Doran O

Uses

Ondansetron is used for:

• Prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy
• Prevention of nausea and vomiting associated with radiotherapy
• Prevention of post operative nausea and vomiting

Ranitidine is used for:

• Treatment of active duodenal ulcer
• Benign gastric ulcer
• Treatment & prevention of ulcer associated with non-steroidal anti-inflammatory agent
• Post operative stress ulcer.
• Zollinger-Ellison Syndrome.
• Gastroesophageal reflux disease (GERD).
• Gastro-intestinal haemorrhage from stress ulcer in seriously ill patient.
• Recurrent haemorrhage in patients with bleeding peptic ulcer.
• Before general anesthesia in patient considered to be at risk of acid aspiration particulary obstetric patients.

Doran O is also used to associated treatment for these conditions: Chemotherapy-Induced Nausea and Vomiting (CINV), Cholestatic pruritus, Post Operative Nausea and Vomiting (PONV), Uremic Pruritus, Radiation therapy induced nausea and vomiting, Severe Hyperemesis gravidarumAcid Aspiration Syndrome, Ankylosing Spondylitis (AS), Duodenal Ulcer, Erosive Esophagitis, Gastric Ulcer, Gastric hypersecretion, Gastro-esophageal Reflux Disease (GERD), Healing, Heartburn, Osteoarthritis (OA), Peptic Ulcer Disease, Rheumatoid Arthritis, Stress Ulcers, Zollinger-Ellison Syndrome, Active duodenal ulcers, Benign gastric ulcer healing, Benign gastric ulcers, Duodenal ulcer healing, Post-operative peptic ulcer, Recurrent hemorrhage from bleeding ulcers

How Doran O works

Ondansetron is a selective antagonist of the serotonin receptor subtype, 5-HT3 .

Cytotoxic chemotherapy and radiotherapy are associated with the release of serotonin (5-HT) from enterochromaffin cells of the small intestine, presumably initiating a vomiting reflex through stimulation of 5-HT3 receptors located on vagal afferents . Ondansetron may block the initiation of this reflex. Activation of vagal afferents may also cause a central release of serotonin from the chemoreceptor trigger zone of the area postrema, located on the floor of the fourth ventricle . Thus, the antiemetic effect of ondansetron is probably due to the selective antagonism of 5-HT3 receptors on neurons located in either the peripheral or central nervous systems, or both .

Although the mechanisms of action of ondansetron in treating postoperative nausea and vomiting and cytotoxic induced nausea and vomiting may share similar pathways, the role of ondansetron in opiate-induced emesis has not yet been formally established .

After a meal, the hormone gastrin, produced by cells in the lining of the stomach, stimulates the release of histamine, which then binds to histamine H2 receptors, leading to the secretion of gastric acid. Ranitidine reduces the secretion of gastric acid by reversible binding to histamine (H2) receptors, which are found on gastric parietal cells. This process leads to the inhibition of histamine binding to this receptor, causing the reduction of gastric acid secretion. The relief of gastric-acid related symptoms can occur as soon as 60 minutes after administration of a single dose, and the effects can last from 4-10 hours, providing fast and effective symptomatic relief.

Dosage

Doran O dosage

Prevention of chemotherapy induced nausea & vomiting (CINV):

Adult-

• Tablet and oral solution: The recommended adult oral dosage of Ondansetron is 24 mg given as three 8 mg tablets in highly emetogenic chemotherapy. In case of moderately emetogenic chemotherapy the oral dose is one 8 mg Ondansetron tablet or 10 ml of Ondansetron oral solution given twice daily.
• Injection: The recommended i.v. dose of Ondansetron is a single 32 mg dose or three 0.15 mg/kg doses. A single 32 mg dose is infused over 15 minutes beginning 30 minutes before the start of emetogenic chemotherapy. Subsequent doses (0.15 mg/kg) are administered 4 and 8 hours after the first dose of Ondansetron.
• Suppository: The recommended adult dose is one 16 mg suppository 1-2 hours before treatment. Ondansetron should be continued for upto 5 days after a course of treatment.The recommended dose is one suppository daily.

Pediatric patients-

• Tablet and oral solution:for pediatric patients 4 through 11 years of age the dosage is one 4 mg Ondansetron tablet or 5ml of Ondansetron solution should be administered 3 times a day for 1 to 2 days after completion of chemotherapy.
• Injection: the dosage in pediatric patients 4 to 18 years of age should three 0.15-mg/kg doses.
• Suppository:Not recommended.

