Clopidogrel/ Aspirin

Registered South African indications:

• Reduction of atherothrombotic events in adult patients already taking both clopidogrel and aspirin
• Continuation therapy in acute coronary syndrome
  - For patients with non-ST-segment elevation acute coronary syndrome (unstable angina/non-Q-wave myocardial infarction (MI)) including patients who are to be managed medically and those who are to be managed with percutaneous coronary intervention (with or without stent) or CABG (coronary artery bypass graft), clopidogrel in combination with aspirin has been shown to decrease the rate of a combined endpoint of cardiovascular death, myocardial infarction (MI), or stroke as well as the rate of a combined endpoint of cardiovascular death, MI, stroke, or refractory ischaemia
  - For patients with ST-segment elevation acute myocardial infarction, clopidogrel in combination with aspirin has been shown to reduce the rate of death from any cause and the rate of a combined endpoint of death, re-infarction or stroke

Thrombotic thrombocytopenic purpura (TTP) has been reported to occur with clopidogrel/ aspirin  during post-marketing experience. Most cases were reported in the first two weeks of treatment. Medical prescribers should also warn patients about the signs and symptoms of thrombotic thrombocytopenic purpura. It is characterised by thrombocytopenia and microangiopathic haemolytic anaemia associated with either neurological findings, renal dysfunction or fever. TTP is a potentially fatal condition requiring prompt treatment, including plasmapheresis (plasma exchange).

Registered South African contraindications

Due to the presence of clopidogrel and aspirin in this combination product it is contraindicated in case of:

• Hypersensitivity to the active ingredients or any of the excipients in this combination product
• Pregnancy
• Breastfeeding
• Severe hepatic impairment
• Active or history of pathological bleeding such as recurrent peptic ulcer/haemorrhage/perforations or intracranial haemorrhage
• Safety and efficacy in children below the age of 18 have not been established. Aspirin has been implicated in Reye's syndrome, a rare but serious illness in children and teenagers with chickenpox and influenza
• Thrombocytopenia and platelet dysfunction

Due to the presence of aspirin in this combination product it is contraindicated in case of:

• Hypersensitivity (allergy) to nonsteroidal anti-inflammatory drugs (NSAIDs) and syndrome of asthma, rhinitis, and nasal polyps
• Pregnancy
• Breastfeeding
• Severe renal impairment
• Patients with pre-existing mastocytosis, in whom the use of acetylsalicylic acid may induce severe hypersensitivity reactions (including circulatory shock with flushing, hypotension, tachycardia and vomiting)
• Heart failure
• History of gastrointestinal bleeding, ulceration or perforation (PUBs) related to previous NSAIDs

South African recommendations

Caution in the following patient groups

• Mild to moderate renal impairment
• Mild to moderate hepatic impairment
• Elderly

Recent transient ischaemic attack or stroke

• In patients with recent transient ischaemic attack or stroke who are at high risk of recurrent ischaemic events, the combination of aspirin and clopidogrel has been shown to increase major bleeding

Acquired haemophilia

• Following use of clopidogrel, acquired haemophilia has been reported
• In cases of confirmed isolated activated partial thromboplastin time (aPTT) prolongation with or without bleeding, acquired haemophilia should be considered
• Patients with a confirmed diagnosis of acquired haemophilia should be managed and treated by specialists, and clopidogrel/ aspirin should be discontinued

Fluid retention and oedema

• In view of the inherent potential of NSAIDs, including aspirin, to cause fluid retention, heart failure may be precipitated in some compromised patients
• As fluid retention and oedema have been reported in association with clopidogrel/ aspirin therapy, caution is required in patients with a history of hypertension and/or heart failure

Elderly

• The elderly have an increased frequency of adverse reactions to NSAIDs, especially gastrointestinal bleeding, ulceration and perforation (PUBs) which may be fatal

