Valdorin

Hard gelatin capsule size '2' having pink coloured cap and clear transparent body containing white and orange colour blended spherical pellets.
Each capsule contains: Clopidogrel (as bisulfate) eq. to Clopidogrel 75 mg, Aspirin 75 mg.

Pharmacology: Pharmacodynamics: Mechanism of action: Clopidogrel is an inhibitor of platelet aggregation. A variety of drugs that inhibit platelet function have been shown to decrease morbid events in people with established atheroschlerotic cardiovascular disease as evidenced by stroke or transient ischemic attacks, myocardial infarction, or need for bypass or angioplasty. This indicates that platelets participate in the initiation and/or evolution of these events and that inhibiting them can reduce the event rate. The salicylates alleviate pain by virtue of both a peripheral and a central nervous system effect. Salicylates, by inhibiting the synthesis of prostaglandins that occur in inflamed tissues, prevent the sensitization of pain receptors to mechanical stimulation or to chemical such as bradykinin, that appear to mediate the pain response. Direct effects on the central nervous system have been described and suggest a hypothalamic site for the analgesic as well as the antipyretic effects.
Pharmacokinetics: Aspirin: Absorption after oral administration of a solution of aspirin is usually complete, while enteric-coated capsule are less reliably absorbed. Absorption of aspirin formulated as regular unbuffered capsules is intermediate between that of solution and of enteric-coated preparations and is usually greater than 80%. Presystemic metabolism of aspirin to salicylate results in little or no systemic availability of low oral doses, and is believed that aspirin in portal venous blood accounts for the effect of low doses on platelets. After 500 mg, peak plasma concentration of aspirin are achieved in about 14 minutes, while peak salicylic acid concentration are obtained at 0.5 to 1 h after dosing. The plasma half-life of aspirin is 15-20 min., salicylic acid exhibits dose-dependent kinetics, the apparent half-life after a 300 mg dose being around 3 h, after 1 g dose, around 5-6 h, after a 10 g dose around 20 h. The volume of distribution of aspirin is 0.15-0.21 kg^-1. Protein binding of aspirin occurs to an unknown but variable extent that is time as well as concentration dependent. Plasma albumin is acetylated by aspirin. Salicylates is also variably bound to plasma protein, the percentage bound decreasing with concentration. Salicylate penetrates into the breast milk, saliva, joint fluids, and cerebrospinal fluid, being detectable in concentration approximately 1.5 times those of blood in these fluids.
Fetal levels exceed concentration in maternal plasma.
Oral Absorption >80%.
Presystemic metabolism high.
Plasma half-life range 15-20 min.
(salicylate: 3-20 h).
Volume of distribution 0.21 kg^-1.
Plasma protein binding variable.

Clopidogrel + Aspirin capsules is indicated for the secondary prevention of atherothrombotic events in adult patients already taking both clopidogrel and acetylsalicylic acid (ASA). Clopidogrel + Aspirin capsules is a fixed-dose combination medicinal product for continuation of therapy in: Non-ST segment elevation acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction) including patients undergoing a stent placement following percutaneous coronary intervention.
ST segment elevation acute myocardial infarction in medically treated patients eligible for thrombolytic therapy.

