Naya Sa

Uses

Aspirin is used for its antiplatelet activity in the initial treatment of cardiovascular disorders such as angina pectoris and myocardial infarction and for the prevention of cardiovascular events in a variety of conditions or procedures for patients at risk.

• Aspirin is used as part of the initial treatment of unstable angina.
• It is given in the early treatment of myocardial infarction.
• It may also be of some benefit in the initial treatment of acute ischaemic stroke.
• It is of value for the secondary prevention of cardiovascular events in patients with stable or unstable angina or those with acute or prior myocardial infarction.
• Aspirin reduces the risk of future serious vascular events, including stroke, in patients who have already suffered an ischaemic stroke or transient ischaemic attack.
• It is of use in the long-term management of atrial fibrillation, for the prevention of stroke in patients with contraindications to warfarin or if there are no other risk factors for stroke.
• It is recommended for use in preventing thrombotic complications associated with procedures such as angioplasty and coronary bypass grafting.

Esomeprazole is used for:

• Treatment of Gastroesophageal Reflux Disease (GERD)
• Healing of Erosive Esophagitis
• Maintenance of Healing of Erosive Esophagitis
• Symptomatic Gastroesophageal Reflux Disease
• H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence
• Zollinger-Ellison Syndrome
• Acid Related Dyspepsia
• Duodenal and Gastric Ulcer

Naya Sa is also used to associated treatment for these conditions: Acute Coronary Syndrome (ACS), Anxiety, Arthritis, Atherothrombotic cerebral infarction, Cardiovascular Disease (CVD), Cardiovascular Events, Cardiovascular Mortality, Colorectal Adenomas, Colorectal Cancers, Common Cold, Coronary artery reocclusion, Death, Dyspeptic signs and symptoms, Fever, Flu Like Symptom, Flu caused by Influenza, Headache, Heterozygous Familial Hypercholesterolemia, Inflammation, Juvenile Idiopathic Arthritis (JIA), Kawasaki Syndrome, Major Adverse Cardiovascular and Cerebrovascular Events (MACCE), Migraine, Morbidity, Mucocutaneous Lymph Node Syndrome, Muscle Contraction, Myocardial Infarction, Myocardial Infarction (MI), first occurrence, Neuralgia, Pain, Pain caused by Common Cold, Pain, Menstrual, Pericarditis, Polycythemia Vera (PV), Preeclampsia, Rheumatic Pain, Rheumatism, Rheumatoid Arthritis, Rhinosinusitis, Severe Pain, Soreness, Muscle, Spondyloarthropathies, Stroke, Systemic Lupus Erythematosus (SLE), Tension Headache, Thromboembolism, Toothache, Transient Ischemic Attack, Venous Thromboembolism, Acute Inflammation, Atherothrombotic events, Death by myocardial infarction, Moderate Pain, Thrombotic events, Antiplatelet Therapy, Hemodialysis Treatment, Secondary PreventionDuodenal Ulcer, Erosive Esophagitis, Gastro-esophageal Reflux Disease (GERD), Heartburn, Helicobacter Pylori Infection, NSAID Associated Gastric Ulcers, Stress Ulcers, Upper Gastrointestinal Hemorrhage, Zollinger-Ellison Syndrome, Acute benign gastric ulcers, Maintenance of healing Erosive esophagitis, Postendoscopy Bleeding

How Naya Sa works

Acetylsalicylic acid (ASA) blocks prostaglandin synthesis. It is non-selective for COX-1 and COX-2 enzymes . Inhibition of COX-1 results in the inhibition of platelet aggregation for about 7-10 days (average platelet lifespan). The acetyl group of acetylsalicylic acid binds with a serine residue of the cyclooxygenase-1 (COX-1) enzyme, leading to irreversible inhibition. This prevents the production of pain-causing prostaglandins. This process also stops the conversion of arachidonic acid to thromboxane A2 (TXA2), which is a potent inducer of platelet aggregation . Platelet aggregation can result in clots and harmful venous and arterial thromboembolism, leading to conditions such as pulmonary embolism and stroke.

It is important to note that there is 60% homology between the protein structures of COX-1 and COX-2. ASA binds to serine 516 residue on the active site of COX-2 in the same fashion as its binding to the serine 530 residue located on the active site of COX-1. The active site of COX-2 is, however, slightly larger than the active site of COX-1, so that arachidonic acid (which later becomes prostaglandins) manages to bypass the aspirin molecule inactivating COX-2 . ASA, therefore, exerts more action on the COX-1 receptor rather than on the COX-2 receptor . A higher dose of acetylsalicylic acid is required for COX-2 inhibition .