Due to the presence of aspirin caution is required in the following

• Patients with a history of asthma or allergic disorders since they are at an increased risk of hypersensitivity reactions
• Patients with gout since low doses of aspirin increase serum uric acid concentrations
• Children, as there is an association between aspirin and Reye’s syndrome (a very rare disease which can be fatal) when aspirin is given to children
• Alcohol may increase the risk of gastrointestinal injury when taken with aspirin
• Alcohol should therefore be used with caution in patients taking clopidogrel/ aspirin
• Patients should be counselled about the bleeding risks involved with chronic, heavy alcohol use while taking clopidogrel/ aspirin
• In patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, clopidogrel/ aspirin must be administered under close medical supervision due to the risk of haemolysis
• Concomitant treatment with levothyroxine and salicylates, specifically at doses greater than 2.0g/day, should be avoided

Bleeding and haematological disorders

• Clopidogrel/ aspirin produces irreversible inhibition of platelet aggregation for the life of the platelet, which is 7-10 days
• Due to the risk of bleeding and haematological undesirable effects, blood cell count determination and/or other appropriate testing should be promptly considered whenever such suspected clinical symptoms arise during the course of treatment
• As there is a risk of bleeding intensity, concomitant administration of clopidogrel/ aspirin with warfarin is not recommended
• Caution is required when administering clopidogrel/ aspirin to patients who may be at risk of increased bleeding from trauma, surgery or other pathological conditions associated with bleeding diathesis as well as in patients receiving treatment with other nonsteroidal anti-inflammatory medicines including COX-2 inhibitors, heparin, glycoprotein IIb/IIIa inhibitors, selective serotonin reuptake inhibitors (SSRIs), or CYP2C19 strong inducers, or thrombolytics
• Patients should be monitored continuously and carefully for any signs of bleeding, including occult bleeding, especially but not limited to during the first weeks of treatment and/or after invasive cardiac procedures or surgery
• Clopidogrel/ aspirin should be discontinued 7 days prior to surgery in those patients who are to undergo elective surgery where an antiplatelet effect is not desired
• The concomitant administration of clopidogrel/ aspirin with oral anticoagulants is not recommended since it may increase the intensity of bleeding
• Clopidogrel/ aspirin prolongs bleeding time and should therefore be used with caution in patients who have lesions with a propensity to bleed, particularly gastrointestinal and intraocular
• Spinal and epidural anaesthesia should not be administered to a patient taking clopidogrel/ aspirin or for 7 days thereafter
• No lumbar puncture should be done during these 7 days due to risk of haematoma formation following lumbar puncture or spinal and epidural anaesthesia
• Patients should be told that it may take longer than usual to stop bleeding whilst on clopidogrel/ aspirin therapy, and that they should report any unusual bleeding, site or duration, to their medical practitioner
• Patients should inform medical practitioners and dentists that they are taking clopidogrel/ aspirin before any surgery is scheduled and before any new medicine is taken

Gastrointestinal cautions

• In patients with a history of gastrointestinal disease (GI) (e.g. ulcerative colitis, Crohn’s disease, hiatus hernia, gastro-oesophageal reflux disease, angiodysplasia), peptic ulcer, gastroduodenal haemorrhage or minor upper gastrointestinal symptoms, clopidogrel/ aspirin should be used with caution as the condition may be exacerbated or may be due to gastric ulceration which in turn may lead to gastric bleeding
• In patients with a history of ulcers, and the elderly, the risk of gastrointestinal bleeding, ulceration or perforation (PUBs) is higher with increasing doses of clopidogrel/ aspirin
• Should gastrointestinal bleeding, perforation or ulceration occur in patients receiving clopidogrel/ aspirin, therapy should be stopped
• Gastrointestinal side effects including stomach pain, heartburn, nausea, vomiting, and GI bleeding may occur
• Although minor upper GI symptoms such as dyspepsia are common and can occur anytime during therapy, medical practitioners should remain alert for signs of ulceration and bleeding, even in the absence of previous GI symptoms
• Patients should be told about signs and symptoms of GI side effects and what steps to take if they occur
• In patients concomitantly receiving nicorandil and NSAIDs including acetylsalicylic acid (ASA) and lysine acetylsalicylate (LAS), there is an increased risk for severe complications such as gastrointestinal ulceration, perforation and haemorrhage

