Active ingredients: Dipyridamole, Acetylsalicylic acid
AGGRENOX 200 mg + 25 mg modified-release hard capsules
Indications Why is Aggrenox used? What is it for?
PHARMACOTHERAPEUTIC CATEGORY
Antithrombotics, antiplatelet agents - combination of dipyridamole / acetylsalicylic acid.
THERAPEUTIC INDICATIONS
Stroke prevention in patients with previous transient ischemic attacks or complete ischemic stroke due to thrombosis (secondary prevention).
Contraindications When Aggrenox should not be used
- Hypersensitivity to the active substances (dipyridamole and acetylsalicylic acid), to salicylates or to any of the excipients.
- Patients with active gastric or duodenal ulcer or with coagulation disorders.
- Pregnancy and breastfeeding: AGGRENOX is generally contraindicated in the first and second trimester of pregnancy and during lactation; contraindicated in the third trimester (see also "Special warnings").
- The use of this medicine is contraindicated in children and young people under the age of sixteen.
- Due to the presence of acetylsalicylic acid, the administration of AGGRENOX should be avoided in patients with severe renal insufficiency (glomerular filtration rate less than 10 ml / min) or hepatic.
In case of rare hereditary conditions that may be incompatible with an excipient of the medicinal product, the same is contraindicated.
Precautions for use What you need to know before taking Aggrenox
Warnings Relating to Acetylsalicylic Acid
Due to the presence of acetylsalicylic acid, AGGRENOX should be used with caution in patients with asthma, allergic rhinitis, nasal polyps, chronic or recurrent gastric or duodenal pain, renal or hepatic insufficiency or glucose-6-phosphate dehydrogenase deficiency. Before initiating therapy with AGGRENOX it must be ensured that the patient has not previously had hypersensitivity reactions to acetylsalicylic acid or other non-steroidal anti-inflammatory drugs.
Cardiovascular pathologies
Among other properties, dipyridamole has a vasodilating action. Dipyridamole should be used with caution in patients with severe coronary artery disease including unstable angina or recent myocardial infarction, ventricular outflow obstruction or haemodynamic instability (e.g., congestive heart failure).
Myasthenia gravis
In patients with myasthenia gravis, a modification of the treatment regimen may be necessary if the dipyridamole dosage is changed (see "Interactions").
The dose of acetylsalicylic acid present in AGGRENOX has not been studied in the secondary prevention of myocardial infarction.
Children and adolescents
There is a possible association between acetylsalicylic acid and Reye's syndrome when given to children. AGGRENOX should therefore not be used in children and adolescents with febrile states or viral infections with or without fever, due to the risk of Reye's syndrome. Reye's syndrome is a very rare disease, which affects the brain and liver, and can be fatal.
Senior citizens
People over the age of 70, especially in the presence of concomitant therapies, should use this medicine only after consulting a doctor.
Interactions Which drugs or foods may change the effect of Aggrenox
Tell your doctor or pharmacist if you have recently taken any other medicines, even those without a prescription.
Non-steroidal anti-inflammatory drugs (NSAIDs) / Corticosteroids / Alcohol
Gastrointestinal side effects are increased when acetylsalicylic acid is administered in combination with NSAIDs, corticosteroids or chronic alcohol consumption.
The association of dipyridamole with acetylsalicylic acid does not increase the incidence of bleeding.
The concomitant administration of ibuprofen, but certainly not that of other NSAIDs or paracetamol, may limit the beneficial cardiovascular effects of aspirin in patients with increased cardiovascular risk.
Substances that affect blood clotting
When dipyridamole is used in combination with any other substance that affects clotting, such as anticoagulants and antiplatelets, the precautions, warnings and tolerability described in the package leaflets of these medicinal products should be taken into account.
Acetylsalicylic acid has been shown to increase the risk of bleeding when given with anticoagulant drugs, antiplatelet drugs, selective serotonin reuptake inhibitors (SSRIs) or anagrelide.
When dipyridamole is given together with warfarin, any bleeding is not more frequent or more intense than that seen with warfarin alone.
Anticonvulsants
Acetylsalicylic acid has been shown to increase the effect of valproic acid and phenytoin, increasing the risk of side effects.
Adenosine
Dipyridamole increases the blood levels and cardiovascular effects of adenosine. Therefore, the advisability of a readjustment of the adenosine dosage should be considered.
Antihypertensives
Dipyridamole may increase the hypotensive effect of antihypertensive medicinal products.
Cholinesterase inhibitors
Dipyridamole can counteract the anticholinesterase effect of cholinesterase inhibitor medicines and potentially worsen cases of myasthenia gravis.
Hypoglycaemics / Methotrexate
The effect of hypoglycemic drugs and the toxicity of methotrexate may be enhanced by the concomitant administration of acetylsalicylic acid.
Spironolactone / Uricosuric agents
Acetylsalicylic acid may decrease the natriuretic effect of spironolactone and may inhibit the effect of uricosuric drugs (such as probenecid, sulfinpyrazone).
The treatment effect may be modified if acetylsalicylic acid is taken concomitantly with other medicines such as:
- anticoagulants (eg warfarin);
- anti-rejection drugs (eg cyclosporine, tacrolimus);
- antihypertensives (eg diuretics and ACE inhibitors);
- painkillers and anti-inflammatories (e.g. steroids, NSAIDs);
- gout medications (probenecid);
- anti-cancer and rheumatoid arthritis drugs (methotrexate).