Radiotherapy induced nausea and vomiting:

Adult-

• Tablet and oral solution: the recommended oral dosage is one 8mg Ondansetron tablet or 10ml of Ondansetron oral solution given 3 times daily.

Post operative nausea & vomiting (PONV):

Adult-

• Tablet and oral solution: The recommended dosage is 16 mg given as two 8 mg Ondansetron tablets or 20 ml of Ondansetron oral solution 1hour before induction of anesthesia.
• Injection: The recommended I.V. dosage of Ondansetron for adults is 4 mg undiluted administered intravenously in not less than 30 seconds, preferably over 2 to 5 minutes, immediately before induction of anesthesia, or postoperatively if the patient experiences nausea and/or vomiting occurring shortly after surgery. Alternatively, 4 mg undiluted may be administered intramuscularly as a single injection for adults. In patients who do not achieve adequate control of postoperative nausea and vomiting following a single, prophylactic, preinduction, I.V. dose of Ondansetron 4 mg, administration of a second I.V. dose of 4 mg Ondansetron postoperatively does not provide additional control of nausea and vomiting.
• Suppository: The recommended adult dose is one 16 mg suppository 1-2 hours before treatment. Ondansetron should be continued for upto 5 days after a course of treatment.The recommended dose is one suppository daily.

Pediatric patients-

• Injection: The recommended I.V. dosage of Ondansetron for pediatric patients (2 to 12 years of age) isa single 0.1-mg/kg dose for pediatric patients weighing 40 kg or less, or a single 4 mg dose for pediatric patients weighing more than 40 kg. The rate of administration should not be less than 30 seconds, preferably over 2 to 5 minutes. Little information is available about dosage in pediatric patients younger than 2 years of age.
• Suppository: Not recommended.

Ranitidine Tablet & Syrup:

Duodenal and gastric ulcer: The usual dosage is 150 mg twice daily taken in the morning and evening or 300 mg as a single daily dose at night for 4 to 8 weeks.

Reflux oesophagitis: 150 mg twice daily or 300 mg at bed time for up to 8 weeks.

Zollinger Ellison syndrome: 150 mg 3 times daily and increased if necessary up to 6 g daily in divided doses. Dosage should be continued as long as clinically indicated.

Episodic dyspepsia: 150 mg twice daily or 300 mg at bed time for up to 6 weeks.

Maintenance: 150 mg at night for preventing recurrences.

Child (peptic ulcer)

Ranitidine IV injection & IV Infusion:

Ranitidine injection may be given either as a slow (over a period of at least two minutes) intravenous injection of 50 mg, after dilution to a volume of 20 ml per 50 mg dose, which may be repeated every six to eight hours; or as an intermittent intravenous infusion at a rate of 25 mg per hour for two hours; the infusion may be repeated at six to eight hour intervals; or as an intramuscular injection of 50 mg (2 ml) every six to eight hours. In the prophylaxis of haemorrhage from stress ulceration in seriously ill patients or the prophylaxis of recurrent haemorrhage in patients bleeding from peptic ulceration, parenteral administration may be continued until oral feeding commences.: 2-4 mg/kg twice daily, maximum 300 mg daily.

In the prophylaxis of upper gastrointestinal haemorrhage from stress ulceration in seriously ill patient sapriming dose of 50 mg as low as intravenous injection followed by a continuous intravenous infusion of 0.125-0.250 mg/kg/hour may be preferred. In patients considered to be at risk of developing aspiration syndrome Ranitidine injection 50 mg may be given intramuscularly or by slow intravenous injection 45 to 60 minutes before induction of general anaesthesia.

Children: The recommended oral dose for the treatment of peptic ulcer in children is 2 mg/kg to 4 mg/kg twice daily to a maximum of 300 mg ranitidine per day. Safety and effectiveness of Ranitidine injection have not been established in case of children.

Prior to IV infusion, dilute in 50 ml dextrose 5% inj or normal saline.

Reconstitutions

Slow IV inj: Ranitidine 50 mg diluted to a concentration ≤2.5 mg/mL (e.g. total of 20 mL) with NaCl 0.9% inj or dextrose 5% or 10%, lactated Ringer's, Na bicarbonate 5% soln.

Intermittent slow IV infusion: Ranitidine 50 mg diluted to a concentration ≤0.5 mg/mL (e.g. total of 100 mL) of dextrose 5% inj or NaCl 0.9%, lactated Ringer's, Na bicarbonate 5% soln.

