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Ranitidine Effervescent 150mg Effervescent Tablets

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SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

Ranitidine Effervescent 150 mg, effervescent tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 168 mg ranitidine hydrochloride, equivalent to 150 mg ranitidine.

Excipients with known effect:

Each tablet contains 120mg sodium and 416 mg lactose (see section 4.4). For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Effervescent tablet.

Yellow-white to light -yellow cylindrical tablets with bevelled edges.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

For the treatment of diseases of the upper gastro-intestinal tract, in which a reduction of gastric acid secretion is indicated:

-    Duodenal ulcer

-    Benign gastric ulcer

-    Long-term treatment of duodenal ulcers to prevent their recurrence. Longterm treatment is indicated in patients with a history of recurrent ulcer

-    Refux oesophagitis

-    Zollinger-Ellison syndrome.

Ranitidine is not indicated for the treatment of minor gastro-intestinal complaints, such as nervous stomach.

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

Posology

Adults/adolescents (12 years and older)

Duodenal and benign gastric ulcers

300mg ranitidine after supper or at bedtime. Alternatively, 150mg ranitidine twice daily, taken in the morning and evening.

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

Duodenal ulcers long-term treatment.

Patients who have responded to such short-term treatment, and only those with a history of recurrent ulcer, may if necessary continue treatment for up to 12 months with 150 mg ranitidine daily at bedtime, for prophylaxis of recurrence. Patients should undergo regular endoscopic examination.

Reflux oesophagitis:

300 mg ranitidine) after supper or at bedtime. Alternatively, 150 mg ranitidine twice daily (if necessary 4 times daily = 600mg ranitidine/day), taken in the morning and evening, for up to 8 weeks (12 weeks if necessary).

Patients with very high gastric acid secretion, e.g. Zollinger-Ellison syndrome, Initially, 150mg ranitidine three times daily (450mg ranitidine daily). If necessary, the dose may be increased to 600-900mg ranitidine daily.

Patients may be stabilised on higher doses if measurement of gastric acid secretion demonstrates this to be necessary. Daily doses of up to 6g ranitidine have been given.

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.

Patients with impaired renal function

Depending on the creatinine clearance (ml/min) or serum creatinine level (mg/100ml), the following dosages are recommended:

Creatinine clearance (ml/min)

Serum creatinine (approx.)* (mg/100ml)

Daily dose (oral)

Up to 30

Over 2.6

150 mg ranitidine

Over 30

Under 2.6

300 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/100ml), 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.

Method of administration

Doses may be administered irrespective of mealtimes.

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

4.3 Contraindications

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

Isolated reports have indicated a relationship between the onset of acute intermittent porphyria and administration of ranitidine hydrochloride. Patients with a history of acute intermittent porphyria should therefore not be treated with Ranitidine.

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.

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

The dosage should be adjusted in renal impairment as detailed above in section 4.2.

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 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 ranitidine alone 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).

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

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

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

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Ranitidine 150mg effervescent tablets contains 120 mg sodium. To be taken into consideration by patients on a controlled sodium diet.

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.

4.6 Fertility, pregnancy and lactation

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

None reported.

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 (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

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 and elderly 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: 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, pruritis

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 in men and breast conditions (such as gynaecomastia and galactorrhoea)

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 website: 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.

Treatment

Symptomatic and supportive therapy should be given as appropriate.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: H2-receptor antagonist, ATC-code: A02B A02.

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 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. 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%. In two studies using the dosage recommended for prophylaxis of recurrence (150mg nocte) ranitidine produced mean reductions in gastric acid secretion of 42% and 69% respectively within 24 hours.

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 approximately 50%, but inter-indiviual variation in bioavailibility is wide, being quoted as 28-76% in one study.

Distribution

Plasma protein binding is approximately 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 150mg ranitidine in tablet form, peak plasma levels of around 400 ng/ml were attained, with wide inter-individual variation. At twelve hours, mean plasma levels were still approximately 40 ng/ml. After administration of 300mg ranitidine, peak plasma levels of approximately 700800 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-Desmethylranitidine, 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 m was found, with a wide degree of scatter.

After oral administration, ranitidine is excreted within 24 hours via the kidneys to approximately 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 renal clearance of about 490-520 ml/min. Additionally, ranitidine is excreted via the bile.

Characteristics in special patient groups

After oral intake, mean elimination half-life in patients with sound kidney 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

Tartaric acid, sodium hydrogen carbonate, lactose monohydrate, povidone, riboflavin 5'-phosphate sodium (E101), simethicone emulsion (contains simethicone, methylcellulose, sorbic acid and purified water), sodium cyclamate, saccharin sodium, lemon flavour (contains citral, citronella oil, coriander oil, lime and acacia), macrogol 6000 and sodium hydroxide.

6.2 Incompatibilities

None known.

6.3    Shelf life

3 years.

6.4    Special precautions for storage

Do not store above 30°C. Keep the container tightly closed.

6.5    Nature and contents of container

Polypropylene container with LDPE cap. A quantity of dessicant (silicagel) is incorporated into the cap.

Pack sizes: 15, 30 or 60 effervescent tablets Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

MARKETING AUTHORISATION HOLDER

7


Actavis UK Limited (Trading style: Actavis)

Whiddon Valley

Barnstaple

N. Devon EX32 8NS

United Kingdom

8. MARKETING AUTHORISATION NUMBER

PL 00142/0519

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

10/10/2006

10    DATE OF REVISION OF THE TEXT

14/10/2013