Before using acetylsalicylic acid, tell your doctor if you are taking any other medicines (including self-medication).
Warnings It is important to know that:
Bleeding
Due to the risk of bleeding, as with other antiplatelet agents, AGGRENOX should be used with caution in patients with increased bleeding risk, they should be followed closely for any signs of bleeding, including occult bleeding (see "Interactions ").
Patients taking concomitant medications that may increase the risk of bleeding, such as anticoagulants, antiplatelet agents, selective serotonin reuptake inhibitors (SSRIs), anagrelide should be treated with caution (see "Interactions").
Biliary disorders
A small number of cases have been reported in which unconjugated dipyridamole has been incorporated into gallstones in varying amounts (up to 70% of the dry weight of the stone). These patients were all elderly, had experienced ascending cholangitis and had been treated with oral dipyridamole for a number of years. Dipyridamole has not been shown to be the trigger for gallstones 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.
Headache or migraine
Headache or migraine which may arise especially at the beginning of therapy with AGGRENOX should not be treated with analgesic doses of acetylsalicylic acid.
Stress test with intravenous dipyridamole
Clinical experience suggests that patients being treated with oral dipyridamole who should also undergo a drug stress test with intravenous dipyridamole, should discontinue oral therapy with dipyridamole-containing drugs 24 hours before being treated with intravenous dipyridamole. Taking dipyridamole by mouth 24 hours prior to the stress test with intravenous dipyridamole may impair the sensitivity of the test.
Use during pregnancy or breastfeeding
Ask your doctor or pharmacist for advice before taking any medicine.
Pregnancy
There is insufficient evidence on the safety of dipyridamole and low dose acetylsalicylic acid in pregnancy. Therefore AGGRENOX should be administered in the first and second trimester of pregnancy only if considered essential by the physician in terms of expected benefits compared to potential risks. Furthermore, AGGRENOX must not be administered during the third trimester of pregnancy (see "Contraindications").
Feeding time
Dipyridamole and salicylates are excreted in breast milk. Therefore, in breastfeeding women AGGRENOX should only be administered if strictly necessary.
Fertility
No studies on the effects of the medicine on human fertility have been performed.
Effects on ability to drive and use machines
No studies on the effect of the medicine on the ability to drive and use machines have been performed.
However, symptoms such as dizziness and confusion have been reported in clinical trials (see "Side Effects"). Patients are therefore advised to use caution when driving or using machines.
If patients experience such symptoms, they should avoid potentially hazardous activities such as driving or operating machinery.
Important information about some of the ingredients of AGGRENOX
AGGRENOX contains lactose and sucrose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.
Dosage and method of use How to use Aggrenox: Dosage
For oral administration. The recommended dose is 1 capsule twice a day, usually 1 in the morning and 1 in the evening, preferably with meals.
The capsules should be swallowed whole without chewing.
If you have any further questions on the use of AGGRENOX, ask your doctor or pharmacist.
Overdose What to do if you have taken too much Aggrenox
In case of accidental ingestion / intake of an excessive dose of AGGRENOX, notify your doctor immediately or go to the nearest hospital.
Symptoms
Given the dose ratio of dipyridamole to acetylsalicylic acid, overdose is dominated by the signs and symptoms of dipyridamole.
Due to the small number of reported cases, there is limited experience of overdose with dipyridamole. Symptoms such as hot sensations, flushing, sweating, restlessness, feelings of weakness, dizziness and angina pains are expected. Drop in blood pressure and tachycardia may be observed.
The signs and symptoms of a modest acute overdose of acetylsalicylic acid are hyperventilation, buzzing, nausea, vomiting, disturbed vision and hearing, dizziness and confusion. Delirium, tremor, dyspnoea, sweating, may be observed in severe poisoning. bleeding, dehydration, disturbances in the acid-base balance and in the electrolyte composition of the blood, hypothermia and coma. Dizziness and ringing in the ears can be a symptom of overdose, particularly in elderly patients.
Therapy
Symptomatic therapy is recommended. Gastric lavage should be considered. Administration of xanthine derivatives (eg, aminophylline) may counteract the haemodynamic effects of dipyridamole overdose. Due to its wide tissue distribution and predominant hepatic elimination, dipyridamole is hardly available. for accelerated removal.
If you have any further questions on the use of AGGRENOX ask your doctor or pharmacist.
Side Effects What are the side effects of Aggrenox
Like all medicines, AGGRENOX can cause side effects, although not everybody gets them.
AGGRENOX side effects listed by systemic-organic classes:
Disorders of the blood and lymphatic system
Thrombocytopenia (reduced platelet count), anemia, iron deficiency anemia due to occult gastrointestinal bleeding.
Disorders of the immune system
Hypersensitivity reactions including rash, urticaria, severe bronchospasm and angioedema.
Nervous system disorders
Intracranial haemorrhage, dizziness, headache, even migraine (especially at the start of treatment).
Eye disorders
Hemorrhage of the eye.
Cardiac pathologies
Tachycardia, worsening of coronary artery disease symptoms, syncope.
Vascular pathologies
Hypotension, hot flashes.
Respiratory, thoracic and mediastinal disorders
Epistaxis.
Gastrointestinal disorders
Vomiting, nausea, diarrhea, dyspepsia, gastric ulcer, duodenal ulcer, erosive gastritis, gastrointestinal haemorrhage, abdominal pain.