Continuous IV infusion: Ranitidine 150 mg diluted in 250 mL of dextrose 5% inj or NaCl 0.9%, lactated Ringer's, Na bicarbonate 5% soln.

Patients with Zollinger-Ellison syndrome or other hypersecretory conditions: Ranitidine should be diluted to a concentration ≤2.5 mg/mL with dextrose 5% or NaCl 0.9%, lactated Ringer's, Na bicarbonate 5% soln.

Side Effects

The most common adverse effects include headache, constipation, diarrhea. In chemotherapy induced nausea and vomiting rash has occurred in approximately 1% of patients receiving Ondansetron. Blurred vision, chest pain with or without ST segment depression, cardiac arrhythmias, hypotension and bradycardia have been rarely reported.

Ranitidine is well tolerated and side effects are usually uncommon. Altered bowel habit, dizziness, rash, tiredness, reversible confusional states, headache, decreased blood counts, muscle or joint pain have rarely been reported.

Toxicity

At present, there is little information concerning overdosage with ondansetron . Nevertheless, there have been certain cases of somewhat idiosyncratic adverse effects associated with particular dosages of ondansetron used .

“Sudden blindness” (amaurosis) of 2 to 3 minutes duration plus severe constipation occurred in one patient that was administered 72 mg of ondansetron intravenously as a single dose . Hypotension (and faintness) occurred in another patient that took 48 mg of oral ondansetron . Following infusion of 32 mg over only a 4-minute period, a vasovagal episode with transient second-degree heart block was observed . Neuromuscular abnormalities, autonomic instability, somnolence, and a brief generalized tonic-clonic seizure (which resolved after a dose of benzodiazepine) were observed in a 12-month-old infant who ingested seven or eight 8-mg ondansetron tablets (approximately forty times the recommended 0.1-0.15 mg/kg dose for a pediatric patient) . In all instances, however, the events resolved completely .

The safety of ondansetron for use in human pregnancy has not been established . Ondansetron is not teratogenic in animals . However, as animal studies are not always predictive of human response, the use of ondansetron in pregnancy is not recommended .

Ondansetron is excreted in the milk of lactating rats . It is not known if it is excreted in human milk, however, nursing is not recommended during treatment with ondansetron .

Insufficient information is available to provide dosage recommendations for children 3 years of age or younger .

Oral doses of 1,000 mg/kg in mice and rats were not found to be lethal. Intravenous LD50 values in mice and rats were 77 and 83 mg/kg, respectively.

Overdose information

There has been limited experience with ranitidine overdose. Reported acute ingestions of up to 18 grams orally were followed by temporary adverse effects similar to the normal adverse effects of this drug, including tachycardia, bradycardia, dizziness, diarrhea, nausea, and vomiting, among other effects. Gait abnormalities and hypotension have also been observed. When an overdose with ranitidine is suspected, remove unabsorbed ranitidine from the gastrointestinal tract if possible, and monitor the patient and provide supportive therapy as required.

Precaution

Hypersensitivity reactions have been reported in patients who have exhibited hypersensitivity to other 5-HT3 receptor antagonists. Ondansetron is not a drug that stimulates gastric or intestinal peristalsis. It should not be used instead of nasogastric suction. The use of Ondansetron in patients following abdominal surgery or in patients with chemotherapy-induced nausea and vomiting may mask a progressive ileus and/or gastric distension.

Ranitidine should be given in reduced dosage to patients with impaired renal and hepatic function.

Interaction

In patients treated with potent inducers of CYP3A4 (i.e Phenytoin, Carbamazepine or Rifampicin), the oral clearance of Ondansetron was increased and Ondansetron blood concentrations were decreased. Data from small studies indicate that Ondansetron may reduce the analgesic effect of tramadol.

Delayed absorption and increased peak serum concentration with propantheline bromide. Ranitidine minimally inhibits hepatic metabolism of coumarin anticoagulants, theophylline, diazepam and propanolol. May alter absorption of pH-dependent drugs (e.g. ketoconazole, midazolam, glipizide). May reduce bioavailability with antacids.

Volume of Distribution

The volume of distribution of ondansetron has been recorded as being approximately 160L .

The volume of distribution is higher than body volume, and measures at approximately 1.4 L/kg. It concentrates in breast milk, but does not readily distribute into the cerebrospinal fluid.

