RANITIDINE TABLET

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Active ingredient:
RANITIDINE (RANITIDINE HYDROCHLORIDE)
Available from:
PRO DOC LIMITEE
ATC code:
A02BA02
INN (International Name):
RANITIDINE
Dosage:
300MG
Pharmaceutical form:
TABLET
Composition:
RANITIDINE (RANITIDINE HYDROCHLORIDE) 300MG
Administration route:
ORAL
Units in package:
100/30
Prescription type:
Prescription
Therapeutic area:
HISTAMINE H2-ANTAGONISTS
Product summary:
Active ingredient group (AIG) number: 0115150001; AHFS: 56:28.12
Authorization status:
APPROVED
Authorization number:
00740756
Authorization date:
2019-09-20

Documents

RANITIDINE

Page 1 of 28

PRODUCT MONOGRAPH

Pr

RANITIDINE

Ranitidine Tablets, USP

150 mg & 300 mg ranitidine (as ranitidine hydrochloride)

Histamine H

-receptor antagonist

PRO DOC LTÉE

2925, boul. Industriel

Laval, Quebec

H7L 3W9

Date of Revision:

September 18, 2019

Submission Control No: 229390

RANITIDINE

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Table of Contents

PART I: HEALTH PROFESSIONAL INFORMATION ..........................................................3

SUMMARY PRODUCT INFORMATION ........................................................................3

INDICATIONS AND CLINICAL USE ..............................................................................3

CONTRAINDICATIONS ...................................................................................................4

WARNINGS AND PRECAUTIONS ..................................................................................4

ADVERSE REACTIONS ....................................................................................................6

DRUG INTERACTIONS ....................................................................................................7

DOSAGE AND ADMINISTRATION ................................................................................8

OVERDOSAGE ................................................................................................................10

ACTION AND CLINICAL PHARMACOLOGY ............................................................10

STORAGE AND STABILITY ..........................................................................................12

DOSAGE FORMS, COMPOSITION AND PACKAGING .............................................12

PART II: SCIENTIFIC INFORMATION ................................................................................13

PHARMACEUTICAL INFORMATION ..........................................................................13

CLINICAL TRIALS ..........................................................................................................14

DETAILED PHARMACOLOGY .....................................................................................15

TOXICOLOGY .................................................................................................................18

REFERENCES ..................................................................................................................23

PART III: CONSUMER INFORMATION...............................................................................26

RANTIDINE

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RANITIDINE

Ranitidine Tablets, USP

PART I: HEALTH PROFESSIONAL INFORMATION

SUMMARY PRODUCT INFORMATION

Route of

Administration

Dosage Form /

Strength

All Nonmedicinal Ingredients

Oral

Tablet / 150 mg &

300 mg

Microcrystalline cellulose, croscarmellose

sodium, and magnesium stearate.

The film-coating suspension contains

hydroxypropyl methylcellulose, titanium

dioxide, polydextrose, polyethylene glycol,

and triethyl citrate.

INDICATIONS AND CLINICAL USE

RANITIDINE (ranitidine hydrochloride) tablets are indicated for the treatment of duodenal

ulcer, benign gastric ulcer, reflux esophagitis, post-operative peptic ulcer, Zollinger-Ellison

Syndrome, and other conditions where reduction of gastric secretion and acid output is desirable.

These include the following:

The treatment of nonsteroidal anti-inflammatory drug (NSAID) – induced lesions, both

ulcers and erosions, and their gastrointestinal (GI) symptoms and the prevention of their

recurrence;

The prophylaxis of GI hemorrhage from stress ulceration in seriously ill patients;

The prophylaxis of recurrent hemorrhage from bleeding ulcers;

The prevention of Acid Aspiration Syndrome from general anaesthesia in patients

considered to be at risk for this, including obstetrical patients in labour, and obese

patients.

In addition, RANITIDINE is indicated for the prophylaxis and maintenance treatment of

duodenal or benign gastric ulcer in patients with a history of recurrent ulceration.