Skin and subcutaneous tissue disorders
Skin bleeding including contusion, bruising and hematoma.
Disorders of the musculoskeletal system, connective tissue
Myalgia.
Diagnostic tests
Prolonged bleeding time.
Injury, poisoning and procedural complications
Post procedural haemorrhage, procedural haemorrhage.
Further known undesirable effects for the individual active ingredients are as follows, they are also considered to be intended for AGGRENOX.
Dipyridamole:
Additional side effects reported with dipyridamole alone are as follows:
Dipyridamole has been reported to be incorporated into gallstones.
Acetylsalicylic acid:
Additional side effects reported with acetylsalicylic acid alone are as follows:
Disorders of the blood and lymphatic system
Disseminated intravascular coagulation, coagulopathy.
Disorders of the immune system
Anaphylactic reactions (especially in patients with asthma).
Metabolism and nutrition disorders
Hypoglycemia (children), hyperglycemia, thirst, dehydration, hyperkalaemia, metabolic acidosis, respiratory alkalosis.
Psychiatric disorders
Confusional state.
Nervous system disorders
Agitation, cerebral edema, lethargy, convulsions. Ear and labyrinth disorders Tinnitus, deafness.
Cardiac pathologies
Arrhythmia.
Respiratory, thoracic and mediastinal disorders
Dyspnoea, gingival bleeding, laryngeal edema, hyperventilation, pulmonary edema, tachypnea.
Gastrointestinal disorders
Perforated gastric ulcer, perforated duodenal ulcer, melaena, haematemesis, pancreatitis.
Hepatobiliary disorders
Hepatitis, Reye's syndrome.
Skin and subcutaneous tissue disorders
Polymorphic erythema.
Disorders of the musculoskeletal system, connective tissue
Rhabdomyolysis.
Renal and urinary disorders
Renal failure, interstitial nephritis, renal papillary necrosis, proteinuria.
Pregnancy, puerperium and perinatal conditions
Prolonged pregnancy, prolonged delivery, small term infants, stillbirth, haemorrhage in pregnancy, postpartum haemorrhage.
General disorders and administration site conditions
Pyrexia, hypothermia.
Diagnostic tests
Abnormal liver function tests, increased blood uric acid (can lead to gout attacks), prolonged prothrombin time.
Compliance with the instructions contained in the package leaflet reduces the risk of undesirable effects.
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. Side effects can also be reported directly via the national reporting system at www.agenziafarmaco.it/it/responsabili. By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Warning: do not use the medicine after the expiry date indicated on the package.
The expiry date indicated refers to the product in intact packaging, correctly stored.
Store below 30 ° C, keep the bottle closed to protect from moisture.
KEEP AGGRENOX OUT OF THE REACH AND SIGHT OF CHILDREN.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Other information
COMPOSITION
One capsule contains: Active ingredients: dipyridamole 200 mg; acetylsalicylic acid 25 mg.
Excipients: tartaric acid, povidone, methacrylic acid-methyl methacrylate copolymer (1: 2), talc, gum arabic, hypromellose phthalate, hypromellose, triacetin, dimethicone 350, stearic / palmitic acid, lactose monohydrate, aluminum stearate, colloidal silica, starch maize, microcrystalline cellulose, sucrose, E 171; capsule (hard): gelatin, E 171, E 172, purified water.
PHARMACEUTICAL FORM AND CONTENT
Modified-release capsules, hard. Packs of: 50, 60 capsules.
Not all pack sizes may be marketed.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
AGGRENOX 200 MG + 25 MG HARD MODIFIED RELEASE CAPSULES
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
One capsule contains:
dipyridamole 200 mg
acetylsalicylic acid 25 mg
Excipients with known effect: one capsule contains 53 mg of lactose and 11.3 mg of sucrose
For the full list of excipients, see section 6.1
03.0 PHARMACEUTICAL FORM
Modified-release capsules, hard.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
AGGRENOX is indicated for the prevention of stroke in patients with previous transient ischemic attacks or complete ischemic stroke due to thrombosis (secondary prevention).
04.2 Posology and method of administration
The recommended dose is one capsule twice a day, usually once in the morning and once in the evening, preferably with meals.
The capsules should be swallowed whole without chewing.
04.3 Contraindications
• Hypersensitivity to the active substances, to salicylates or to any of the excipients.
• Patients with active gastric or duodenal ulcer or with coagulation disorders.
• Pregnancy and lactation: AGGRENOX is generally contraindicated in the first and second trimester of pregnancy and during lactation; contraindicated in the third trimester (See section 4.6).
• The use of this medicine is contraindicated in children and young people under the age of sixteen.
• Due to the presence of acetylsalicylic acid the administration of AGGRENOX should be avoided in patients with severe renal insufficiency (glomerular filtration rate less than 10 ml / min) or hepatic (see also section 5.2).
In case of rare hereditary conditions that may be incompatible with an excipient of the medicinal product, the same is contraindicated.
04.4 Special warnings and appropriate precautions for use
Bleeding
Due to the risk of bleeding, as with other antiplatelet agents, AGGRENOX should be used with caution in patients with an increased risk of bleeding, they should be followed closely for any signs of bleeding, including occult bleeding (see section 4.5 ).
Patients taking concomitant medications that may increase the risk of bleeding, such as anticoagulants, antiplatelet agents, selective serotonin reuptake inhibitors (SSRIs), or anagrelide should be treated with caution (see section 4.5).
