thrombosis.

5 Contraindications Hypersensitivity to any of the components of the product or salicylates Patients with active gastric or duodenal ulcers or with bleeding disorders Pregnancy: during the third trimester. In case of rare hereditary conditions that may be incompatible with an excipient of the product (please refer to special warnings and precautions ) the use of the product is contraindicated. Special warnings and precautions Among other properties dipyridamole acts as a vasodilator. It should be used with caution in patients with severe coronary artery disease, including unstable angina and recent myocardial infarction, left ventricular outflow obstruction, or haemodynamic instability (e.g. decompensated heart failure). Patients being treated with regular oral doses of AGGRENOX should not receive additional intravenous dipyridamole. If pharmacological stress testing with intravenous dipyridamole for coronary artery disease is considered necessary, then AGGRENOX should be discontinued twenty-four hours prior to testing, otherwise the sensitivity of the intravenous stress test could be limited. In patients with myasthenia gravis readjustment of therapy may be necessary after changes in dipyridamole dosage (see Interactions). 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, and 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 bile may be the mechanism responsible for the presence of dipyridamole in gallstones. Due to the acetylsalicylic acid component, AGGRENOX should be used with caution in patients with asthma, allergic rhinitis, nasal polyps, chronic respiratory infections (especially when associated with hay fever-like symptoms), chronic or recurring gastric or duodenal complaints, impaired renal or hepatic function or glucose-6-phosphate dehydrogenase deficiency. In addition, caution is advised in patients hypersensitive to non-steroidal anti-inflammatory drugs. The dose of acetylsalicylic acid in AGGRENOX has not been studied in secondary prevention of myocardial infarction. Caution should be advised in patients receiving concomitant medication which may increase the risk of bleeding, such as anti-platelet agents (e.g. clopidogrel, ticlopidine) or selective serotonin reuptake inhibitors (SSRIs) Patients should consult or inform their doctor or dentist when taking AGGRENOX before surgical procedures. This product contains 106 mg of lactose and 22.5 mg sucrose per maximum recommended daily dose. Patients with rare hereditary problems of fructose intolerance and/ or galactose intolerance e.g. galactosaemia should not take this medicine. AGGRENOX is not recommended for children because of a lack of experience with this patient group. Effects on ability to drive and use machines: In studies in two groups each of 24 volunteers AGGRENOX did not have any effect on safety related performance compared with placebo. In particular neither sedative effects nor interaction with alcohol were observed. There is therefore no evidence that when AGGRENOX is used as prescribed the ability to drive, operate machinery or work without reliable support will be impaired. Interactions When dipyridamole is used in combination with acetylsalicylic acid or with warfarin the statements regarding precautions, warnings and tolerance for these preparations must be observed. Acetylsalicylic acid have been shown to enhance the effect of anticoagulants (e.g. coumarin derivatives and heparin), ], antiplatelet drugs (e.g. clopidogrel, ticlopidine) and valproic acid which may result in an increased

6 risk of side effects. Selective serotonin reuptake inhibitors (SSRIs) may increase the risk of bleeding. Gastro-intestinal side effects also increase when acetylsalicylic acid is administered concomitantly with NSAIDs, corticosteroids or chronic alcohol use. The addition of dipyridamole to acetylsalicylic acid does not increase the incidence of bleeding events. Dipyridamole increases the plasma levels and cardiovascular effects of adenosine. Adjustment of adenosine dosage should be considered. 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 drugs, which reduce blood pressure and may counteract the anticholinesterase effect of cholinesterase inhibitors thereby potentially aggravating myasthenia gravis. The effect of hypoglycaemic agents and the toxicity of methotrexate may be increased; effect of triiodothyronine and the effect of sulphonamide chemotherapeutic agents, including cotrimoxazole are increased by the concomitant administration of acetylsalicylic acid. Acetylsalicylic acid may decrease the natriuretic effect of spironolactone and loop diuretics and inhibit the effect of uricosuric agents (e.g. probenecid, sulphinpyrazone). The desired cardiovascular effects of ASA may be reduced by ibuprofen (but not by other NSAIDs or paracetamol). Pregnancy and lactation There is insufficient evidence of safety in human pregnancy regarding dipyridamole and acetylsalicylic acid at low dose. Preclinical studies have shown no hazard. Dipyridamole and salicylates are excreted in breast milk. AGGRENOX should only be administered during early pregnancy or lactation if considered essential by the physician in terms of benefit and risk. AGGRENOX is contraindicated in the third trimester of pregnancy. Side effects The undesirable effects of AGGRENOX are listed below according to system organ class and frequency. The frequency data are defined as follows: 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). Disorders of the blood and lymph system Common: Iron deficiency anaemia Rare: Increase in bleeding time, increased bleeding during or after surgery, thrombocytopenia Immune system disorders Rare: Hypersensitivity reactions such as rash and urticaria, severe bronchospasms and angiooedema, including immediate reactions Nervous system disorders Common: Headache*, dizziness* and drowsiness Frequency not known: Migraine-like headaches* (especially at the start of treatment) Cardiac disorders Uncommon: Increase in symptoms of coronary heart disease Rare: Tachycardia Functional disorders of the vessels Uncommon: Hot flushes Rare: Hypotension Gastrointestinal disorders Common: Abdominal pain, vomiting*, nausea*, diarrhoea*, dyspepsia Uncommon: Erosive gastritis, gastric and duodenal ulcers, severe gastrointestinal bleeding Functional disorders of liver and gallbladder Rare: Detection of dipyridamole in gallstones (see Section 4.3) Functional disorders of the locomotor system Uncommon: Muscle pains* Skin and subcutaneous tissue disorders Frequency not known: Cutaneous bleeding e.g. haematomas or ecchymosis