RANTIDINE

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CONTRAINDICATIONS

RANITIDINE (ranitidine hydrochloride) is contraindicated for patients known to have

hypersensitivity to ranitidine or to any ingredient in the formulation. For a complete listing, see

Dosage Forms, Composition and Packaging section.

WARNINGS AND PRECAUTIONS

General

Concomitant NSAID Use

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. Baseline endoscopy and histological evaluation is necessary to rule out

gastric carcinoma.

Cyanocobalamin (Vitamin B12) Deficiency

The prolonged use of H2-receptor antagonists, may impair the absorption of protein-bound

Vitamin B12 and may contribute to the development of cyanocobalamin (vitamin B12)

deficiency.

Gastrointestinal

Gastric Ulcer

Treatment with a histamine H

-antagonist may mask symptoms associated with carcinoma of the

stomach and, therefore, may delay diagnosis of that condition. Accordingly, where gastric ulcer

is suspected the possibility of malignancy should be excluded before therapy with RANITIDINE

(ranitidine hydrochloride) is instituted.

Hematologic

Use in Patients with a History of Acute Porphyria

Rare clinical reports suggest that ranitidine may precipitate acute porphyric attacks. Therefore,

ranitidine should be avoided in patients with a history of acute porphyria.

Renal

Use in Impaired Renal Function

Ranitidine is excreted via the kidneys and, in the presence of renal impairment, plasma levels of

ranitidine are increased and elimination prolonged. Accordingly, it is recommended in such

patients, to decrease the dosage of RANITIDINE by one half. Accumulation of ranitidine with

resulting elevated plasma concentrations will occur in patients with renal impairment (creatinine

clearance less than 50 ml/min); a recommended daily dose of oral ranitidine in such patients

should be 150 mg.

RANTIDINE

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Special Populations

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 TOXICOLOGY).

Pregnant Women: The safety of ranitidine in the treatment of conditions where a controlled

reduction of gastric secretion is required during pregnancy has not been established.

Reproduction studies performed in rats and rabbits have revealed no evidence of ranitidine

hydrochloride induced impaired fertility or harm to the fetus. Ranitidine crosses the placenta.

Nevertheless, if the administration of RANITIDINE is considered to be necessary, its use

requires that the potential benefits be weighed against possible hazards to the patient and to the

fetus.

Nursing Women: Ranitidine is secreted in breast milk in lactating mothers but the clinical

significance of this has not been fully evaluated. Like other drugs, ranitidine should only be used

during nursing if considered essential.

Pediatrics: Experience with ranitidine products in children is limited. It has, however, been used

successfully in children aged 8 to 18 years in oral doses up to 150 mg twice daily.

Geriatrics: 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 H

receptor antagonists versus those who had stopped

treatment, with an observed adjusted relative risk increase of 1.63 (95% CI, 1.07-2.48).

Use in the Elderly

Since malignancy is more common in the elderly, particular consideration must be given to this

before therapy with RANITIDINE is instituted. Elderly patients receiving non-steroidal anti-

inflammatory drugs concomitantly with RANITIDINE should be closely supervised.

As with all medication in the elderly, when prescribing RANITIDINE, consideration should be

given to the patient's concurrent drug therapy. Sporadic cases of drug interaction have been

reported in elderly patients involving both hypoglycaemic drugs and theophylline. The

significance of these reports cannot be determined at present, as controlled clinical trials with

theophylline and ranitidine have not shown interaction. Elderly patients may be at increased risk

for confusional states and depression.

Patients over 50 years of age

In patients over 50 years of age, half-life is prolonged (3 to 4 hours) and clearance is reduced,

consistent with the age-related 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.

RANTIDINE

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ADVERSE REACTIONS

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction

rates observed in the clinical trials may not reflect the rates observed in practice and

should not be compared to the rates in the clinical trials of another drug. Adverse drug

reaction information from clinical trials is useful for identifying drug-related adverse

events and for approximating rates.