Cardiovascular pathologies
Among other properties, dipyridamole has a vasodilating action. Dipyridamole should be used with caution in patients with severe coronary artery disease including unstable angina or recent myocardial infarction, ventricular outflow obstruction or haemodynamic instability (e.g., congestive heart failure).
The dose of acetylsalicylic acid present in AGGRENOX has not been studied in the secondary prevention of myocardial infarction.
Myasthenia gravis
In patients with myasthenia gravis, a modification of the treatment schedule may be necessary in case of a change in the dipyridamole dosage (see section 4.5).
Biliary disorders
A small number of cases have been reported in which unconjugated dipyridamole has been incorporated into gallstones in varying amounts (up to 70% of the dry weight of the stone). These patients were all elderly, had experienced ascending cholangitis and had been treated with oral dipyridamole for a number of years. Dipyridamole has not been shown to be the trigger for gallstones 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.
Headache or migraine
Headache or migraine which may arise especially at the start of therapy with AGGRENOX should not be treated with analgesic doses of acetylsalicylic acid.
Hypersensitivity
In addition, caution is advised in patients hypersensitive to NSAIDs.
Warnings Relating to Acetylsalicylic Acid
Due to the presence of acetylsalicylic acid, AGGRENOX should be used with caution in patients with asthma, allergic rhinitis, nasal polyps, chronic or recurrent gastric or duodenal pain, renal or hepatic insufficiency (see section 5.2) or glucose-6-phosphate deficiency. dehydrogenase.
Children and adolescents
There is a possible association between acetylsalicylic acid and Reye's syndrome when given to children. AGGRENOX should therefore not be used in children and adolescents with febrile states or viral infections with or without fever, due to the risk of Reye's syndrome. Reye's syndrome is a very rare disease, which affects the brain and liver, and can be fatal.
Senior citizens
People over the age of 70, especially in the presence of concomitant therapies, should use this medicine only after consulting a doctor.
Stress test with intravenous dipyridamole
Clinical experience suggests that patients being treated with oral dipyridamole who should also undergo a drug stress test with intravenous dipyridamole, should discontinue oral therapy with dipyridamole-containing drugs 24 hours before being treated with intravenous dipyridamole. Taking dipyridamole by mouth 24 hours prior to the stress test with intravenous dipyridamole may impair the sensitivity of the test.
Warnings relating to some of the ingredients of AGGRENOX
One capsule contains 53 mg of lactose and 11.3 mg of sucrose, which make up 106 mg of lactose and 22.6 mg of sucrose at the maximum recommended daily dose: patients with rare hereditary problems of fructose and / or galactose intolerance, lactase deficiency or glucose-galactose malabsorption or sucrase isomaltase insufficiency should not take this medicine.
04.5 Interactions with other medicinal products and other forms of interaction
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) / Corticosteroids / Alcohol
Gastrointestinal side effects are increased when acetylsalicylic acid is administered in combination with NSAIDs, corticosteroids or chronic alcohol consumption.
The concomitant administration of ibuprofen, but certainly not that of other NSAIDs or paracetamol, may limit the beneficial cardiovascular effects of aspirin in patients with increased cardiovascular risk.
Substances that affect blood clotting
When dipyridamole is used in combination with any other substance that affects clotting, such as anticoagulants and antiplatelets, the safety profile of these medicinal products should be taken into account.
Acetylsalicylic acid has been shown to increase the risk of bleeding when given with anticoagulants, antiplatelet drugs, selective serotonin reuptake inhibitors (SSRIs) or anagrelide.
The association of dipyridamole with acetylsalicylic acid does not increase the incidence of bleeding.
When dipyridamole is given together with warfarin, any bleeding is not more frequent or more intense than that seen with warfarin alone.
Anticonvulsants
Acetylsalicylic acid has been shown to increase the effect of valproic acid and phenytoin, increasing the risk of side effects.
Adenosine
Dipyridamole increases the blood levels and cardiovascular effects of adenosine. Therefore, the advisability of a readjustment of the adenosine dosage should be considered.
Antihypertensives
Dipyridamole may increase the hypotensive effect of antihypertensive medicinal products.
Cholinesterase inhibitors
Dipyridamole may counteract the anticholinesterase effect of cholinesterase inhibitor medicinal products, and potentially could worsen cases of myasthenia gravis (see section 4.4).
Hypoglycaemics / Methotrexate
The effect of hypoglycemic drugs and the toxicity of methotrexate may be enhanced by the concomitant administration of acetylsalicylic acid.
Spironolactone / Uricosuric agents
Acetylsalicylic acid may decrease the natriuretic effect of spironolactone and may inhibit the effect of uricosuric drugs (such as probenecid, sulfinpyrazone).
Experimental data indicate that ibuprofen may inhibit the effects of low-dose acetylsalicylic acid on platelet aggregation when the drugs are administered concomitantly. However, the limited data and uncertainties relating to their application to the clinical situation do not allow to draw firm conclusions for continued use of ibuprofen; there appears to be no clinically relevant effect from occasional use of ibuprofen (see section 5.1).
04.6 Pregnancy and breastfeeding
Pregnancy
Although preclinical studies have shown no health risk (see section 5.3), there is insufficient evidence on the safety of dipyridamole and low dose acetylsalicylic acid in pregnancy. Therefore AGGRENOX should be administered in the first and second trimester of pregnancy only if considered essential by the physician in terms of expected benefits compared to potential risks.
