SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Ranitidine 75mg Tablets Ranzac 75mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 84mg of ranitidine hydrochloride of which 75mg is ranitidine.

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film Coated Tablets

White to off-white, round, biconvex film coated tablets with a break line on one side and the imprint ‘R75’’ on the other side

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Ranitidine 75mg Tablets are indicated for the short term symptomatic relief of heartburn, indigestion, acid indigestion and hyperacidity.

4.2 Posology and method of administration

Dose

Adults:

One Ranitidine 75mg Tablet should be taken as soon as symptoms appear. If symptoms persist for more than one hour, or return, a second Ranitidine 75mg Tablet should be taken. The maximum daily dose is two Ranitidine 75mg Tablets.

Children:

Ranitidine 75mg Tablets should not be taken by children under the age of 16 years.

Length of treatment:

Do not take the tablets for more than 6 days without the advice of a pharmacist or doctor. Medical attention should be sought if symptoms worsen.

Method of administration

Ranitidine 75mg tablets should be swallowed whole with fluid.

4.3 Contraindications

Ranitidine 75mg Tablets should not be given to patients known to have hypersensitivity to Ranitidine or any component of the tablet.

Ranitidine 75mg Tablets should not be given to children under 16 years because safety and efficacy have not been established in this patient group.

4.4 Special warnings and precautions for use

Patients should be advised not to purchase a second pack of tablets without the advice of a pharmacist or doctor.

Patients taking NSAIDS, especially the elderly and in those with a history of peptic ulcer, should seek their doctor’s advice before using this product. Current evidence shows that ranitidine protects against NSAID associated ulceration in the duodenum and not in the stomach.

In patients such as 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 versus those who had stopped treatment, with an observed adjusted relative risk increase of 1.82 (95% CI 1.26-2.64). Postmarketing data indicate reversible mental confusion, depression, and hallucinations have been reported most frequently in severely ill and elderly patients (see section 4.8).

If gastric ulcer (patients of middle age) has been diagnosed or there is a new or recently changed presentation or dyspeptic symptoms, then the possibility of malignancy should be excluded. Isolated reports suggest a relationship between the intake of Ranitidine 75mg and the occurrence of acute porphyria. Administration of Ranitidine 75mg Tablets to patients with a history of acute porphyria should, therefore be avoided.

Patients should consult their doctor before taking Ranitidine 75mg Tablets if:

-    the patient has unintended weight loss

-    the patient has problems swallowing

-    the patient has constant stomach pains

-    the patient is middle-aged or elderly with new or recently changed symptoms.

Ranitidine is excreted via the kidney and so plasma levels of the drug are increased in patients with severe renal impairment. The dose should be adjusted in Renal Impairment.

4.5 Interaction with other medicinal products and other forms of interaction

At normal dosage, Ranitidine does not inhibit cytochrome P450; although some minor interactions have been seen with some products these have not been shown to be of clinical relevance.

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, propanolol 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 secrection:

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 level 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 or metronidazole. If high doses of sucralfate (2g) 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 2h.

4.6 Fertility, Pregnancy and lactation

Pregnancy:

Ranitidine crosses the placenta but therapeutic doses administered to obstetric patients in labour or undergoing caesarean section have been without any adverse effect on labour, delivery or subsequent neonatal progress. There are no adequate studies on the effect of Ranitidine in pregnancy although animal studies have not produced evidence that it will harm the foetus. Like other medicines, Ranitidine should only be used during pregnancy if absolutely necessary following appropriate medical consultation.

Lactation:

Ranitidine is found in human breast milk so nursing mothers should avoid taking ranitidine. Like other drugs, Ranitidine should only be used during pregnancy and nursing if considered essential.

4.7 Effects on ability to drive and use machines

No effects have been reported.

4.8 Undesirable effects

Ranitidine is well tolerated although as with all drugs, some patients occasionally experience side effects. Listed below are side effects which have been reported for Ranitidine 75mg Tablets. These have not necessarily occurred after taking Ranitidine 75mg Tablets and could have occurred after taking 150mg and 300mg Ranitidine.

The following convention has been utilised for the classification of undesirable effects: very common (1/10), common (1/100, <1/10), uncommon (1/1000, 1/100), rare (1/10,000, 1/1000), very rare (1/10,000). Adverse event frequencies have been estimated from spontaneous reports from post marketing data.

Blood & Lymphatic System Disorders

Very Rare: Blood count changes (leucopenia, thrombocytopenia), aplastic anaemia. 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. visual disturbances. 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 , Arrhythmia, such as tachycardia or bradycardia and A-V Block/Conduction disturbances.

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: Hypersensitivity reactions, 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, erectile dysfunction, breast symptoms and breast conditions (such as gynaecomastia and galactorrhoea).