Clopidogrel + Aspirin capsules should be given as a single daily 75 mg/75 mg dose.
Clopidogrel + Aspirin capsules fixed-dose combination is used following initiation of therapy with Clopidogrel and ASA given separately, and replaces the individual Clopidogrel and ASA products.
In patients with non-ST segment elevation acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction): The optimal duration of treatment has not been formally established. Clinical trial data support use up to 12 months, and the maximum benefit was seen at 3 months. If the use of Clopidogrel + Aspirin capsules is discontinued, patients may benefit with continuation of one antiplatelet medicinal product.
In patients with ST segment elevation acute myocardial infarction: Therapy should be started as early as possible after symptoms start and continued for at least four weeks. The benefit of the combination of Clopidogrel with ASA beyond four weeks has not been studied in this setting. If the use of Clopidogrel + Aspirin capsules is discontinued, patients may benefit with continuation of one antiplatelet medicinal product.
If a dose is missed: Within less than 12 hours after regular scheduled time: patients should take the dose immediately and then take the next dose at the regular scheduled time.
For more than 12 hours: patients should take the next dose at the regular scheduled time and should not double the dose.
Pediatrics population: The safety and efficacy of Clopidogrel + Aspirin capsules in children and adolescents under 18 years old have not been established. Clopidogrel + Aspirin capsules is not recommended in this population.
Renal impairment: Clopidogrel + Aspirin capsules must not be used in patients with severe renal impairment. Therapeutic experience is limited in patients with mild to moderate renal impairment. Therefore, Clopidogrel + Aspirin capsules should be used with caution in these patients.
Hepatic impairment: Clopidogrel + Aspirin capsules must not be used in patients with severe hepatic impairment.
Therapeutic experience is limited in patients with moderate hepatic disease who may have bleeding diatheses.
Therefore, Clopidogrel + Aspirin capsules should be used with caution in these patients.

Clopidogrel: Overdose following clopidogrel administration may lead to prolonged bleeding time and subsequent bleeding complications. A single oral dose of clopidogrel at 1500 or 2000 mg/kg was lethal to mice and to rats and at 3000 mg/kg to baboons. Symptoms of acute toxicity were vomiting (in baboons), prostration, difficult breathing, and gastrointestinal hemorrhage in all species.
Recommendations About Specific Treatment: Based on biological plausibility, platelet transfusion may be appropriate to reverse the pharmacological effects of Clopidogrel if quick reversal is required.
Aspirin: Salicylate poisoning is usually associated with plasma concentrations >350 mg/L (2.5 mmol/L). Most adult deaths occur in patients whose concentrations exceed 700 mg/L (5.1 mmol/L). Single doses less than 100 mg/kg are unlikely to cause serious poisoning.
Symptoms: Common features include vomiting, dehydration, tinnitus, vertigo, deafness, sweating, warm extremities with bounding pulses, increased respiratory rate and hyperventilation. Some degree of acid-base disturbance is present in most cases. A mixed respiratory alkalosis and metabolic acidosis with normal or high arterial pH (normal or reduced hydrogen ion concentration) is usual in adults or children over the age of four years. In children four years or less, a dominant metabolic acidosis with low arterial pH (raised hydrogen ion concentration) is common.
Acidosis may increase salicylate transfer across the blood brain barrier.
Uncommon features include haematemesis, hyperpyrexia, hypoglycaemia, hypokalaemia, thrombocytopaenia, increased INR/PTR, intravascular coagulation, renal failure and noncardiac pulmonary oedema. Central nervous system features including confusion, disorientation, coma and convulsions are less common in adults than in children.
Management: Give activated charcoal if an adult presents within one hour of ingestion of more than 250 mg/kg. The plasma salicylate concentration should be measured, although the severity of poisoning cannot be determined from this alone and the clinical and biochemical features must be taken into account. Elimination is increased by urinary alkalinisation, which is achieved by the administration of 1.26% sodium bicarbonate. The urine pH should be monitored. Correct metabolic acidosis with intravenous 8.4% sodium bicarbonate (first check serum potassium).
Forced diuresis should not be used since it does not enhance salicylate excretion and may cause pulmonary oedema. Haemodialysis is the treatment of choice for severe poisoning and should be considered in patients with plasma salicylate concentrations >700 mg/L (5.1 mmol/L) or lower concentrations associated with severe clinical or metabolic features. Patients under ten years or over 70 have increased risk of salicylate toxicity and may require dialysis at an earlier stage.

Hypersensitivity to the drug substance or any component of the product.
Active pathological bleeding such as peptic ulcer or intracranial hemorrhage.
Hypoprothrombinaemia, haemophilia and other bleeding disorders.
Active peptic ulceration or a history of peptic ulceration.
Gout.
Do not give to children aged under 16 years, unless specifically indicated (e.g. for Kawasaki's disease).