AGGRENOX is also contraindicated during the third trimester of pregnancy.
Feeding time
Dipyridamole and salicylates are excreted in breast milk (see sections 5.2 and 5.3).
Therefore, in breastfeeding women, AGGRENOX should only be administered if strictly necessary.
Fertility
No studies on the effects of the medicine on human fertility have been performed. In preclinical studies with dipyridamole or acetylsalicylic acid, no impairment of fertility was observed (see section 5.3).
04.7 Effects on ability to drive and use machines
No studies on the effect of the medicine on the ability to drive and use machines have been performed.
However, patients should be advised that symptoms such as dizziness and confusion have been reported in clinical trials. Therefore caution should be advised when driving or operating machinery.
If patients experience such symptoms, they should avoid potentially hazardous activities such as driving or operating machinery.
04.8 Undesirable effects
Summary of the safety profile
The results of two large-scale studies (ESPS-2, PRoFESS) in which a total of 26,934 patients were enrolled, 11,831 of whom were assigned to the AGGRENOX treatment group, were used to define the safety profile of AGGRENOX. . These data have been integrated with the extensive post marketing experience of AGGRENOX.
The most frequently reported adverse reactions are headache, dizziness and gastrointestinal events such as dyspepsia, diarrhea, nausea and abdominal pain. The most important serious adverse reactions associated with the use of AGGRENOX were bleeding events.
Table of undesirable effects
The following adverse reactions were reported during the use of AGGRENOX in the ESPS-2 and PRoFESS studies and following spontaneous reporting.
1 Known adverse reactions of dipyridamole alone
2 Known adverse reactions of acetylsalicylic acid monotherapy
Description of selected adverse reactions
The most important serious adverse reactions associated with the use of AGGRENOX were bleeding events. Data from ESPS-2 and PRoFESS studies were evaluated for bleeding events, including major bleeding. Bleeding events were classified. such as any bleeding, severe bleeding, intracranial haemorrhage and gastrointestinal haemorrhage:
In the ESPS-2 controlled study, 1,650 patients were treated in the AGGRENOX group (100%) and 1,649 in the placebo group (100%). The mean duration of treatment was 1.4 years. The overall incidence of bleeding was 8.7% in the AGGRENOX group and 4.5% in the placebo group. The incidence of severe bleeding was 1.6% and 0.4%, respectively. The incidence of intracranial bleeding was 0.6% and 0.4%, respectively, while the incidence of gastrointestinal bleeding was 4.3% and 2.6%, respectively.
In the PRoFESS study, 10,055 patients were treated in the AGGRENOX group (100%). The mean duration of treatment was 1.9 years. The overall incidence of bleeding was 5.3%. The incidence of severe bleeding was 3.3%. The incidence of intracranial haemorrhage was 1.2% (including intraocular haemorrhage (0 , 2%)), while the incidence of gastrointestinal bleeding was 1.9%.
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous 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. "address www.agenziafarmaco.gov.it/it/responsabili.
04.9 Overdose
Symptoms
Given the dose ratio of dipyridamole to acetylsalicylic acid, overdose is dominated by the signs and symptoms of dipyridamole.
Due to the small number of reported cases, there is limited experience of overdose with dipyridamole. Symptoms such as feeling hot, flushing, sweating, restlessness, feeling of weakness, dizziness and angina pains are expected. Drop in blood pressure and tachycardia may be observed.
The signs and symptoms of a modest acute overdose of acetylsalicylic acid are hyperventilation, buzzing, nausea, vomiting, disturbed vision and hearing, dizziness and confusion.
In case of severe poisoning, delirium, tremor, dyspnoea, sweating, bleeding, dehydration, disturbances of acid-base balance and electrolyte composition of the blood, hypothermia and coma may be observed.
Dizziness and ringing in the ears can be a symptom of overdose, particularly in elderly patients.
Therapy
Symptomatic therapy is recommended. Gastric lavage should be considered. Administration of xanthine derivatives (eg: aminophylline) may counteract the haemodynamic effects of dipyridamole overdose. Due to its wide tissue distribution and predominant hepatic elimination, dipyridamole is hardly available. for accelerated removal.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: antithrombotics, antiplatelet agents; ATC code: B01AC.
The antithrombotic action of the acetylsalicylic acid / dipyridamole combination is based on the various biochemical mechanisms involved.
L "acetylsalicylic acid irreversibly inactivates the cyclo-oxygenase enzyme in platelets, thus preventing the production of thromboxane A2, a potent inducer of platelet aggregation and vasoconstriction.
The dipyridamole inhibits the uptake of adenosine in erythrocytes, platelets and endothelial cells in vitro and in vivo; inhibition amounts to approximately 80% as a maximum and occurs dose-dependent at therapeutic concentrations (0.5 - 2 mcg / ml). As a result, there is an increase in the local concentration of adenosine which acts on the A2 receptor of platelets, stimulating platelet adenyl cyclase and thereby increasing the levels of cyclic adenosine monophosphate (AMPc) in platelets.
Therefore, platelet aggregation is inhibited in response to various stimuli such as platelet activating factor (PAF), collagen and adenosine diphosphate (ADP). Reduced platelet aggregation reduces platelet consumption to normal levels. In addition, adenosine has a vasodilator effect and this is one of the mechanisms by which dipyridamole produces vasodilation.