Esomeprazole exerts its stomach acid-suppressing effects by preventing the final step in gastric acid production by covalently binding to sulfhydryl groups of cysteines found on the (H+, K+)-ATPase enzyme at the secretory surface of gastric parietal cells. This effect leads to inhibition of both basal and stimulated gastric acid secretion, irrespective of the stimulus. As the binding of esomeprazole to the (H+, K+)-ATPase enzyme is irreversible and new enzyme needs to be expressed in order to resume acid secretion, esomeprazole's duration of antisecretory effect that persists longer than 24 hours.

Dosage

Naya Sa dosage

Pain, Inflammatory diseases and as Antipyretic: Aspirin 300 mg 1-3 tablets 6 hourly with a maximum daily dose of 4 g.

Thrombotic cerebrovascular or Cardiovascular disease: Aspirin 300 mg 1 tablet or Aspirin 75 mg 4 tablets daily.

After Myocardial infarction: Aspirin 75 mg 2 tablets daily for 1 month.

Following By-pass surgery: Aspirin 75 mg 1 tablet daily.

Tablet:

Healing of erosive esophagitis: 20 mg or 40 mg once daily for 4 to 8 Weeks. For those patients who have not healed after 4-8 weeks of treatment, an additional 4-8 weeks course of Esomeprazole may be considered.

Long-term management of esophagitis: 20 mg once daily.

Symptomatic gastroesophageal reflux disease: 20 mg once daily for 4 weeks.

H. pylori eradication for treatment of duodenal ulcer:

Triple therapy: 20 mg Esomeprazole once daily with 500 mg Clarithromycin twice daily, and 1 g Amoxicillin twice daily for 7-10 days.

Injection:

The recommended adult dose in GERD with Erosive Esophagitis is either 20 or 40 mg Esomeprazole given once daily by intravenous injection (no less than 3 minutes) or intravenous infusion (10 to 30 minutes). Pediatric dose (1 to 11 years old):

• Short term treatment of symptomatic GERD: 10 mg once daily for up to 8 weeks.

Healing of erosive esophagitis:

• Weight <20 kg: 10 mg once daily for up to 8 weeks.
• Weight ≥20 kg: 10 mg or 20 mg once daily forup to 8 weeks.

Directions for reconstitution of solution: Solution for injection is prepared by adding 5 ml of 0.9% Sodium Chloride for intravenous injection into the vial containing the dry powder. The reconstituted solution for injection is clear and colorless to very slightly yellow.

Preparations for Use and Administration of Esomeprazole 40 IV Injection: A solution for intravenous infusion is prepared by first reconstituting the contents of one vial with 5 ml of 0.9% Sodium Chloride and further diluting the resulting solution to a final volume of 50 ml. The resultant concentration after diluting to a final volume of 50 ml is 0.8 mg/ml.

• 20 mg dose: Withdraw 25 ml of the final solution and administer as an intravenous infusion over 10 minutes to 30 minutes.
• 10 mg dose: Withdraw 12.5 ml of the final solution and administer as an intravenous infusion over 10 minutes to 30 minutes.

Side Effects

Side effects for usual dosage of Aspirin are mild including nausea, dyspepsia, gastrointestinal ulceration and bronchospasm etc.

In general, esomeprazole is well tolerated in both short and long term use. Adverse events reported with esomeprazole include headache, diarrhoea, nausea, flatulence, abdominal pain, constipation and dry mouth.

Toxicity

Lethal doses

Acute oral LD50 values have been reported as over 1.0 g/kg in humans, cats, and dogs, 0.92 g/kg - 1.48 g/kg in albino rats, 1.19 g/kg in guinea pigs, 1.1 g/kg in mice, and 1.8 g/kg in rabbit models .

Acute toxicity

Salicylate toxicity is a problem that may develop with both acute and chronic salicylate exposure . Multiple organ systems may be affected by salicylate toxicity, including the central nervous system, the pulmonary system, and the gastrointestinal system. Severe bleeding may occur. In the majority of cases, patients suffering from salicylate toxicity are volume-depleted at the time of presentation for medical attention. Fluid resuscitation should occur immediately and volume status should be monitored closely. Disruptions in acid-base balance are frequent in ASA toxicity .

The acute toxicity of acetylsalicylic in animals has been widely studied. The signs of poisoning in rats from lethal doses are mild to severe gastroenteritis, hepatitis, nephritis, pulmonary edema, encephalopathy, shock and some toxic effects on other organs and tissues. Mortality has been observed following convulsions or cardiovascular shock. An important differentiating property between various animal species is the ability to vomit toxic doses. Humans, cats and dogs have this ability, but rodents or rabbits do not .