7 * in most cases these symptoms disappear when the medicine is taken over a longer period. In isolated cases, especially in high doses and in predisposed patients, the following undesirable effects can also occur after the ingestion of ASA: Metabolism and nutrition disorders Hypoglycaemia Nervous system disorders Tinnitus Functional disorders of the vessels Drop in blood pressure and possibly shock (especially in asthmatic patients) Gastrointestinal disorders Microhaemorrhages Functional disorders of liver and gallbladder Impairment of liver function Skin and subcutaneous tissue disorders Severe skin reactions (even erythema multiforme) Functional disorders of the kidneys and the lower urinary tract Impairment of kidney function, reduction in excretion of uric acid, possibly resulting in an attack of gout in susceptible patients Dosage and administration The recommended dose is one capsule twice daily. The sustained-release capsules should be swallowed whole with some liquid with or after meals; usually they should be taken in the morning and the evening. AGGRENOX is intended for long-term treatment; your doctor will decide on the duration of treatment. Overdosage Symptoms of Dipyridamole overdose Because of the dose ratio of dipyridamole to acetylsalicylic acid, overdosage is likely to be dominated by signs and symptoms of dipyridamole overdose. Due to the low number of observations, experience with dipyridamole overdose is limited. Symptoms such as a warm feeling, flushes, sweating, restlessness, feeling of weakness, dizziness, and anginal complaints can be expected. A drop in blood pressure and tachycardia might be observed. The signs and symptoms of mild acute acetylsalicylic acid overdose are hyperventilation, tinnitus, nausea, vomiting, impairment of vision and hearing, dizziness and confusional states. Dizziness and tinnitus can, particularly in elderly patients, be symptoms of overdosage. Therapy Symptomatic therapy is recommended. A gastric decontamination procedure should be considered. Administration of xanthine derivatives (e.g. aminophylline) may reverse the haemodynamic effects of dipyridamole overdose. Due to its wide distribution to tissues and its predominantly hepatic elimination, dipyridamole is not likely to be accessible to enhanced removal procedures. Symptoms of Acute intoxication with Acetylsalicylic acid: Symptoms of mild acute intoxication ( μg/ ml): In addition to disturbances of the acid-base balance and electrolyte balance (e.g. loss of potassium), hypoglycaemia, rashes and gastrointestinal bleeding, hyperventilation, tinnitus, nausea, vomiting, impaired sight and hearing, headache, dizziness, and confusional states may be seen. In cases of severe poisoning (more than 400 μg/ ml), delirium, tremor, dyspnoea, sweating, dehydration, hyperthermia and coma may occur. In cases of intoxication with fatal outcome, death is generally caused by respiratory failure. Therapy: Treatment of ASA intoxication will depend on the scale, stage and clinical symptoms of the intoxication. They include the usual measures to reduce the absorption of the active ingredient, to control the fluid and electrolyte balance, the disturbed temperature regulation and respiration. Treatment essentially consists of accelerating elimination and correcting the disturbed acid base and electrolyte balances. Diuretics may be given in addition to infusions of sodium bicarbonate and potassium chlo-

8 ride. Urine should become alkaline so that the degree of ionisation of the salicylates increases and thus the back-diffusion rate into the tubules decreases. A blood test (ph, PCO2, bicarbonate, potassium, etc) is strongly advised. In severe cases, haemodialysis may be necessary. Storage conditions To be stored below 30ºC. Store in a safe place out of the reach of children! Do not take the medicine after the expiry date printed on the pack. Availability Modified release capsules 200/25 mg