In stroke patients, dipyridamole has been shown to reduce the density of surface prothrombotic proteins (PAR-1: Thrombin receptor) present on platelets as well as to reduce levels of c-reactive protein (CRP) and von Willebrand factor (vWF). ). In-vitro research has shown that dipyridamole selectively inhibits inflammatory cytokines (MCP-1 and MMP-9) that result from platelet-monocyte interaction.
Pharmacodynamics
Dipyridamole inhibits phosphodiesterase (PDE) in various tissues.
While inhibition of AMPc-PDE is weak, therapeutic levels of dipyridamole inhibit cyclic guanosine monophosphate-PDE (GMPc-PDE), thereby increasing the "increase in GMPc produced by" EDRF (endothelium-derived relaxing factor, " identified as nitric oxide (NO)).
Dipyridamole increases the release of Tissue Plasminogen Activator from microvascular endothelial cells and has been shown to increase the antithrombotic properties of endothelial cells on thrombus formation on the adjacent subendothelial matrix in a dose dependent manner. Dipyridamole is a powerful cleaner of oxi- and peroxi-radicals.
Dipyridamole also stimulates the biosynthesis and release of prostacyclin by the endothelium and reduces the thrombogenicity of subendothelial structures by increasing the concentration of the protective mediator 13-HODE (13-hydroxyoctadecadienoic acid).
While acetylsalicylic acid only inhibits platelet aggregation, dipyridamole also inhibits platelet activation and adhesion. Therefore, the antithrombotic effects of acetylsalicylic acid and dipyridamole are additive.
Clinical Studies
AGGRENOX was studied in a 24-month, double-blind, placebo-controlled study (European Stroke Prevention Study 2, ESPS2) in which 6,602 patients had an ischemic stroke or transient ischemic attack (TIA) within three months. prior to enrollment.
Patients were randomized to one of four treatment groups: AGGRENOX (ASA / extended-release dipyridamole) 25 mg / 200 mg; extended-release dipyridamole (ER-DP) 200 mg alone; ASA 25 mg alone or placebo. Patients received one capsule twice a day (morning and evening).
Evaluations of efficacy included analyzes of stroke (fatal or non-fatal) and death (from any cause) by a blinded morbidity and mortality group. AGGRENOX in ESPS-2 reduced the risk of stroke by 23.1% compared to ASA 50 mg / day alone (p = 0.006) and reduced the risk of stroke by 24.7% compared to release dipyridamole. prolonged 400 mg / day alone (p = 0.002). AGGRENOX reduced the risk of stroke by 37% compared to placebo (p
The results of the ESPS-2 study are supported by the study of the European / Australasian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT) which studied a combination treatment of dipyridamole 400 mg per day (83% of patients treated with a formulation of extended-release dipyridamole) and ASA 30-325 mg per day. A total of 2,739 patients who had had arterial ischemic stroke were enrolled, 1,376 in the ASA alone arm and 1,363 in the ASA plus dipyridamole arm. The main outcome was the combination of death from all vascular causes, non-fatal stroke, non-fatal myocardial infarction, or complications from major bleeding. Patients in the ASA plus dipyridamole group showed a 20% risk reduction (p
PRoFESS (PRevention Regimen For Effectively avoiding Second Strokes) is a parallel group, randomized, international, double-blind, double-dummy, active-controlled and placebo-controlled study with a 2x2 factorial design comparing AGGRENOX to clopidogrel, and telmisartan to placebo. in the prevention of stroke in patients who had previously experienced an ischemic stroke of non-cardioembolic origin.
A total of 20,332 patients were randomized to treatment with AGGRENOX (n = 10,181) or clopidogrel (n = 10,151). The primary endpoint was the time to first recurrence of any stroke.
The incidence of the primary endpoint was similar in both treatment groups (9.0% for AGGRENOX versus 8.8% for clopidogrel; HR 1.01, 95% CI 0.92 - 1.11).No significant difference between the AGGRENOX and clopidogrel treatment groups was found for several other important pre-specified endpoints, including the composite endpoint of recurrent stroke, myocardial infarction, or death from vascular causes (13.1% in both treatment groups; HR 0.99, 95% CI 0.92 - 1.07) and the composite endpoint of recurrent stroke or major bleeding event (11.7% for AGGRENOX versus 11.4% for clopidogrel ; HR 1.03, 95% CI 0.95 - 1.11).
Neurological functional outcome 3 months after recurrent stroke was assessed by the Modified Rankin Scale (mRS) and no significant difference in mRS distribution was observed between AGGRENOX and clopidogrel (p = 0.3073 from the Cochran-Armitage test. by linear trend).
Experimental data indicate that ibuprofen may inhibit the effects of low-dose acetylsalicylic acid on platelet aggregation when the drugs are administered concomitantly. In one study, following administration of a single 400 mg dose of ibuprofen, taken within 8 hours before or 30 minutes after the administration of acetylsalicylic acid (81 mg), there was a decrease in the effect of acetylsalicylic acid on thromboxane formation and platelet aggregation. However, the limited data and the uncertainties relating to their application to the clinical situation do not allow definitive conclusions to be drawn for the continued use of ibuprofen; there appears to be no clinically relevant effect from the occasional use of ibuprofen.
05.2 Pharmacokinetic properties
There is no significant interaction between dipyridamole sustained release pellets and acetylsalicylic acid. Therefore, the pharmacokinetics of AGGRENOX are related to the individual pharmacokinetics of the two components.
Dipyridamole
(Most of the data refer to healthy volunteers).
Dose - linearity was observed with dipyridamole at all doses used in therapy.
