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Ranitidine Information Ranitidine Information

APO-RANITIDINE

Ranitidine hydrochloride tablets equivalent to Ranitidine 150mg and 300mg tablets USP

Presentation

APO-RANITIDINE 150mg tablets are round, white, film-coated, biconvex, 9.5mm in diameter and identified APO over 150 on one side. Each tablet contains 167.4mg ranitidine hydrochloride (equivalent to 150mg ranitidine) and typically weighs 332mg.

APO-RANITIDINE 300mg tablets are capsule shaped, white, film-coated, 17mm by 7.5mm in size and identified APO300 on one side. Each tablet contains 334.8mg ranitidine hydrochloride (equivalent to 300mg ranitidine) and typically weighs 664mg.

Uses

Actions

Ranitidine is a histamine H₂-receptor antagonist that competitively inhibits the action of histamine on the H₂-receptors of the parietal cells. As a result, ranitidine reduces the volume of acid and pepsin secreted under basal conditions, and in response to a variety of stimuli, such as food and pentagastrin. Ranitidine has little or no anti-androgenic effect. A single 150mg dose of ranitidine suppresses acid secretion for 12 hours due to its long action duration.

When ranitidine is used in combination with amoxycillin and metronidazole Heliobacter pylori is eradicated in approximately 90% of patients. This results in a significant decrease in the recurrence of duodenal ulcers. H. Pylori infects approximately 95% patients with duodenal ulcers and 80% of patients with gastric ulcers.

Pharmacokinetics

After oral administration, ranitidine is rapidly absorbed and peak plasma concentrations occur within 2 to 3 hours. Concomitant administration of food and small doses (10mL) of low potency antacids does not affect the rate and extent of absorption. However, absorption may be decreased by large doses of antacids.

The oral bioavailability of ranitidine is about 50% due to extensive first-pass metabolism. This may increase to 70% in people with hepatic cirrhosis. Ranitidine is widely distributed in the body and is 10 to 19% protein bound. The average apparent volume of distribution (Vd) in adults is 1.9L/kg and in children of 3.5 to 16 years is approximately 2.4L/kg.

Ranitidine is partially metabolised in the liver and excreted principally in the urine via glomerular filtration and tubular secretion. The normal elimination half-life of ranitidine in adults is 2 to 3 hours and renal clearance is 410 to 512mL/minute. Within 24 hours of a single 150mg dose, about 40% of the administered dose is excreted in the urine as unchanged drug and metabolites, respectively. Metabolites found in the urine are the N-oxide, S-oxide, desmethylranitidine and the furoic acid analogue. The remainder of the absorbed dose is eliminated in faeces, via biliary excretion.

In patients with renal dysfunction, the elimination half-life is prolonged; dosage reduction may be necessary. Ranitidine is removed by haemodialysis.

Indications

Ranitidine is indicated in the treatment of duodenal ulcers and benign gastric ulcers. The pathogenesis of duodenal ulcer includes a number of factors with infection with H. Pylori being a major factor. Eradication of H. Pylori reduces the relapse rate for duodenal ulcers. A treatment regimen comprising ranitidine, amoxycillin and metronidazole is effective for the eradication of H. Pylori and for the treatment of duodenal ulcers associated with this organism.

Ranitidine is also indicated for the treatment and prevention of duodenal ulcers and benign gastric ulcers associated with nonsteroidal anti-inflammatory agents.

Ranitidine is also indicated for reflux oesophagitis with or without oesophageal erosions, chronic non-ulcer dyspepsia, Zollinger-Ellison syndrome and other gastric hypersecretory states.

Ranitidine may be used at reduced dosage, as maintenance therapy in patients with a history of recurrence or complication of duodenal or benign gastric ulcer, or in patients for whom surgery would be contra-indicated.

Ranitidine may be used prophylactically to prevent ulceration in patients who are on long-term NSAID therapy and who have a previous history of ulceration. It may also be used prophylactically to prevent haemorrhage from stress ulceration in seriously ill patients, and recurrent haemorrhage in patients with bleeding peptic ulcers. It may also be used before general anaesthesia in patients at high risk of acid aspiration or by obstetric patients during labour.

Dosage and Administration

Low doses of antacids may be given concomitantly with ranitidine for additional pain relief if needed.

ADULTS:

Duodenal Ulcer and Benign Gastric Ulcer:

Eradication of H. Pylori : Ranitidine 300mg at bedtime or 150mg twice daily together with amoxycillin 750mg three times daily and metronidazole 400-600mg three times daily for two weeks followed by two weeks on ranitidine only has been found to eradicate H. Pylori and reduce the frequency of duodenal ulcer recurrence.

Acute Therapy: The usual recommended dose for adults is 150mg twice daily. Alternatively, 300mg may be taken at bedtime. Healing of duodenal ulcers will occur in most cases (85%) within 4 weeks. For more resistant cases, complete healing is usually achieved with a further 4 weeks of therapy. The dose may need to be increased to 300mg twice daily for refractory ulcers. Healing of benign gastric ulcers is usually demonstrated within 8 weeks but therapy may be shortened if endoscopy reveals earlier healing.

Maintenance therapy: i.e. prevention of ulcer relapse in patients with a history of recurrence or complications. Therapy may be continued at a reduced dosage of 150mg daily at bedtime for up to 6 to 12 months. As maintenance in patients who smoke, a dose of 300mg at night may need to be considered.

NSAID-induced Ulcer:

Treatment: 150mg twice daily or 300mg at bedtime for 4 to 8 weeks.