Skin reactions

• Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported
• Clopidogrel/ aspirin should be discontinued at the first appearance of a skin rash, mucosal lesions, or any other sign of hypersensitivity

CYP2C19 pharmacogenetics

• In patients who are poor CYP2C19 metabolisers, clopidogrel at recommended doses forms less of the active metabolite of clopidogrel and has a smaller effect on platelet function
• Poor metabolisers with acute coronary syndrome or undergoing percutaneous coronary intervention treated with clopidogrel at recommended doses may exhibit higher cardiovascular event rates than patients with normal CYP2C19 function
• Tests are available to identify a patient’s CYP2C19 genotype; these tests can be used as an aid in determining therapeutic strategy
• Use of medicines that induce the activity of CYP2C19 would be expected to result in increased medicine levels of the active metabolite of clopidogrel and might potentiate the bleeding risk
• As a precaution, concomitant use of strong CYP2C19 inducers should be discouraged

CYP2C8 substrates

• Caution is required in patients treated concomitantly with clopidogrel and CYP2C8 substrate medicinal products

Cross-reactivity among thienopyridines

• As cross-reactivity among thienopyridines has been reported, patients should be evaluated for history of hypersensitivity to another thienopyridine such as ticlopidine, prasugrel
• Thienopyridines may cause mild to severe allergic reactions such as rash, angioedema, or haematological reactions such as thrombocytopenia and neutropenia
• Patients who had developed a previous allergic reaction and/or haematological reaction to one thienopyridine may have an increased risk of developing the same or another reaction to another thienopyridine
• Monitoring for cross-reactivity is advised

Hepatic impairment

• Clopidogrel/ aspirin is contraindicated in patients with severe hepatic impairment (see Contraindications)
• Caution is advised in patients with mild to moderate hepatic impairment
• Therapeutic experience is limited in patients with moderate hepatic disease who may have bleeding diatheses
• Therefore clopidogrel/ aspirin should be used with caution in this population

Renal impairment

• Clopidogrel/ aspirin is contraindicated in patients with severe renal impairment (see Contraindications)
• Therapeutic experience with clopidogrel/ aspirin is limited in patients with mild to moderate renal impairment
• Clopidogrel/ aspirin should therefore be used with caution in this population

Excipients with known effect

• Clopidogrel/ aspirin contains lactose
• Patients with the rare hereditary conditions of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take clopidogrel/ aspirin
• Clopidogrel/ aspirin contains hydrogenated castor oil which may cause stomach upset and diarrhoea

Effects on ability to drive and use machines

• Clopidogrel/ aspirin has no or negligible influence on the ability to drive and use machines

Forms avail in SA and covered in this monograph: fct, tab

South African registered indications and dosages

Acute Coronary Syndrome

Clopidogrel/ Aspirin
75/75 (mg) 

• Oral (fct, tab): 1 tab, as a single daily dose; Clopidogrel/ aspirin is used following an initial loading dose of clopidogrel in combination with aspirin

- In patients with non-ST segment elevation acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction)

• Oral (fct, tab): 1 tab, as a single daily dose; Treatment duration: 3-12 months

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The optimal duration of treatment has not been formally established. Clinical trial data support use up to 12 months, but the maximum benefit was seen at 3 months

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- In patients with ST segment elevation acute myocardial infarction

• Oral (fct, tab): 1 tab, as a single daily dose; Therapy should be started as early as possible after symptoms start; Max treatment duration: 4 weeks

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The benefit of the combination of clopidogrel with aspirin beyond 4 weeks has not been studied in this setting. See Elderly for dose recommendations for patients older than 75 years

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Pharmacogenetics: CYP2C19 poor metaboliser status is associated with diminished antiplatelet response to clopidogrel. An appropriate dose regimen for this patient population has not been established in clinical outcome trials