The following adverse reactions have been reported as events in clinical trials or in the routine

management of patients treated with ranitidine. A cause and effect relationship to ranitidine

hydrochloride is not always established.

Central Nervous System

Headache, sometimes severe; malaise; dizziness; somnolence; insomnia; vertigo; and reversible

blurred vision suggestive of a change in accommodation. Isolated cases of reversible mental

confusion, agitation, depression, hallucinations have been reported, predominantly in severely ill

elderly patients. In addition, reversible involuntary movement disorders have been reported

rarely.

Cardiovascular

Isolated reports of tachycardia, bradycardia, premature ventricular beats, AV block have been

noted. Asystole has been reported in very few individuals with and without predisposing

conditions following IV administration and has not been reported following oral administration

of ranitidine (See WARNINGS AND PRECAUTIONS, DOSAGE AND ADMINISTRATION).

Gastrointestinal

Constipation, diarrhea, nausea/vomiting and abdominal discomfort/pain.

Hepatic

In normal volunteers, transient and reversible SGPT and SGOT values were increased to at least

twice the pretreatment levels in 6 of 12 subjects receiving ranitidine 100 mg q.i.d intravenously

for seven days, and in 4 of 24 subjects receiving 50 mg q.i.d intravenously for five days.

Therefore, it may be prudent to monitor SGOT and SGPT in patients receiving intravenous

treatment for five days or longer and in those with pre-existing liver diseases. With oral

administration, there have been occasional reports of hepatitis, hepatocellular or

hepatocanalicular or mixed, with or without jaundice. In such circumstances, ranitidine should be

discontinued immediately. These are usually reversible, but in exceedingly rare circumstances,

death has occurred.

Renal

Very rare cases of acute interstitial nephritis have been reported.

RANTIDINE

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Musculoskeletal

Rare reports of arthralgia and myalgia.

Haematologic

Blood count changes (leukopenia, thrombocytopenia) have occurred in a few patients. These are

usually reversible. Rare cases of agranulocytosis or pancytopenia, sometimes with marrow

hypoplasia or aplasia have been reported.

Endocrine

No clinically significant interference with endocrine or gonadal function has been reported.

There have been a few reports of breast symptoms and breast conditions (such as gynaecomastia

and galactorrhoea).

Dermatologic

Rash, including cases suggestive of mild erythema multiforme. Rare cases of vasculitis and

alopecia have been reported.

Other

Rare cases of hypersensitivity reactions (including chest pain, bronchospasm, fever, rash,

eosinophilia, anaphylaxis, urticaria, angioneurotic edema, hypotension) and small increases in

serum creatinine have occasionally occurred after a single dose. Acute pancreatitis and reversible

impotence has been reported rarely.

DRUG INTERACTIONS

Interactions with Other Drugs

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:

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.

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.

RANTIDINE

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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) or a decrease in absorption (e.g. ketoconazole,

atazanavir, delaviridine, gefitnib).

Sporadic cases of drug interactions have been reported in elderly patients involving both

hypoglycaemic drugs and theophylline. The significance of these reports cannot be

determined at present, as controlled clinical trials with theophylline and ranitidine have not

shown interaction.

If high doses (two grams) of sucralfate are coadministered with ranitidine, the absorption

of ranitidine may be reduced. This effect is not seen if sucralfate is taken at least two hours

after ranitidine administration.

Drug-Food Interactions

Interactions with food have not been established.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Interactions

Interactions with laboratory tests have not been established.

Drug-Lifestyle Interactions

(See DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment,

Maintenance Therapy).

DOSAGE AND ADMINISTRATION

Recommended Dose and Dosage Adjustment

Duodenal ulcer or benign gastric ulcer

300 mg once daily at bedtime or 150 mg twice daily taken in the morning and before retiring. It

is not necessary to time the dose in relation to meals. In most cases of duodenal ulcer and benign

gastric ulcer, healing will occur in four weeks. In the small number of patients whose ulcers may

not have fully healed, these are likely to respond to a further four-week course of therapy. In the

treatment of duodenal ulcers, 300 mg twice daily for 4 weeks may be of benefit when more rapid

healing is desired.