Prevention of NSAID-associated duodenal ulcer: 150mg twice daily may be prescribed concomitantly with the NSAID.

Postoperative Ulcer:

150mg twice daily for 4 weeks. If not fully healed after this time an additional 4 weeks of treatment should complete the healing process.

Chronic Episodic Dyspepsia:

150mg twice daily for up to 6 weeks. Patients not responding or relapsing shortly afterwards should be investigated.

Reflux oesophagitis:

Symptom relief: 150mg twice daily for 2 weeks. Treatment may be continued for a further 2 weeks if the initial response to the drug is inadequate.

Mild to moderate disease: 300mg at night or 150mg twice daily for 8 weeks.

Severe or erosive oesophagitis: Dosage of ranitidine can be increased to 150mg 3 or 4 times daily for up to 12 weeks.

Zollinger-Ellison syndrome:

The starting dose is 150mg three times daily and this can be individually titrated upwards as necessary. Doses of up to 6g per day have been tolerated.

Prophylaxis in patients at risk of developing acid aspiration:

150mg ranitidine 2 hours before induction of general anaesthesia, and preferably also 150mg the previous evening.

In obstetric patients:

150mg at the onset of labour; this may be repeated every 6 hours. If emergency anaesthesia is required, it is recommended that additional antacid with immediate action also be given prior to induction (e.g. sodium citrate).

CHILDREN

The safety and efficacy of ranitidine in children of all ages has not been fully studied. However, it has been used in children aged from 8 to 18 years in doses up to 150mg twice daily.

USE IN IMPAIRED RENAL FUNCTION

In patients with creatinine clearances (CL_CR) less than 50mL/min, the daily dose of ranitidine should not exceed 150mg. For severe renal dysfunction (i.e. CL_CR < 10mL/min), 150mg ranitidine should be prescribed on alternate days or avoided.

USE IN HAEMODIALYSIS

The scheduled dose of ranitidine should be administered at the end of dialysis.

Contraindications

Hypersensitivity to ranitidine or any of the tablet components.

Warnings and Precautions

Ranitidine is renally excreted and caution is required in patients with impaired kidney function due to the potential for increased plasma levels.(see Dosage and Administration).

Ranitidine may mask the symptoms of carcinoma of the stomach thus delaying correct diagnosis. This possibility should be excluded before starting therapy especially in patients with gastric ulcer or in middle-aged or older patients with new or changed dyspeptic symptoms.

Regular supervision is recommended for patients taking NSAID concomitantly with ranitidine.

Ranitidine may precipitate acute porphyric attacks and its use should therefore be avoided in patients with a history of acute porphyria.

USE IN PREGNANCY:

Category B1. Ranitidine crosses the placenta. Therapeutic doses administered to women in labour have been without adverse effect on labour, delivery or neonatal outcome. However, there have been no well controlled studies of use in pregnant women, and although animal studies have not indicated any evidence of teratogenicity, they are not always predictive of response in humans. Ranitidine should only be used in pregnancy where there is a clearly identified need.

USE IN NURSING MOTHERS:

Ranitidine crosses into breast milk and multiple dosing results in higher concentrations in breast milk than in serum, especially towards the end of a 12 hour dosing interval. Minimum milk concentration occurs 1 to 2 hours after maternal administration. Nursing is best avoided if possible.

Adverse Effects

Ranitidine is well tolerated, and any adverse effects are generally of mild to moderate severity and appear to be reversible on reduction of dose or stopping therapy.

The following effects have been reported although a relationship to ranitidine therapy has not always been established. Headache, sometimes severe, has been reported.

Gastrointestinal:

Nausea, constipation, diarrhoea and abdominal discomfort.

Central nervous system:

Malaise, dizziness, somnolence, insomnia and vertigo have been reported, as have rare cases of reversible mental confusion, depression and hallucinations. Reversible effects on accommodation resulting in blurred vision have also been reported.

Cardiovascular:

Rare instances of tachycardia, bradycardia, hypotension, AV block and asystole.

Hepatic:

Raised liver enzymes, interstitial nephritis and hepatotoxicity (with or without jaundice).

Dermatological:

Rash including rare cases of erythema mulltiforme.

Haematological:

Thrombocytopenia, granulocytosis and neutropenia have been associated with the use of H₂antagonists in some people. Rare cases of aplastic anaemia, agranulocytosis or panycytopenia, sometimes with bone marrow hypoplasia or aplasia have been reported.

Musculoskeletal:

Rare reports of arthralgia and myalgia.

Other:

Hypersensitivity reactions may result in urticaria, fever, angioneurotic oedema, bronchospasm, chest pain or anaphylactic shock. Rare cases of pancreatitis have also been reported

Interactions

Ranitidine does not interact with cytochrome p-450 (microsomal) enzymes to any clinically significant degree when taken in recommended doses. The hepatic metabolism of drugs such as theophylline, diazepam, warfarin, phenytoin, propranolol and lignocaine appear unaffected.

Sporadic cases of interactions between ranitidine and both hypoglycaemic drugs and theophylline have been reported in elderly patients. The significance if these reports is unknown as controlled trials have not shown any interaction.

Sucralfate interferes with the absorption of ranitidine and should given at least 2 hours after ranitidine.

Overdosage

Ranitidine appears to be well tolerated even after large doses. However, in the event of overdose symptomatic and supportive therapy should be instituted as appropriate. If considered necessary, ranitidine may be removed from the plasma by haemodialysis.