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Ranitidine 300 Mg Effervescent Tablets

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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Ranitidine 300 mg Effervescent Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Ranitidine 300 mg Effervescent Tablets

One effervescent tablet contains 335 mg ranitidine hydrochloride, equivalent to 300 mg ranitidine.

Excipient:

sodium (23 mmol or 533 mg)

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Effervescent tablet.

Ranitidine Effervescent Tablets 300 mg

White to pale yellow, round, flat faced beveled edges tablets plain on both sides with faint odour of peppermint.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Adult

-    Duodenal ulcer

-    Benign gastric ulcer

-    Reflux oesophagitis

-    Zollinger-Ellison syndrome.

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

Dissolve an effervescent tablet in a glass of water. Do not break the effervescent tablet. Wait until the effervescent tablet has been completely dissolved and drink the solution directly.

ADULTS (INCLUDING THE ELDERLY)/ADOLESCENTS (12 YEARS AND OLDER)

For adults (including the elderly) and adolescents (12 years and older) with normal renal function, the following dosing guidelines apply:

DUODENAL AND BENIGN GASTRIC ULCERS:

1 effervescent tablet (= 300 mg ranitidine) after supper or at bedtime.

The therapy should last for four weeks. In the occasional patient in whom the gastric ulcer is not fully healed after four weeks treatment, the treatment should be continued for a further four weeks at the same dose.

FOR REFLUX OESOPHAGITIS, 1 effervescent tablet of ranitidine 300 mg (= 300 mg ranitidine) after supper or at bedtime for up to 8 weeks if necessary.

PATIENTS WITH VERY HIGH GASTRIC ACID SECRETION, EG. ZOLLINGER-ELLISON SYNDROME, should initially receive treatment with 150 mg ranitidine three times daily (= 450 mg ranitidine daily). If necessary, the dose may be increased to 2-3 Ranitidine effervescent tablets 300 mg daily (=600-900 mg ranitidine daily).

Patients may be stabilised on higher doses (e.g. 1200 mg daily) if considered clinically as being necessary Daily doses of up to 6 g ranitidine have been given.

With Ranitidine Effervescent tablets 300 mg, a dose of 150 mg cannot be realised. To realise this dose, Ranitidine Effervescent tablets 150 mg should be used.

Doses may be administered irrespective of mealtimes.

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

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).

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

DOSAGE GUIDE FOR PATIENTS WITH RENAL IMPAIRMENT Depending on the creatinine clearance (ml/min) or serum creatinine level (mg/100 ml), the following dosages are recommended:

(ml/min)

(mg/100 ml)

Over 30

Under 2.6

300 mg Ranitidine

Up to 30

Over 2.6

150 mg Ranitidine

*The serum creatinine values are guidelines, which do not represent the same level of impairment for all patients with reduced kidney function. This is especially the case in elderly patients in whom there is an overestimation of kidney function through the serum creatinine concentration.

The following formula can be used to estimate creatinine clearance from the measured serum creatinine (mg/100 ml), age (in years) and body weight (in kg). For women, the result needs to be multiplied by the factor 0.85.

Creatinine clearance (ml/min)= (140-age) x body weight

72 x serum creatinine

Ranitidine is dialysable. Haemodialysis reduces blood ranitidine levels. Thus, dialysis patients should receive the above dose of ranitidine after completion of dialysis.

4.3 Contraindications

Ranitidine effervescent tablets must not be administered to patients with known hypersensitivity to the active ingredient, ranitidine hydrochloride, or to any of the other 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 as treatment with ranitidine may mask symptoms of gastric carcinoma.

Patients with peptic ulcer must be tested for the presence of H. pylori. If the findings are positive, adequate eradication therapy should be administered.

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

In accordance with the recommendations for good clinical practice, a regular routine examination is recommended for patients undergoing long-term maintenance therapy.

In the case of concurrent use of ranitidine and theophylline, the plasma concentrations of theophylline should be monitored and, if necessary, the dose of theophylline should be adjusted.

Ranitidine is excreted via the kidney and so plasma levels of the drug are

increased in patients with severe renal impairment. A dose reduction is necessary in patients with impaired renal function (see section 4.2).

Treatment must be discontinued immediately in the event of confusion in patients with renal impairment or in elderly patients.

Since ranitidine is metabolised in the liver, ranitidine should be used with caution in patients with severe hepatic dysfunction.

In patients such as the elderly, persons with chronic lung disease, diabetes or the immuno-compromised, 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).

Rare clinical reports suggest that ranitidine may precipitate acute porphyric attacks. Patients with a history of acute intermittent porphyria should not be treated with ranitidine.

Each tablet contains 23 mmol (or 533 mg) sodium. Care should therefore be taken in treating patients in whom sodium restriction is indicated.

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 hours.

