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Ranitidine 150mg Film-Coated Tablets

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Document: spc-doc_PL 14894-0005 change

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Ranitidine 150mg Film-coated Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains Ranitidine Hydrochloride equivalent to Ranitidine 150mg.

Excipients with known effect:

Each film-coated tablet contains 1.52mg of castor oil.

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Film-coated Tablets

White to off-white, round biconvex, film-coated tablets imprinted with ‘RAN 150’ in black edible ink on one side.

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 a history of recurrent ulcer.

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

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

Severe oesophagitis:

The dose is 150mg, four times a day for up to a maximum of 12 weeks. This raised level of dosing has not been associated with a raised level of side effects. Long-term treatment in patients with unhealed oesophagitis is not indicated, either in the presence of Barrett’s epithelium or its absence.

Zollinger-Ellison syndrome:

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

Older 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 aged 3 to 11 years and over 30kg of weight: see section 5.2 Other special populations.

Peptic Ulcer Acute Treatment

The recommended oral dose for the treatment of peptic ulcer in children is 4mg/kg/day to 8mg/kg/day administered as two divided doses to a maximum of 300mg 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 5mg/kg/day to 10mg/kg/day administered as two divided doses in a maximum of 600mg (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 yet been established.

Patients with Renal Impairment

In patients with severe renal impairment, plasma levels of the drug are increased. The dose in such patients is 150mg at night for 4-8 weeks. The same dose is used for maintenance. If healing has not occurred, 150mg twice daily should be used, followed by 150mg at night for maintenance.

creatinine clearance mL/min

Dose of ranitidine

<50

150 mg

>50

300 mg

Ranitidine is removed by haemodialysis. Dialysis patients should therefore take Ranitidine Ranbaxy after each dialysis occasion.

Method of administration

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

4.3 Contraindications

Hypersensitivity to the active substance or any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

Treatment with histamine H2 antagonists may mask symptoms of stomach carcinoma and therefore delay its diagnosis. . The possibility of malignancy should be excluded before commencement of therapy in patients with gastric ulcer as treatment with ranitidine may mask symptoms of gastric carcinoma.

Ranitidine is excreted via the kidney and so plasma levels of the drug are increased in patients with renal impairment. The dosage should be adjusted as detailed above under Dosage and Administration in section 4.2 in Patients with renal impairment.

Rare clinical reports suggest that ranitidine may precipitate acute porphyric attacks. Ranitidine should therefore be avoided in patients with a history of acute porphyria.

In patients such as older people, 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 ranitidine alone 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 older people and in those with a history of peptic ulcer.

This medicinal product contains castor oil which may cause stomach upset and diarrhoea

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 Nacetylprocainamide 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).

The combination of ranitidine and ketoconazole should be avoided, since the dissolution of ketoconazole is decreased at higher pH so that effective plasma levels of ketoconazole are not reached.

Ranitidine can increase the plasma levels and potentiate the hypoglycaemic effect of glipizide. Dose adjustments may be needed.

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.

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

4.6 Fertility, pregnancy and lactation

Fertility

There are no data on the effects of ranitidine on human fertility. There were no effects on male and female fertility in animal studies (see section 5.3).

Pregnancy

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. Like other drugs ranitidine should only be used during nursing if considered essential.

4.7 Effects on ability to drive and use machines

Not relevant

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 (>1/1000 to <1/100), rare (>1/10,000 to <1/1000), very rare (<1/10,000).

Adverse event frequencies have been estimated from spontaneous reports from postmarketing data.

Blood & Lymphatic System Disorders

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

Immune System Disorders

Rare: Hypersensitivity reactions (urticaria, angioneurotic oedema, fever, bronchospasm, hypotension and chest pain).

Very Rare: Anaphylactic shock Unknown: dyspnoea

These events have been reported after a single dose.

Psychiatric Disorders

Very Rare: Reversible mental confusion, depression and hallucinations.

These have been reported predominantly in severely ill, older patients and nephropatic patients.

Nervous System Disorders

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 bradycardia, A-V block and

tachycardia

Vascular Disorders

Very Rare: Vasculitis.

Gastrointestinal Disorders

Very Rare: Acute pancreatitis, diarrhoea

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

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.

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, breast symptoms and breast conditions (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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Symptoms

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

Management

Symptomatic and supportive therapy should be given as appropriate.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: H2-receptor antagonists ATC code: A02BA02 Mechanism of action

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 150mg 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 forms, 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, raniditine 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.

Other special 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 agove: 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.

Patients over 50 years of age

In patients over 50 years of age, half-life is prolonged (3-4 h) and clearance is reduced, consistent with the agerelated decline of renal function. However, systemic exposure and accumulation are 50% higher. This difference exceeds the effect of declining renal function, and indicates increased bioavailability in older patients.

5.3. Preclinical safety data

The pharmacological and toxicological properties of ranitidine are well established. There are no additional data from preclinical studies of clinical concern. In particular, there are no findings from chronic toxicity investigations suggesting that any side effects unknown to date could occur in humans. Furthermore, in vivo and in vitro studies did not yield any indication of a potential to cause reproductive toxicity, mutagenicity or carcinogenicity.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core

Microcrystalline cellulose Croscarmellose sodium Colloidal anhydrous silica Talc

Magnesium stearate

Film-coating Hypromellose Castor oil

Titanium dioxide [E171]

Talc

Isopropyl alcohol Purified water

Printing ink

Opacode S-1-17823 containing: Shellac

Isopropyl alcohol Iron oxide black [E172] N-Butyl alcohol Propylene glycol Ammonium hydroxide 28%

6.2 Incompatibilities

Not applicable 6.3. Shelf life

3 years

6.4 Special precautions for storage

Store in the original package in order to protect from moisture 6.5. Nature and contents of container

Ranitidine Tablets are packed in the following packs:

Cold-form blister sheets (structure from outer to inner side: oriented polyamide/aluminium foil/hard PVC film with a backing of aluminium foil coated with heat seal lacquer).

Aluminium strips comprising of aluminium foil laminated with LDPE.

The tablets are available in the following pack sizes:-

blister sheets/ aluminium strips of five tablets each, in boxes of 5 tablets per carton.

blister sheets/ aluminium strips of seven tablets each, in boxes of 7, 14, 28,

56, 98 and 112 tablets per carton.

blister sheets/ aluminium strips of eight tablets each, in boxes of 8, 16, 24, 32, 40, 48, 56, 64, 72, 80, 88 and 96 tablets per carton

blister sheets/ aluminium strips of ten tablets each, in boxes of 10, 20, 30, 50, 60, 80, 100 and 120 tablets per carton.

blister sheets/ aluminium strips of fifteen tablets each, in boxes of 15, 30, 45, 60, 75, 90, 105 and 120 tablets per carton.

blister sheets/ aluminium strips of thirty tablets each, in boxes of 30, 60, 90, 120 and 150 tablets per carton

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements

7    MARKETING AUTHORISATION HOLDER

Ranbaxy (UK) Limited Building 4, Chiswick Park 566 Chiswick High Road London, W4 5YE United Kingdom

8. MARKETING AUTHORISATION NUMBER(S)

PL 14894/0005

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

16/09/2007

10 DATE OF REVISION OF THE TEXT

25/02/2015