Ranitidine 150mg Tablets PL 15627/0005

Sandoz Ltd Page 1

1 NAME OF THE MEDICINAL PRODUCT

Ranitidine 150 mg Film-coated Tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains Ranitidine hydrochloride equivalent to Ranitidine 150 mg. For a full list of excipients, see section 6.1.

3.    PHARMACEUTICAL FORM

Film-coated tablet.

Circular, biconvex, white to yellowish, film-coated tablets, inscription R 150. Diameter 10 mm.

4.    CLINICAL PARTICULARS

4.1    Therapeutic indications

Ranitidine Tablets are indicated for the treatment of benign gastric ulcers and duodenal ulcers.

Ranitidine Tablets are also indicated for Zollinger-Ellison syndrome and for the treatment of reflux oesophagitis.

Ranitidine Tablets are indicated for the long-term treatment of duodenal and benign gastric ulcers to prevent their recurrence. Long-term treatment is indicated in patients with history of recurrent ulcer.

Children (3 to 18 years)

• Short term treatment of peptic ulcer

• Treatment of gastro-oesophageal reflux, including reflux oesophagitis and symptomatic relief of gastro-oesophageal reflux disease

4.2 Posology and method of administration

Adults

The usual dose is 150 mg twice daily, taken in the morning and evening. A single bedtime dose of 300 mg may be given to patients with duodenal or gastric ulcers. Treatment may be continued for 4 - 8 weeks. For maintenance, the usual dose is 150 mg at bedtime.

For the management of reflux oesophagitis, the recommended dose is 150 mg twice daily or 300 mg at bedtime, usually for up to 8 weeks, this may be extended to a maximum of 12 weeks if necessary.

Zollinger-Ellison syndrome:

An initial dose of 150 mg, three times a day, may be increased up to 300 mg three times a day. Daily divided doses of up to 6 g have been used and found to be well tolerated.

Elderly patients

In patients with normal renal function, the doses of Ranitidine Tablets are the same as for younger adults.

Paediatric population

Children 12 years and over

For children 12 years and over the adult dosage is given.

Children from 3 to 11 years and over 30 kg of weight

See Section 5.2 Pharmacokinetic Properties - Special Patient Populations.

Peptic Ulcer Acute Treatment

The recommended oral dose for the treatment of peptic ulcer in children is 4 mg/kg/day to 8 mg/kg/day administered as two divided doses to a maximum of 300 mg ranitidine per day for a duration of 4 weeks. For those patients with incomplete healing, another 4 weeks of therapy is indicated, as healing usually occurs after eight weeks of treatment.

Gastro-Oesophageal Reflux

The recommended oral dose for the treatment of gastro-oesophageal reflux in children is 5 mg/kg/day to 10 mg/kg/day administered as two divided doses in a maximum dose of 600 mg (the maximum dose is likely to apply to heavier children or adolescents with severe symptoms).

Neonates

Safety and efficacy in new-born patients has not been established.

Renal impairment

In patients with renal impairment (creatinine clearance 5-50 ml/min), plasma levels of the drug are increased. The dose in such patients is 150 mg at night for 4-8 weeks.

The same dose is used for maintenance. If healing has not occurred, 150 mg twice daily should be used, followed by 150 mg at night for maintenance.

Ranitidine is removed by hemodialysis. Dialysis patients should therefore take ranitidine after each dialysis occasion.

Method of administration

The tablet should be swallowed whole with a sufficient amount of fluid. In children the tablet may be dissolved in water or crushed. The application of a more convenient dosage form may be considered.

4.3 Contraindications

Hypersensitivity to ranitidine or to any of the excipients

4.4 Special warnings and precautions for use

The possibility of malignancy should be excluded before commencement of therapy in patients with gastric ulcer [and if indications include dyspepsia; patients of middle age and over with new or recently changed dyspeptic symptoms must be included] as treatment with ranitidine may mask symptoms of gastric carcinoma.

Patients with peptic ulcers should be tested for the presence of Helicobacter pylori. If they are found positive an adequate eradication regimen should be given.

Caution should be observed in patients with severe hepatic dysfunction since ranitidine is metabolised in the liver.

Ranitidine is excreted via the kidney and so plasma levels of the drug are increased in patients with severe renal impairment.

Dosage reduction is required in patients with renal impairment (see section 4.2).

As rare clinical reports suggest that ranitidine may precipitate acute porphyric attacks, ranitidine should therefore be avoided in patients with a history of acute intermittent porphyria.