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

Experience with the use of ranitidine in pregnant women (>1000) does not reveal evidence for an increased risk of congenital defects or other adverse effects of ranitidine on pregnancy or the unborn child.. Ranitidine crosses the placenta. Like other drugs ranitidine should only be used during pregnancy if it is considered essential.

Lactation

Ranitidine is excreted in human breast milk. Like other drugs ranitidine should only be used during breast-feeding if considered essential.

4.7 Effects on ability to drive and use machines

None reported.

4.8 Undesirable effects

The frequencies are defined as follows:

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), not known (frequency cannot be estimated from the available 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 patients, in elderly and in 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

Very rare: Acute interstitial nephritis .

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

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 established in children aged 0-16 years with gastric acid-related disease and was generally well tolerated with an adverse event profile resembling that in adults. There are limited safety data available on long-term use, in particular in relation to 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 and Signs

Ranitidine is very specific in action and no particular problems are expected following overdosage with ranitidine formulations. Physicians must be aware that ranitidine contains sodium.

Treatment

If necessary, symptomatic and supportive treatment should be given.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: H2-receptor antagonists

ATC-code: A02BA02.

Ranitidine is a competitive histamine H2 -receptor antagonist. It inhibits basal gastric secretion and gastric secretion stimulated e.g. by histamine, pentagastrin and food.

Ranitidine decreases both the acid content and also to a smaller extent the pepsin content and volume of the gastric juice.

In two studies using therapeutic doses of Ranitidine 150 mg twice daily, gastric acid secretion was reduced by a mean of 63% and 69% respectively over 24 hours, with reductions of 73% and 90% respectively in nocturnal acid secretion. In two studies using the dosage recommended for prophylaxis of recurrence (150 mg nocte) ranitidine produced mean reductions in gastric acid secretion of 42% and 69% respectively within 24 hours.

The gastric acid secretion was reduced by a mean of 50 to 60% within 24 hours after administration of therapeutic doses of 300 mg ranitidine nocte, while the nocturnal acid secretion was reduced by approximately 90%.

5.2. Pharmacokinetic properties

Absorption:

Ranitidine is rapidly absorbed after oral administration and attains peak blood concentrations after a mean of 1,25 - 3 hours. The mean bioavailability of ranitidine in tablet form is approx. 50 % but inter-individual variation in bioavailability is wide, being quoted as 28 - 76 % in one study.

Distribution:

Plasma protein binding is approx. 15%. The apparent distribution volume in adults is 1.2-1.8 l/kg and in children 2.5 l/kg.

After oral ingestion of 150 mg ranitidine as tablet, peak plasma levels of around 400 ng/ml were attained, with wide-individual variation. At twelve hours, mean plasma levels were still approx. 40 ng/ml. After administration of 300 mg ranitidine, peak plasma levels of approx. 700-800 ng/ml were attained.

The plasma concentration required for 50% inhibition of acid secretion in adults averaged 73-165 ng/ml in a number of studies.

To a very small extent, ranitidine passes into the cerebrospinal fluid.

Biotransformation:

Ranitidine is metabolised in the liver to ranitidine-N-oxide, N-desmethyl ranitidine, ranitidine-S-oxide and the furane acid analogue.

Elimination:

Measurements of total clearance yielded mean values of 570-710 ml/min in adults. In children and adolescents a total clearance of almost 800 ml/min/1.73 m2 was found, with a wide degree of scatter.

After oral administration, ranitidine is excreted within 24 hours via the kidneys to approx. 30% as unchanged ranitidine, up to 6% as N-oxide, to a small degree in demethylised and in S-oxidised 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.

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

Sodium dihydrogen citrate Sodium hydrogen carbonate (E500)

Povidone 30 Simethicone

Sunset yellow supra (E110) (only for 150 mg strength) Glycine

Powdarome peppermint premium Sodium benzoate Saccharin Sodium (E954)

Qualitative composition of Powdarome peppermint premium

Flavouring preparations Natural flavouring substance

Flavouring substances identical to natural substances Maize maltodextrin E 414 Acacia gum (gum arabic)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years

Use within 1 month from the date of first opening.

6.4


Special precautions for storage

Store below 30°C. Keep the container tightly closed in order to protect from moisture and light.


6.5


Nature and contents of container

Polypropylene tubes with desiccant as part of polyethylene tamper evident cap, each tube contains 20 tablets is packed in a carton of 60 (3 x 20) tablets along with package inserts.


6.6


Special precautions for disposal

Not applicable


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MARKETING AUTHORISATION HOLDER

Accord Healthcare Limited Sage House,

319 Pinner Road,

North Harrow,

Middlesex, HA1 4HF,

United Kingdom


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MARKETING AUTHORISATION NUMBER(S)

PL 20075/0120


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DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

21/09/2009

DATE OF REVISION OF THE TEXT


26/11/2014