Modified release capsules containing dipyridamole formulated in pellets have been developed for long-term treatment. The pH-dependent solubility of dipyridamole, which prevents dissolution in the lower gastrointestinal tract (where prolonged-release formulations have yet to release the active ingredient) has been overcome by association with tartaric acid; the retard effect is obtained with a diffusion membrane which is sprayed onto the pellets.
Several steady state kinetic studies demonstrate that all appropriate pharmacokinetic parameters to characterize the properties of the modified-release preparation are equivalent or somewhat improved with modified-release dipyridamole capsules administered twice daily compared with dipyridamole three tablets. / four times a day. Bioavailability is slightly higher, peak concentrations are similar, downstream concentrations are considerably higher, and peak / trough fluctuation is small.
Absorption
Absolute bioavailability is approximately 70%. Since the first pass effect removes approximately 1/3 of the administered dose, it can be assumed that the absorption of dipyridamole is almost complete after administration of AGGRENOX.
Peak plasma concentrations are reached approximately 2 - 3 hours after administration of 400 mg of AGGRENOX (200 mg twice daily). Mean peak steady state concentrations are 1.98 mcg / mL (range 1.01 - 3.99 mcg / mL) and trough concentrations are 0.53 mcg / mL (range 0.18 - 1.01 mcg / ml).
Food has no relevant effect on the pharmacokinetics of dipyridamole in AGGRENOX.
Distribution
Due to its high lipophilicity, log P 3.92 (n-octanol / 0.1 n, NaOH), dipyridamole is distributed in many organs. In animals, dipyridamole is preferably distributed in the liver, then in the lungs, kidneys, spleen and heart.
The rapid distribution phase observed with intravenous administration cannot be seen following oral administration.
The apparent volume of distribution of the central compartment (Vc) is approximately 5 l (similar to plasma volume). The apparent volume of distribution at steady state is approximately 100 l and reflects the distribution to the various compartments.
The drug does not cross the blood brain barrier to any significant extent.
Placental transfer of dipyridamole is very low. In one woman, approximately one seventeenth of the plasma concentration was detectable in breast milk.
Protein binding of dipyridamole is approximately 97 - 99% and occurs mainly with alpha 1-acid glycoprotein and albumin.
Biotransformation
The metabolism of dipyridamole occurs in the liver. Dipyridamole is metabolized primarily by conjugation with glucuronic acid to form mainly a monoglycuronide and only small amounts of diglicuronide. In plasma, about 80% of the total amount is made up of the original compound and 20% of the total amount is made up of monoglicuronide.
The pharmacodynamic activity of the glucuronides of dipyridamole is considerably lower than that of dipyridamole.
Elimination
The dominant half-life following oral administration is approximately 40 minutes, as well as following intravenous administration.
Renal excretion of the parent compound is negligible (faeces via bile, with some trace of enterohepatic recirculation.
Total clearance is approximately 250 ml / min and the average residence time is approximately 11 hours (resulting from an intrinsic average residence time of approximately 6.4 hours and an average absorption time of 4.6 hours).
As with intravenous administration, a prolonged terminal elimination half-life of approximately 13 hours was observed.
This terminal phase of elimination is of relatively minor importance as it represents a small proportion of the total AUC, as evidenced by the fact that steady state is reached within two days with a regimen of two daily doses of modified-release capsules.
There was no significant drug accumulation following repeated dosing.
Kinetics in the elderly
Plasma concentrations (determined as AUC) in the elderly (> 65 years) were approximately 50% higher following treatment with tablets and approximately 30% following treatment with AGGRENOX compared to younger subjects (
Similar increases in plasma concentrations in elderly patients were observed in the ESPS-2 study for Persantin, modified-release capsules, as well as for AGGRENOX.
Kinetics in patients with renal impairment
Since renal excretion is very low (5%), no change in pharmacokinetics is expected in cases of renal insufficiency. In the ESPS-2 study, in patients with creatinine clearance ranging from 15 ml / min to> 100 ml / min, there was no alteration in the pharmacokinetics of dipyridamole or its metabolic glucuronide if the data were corrected for age differences.
Kinetics in patients with hepatic impairment
Patients with hepatic insufficiency show no change in the plasma concentrations of dipyridamole, but an increase in glucuronides (pharmacodynamically inactive). It is suggested that dipyridamole be dosed without restriction, as long as there is no clinical evidence of liver failure.
Acetylsalicylic acid
Absorption
After oral administration, acetylsalicylic acid is rapidly and completely absorbed in the stomach and intestines. Approximately 30% of the acetylsalicylic acid dose is presystematically hydrolyzed into salicylic acid.
Maximum plasma concentrations after a dose of 50 mg of acetylsalicylic acid contained in AGGRENOX (25 mg administered twice daily) are reached after 30 minutes of each dose, and peak concentrations at steady state are approximately 360 ng / ml. for acetylsalicylic acid. The maximum plasma concentrations of salicylic acid are reached after 60-90 minutes and amount to approximately 1,100 ng / ml.
Food does not exert a significant effect on the pharmacodynamics of the acetylsalicylic acid contained in AGGRENOX.
Distribution
Acetylsalicylic acid is rapidly converted to salicylate but is the predominant form of the drug in plasma during the first 20 minutes after oral administration.