Clopidogrel: Thrombotic thrombocytopenic purpura (TTP): TTP has been reported rarely following use of Clopidogrel, sometimes after a short exposure (<2 weeks). TTP is a serious condition that can be fatal and requires urgent treatment including plasmapheresis (plasma exchange). It is characterized by thrombocytopenia, microangiopathic hemolytic anemia (schistocytes [fragmented RBCs] seen on peripheral smear), neurological findings, renal dysfunction, and fever.
General Precautions: Clopidogrel prolongs the bleeding time and therefore should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery, or other pathological conditions (particularly gastrointestinal and intraocular). If a patient is to undergo elective surgery and an antiplatelet effect is not desired, Clopidogrel should be discontinued 5 days prior to surgery. Due to the risk of bleeding and undesirable hematological 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.
In patients with recent TIA or stroke who are at high risk of recurrent ischemic events, the combination of aspirin and Clopidogrel has not been shown to be more effective than Clopidogrel alone, but the combination has been shown to increase major bleeding.
GI Bleeding: In CAPRIE, Clopidogrel was associated with a rate of gastrointestinal bleeding of 2.0%, vs. 2.7% on aspirin. In CURE, the incidence of major gastrointestinal bleeding was 1.3% vs. 0.7% (Clopidogrel + aspirin vs. placebo + aspirin, respectively).
Clopidogrel should be used with caution in patients who have lesions with a propensity to bleed (such as ulcers). Drugs that might induce such lesions should be used with caution in patients taking Clopidogrel.
Use in Hepatically Impaired Patients: Experience is limited in patients with severe hepatic disease, who may have bleeding diatheses. Clopidogrel should be used with caution in this population.
Use in Renally-impaired Patients: Experience is limited in patients with severe renal impairment. Clopidogrel should be used with caution in this population.
Aspirin: Caution should be exercised in patients with allergic disease, impairment of hepatic or renal function (avoid if severe) and dehydration.
Aspirin may also precipitate bronchospasm or induce attacks of asthma in susceptible subjects.
The elderly may be more susceptible to the toxic effects of salicylates. Continuous prolonged use of aspirin should be avoided in the elderly because of the risk of gastrointestinal bleeding.
Caution should be taken in patients with glucose-6-phosphate dehydrogenase deficiency as haemolytic anaemia may occur.
Aspirin may interfere with insulin and glucagon in diabetes.
Aspirin prolongs bleeding time, mainly by inhibiting platelet aggregation and therefore it should be discontinued several days before scheduled surgical procedures. Haematological & haemorrhagic effects can occur, and may be severe. Patients should report any unusual bleeding symptoms to their physician.
There is a possible association between aspirin and Reye's Syndrome when given to children. Reye's syndrome is a very rare disease, which affects the brain and liver, and can be fatal. For this reason aspirin should not be given to children aged under 16 years unless specifically indicated (e.g. for Kawasaki's disease).
Salicylates should not be used in patients with a history of coagulation abnormalities as they may also induce gastro-intestinal haemorrhage, occasionally major.
Aspirin should not be taken by patients with a stomach ulcer or a history of stomach ulcers.
Before commencing long term aspirin therapy for the management of cardiovascular or cerebrovascular disease patients should consult their doctor who can advise on the relative benefits versus the risks for the individual patient.
Use in Children: Safety and effectiveness in the pediatric population have not been established.

Pregnancy: There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of a human response, Clopidogrel should be used during pregnancy only if clearly needed. Caution should be exercised when considering use in pregnant patients. Maternal use of aspirin prior to birth may increase the risk of intracranial haemorrhage in premature or low birth weight infants and may contribute to maternal and neonatal bleeding.
Lactation: Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the nursing woman.
As aspirin is excreted in breast milk, Aspirin should not be taken by patients who are breastfeeding, as there is a risk of Reye's syndrome in the infant. High maternal doses may impair platelet function in the infant.