Maintenance therapy

Duodenal ulcers, benign gastric ulcers: Patients who have responded to short-term therapy,

particularly those with a history of recurrent ulcer, may benefit from chronic maintenance

therapy at a reduced oral dosage of 150 mg once daily at bedtime.

RANTIDINE

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In the management of duodenal ulcers, smoking is associated with a higher rate of ulcer relapse

(up to 9.2 times higher in one trial), and such patients should be advised to stop smoking. In

those patients who fail to comply with such advice, 300 mg nightly provides additional

therapeutic benefit over the 150 mg once daily dosage regimen.

Reflux esophagitis

Acute treatment

300 mg once daily at bedtime, or alternatively 150 mg twice daily, taken in the morning and

before retiring for up to eight weeks. In patients with moderate to severe esophagitis, the dosage

of ranitidine may be increased to 150 mg four times daily for up to 12 weeks.

Long-term Management

For the long-term management of reflux esophagitis, the recommended adult oral dose is 150 mg

twice daily.

Post-operative peptic ulcer

150 mg twice daily, taken in the morning and before retiring.

Pathological hypersecretory conditions (Zollinger-Ellison Syndrome)

150 mg three times daily may be administered initially. In some patients, it may be necessary to

administer RANITIDINE (ranitidine hydrochloride)150 mg doses more frequently. Doses should

be adjusted to individual patient needs. Doses up to six grams per day have been well tolerated.

Treatment of NSAID-induced lesions (both ulcers and erosions) and their gastrointestinal

symptoms and prevention of their recurrence

In ulcers following non-steroidal anti-inflammatory drug therapy or associated with continued

non-steroidal anti-inflammatory drugs, 150 mg twice daily for 8-12 weeks may be necessary. For

the prevention of non-steroidal anti-inflammatory drug associated ulcer recurrence, 150 mg twice

daily may be given concomitantly with non-steroidal anti-inflammatory drug therapy.

Prophylaxis of acid aspiration syndrome (AAS)

150 mg the evening prior to anaesthesia induction is recommended, however, 150 mg two hours

before anaesthesia induction is also effective. For the prevention of AAS in pre-partum patients

who elect for anaesthesia, 150 mg every six hours may be employed, but if general anaesthesia is

warranted, a non-particulate oral antacid (for example, sodium citrate) could supplement

RANITIDINE therapy. In an emergency situation, the use of alkalis, antacids, and meticulous

anaesthetic technique is still necessary as ranitidine does not affect the pH and volume of the

existing gastric content.

Prophylaxis of hemorrhage from stress ulceration in seriously ill patients or prophylaxis of

recurrent hemorrhage in patients bleeding from peptic ulceration who are currently managed

by intravenous ranitidine

.

RANITIDINE is NOT available in injectable dosage form.

RANTIDINE

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An oral dose of 150 mg twice daily may be substituted for the injection once oral feeding

commences.

Dosage for the Elderly

For all conditions listed above, the drug dosage for the elderly who are seriously ill should start

at the lowest recommended dose and be adjusted as necessary with close supervision.

Patients over 50 years of age (see WARNINGS AND PRECAUTIONS, Patients over 50 years of

age).

OVERDOSAGE

There is no experience to date with deliberate overdosage. The usual measures to remove

unabsorbed drug from the gastrointestinal tract (including activated charcoal or syrup of ipecac),

clinical monitoring and supportive therapy should be employed.

For management of a suspected drug overdose, contact your regional poison control centre

immediately.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Ranitidine is an antagonist of histamine at gastric H

-receptor sites. Thus, ranitidine inhibits both

basal gastric secretion and gastric acid secretion induced by histamine, pentagastrin and other

secretagogues. On a weight basis ranitidine is between 4 and 9 times more potent than

cimetidine. Inhibition of gastric acid secretion has been observed following intravenous,

intraduodenal and oral administration of ranitidine. This response is dose-related, a maximum

response being achieved at an oral dose of 300 mg/day.