Plasma concentrations of acetylsalicylic acid decrease rapidly with a half-life of approximately 15 minutes. Its major metabolite, salicylic acid, is highly bound to plasma proteins, and its binding is concentration-dependent (non-linear). At low concentrations (central nervous system, breast milk and fetal tissues.
Biotransformation
Acetylsalicylic acid is rapidly metabolized by non-specific esterases to salicylic acid.
Salicylic acid is metabolized into salicyluric acid, salicyl-phenolic glucuronide, acyl-salicylic glucuronide, and to a lesser extent into gentisic acid and gentisuric acid. The formation of the major metabolites salicyluric acid and salicyl-phenolic glucuronide is easily saturated and follows the Michaelis-Menten kinetics; the other metabolic pathways are first-order processes.
Elimination
Acetylsalicylic acid has an elimination half-life of 15-20 minutes in plasma; the major metabolite, salicylic acid, has an elimination half-life of 2-3 hours at low doses (eg 325 mg), which may increase to 30 hours at higher doses due to non-linearity in metabolism and binding to plasma proteins.
More than 90% of acetylsalicylic acid is eliminated as metabolites via the kidney.
The portion of unchanged eliminated salicylic acid in urine increases with increasing dose and renal clearance of total salicylate also increases with increasing urine pH.
Kinetics in patients with renal impairment
Administration of acetylsalicylic acid should be avoided in patients with severe renal insufficiency (glomerular filtration rate less than 10 ml / min).
An increase in total plasma concentrations and in the unbound fraction of salicylic acid has been reported.
Kinetics in patients with hepatic impairment
Administration of acetylsalicylic acid should be avoided in patients with severe hepatic insufficiency. An increase in the unbound fraction of salicylic acid has been reported.
05.3 Preclinical safety data
In single dose toxicity studies following oral administration of the combination of dipyridamole and acetylsalicylic acid, acute toxicity was associated with several grams per kg in rodents and 900 mg / kg in dogs.
This corresponded to the amount of acetylsalicylic acid contained in the mixture. The amount of dipyridamole was not found to have any additional or synergistic effect, regardless of the actual ratio (dipyridamole: acetylsalicylic acid = 1: 0.125 or 1: 4 to 1: 6). Cardiovascular insufficiency is considered a cause of death.
In repeat dose toxicity studies with a dipyridamole: acetylsalicylic acid ratio of 1: 4 to 1: 5 for up to 6 months, up to 400 mg / kg were administered to rats and dogs. The rats tolerated these doses with no obvious signs of intoxication.
Doses of 200 mg / kg and above have been shown to be toxic to dogs, causing gastrointestinal changes caused by a level of 320 mg / kg of acetylsalicylic acid and myocardial and endocardial disorders and nephritis caused by a level of 40 mg / kg of dipyridamole. Comparable changes were also found with the individual components at similar doses. It can therefore be said that the combination did not produce any signs indicating additional or enhanced toxic effects.
Teratogenicity studies were conducted in rats and rabbits with doses up to maternotoxicity with a dipyridamole: acetylsalicylic acid ratio of 1: 5.4. Parallel to the group treated with the maximum dose, another group was treated with aspirin only, at the corresponding dose. Secondary to maternotoxicity at associated high doses (405 mg / kg in rats, 135 mg / kg in rabbits), a higher resorption rate, reaching 100% in rats, and a reduction in the weight of the offspring were determined. Malformations were observed only in the groups treated with acetylsalicylic acid only, but not in the groups treated with dipyridamole / acetylsalicylic acid.
Fertility studies and perinatal period studies have only been conducted with the individual components. No impairment of fertility was found. Due to the known effects of acetylsalicylic acid in advanced pregnancy, treatment with a combination of dipyridamole and acetylsalicylic acid is only recommended when there is real priority.
Treatment with this combination is particularly contraindicated during the last trimester of pregnancy. Since both components of the combination pass into breast milk, treatment during breastfeeding is not recommended, despite low milk concentrations.
Thorough screening for mutagenicity in in vitro and in vivo studies revealed no signs indicating a risk of mutagenicity.
Carcinogenic potential was studied in rats and mice at maximum doses of 450 mg / kg, corresponding to 75 mg / kg of dipyridamole and 375 mg / kg of acetylsalicylic acid. There was no indication of carcinogenic potential.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Tartaric acid, povidone, methacrylic acid-methyl methacrylate copolymer (1: 2), talc, gum arabic, hypromellose phthalate, hypromellose, triacetin, dimethicone 350, stearic / palmitic acid, lactose monohydrate, aluminum stearate, colloidal silica, corn starch, microcrystalline cellulose, sucrose, E 171; capsule (hard): gelatine, E 171, E 172, purified water.
06.2 Incompatibility
Incompatibilities with other medicines are unknown.
06.3 Period of validity
3 years.
06.4 Special precautions for storage
Store below 30 ° C, keep the bottle closed to protect from moisture.
06.5 Nature of the immediate packaging and contents of the package
White opaque polypropylene bottle with child resistant polyethylene and polypropylene screw cap.
06.6 Instructions for use and handling
No special instructions.
07.0 MARKETING AUTHORIZATION HOLDER
BOEHRINGER INGELHEIM ITALIA S.p.A.
Via Lorenzini, 8
20139 Milan
08.0 MARKETING AUTHORIZATION NUMBER
50 capsules A.I.C. n. 033181037
60 capsules A.I.C. n. 033181049
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
01.10.2001/01.10.2006
10.0 DATE OF REVISION OF THE TEXT
July 14, 2015
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