Clopidogrel: Hemorrhagic events: In CAPRIE patients receiving Clopidogrel, gastrointestinal hemorrhage occurred at a rate of 2.0%, and required hospitalization in 0.7%. In patients receiving aspirin, the corresponding rates were 2.7% and 1.1%, respectively. The incidence of intracranial hemorrhage was 0.4% for Clopidogrel compared to 0.5% for aspirin.
In CURE, Clopidogrel use with aspirin was associated with an increase in bleeding compared to placebo with aspirin. There was an excess in major bleeding in patients receiving Clopidogrel plus aspirin compared with placebo plus aspirin, primarily gastrointestinal and at puncture sites. The incidence of intracranial hemorrhage (0.1%), and fatal bleeding (0.2%), were the same in both groups.
Adverse Events occurring in ≥2.5% of patients using Clopidogrel in CAPRIE trial: Body as a Whole - general disorders: Chest pain, Accidental/inflicted injury, Influenza like symptoms, Pain and fatigue.
Cardiovascular disorders, general: Oedema, Hypertension.
Central and peripheral nervous system disorders: Headache, Dizziness.
GIT disorders: Abdominal pain, Diarrhea, Dyspepsia, Nausea.
Metabolic and nutritional: Hypercholesterolemia.
Musculoskeletal system disorder: Arthralgia, Back pain.
Platelets/bleeding and clotting disorders: Bruise/purpura, Epistaxis.
Psychiatric disorders: Depression.
Respiratory system disorders: Upper respiratory tract infection, Dyspnea, Rhinitis, Bronchitis, Coughing.
Dermatological: Rash/pruritus.
Urinary system disorders: Urinary tract infection.
Aspirin: Side effects are generally mild and infrequent: Blood and the lymphatic system disorders: Aspirin prolongs bleeding time, decreases platelet adhesiveness and, in large doses, may cause hypoprothrombinaemia. Thrombocytopenia may also occur. Bleeding disorders such as epistaxis, haematuria, purpura, ecchymoses, haemoptysis, gastrointestinal bleeding, haematoma and cerebral haemorrhage have occasionally been reported. Fatalities have occurred. Haemolytic anaemia can occur in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency.
Immune system disorder: Hypersensitivity reactions include skin rashes, urticaria, angioedema, asthma, bronchospasm, rhinitis and rarely, anaphylaxis.
Ear & Labyrinth disorder: Tinnitus.
Gastrointestinal disorders: Gastrointestinal irritation is common in patients taking aspirin preparations, and nausea, vomiting, dyspepsia, gastritis, gastrointestinal erosions and ulceration have been reported. Anaemia may occur following chronic gastrointestinal blood loss or acute haemorrhage.
Skin and subcutaneous tissue disorders: Skin reactions may occur in susceptible patients.
Renal and Urinary disorders: Urate kidney stones.