Chronic toxicity and carcinogenesis

Chronic ASA toxicity is frequently accompanied by atypical clinical presentations that may be similar to diabetic ketoacidosis, delirium, cerebrovascular accident (CVA), myocardial infarction (MI) or cardiac failure. Plasma salicylate concentrations should be measured if salicylate intoxication is suspected, even if there no documentation available to suggest ASA was ingested. In older age, nephrotoxicity from salicylates increases, and the risk of upper gastrointestinal hemorrhage is increased, with higher rates of mortality . It is also important to note that ASA toxicity may occur even with close to normal serum concentrations. Prevention of chronic ASA includes the administration of smallest possible doses, avoidance of concurrent use of salicylate drugs, and therapeutic drug monitoring. Renal function should be regularly monitored and screening for gastrointestinal bleeding should be done at regular intervals .

Chronic toxicity studies were performed in rodents. ASA was administered at doses measured to be 2 to 20 times the maximum tolerated clinical dose to mice for up to one year. Negative dose-related effects were seen. These include decreased mean survival time, decreased number of births and progeny reaching an appropriate age for weaning. No evidence of carcinogenesis was found in 1-year studies . At daily doses of 0.24 g/kg/day given for 100 days to albino rats, ASA led to signs to excessive thirst, aciduria, diuresis, drowsiness, hyperreflexia, piloerection, changes in respiration, tachycardia, followed by soft stools, epistaxis, sialorrhea, dacryorrhea and mortality during hypothermic coma in the second study month .

Use in pregnancy and lactation

While teratogenic effects were observed in animals nearly lethal doses, no evidence suggests that this drug is teratogenic in humans . It is advisable, however, to avoid ASA use the first and second trimester of pregnancy, unless it is clearly required. If acetylsalicylic acid containing drugs are ingested by a patient attempting to conceive, or during the first and second trimester of pregnancy, the lowest possible dose at the shortest possible duration should be taken . This drug is contraindicated in the 3rd trimester of pregnancy .

Blurred vision, confusion, drowsiness, dry mouth, flushing headache, nausea, rapid heartbeat, sweating

Precaution

It should be administered cautiously in asthma, uncontrolled blood pressure and pregnant women.It is specially important not to use aspirin during the last 3 months of pregnancy unless specifically directed to do so by a doctor because it may cause problems in unborn child or complication during delivery. It should be administered with caution to patients in nasal polyp and nasal allergy. Aspirin penetrates into breast milk. So, it should be administered with caution to lactating mothers.

Symptomatic response to therapy with Esomeprazole does not preclude the presence of gastric malignancy. Atrophic gastritis has been noted occasionally in gastric corpus biopsies from patients treated long-term with omeprazole, of which Esomeprazole is an enantiomer.

Interaction

Salicylates may enhance the effect of anticoagulants, oral hypoglycaemic agents, phenytoin and sodium valporate. They inhibit the uricosuric effect of probenecid and may increase the toxicity of sulphonamides. They may also precipitate bronchospasm or induce attacks of asthma in susceptible subjects.

Drug interaction studies have shown that Esomeparzole does not have any clinically significant interactions with Phenytoin, Warfarin, Quinidine, Clarithromycin or Amoxicillin. Esomeprazole inhibits gastric acid secretion. Therefore, Esomeprazole may interfere with the absorption of drugs where gastric pH is an important determinant of bioavailability (eg, Ketoconazole, Iron salts and Dogoxin). Coadministration of oral contraceptives, Diazepam, Phenytoin or Quinidine did not seem to change the pharmacokinetic profile of Esomeprazole.

Volume of Distribution

This drug is distributed to body tissues shortly after administration. It is known to cross the placenta. The plasma contains high levels of salicylate, as well as tissues such as spinal, peritoneal and synovial fluids, saliva and milk. The kidney, liver, heart, and lungs are also found to be rich in salicylate concentration after dosing. Low concentrations of salicylate are usually low, and minimal concentrations are found in feces, bile, and sweat .

The apparent volume of distribution at steady state in healthy volunteers is approximately 16 L.

Elimination Route

Absorption is generally rapid and complete following oral administration but absorption may be variable depending on the route, dosage form, and other factors including but not limited to the rate of tablet dissolution, gastric contents, gastric emptying time, and gastric pH .

Detailed absorption information

When ingested orally, acetylsalicylic acid is rapidly absorbed in both the stomach and proximal small intestine. The non-ionized acetylsalicylic acid passes through the stomach lining by passive diffusion. Ideal absorption of salicylate in the stomach occurs in the pH range of 2.15 - 4.10. Intestinal absorption of acetylsalicylic acid occurs at a much faster rate. At least half of the ingested dose is hydrolyzed to salicylic acid in the first-hour post-ingestion by esterases found in the gastrointestinal tract. Peak plasma salicylate concentrations occur between 1-2 hours post-administration .