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Method of administration: For oral use. Clopidogrel/ aspirin may be given with or without food

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Missed dose: Medical practitioners should advise patients who forget to take clopidogrel/ aspirin to take a dose as soon as possible and then continue with the normal dose. Patients should not take a double dose to compensate for the missed dose

Not established for use in children below 18 years

Pregnancy

South African recommendations

• Contraindicated
• Clopidogrel/ aspirin is contraindicated during pregnancy

Breastfeeding

South African recommendations

• Contraindicated
• Clopidogrel/ aspirin is contraindicated whilst breastfeeding
• Studies in rats have shown that clopidogrel and/or its metabolites are excreted in the milk. It is not known whether clopidogrel is excreted in human breast milk. Aspirin is known to be excreted in human breast milk

Fertility

South African recommendations

• There are no fertility data with clopidogrel/ aspirin

South African recommendations

• Mild to moderate: Caution; no dose adjustment recommended
• Therapeutic experience with clopidogrel/ aspirin is limited in patients with mild to moderate renal impairment. Clopidogrel/ aspirin should therefore be used with caution in this population
• Severe: Contraindicated

South African recommendations

• Mild to moderate: Caution; no dose adjustment recommended
  Caution is advised in patients with mild to moderate hepatic impairment
  Therapeutic experience is limited in patients with moderate hepatic disease who may have bleeding diatheses. Therefore clopidogrel/ aspirin should be used with caution in this population
• Severe: Contraindicated

South African recommendations

• Caution; dose adjustment recommended
  For patients older than 75 years of age therapy should be initiated without a loading dose of clopidogrel
  The elderly have an increased frequency of adverse reactions to NSAIDs, especially gastrointestinal bleeding, ulceration and perforation (PUBs) which may be fatal

Clopidogrel/ Aspirin

Blood and Lymphatic System Disorders

Less frequent

• Thrombocytopenia (sometimes severe)
• Increased bleeding time
• Leucopenia
• Eosinophilia
• Neutropenia (sometimes severe)
• Decreased platelets 
• Aplastic anaemia

Frequency unknown

• Bleeding (post-marketing) 

Nervous System Disorders

Less frequent

• Intracranial bleeding
• Headache
• Dizziness
• Paraesthesia

Eye Disorders

Less frequent

• Eye bleeding (mainly conjunctival, ocular, retinal)

Ear and Labyrinth Disorders

Less frequent

• Vertigo

Vascular Disorders

Frequent

• Haematoma

Respiratory, Thoracic and Mediastinal Disorders

Frequent

• Epistaxis

Gastrointestinal Disorders

Frequent

• Dyspepsia
• Abdominal pain
• Diarrhoea
• Gastrointestinal haemorrhage

Less frequent

• Nausea
• Gastritis
• Flatulence
• Constipation
• Vomiting
• Gastric ulcer
• Duodenal ulcer

Skin and Subcutaneous Tissue Disorders

Frequent

• Bruising

Less frequent

• Rash
• Pruritus
• Purpura

Renal and Urinary Disorders

Less frequent

• Haematuria

General Disorders and Administrative Site Conditions

Frequent

• Bleeding at the puncture site

Clopidogrel

Blood and Lymphatic System Disorders

Frequency unknown

• Serious cases of bleeding, mainly skin, musculoskeletal (haemarthrosis), eye (conjunctival, ocular, retinal) and respiratory tract bleeding (haemoptysis, pulmonary haemorrhage)
• Epistaxis
• Haematuria
• Haemorrhage of operative wound
• Cases of bleeding with fatal outcome, especially intracranial, gastrointestinal and retroperitoneal haemorrhage
• Acquired haemophilia A
• Serious haemorrhage in patients taking clopidogrel/ aspirin with or without heparin
• Thrombotic thrombocytopenic purpura (TTP)
• Aplastic anaemia/pancytopenia
• Agranulocytosis
• Severe thrombocytopenia
• Granulocytopenia
• Anaemia