Clopidogrel: Study of specific drug interactions yielded the following results: Aspirin: Aspirin did not modify the clopidogrel-mediated inhibition of ADP-induced platelet aggregation. Concomitant administration of 500 mg of aspirin twice a day for 1 day did not significantly increase the prolongation of bleeding time induced by Clopidogrel. Clopidogrel potentiated the effect of aspirin on collagen-induced platelet aggregation. Clopidogrel and aspirin have been administered together for up to one year.
Heparin: In a study in healthy volunteers, Clopidogrel did not necessitate modification of the heparin dose or alter the effect of heparin on coagulation. Coadministration of heparin had no effect on inhibition of platelet aggregation induced by Clopidogrel.
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): In healthy volunteers receiving naproxen, concomitant administration of Clopidogrel was associated with increased occult gastrointestinal blood loss. NSAIDS and Clopidogrel should be coadministered with caution.
Warfarin: Because of the increased risk of bleeding, the concomitant administration of warfarin with Clopidogrel should be undertaken with caution.
Other Concomitant Therapy: No clinically significant pharmacodynamic interactions were observed when Clopidogrel was coadministered with atenolol, nifedipine, or both atenolol and nifedipine. The pharmacodynamic activity of Clopidogrel was also not significantly influenced by the coadministration of phenobarbital, cimetidine or estrogen. The pharmacokinetics of digoxin or theophylline were not modified by the coadministration of Clopidogrel (clopidogrel bisulfate).
At high concentrations in vitro, clopidogrel inhibits P450 (2C9). Accordingly, Clopidogrel may interfere with the metabolism of phenytoin, tamoxifen, tolbutamide, warfarin, torsemide, fluvastatin, and many non-steroidal anti-inflammatory agents, but there are no data with which to predict the magnitude of these interactions. Caution should be used when any of these drugs is coadministered with Clopidogrel.
In addition to the above specific interaction studies, patients entered into clinical trials with Clopidogrel received a variety of concomitant medications including diuretics, beta-blocking agents, angiotensin converting enzyme inhibitors, calcium antagonists, cholesterol lowering agents, coronary vasodilators, antidiabetic agents (including insulin), thrombolytics, heparins (unfractionated and LMWH), GPIIb/IIIa antagonists, antiepileptic agents and hormone replacement therapy without evidence of clinically significant adverse interactions.
There are no data on the concomitant use of oral anticoagulants, non study oral antiplatelet drugs and chronic NSAIDs with clopidogrel.
Drug/Laboratory Test Interactions: None known.
Aspirin: Anticoagulants: Aspirin may potentiate the effect of heparin and increases the risk of bleeding with oral anticoagulants, antiplatelet agents and fibrinolytics. Concomitant use is not recommended.
Other non-steroidal anti-inflammatory drugs (NSAIDs): Concurrent administration can increase side effects. Use of two or more NSAIDs increases risk of gastrointestinal haemorrhage. Experimental data suggest that ibuprofen may inhibit the effect of low dose aspirin on platelet aggregation when they are dosed concomitantly. However, the limitations of these data and the uncertainties regarding extrapolation of ex vivo data to the clinical situation imply that no firm conclusions can be made for regular ibuprofen use, and no clinically relevant effect is considered to be likely for occasional ibuprofen use.
Corticosteroids: The risk of gastrointestinal bleeding and ulceration is increased. Corticosteroids reduce the plasma salicylate concentration and salicylate toxicity may occur following withdrawal of corticosteroids.
Carbonic anhydrase inhibitors: Reduced excretion of acetazolamide; salicylate intoxication has occurred in patients on high dose salicylate regimes and carbonic anhydrase inhibitors. Concurrent administration of carbonic anhydrase inhibitors such as acetazolamide and salicylates may result in severe acidosis and increased central nervous system toxicity.
Antacids and adsorbents: The excretion of aspirin is increased in alkaline urine; kaolin possibly reduces absorption. Patients should be advised against ingesting antacids simultaneously to avoid premature drug release.
Mifepristone: The manufacturer of mifepristone recommends that aspirin should be avoided until eight to twelve days after mifepristone has been discontinued.
Antimetabolites: The activity of methotrexate may be markedly enhanced and its toxicity increased.
Antibacterials: The toxicity of sulfonamides may be increased.
Alcohol: Some of the effects of aspirin on the gastrointestinal tract are enhanced by alcohol.
Antiemetics: Metoclopramide enhances the effects of aspirin by increasing the rate of absorption.
ACE inhibitors: Aspirin may reduce the antihypertensive effect of ACE inhibitors.
Anti-epileptics: May enhance the effects of phenytoin and sodium valproate.
Diuretics: Antagonism of the diuretic effect of spironolactone.
Hypoglycaemic agents: Aspirin may enhance the effects of insulin and oral hypoglycaemic agents.
Leukotriene antagonists: The plasma concentration of zafirlukast is increased.
Uricosurics: Effect of probenecid and sulfinpyrazone may be reduced.
Thyroid function tests: Aspirin may interfere with thyroid function tests.

Shelf-life: 36 months.
Special precautions for storage: This medicinal product does not require any special storage conditions.
Storage conditions: Store at temperatures not exceeding 30°C.

Anticoagulants, Antiplatelets & Fibrinolytics (Thrombolytics)

B01AC30 - combinations ; Belongs to the class of platelet aggregation inhibitors excluding heparin. Used in the treatment of thrombosis.
N02BA01 - acetylsalicylic acid ; Belongs to the class of salicylic acids and derivatives agents. Used to relieve pain and fever.

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