In patients such as the elderly, persons with chronic lung disease, diabetes or the immunocompromised, there may be an increased risk of developing community acquired pneumonia.

A large epidemiological study showed an increased risk of developing community acquired pneumonia in current users of H2 receptor antagonists versus those who had stopped treatment, with an observed adjusted relative risk increase of 1,82 (95% CI 1,26-2,64).

Regular supervision of patients who are taking non-steroidal anti-inflammatory drugs concomitantly with ranitidine is recommended, especially in the elderly and in those with a history of peptic ulcer.

4.5 Interaction with other medicinal products and other forms of interaction

Ranitidine has the potential to affect the absorption, metabolism or renal excretion of other drugs. The altered pharmacokinetics may necessitate dosage adjustment of the affected drug or discontinuation of treatment. Interactions occur by several mechanisms including:

1) Inhibition of cytochrome P450-linked mixed function oxygenase system:

Ranitidine at usual therapeutic doses does not potentiate the actions of drugs which are inactivated by this enzyme system such as diazepam, lidocaine, phenytoin, propranolol and theophylline.

There have been reports of altered prothrombin time with coumarin anticoagulants (e.g. warfarin). Due to the narrow therapeutic index, close monitoring of increased or decreased prothrombin time is recommended during concurrent treatment with ranitidine.

2) Competition for renal tubular secretion:

Since ranitidine is partially eliminated by the cationic system, it may affect the clearance of other drugs eliminated by this route. High doses of ranitidine (e.g. such as those used in the treatment of Zollinger-Ellison syndrome) may reduce the excretion of procainamide and N-acetylprocainamide resulting in increased plasma levels of these drugs.

3) Alteration of gastric pH:

The bioavailability of certain drugs may be affected. This can result in either an increase in absorption (e.g. triazolam, midazolam, glipizide) or a decrease in absorption (e.g. ketoconazole, atazanavir, delaviridine, gefitnib).

There is no evidence of an interaction between ranitidine and amoxicillin and metronidazole.

If high doses (2 g) of sucralfate are co-administered with ranitidine the absorption of the latter may be reduced. This effect is not seen if sucralfate is taken after an interval of 2 h.

A reduction of bioavailability of ranitidine occurs with the concomitant administration of strong antacids.

The effect of alcohol may be increased by taking ranitidine tablets.

4.6 Fertility, pregnancy and lactation

Pregnancy

Clinical experience from pregnant women is limited. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development. Ranitidine crosses the placenta. Like other drugs ranitidine should only be used during pregnancy if considered essential.

Breastfeeding

Ranitidine is excreted in human breast milk. Since nothing is known of the effects of Ranitidine ingestion by neonates, and since impairment of gastric acid secretion cannot be excluded, ranitidine should only be used during nursing if considered essential.

4.7 Effects on ability to drive and use machines

None reported. However, taking ranitidine tablets may increase the effect of alcohol,

furthermore side-effects as e.g. headache, dizziness, fatigue, confusion and agitation as well as hallucinations may possibly occur. Under these circumstances the ability to react as well as the power of judgement may be reduced, thus impairing the ability to drive and the ability to operate machinery.

4.8 Undesirable effects

The following convention has been utilised for the classification of undesirable effects: Very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1,000 to <1/100), rare (>1/10,000 to <1/1,000), very rare (<1/10,000). Adverse event frequencies have been estimated from spontaneous reports from post-marketing data.

Blood and lymphatic system disorders

Very rare: Blood count changes (leukocytopenia, thrombocytopenia). These are usually reversible. Agranulocytosis or pancytopenia, sometimes with marrow hypoplasia or marrow aplasia)

Immune system disorders

Rare: Hypersensitivity reactions (eosinophilia, urticaria, angioneurotic oedema, fever, bronchospasm, hypotension, laryngeal spasm, acute pancreatitis and chest pain).

Very rare: Anaphylactic shock

These events have been reported after a single dose.

Psychiatric disorders

Very rare: Reversible mental confusion and restlessness depression and hallucinations.

These have been reported predominantly in severely ill and elderly patients.

Nervous system disorders Uncommon: Fatigue

Very rare: Headache (sometimes severe), dizziness and reversible involuntary movement disorders.

Eye disorders

Very rare: Reversible blurred vision

There have been reports of blurred vision, which is suggestive of a change in accommodation.

Cardiac disorders

Very rare: As with other H2 receptor antagonists tachycardia, bradycardia and A-V block.