Immune System Disorders

Frequency unknown

• Anaphylactoid reactions
• Serum sickness
• Cross-reactive medicine hypersensitivity among thienopyridines, such as ticlopidine or prasugrel
• Insulin autoimmune syndrome, which can lead to severe hypoglycaemia, particularly in patients with HLA DRA4 subtype (more frequent in the Japanese population)

Cardiac Disorders

Frequency unknown

• Kounis syndrome (vasospastic allergic angina/allergic myocardial infarction) in the context of a hypersensitivity reaction due to clopidogrel

Psychiatric Disorders

Frequency unknown

• Confusion
• Hallucinations

Nervous System Disorders

Frequency unknown

• Taste disturbances
• Ageusia

Vascular Disorders

Frequency unknown

• Vasculitis
• Hypotension

Respiratory, Thoracic and Mediastinal Disorders

Frequency unknown

• Bronchospasm
• Interstitial pneumonitis
• Eosinophilic pneumonia

Gastrointestinal Disorders

Frequency unknown

• Colitis (including ulcerative or lymphocytic colitis)
• Stomatitis
• Pancreatitis

Hepatobiliary Disorders

Frequency unknown

• Acute liver failure
• Hepatitis
• Abnormal liver function test

Skin and Subcutaneous Tissue Disorders

Frequency unknown

• Maculopapular, erythematous or exfoliative rash
• Urticaria
• Pruritus
• Angioedema
• Bullous dermatitis
  - Erythema multiforme
  - Stevens-Johnson syndrome
  - Toxic epidermal necrolysis
  - Acute generalised exanthematous pustulosis (AGEP))
• Drug-induced hypersensitivity syndrome (DiHS)
• Drug rash with eosinophilia and systemic symptoms (DRESS)
• Eczema
• Lichen planus

Musculoskeletal, Connective Tissue and Bone Disorders

Frequency unknown

• Arthritis
• Arthralgia
• Myalgia

Renal and Urinary Disorders

Frequency unknown

• Glomerulonephritis
• Increased blood creatinine

Reproductive System and Breast Disorders

Frequency unknown

• Gynaecomastia

General Disorders and Administrative Site Conditions

Frequency unknown

• Fever

Aspirin

Blood and Lymphatic System Disorders

Frequency unknown

• Thrombocytopenia
• Haemolytic anaemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency
• Pancytopenia
• Bicytopenia
• Aplastic anaemia
• Bone marrow failure
• Agranulocytosis
• Neutropenia
• Leukopenia

Immune System Disorders

Frequency unknown

• Anaphylactic shock
• Aggravation of allergic symptoms of food allergy

Cardiac Disorders

Frequency unknown

• Kounis syndrome in the context of a hypersensitivity reaction due to aspirin 

Metabolism and Nutrition Disorders

Frequency unknown

• Hypoglycaemia
• Gout

Nervous System Disorders

Frequency unknown

• Intracranial haemorrhage (may be fatal, especially in the elderly)

Ear and Labyrinth Disorders

Frequency unknown

• Hearing loss
• Tinnitus

Vascular Disorders

Frequency unknown

• Hypertension
• Cardiac failure
• Vasculitis including Henoch-Schönlein purpura

Respiratory, Thoracic and Mediastinal Disorders

Frequency unknown

• Non-cardiogenic pulmonary oedema with chronic use and in the context of a hypersensitivity reaction due to aspirin 

Gastrointestinal Disorders

Frequent

• Gastro-duodenal ulcer/perforations
• Upper gastrointestinal symptoms such as gastralgia
• Peptic ulcers
• Small (jejunum and ileum) and large (colon and rectum) intestinal ulcers
• Perforation or gastrointestinal bleeding, sometimes fatal
• Oesophagitis
• Oesophageal ulceration
• Perforation
• Erosive gastritis
• Erosive duodenitis
• Colitis