The safety of ranitidine has been assessed in children ages 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 data available, in particular regarding growth and development.

4.9 Overdose

Complications from overdose are not expected after oral administration. Daily doses of 6300mg of ranitidine administered orally for several months were well tolerated.

Treatment for overdose:

If there are signs of intoxication, unabsorbed tablets should be removed by gastric lavage.

Haemodialysis can be used to remove drug from the plasma.

Symptomatic and supportive treatment should be given as required.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Ranitidine is a competitive inhibitor of the action of histamine at the histamine H2-receptors. It inhibits basal gastric acid secretion as well as gastric acid secretion stimulated by e.g. histamine, pentagastrin or food. Ranitidine reduces gastric acid secretion as well as to a limited degree total pepsin output and total gastric juice volume.

Studies showed that therapeutic doses of 150 mg ranitidine twice a day, on average, inhibit gastric acid secretion by more than 60% for 24 hours. At night these doses were sufficient to inhibit gastric acid secretion by 70 - 90%. Doses of 150 mg in the evening were shown to inhibit gastric acid secretion by 40 -70% for 24 hours on average.

Therapeutic doses necessary to inhibit gastric acid secretion by 50-60% for 24 hours were 300 mg ranitidine. Nocturnal gastric acid secretion was reduced by almost 90%.

5.2 Pharmacokinetic properties

Ranitidine is rapidly absorbed after oral administration with mean peak levels occurring at 1.25 to 3 hours. Bioavailability of ranitidine tablets is 50% on average with an interindividual variability of 28 - 76%.

After oral administration of 150 mg ranitidine mean peak plasma levels were about 400 ng/ml.

Interindividual variability was observed. After 12 hours, mean plasma levels were 40 ng/ml. After oral administration of 300 mg ranitidine mean peak plasma levels were 700 to 800 ng/ml.

In several studies, the plasma concentration necessary to inhibit 50% of gastric acid secretion in adults was between 73 and 165 ng/ml.

Plasma-protein binding is approximately 15%. The volume of distribution is

1.2 - 1.8 l/kg in adults and 2.5 l/kg in children. Mean total clearance is 570 -710 ml/min in adults and about 800 ml/min in children and young persons.

In the liver ranitidine is metabolised to ranitidine-N-oxide, N-desmethylranitidine, ranitidine-S-oxide and a furan acid analogue. About 35 % of the orally administered dose is excreted unchanged in the urine within 24 hours, 6% of the dose is excreted as the N-oxide, 2% as the S-oxide, 2% as desmethyl ranitidine and 1-2% as the furoic acid analogue.

In persons with normal renal functions the elimination half-life after oral administration is 2.3 to 3 hours. In patients with impaired renal function elimination half-life maybe 2 to 3 times longer than this. Only small amounts of ranitidine are found in cerebrospinal fluid.

Ranitidine passes the placental barrier. Following intravenous and oral administration of ranitidine during parturition, ranitidine concentrations corresponding to those in the mother's serum have been found in umbilical cord blood of the new-born. Twelve hours later only very small amounts were present.

Ranitidine is found in human breast milk, the ratio milk/plasma concentration being 1.9 (range: 0.6 to 20.9) two hours after administration.

Unless otherwise stated, the pharmacokinetics of ranitidine in children is the same as for adults.

5.3 Preclinical safety data

Ranitidine has a high safety margin. In dogs, oral doses of ranitidine of up to 400mg/kg/day for 54 weeks resulted in dose related occasional cases of mild diarrhoea, increased salivation and vomiting. Rapid respiration and muscular tremors with one fatality occurred in dogs receiving 450mg/kg ranitidine. Rats tolerated daily doses of 2,000mg/kg for 78 weeks well.

In animal tests ranitidine has shown no mutagenic, carcinogenic or teratogenic potential and does not impair fertility.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Microcrystalline Cellulose, Polyvidone, Magnesium Stearate, Methylhydroxypropylcellulose, Titanium dioxide (E171), Talc, Macrogol 6000 and Methacrylic acid copolymer.

6.2 Incompatibilities

None known.

6.3 Shelf life

3 years

6.4 Special precautions for storage

No special precautions are required

Do not store above 25°C. Store in the original Package

6.5 Nature and contents of container

Blister strip comprising aluminium foil on both sides. The strips are packed in cartons to contain 5, 6, 10 or 12 tablets.

6.6 Special precautions for disposal

None.

7    MARKETING AUTHORISATION HOLDER

OTC Concepts Ltd 2 Park Street Woburn Bedfordshire MK17 9PG

MARKETING AUTHORISATION NUMBER(S)

PL 20338/0020

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

01/03/2006

DATE OF REVISION OF THE TEXT

07/05/2014

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