Vascular disorders Very rare: Vasculitis

Gastrointestinal disorders

Uncommon: Abdominal pain, diarrhoea, constipation, nausea (these symptoms mostly improved during continued treatment).

Very rare: Acute pancreatitis Hepatobiliary disorders

Rare: Transient and reversible changes in liver function tests.

Very rare: Hepatitis (hepatocellular, hepatocanalicular or mixed) with or without jaundice, these were usually reversible.

Skin and subcutaneous tissue disorders Rare: Skin rash, pruritus.

Very rare: Erythema multiforme, alopecia.

Musculoskeletal and connective tissue disorders

Very rare: Musculoskeletal symptoms such as arthralgia and myalgia.

Renal and urinary disorders

Rare: Elevation of plasma creatinine (usually slight; normalised during continued treatment)

Very rare: Acute interstitial nephritis.

Reproductive system and breast disorders

Very rare: Reversible impotence (erectile dysfunction), breast symptoms and breast conditions in men (such as gynaecomastia and galactorrhoea)

Paediatric population

The safety of ranitidine has been assessed in children aged 0 to 16 years with acid-related disease and was generally well tolerated with an adverse event profile resembling that in adults. There are limited long term safety data available, in particular regarding growth and development.

4.9 Overdose

Symptoms and Signs

Ranitidine is very specific in action and no particular problems are expected following overdosage with ranitidine formulations.

Treatment

Symptomatic and supportive therapy should be given as appropriate. Gastric lavage should be carried out and / or emesis induced. Seizures may be managed with diazepam, bradycardia with atropine and ventricular arrhythmias with lignocaine. Ranitidine may be removed from plasma by haemodialysis.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: H2-receptor antagonists

ATC-code: A02B A02

Ranitidine is a specific histamine H2 - antagonist with a rapid onset of action. Both basal and stimulated gastric acid secretion are inhibited, reducing both the acid content and also to a smaller extent the pepsin content and volume of the gastric juice. Ranitidine has a relatively long duration of action, a 150 mg dose effectively suppressing acid secretion for 12 hours.

5.2 Pharmacokinetic properties

Ranitidine has a bioavailability of approximately 50%. In patients with severely impaired liver function, the first-pass metabolism of ranitidine is decreased, resulting in a slightly higher bioavailability of ranitidine.

Ranitidine is metabolised in the liver to ranitidine-N-oxide, N-Desmethylranitidine, ranitidine-S-oxide and the furane acid analogue. After oral administration, ranitidine is excreted within 24 hours via the kidney to approximately 30% as unchanged ranitidine, up to 6% as N-oxide, to a smaller degree in demethylised and in S-oxide form, and as furane acid analogue. In patients with sound kidneys, renal excretion is effected predominantly by tubular secretion with a renal clearance of about 490-520 ml/min.

Additionally, ranitidine is excreted via the bile.

After oral intake, mean elimination half-life in patients with sound kidneys is 2.3-3 hours. In patients with renal insufficiency, the half-life is prolonged two- to threefold.

Special Patient Populations

Children (3 years and above)

Limited pharmacokinetic data have shown that there are no significant differences in half-life (range for children 3 years and above: 1.7 - 2.2 h) and plasma clearance (range for children 3 years and above: 9 - 22 ml/min/kg) between children and healthy adults receiving oral ranitidine when correction is made for body weight.

5.3 Preclinical safety data

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction.

6.    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Core

Croscarmellose sodium Magnesium stearate (E572)

Microcrystalline cellulose (E460)

Film coating suspension 1

Polymethylmethacrylic acid copolymer (Eudragit E)

Film coating suspension 2 Hypromellose (E464)

Titanium dioxide (E171)

Talc

Macrogol 6000

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Do not store above 25°C.

6.5 Nature and content of container

Aluminium/aluminium blister pack containing 10 tablets. Cartons containing 10, 20, 30, 50, 60, 100 and 120 tablets. Not all pack sizes may be marketed.

The blister packs consist of:

Push-through Aluminium foil, 20 microns, one side bright, hard, plain, dull side lacquered, bright side heat seal lacquered suitable for sealing against PVC.

Form/packaging Aluminium bottom strip, 45 microns, one side bright, soft, plain, dull side lacquer-laminated to OPA film, 25 microns, bright side lacquer-laminated to hard PVC film, 60 microns.

6.6 Instructions for use, handling and disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Sandoz B.V.

Postbus 10332

1301 AH Almere The Netherlands

SPC.0005.002    13.03.2008 Reason: Renewal 002, end of procedure KG