(These reactions may or may not be associated with haemorrhage, and may occur at any dose of aspirin and in patients with or without warning symptoms or a previous history of serious gastrointestinal events)

• Nausea
• Vomiting
• Diarrhoea
• Flatulence
• Constipation
• Dyspepsia
• Abdominal pain
• Melaena
• Haematemesis
• Ulcerative stomatitis
• Exacerbation of colitis and Crohn’s disease
• Gastritis
• Acute pancreatitis in the context of a hypersensitivity reaction due to aspirin 

Hepatobiliary Disorders

Frequency unknown

• Elevation of hepatic enzymes
• Liver injury, mainly hepatocellular
• Chronic hepatitis

Skin and Subcutaneous Tissue Disorders

Frequency unknown

• Bullous reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis
• Fixed eruption

Renal and Urinary Disorders

Frequency unknown

• Renal failure
• Acute renal impairment (especially in patients with existing renal impairment, heart decompensation, nephritic syndrome, or concomitant treatment with diuretics)

General Disorders and Administrative Site Conditions

Frequency unknown

• Oedema

Clopidogrel/ Aspirin

• Medicines associated with bleeding risk
• Nicorandil
• Injectable anticoagulants
• Heparins
• Thrombolytics
• Fibrin-specific thrombolytic agents
• Non-fibrin specific thrombolytic agents
• Oral anticoagulants
• Warfarin
• Glycoprotein IIb/IIIa inhibitors
• Nonsteroidal anti-inflammatory drugs (NSAIDs)
• Naproxen
• COX-2 inhibitors
• Ibuprofen
• Selective serotonin reuptake inhibitors (SSRIs)
• Moderate and strong CYP2C19 inhibitors
• Rifampicin
• Omeprazole
• Esomeprazole
• Proton pump inhibitors
• CYP2C8 substrate medicines
• Repaglinide
• Paclitaxel
• Rosuvastatin
• CYP2C9 substrate medicines
• Torsemide
• Tamoxifen
• Fluvastatin
• Opioid agonists
• Morphine

Aspirin

• Uricosurics
• Methotrexate (doses higher than 20mg/week)
• Metamizole
• NSAIDs
• Corticosteroids
• Selective serotonin reuptake inhibitors (SSRIs)
• Acetazolamide
• Varicella vaccine
• Levothyroxine
• Valproic acid
• Tenofovir disoproxil fumarate
• Angiotensin converting enzyme (ACE) inhibitors
• Anticonvulsants
• Phenytoin
• Valproic acid
• Beta blockers
• Diuretics
• Oral hypoglycaemic medicines

Other interactions

• Alcohol

None routine. Specific cases may require

• Renal function
• Hepatic function
• Platelet count
• Thyroid hormone levels (when coadministered with levothyroxine)
• CYP2C19 genotype

Additional observations

• Monitoring for cross-reactivity
• Bleeding

Clopidogrel
Clopidogrel is a specific and potent inhibitor of platelet aggregation. Clopidogrel is a promedicine, one of whose metabolites is an inhibitor of platelet aggregation. Clopidogrel must be metabolised by CYP450 enzymes to produce the active metabolite that inhibits platelet aggregation. The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet P2Y12 receptor and the subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. Due to the irreversible binding, platelets exposed are affected for the remainder of the lifespan (approximately 7-10 days) and recovery of normal platelet function occurs at a rate consistent with platelet turnover. Platelet aggregation induced by agonists other than ADP is also inhibited by blocking the amplification of platelet activation by released ADP.

Aspirin (Acetylsalicylic acid)

Aspirin inhibits platelet aggregation by irreversible inhibition of prostaglandin cyclo-oxygenase and thus inhibits the generation of thromboxane A2, an inducer of platelet aggregation and vasoconstriction. This effect lasts for the life of the platelet.

COMBINATION PREPARATIONS

Clopidogrel/ Acetylsalicylic

Tablet 75mg/75mg 

• Clopiwin Plus 75/75 (Zentiva) Originator