After oral administration, peak plasma levels (Cmax) occur at approximately 1.5 hours (Tmax). The Cmax increases proportionally when the dose is increased, and there is a three-fold increase in the area under the plasma concentration-time curve (AUC) from 20 to 40 mg. At repeated once-daily dosing with 40 mg, the systemic bioavailability is approximately 90% compared to 64% after a single dose of 40 mg. The mean exposure (AUC) to esomeprazole increases from 4.32 μmolhr/L on Day 1 to 11.2 μmolhr/L on Day 5 after 40 mg once daily dosing. The AUC after administration of a single 40 mg dose of Esomeprazole is decreased by 43% to 53% after food intake compared to fasting conditions. Esomeprazole should be taken at least one hour before meals.

Combination Therapy with Antimicrobials:

Esomeprazole magnesium 40 mg once daily was given in combination with Clarithromycin 500 mg twice daily and Amoxicillin 1000 mg twice daily for 7 days to 17 healthy male and female subjects. The mean steady state AUC and Cmax of esomeprazole increased by 70% and 18%, respectively during triple combination therapy compared to treatment with esomeprazole alone. The observed increase in esomeprazole exposure during co-administration with clarithromycin and amoxicillin is not expected to produce significant safety concerns.

Half Life

The half-life of ASA in the circulation ranges from 13 - 19 minutes. Blood concentrations drop rapidly after complete absorption. The half-life of the salicylate ranges between 3.5 and 4.5 hours .

1-1.5 hours

Clearance

The clearance rate of acetylsalicylic acid is extremely variable, depending on several factors . Dosage adjustments may be required in patients with renal impairment . The extended-release tablet should not be administered to patients with eGFR of less than 10 mL/min .

Elimination Route

Excretion of salicylates occurs mainly through the kidney, by the processes of glomerular filtration and tubular excretion, in the form of free salicylic acid, salicyluric acid, and, additionally, phenolic and acyl glucuronides .

Salicylate can be found in the urine soon after administration, however, the entire dose takes about 48 hours to be completely eliminated. The rate of salicylate is often variable, ranging from 10% to 85% in the urine, and heavily depends on urinary pH. Acidic urine generally aids in reabsorption of salicylate by the renal tubules, while alkaline urine increases excretion .

After the administration of a typical 325mg dose, the elimination of ASA is found to follow first order kinetics in a linear fashion. At high concentrations, the elimination half-life increases .

The plasma elimination half-life of esomeprazole is approximately 1 to 1.5 hours. Less than 1% of parent drug is excreted in the urine. Approximately 80% of an oral dose of esomeprazole is excreted as inactive metabolites in the urine, and the remainder is found as inactive metabolites in the feces.

Pregnancy & Breastfeeding use

Aspirin should be avoided during the last 3 months of pregnancy. As aspirin is excreted in breast milk, aspirin should not be taken by patients who are breast-feeding.

Pregnancy: There are no adequate and well-controlled studies on the use of Esomeprazole in pregnant women. Therapeutic doses during pregnancy are unlikely to pose a substantial teratogenic risk. Esomeprazole should be used during pregnancy only if the potential benefit to pregnant women justifies the potential risk to the fetus.

Lactation: Esomeprazole is excreted in human milk. Thus, a decision should be taken to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Contraindication

Aspirin is contraindicated to the children (Reye's syndrome) under 12 years, in breast-feeding and active peptic ulcer. It is also contraindicated in bleeding due to haemophilia and other ulceration. Hypersensitivity to aspirin, hypoprothrombinaemia is also contraindicated

Esomeprazole is contraindicated in patients with known hypersensitivity to any component of the formulation or to substituted Benzimidazoles.

Special Warning

Geriatric: Dosage adjustment is not necessary.

Pediatric: Safety and effectiveness in pediatric patients have not been established.

Hepatic insufficiency: No dosage adjustment is recommended for patients with mild to moderate hepatic insufficiency. However, in patients with severe hepatic insufficiency a dose of 20 mg once daily should not be exceeded.

Renal insufficiency: Dosage adjustment is not necessary.

Acute Overdose

Overdosage produces dizziness, tinnitus, sweating, nausea and vomiting, confusion and hyperventilation. Gross overdosage may lead to CNS depression with coma, cardiovascular collapse and respiratory depression. If overdosage is suspected, the patient should be kept under observation for at least 24 hours, as symptoms and salicylate blood levels may not become apparent for several hours. Treatment of overdosage consists of gastric lavage and forced alkaline diuresis. Haemodialysis may be necessary in severe cases.

There is no experience to data with deliverate overdose. Data are limited but single doses of 80 mg Esomeprazole were uneventful. Esomeprazole is extensively plasma protein bound and is therefore not readily dialyzable. As in any case of overdose, treatment should be symptomatic and general supportive measures should be utilised.

Storage Condition

Store in a cool and dry place, protected from light.

Store between 15-30°C. Protect from light.

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