Elimination Route

Ondansetron is absorbed from the gastrointestinal tract and undergoes some limited first-pass metabolism . Mean bioavailability in healthy subjects, following administration of a single 8-mg tablet, was recorded as being approximately 56% to 60% . Bioavailability is also slightly enhanced by the presence of food .

Ondansetron systemic exposure does not increase proportionately to dose . The AUC from a 16-mg tablet was 24% greater than predicted from an 8-mg tablet dose . This may reflect some reduction of first-pass metabolism at higher oral doses .

Ranitidine is rapidly absorbed with peak concentrations reached within 1-3 hours after administration, and varying greatly among patients. Bioavailability is about 50%-60% due to hepatic metabolism. In a pharmacokinetic study of healthy males, the AUC 0-infinity was about 2,488.6 ng x h/mL and the median Tmax was 2.83 hours. Food or antacids have limited effects on absorption. One clinical study found that the administration of a potent antacid (150 mmol) in subjects in the fasted state led to decreased absorption of ranitidine.

Half Life

The half-life of ondansetron after either an 8 mg oral dose or intravenous dose was approximately 3-4 hours and could be extended to 6-8 hours in the elderly .

The elimination half-life or ranitidine is about 2.5-3 hours. It may be longer after oral administration versus injection. The plasma half-life is longer for elderly patients population due to a decrease in renal function, and is measured at 3-4 hours.

Clearance

The clearance values determined for ondansetron in various patient age groups were recorded as approximately 0.38 L/h/kg in normal adult volunteers aged 19-40 yrs, 0.32 L/h/kg in normal adult volunteers aged 61-74 yrs, 0.26 L/h/kg in normal adult volunteers aged >=75 yrs .

Renal clearance is about 410 mL/min according to FDA prescribing information. Another resource mentions a plasma clearance of approximately 600 ml/min. Clearance is decreased in the elderly and those with impaired or hepatic renal function. It is recommended to decrease the dose of ranitidine by one-half in patients with renal impairment.

Elimination Route

Following oral or IV administration, ondansetron is extensively metabolised and excreted in the urine and faeces .

This drug is mainly excreted in the urine but also excreted in the feces. About 30% of a single oral dose has been measured in the urine as unchanged drug within 24 hours of ingestion.

Pregnancy & Breastfeeding use

In pregnancy: Pregnancy category B. Reproduction studies at daily oral dose up to 10 and 30 mg/kg/day have been performed in animals and have revealed no evidence of impaired fertility harm to the fetus due to Ondansetron. There are, however, no adequate and well-controlled studies in pregnant women. So the drug should be used in pregnancy only if clearly needed.

In lactation: Ondansetron excretes in milk of lactating animals. Caution should be exercised when Ondansetron is administered to nursing mother.

Pregnancy: Ranitidine crosses the placenta. But there is no evidence of impaired fertility or harm to the foetus due to Ranitidine. Like other drugs, Ranitidine should only be used during pregnancy if considered essential.

Lactation: Ranitidine is excreted in human breast milk. Caution should be exercised when the drug is administered to a nursing mother.

Contraindication

Ondansetron is contraindicated in patients with known hypersensitivity to the drug.

Patients hypersensitive to Ranitidine

Special Warning

Pediatric use: Can be given in children 1 month of age and above.

Geriatric use: No dosage adjustment is necessary in the elderly.Dosage adjustment for patients with impaired hepatic function:

• Tablet and Oral Solution: The total daily dose of 8 mg should not be exceeded.
• Injection: A single maximal dose of 8 mg to be infused over 15 minutes beginning 30 minutes before the start of the emetogenic chemotherapy is recommended.
• Suppository: Not recommended

Use in elderly patients: In clinical trial the ulcer healing rates have been found similar in patients age 65 and over with those in younger patients. Additionally, there was no difference in the incidence of adverse effects.

Acute Overdose

There is no specific antidote for Ondansetron overdose. In addition to the adverse events, hypotension (and faintness) occurred in a patient that took 48 mg of AVONA tablets. In all instances, the events resolved completely.

Ranitidine is very specific in action and accordingly no particular problems are expected following overdosage with the drug. Symptomatic and supportive therapy should be given as appropriate. If required, the drug may be removed from the plasma by haemodiaiysis.

Storage Condition

Store in a cool and dry place, protected from light and moisture. For suppository- Store below 25º c.

Store in a cool and dry place. protect from light.

Innovators Monograph

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