Pepsin secretion is also inhibited but secretion of gastric mucus is not affected. Ranitidine does

not alter the secretion of bicarbonate or enzymes from the pancreas in response to secretin and

pancreozymin.

There is a significant linear correlation between the dose administered and the inhibitory effect

upon gastric acid secretion for oral doses up to 300 mg. A plasma ranitidine concentration of

50 ng/mL has an inhibitory effect upon stimulated gastric acid secretion of approximately 50%.

Estimates of the IC

range from 36 to 94 ng/mL. Following the administration of 150 mg

ranitidine orally, plasma concentrations in excess of this lasted for more than 8 hours and after

12 hours, the plasma concentrations were sufficiently high to have a significant inhibitory effect

upon gastric secretion. In patients with duodenal ulcer, 150 mg oral ranitidine every 12 hours

significantly reduced mean 24-hour hydrogen ion activity by 69% and nocturnal gastric acid

RANTIDINE

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output by 90%. Furthermore, 300 mg oral ranitidine at night is as effective in reducing 24-hour

intragastric acidity as 150 mg ranitidine given orally twice daily.

Tablets

In respect of both 24-hour acidity and nocturnal acid output, an oral dose of ranitidine 150 mg

twice daily was superior to cimetidine 200 mg three times daily and 400 mg at night (p<0.001

and p<0.05, respectively).

Treatment of volunteers with an oral dose of ranitidine 150 mg twice daily for 7 days did not

cause bacterial overgrowth in the stomach.

Volunteers treated with an oral dose of ranitidine have reported no significant gastrointestinal or

central nervous system side effects; moreover, pulse rate, blood pressure, electrocardiogram and

electroencephalogram were not significantly affected in man following ranitidine administration.

In healthy human volunteers and patients, ranitidine, when administered orally did not influence

plasma levels of the following hormones: cortisol, testosterone, estrogens, growth hormone,

follicle-stimulating hormone, luteinizing hormone, thyroid-stimulating hormone, aldosterone or

gastrin; although like cimetidine, ranitidine reduced vasopressin output. Treatment for up to 6

weeks with ranitidine 150 mg twice daily by mouth did not affect the human hypothalamic-

pituitary-testicular-ovarian or -adrenal axes.

Pharmacokinetics

Absorption: Ranitidine is rapidly absorbed after oral administration of 150 mg ranitidine, peak

plasma concentrations (300 to 550 ng/mL) occurred after 1 to 3 hours. Two distinct peaks or a

plateau in the absorption phase result from reabsorption of drug excreted into the intestine. These

plasma concentrations are not significantly influenced by the presence of food in the stomach at

the time of the oral administration nor by regular doses of antacids.

Distribution, Metabolism and Excretion: Bioavailability of oral ranitidine is approximately

50% to 60%. Serum protein binding of ranitidine in man is in the range of 10 to 19%. The

elimination half-life is approximately 2 to 3 hours. The principal route of excretion is the urine

(40% recovery of free and metabolized drug in 24 hours).

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STORAGE AND STABILITY

Store between 15°C and 30°C. Protect from light and moisture.

DOSAGE FORMS, COMPOSITION AND PACKAGING

150 mg:

White to off-white, round biconvex, film-coated tablets with “> ” on one side and

150 on the other, available in HDPE bottles of 500 tablets.

Each tablet contains 150 mg ranitidine (as ranitidine hydrochloride). Tablets also

contain the following excipients: microcrystalline cellulose, croscarmellose

sodium, and magnesium stearate. The film-coating suspension contains the

following excipients: hydroxypropyl methylcellulose, titanium dioxide,

polydextrose, polyethylene glycol, and triethyl citrate.

300 mg:

White to off-white, capsule-shaped film-coated tablets with “>” on one side and

300 on the other, available in HDPE bottles of 100 tablets.

Each tablet contains 300 mg ranitidine (as ranitidine hydrochloride). Tablets also

contain the following excipients: microcrystalline cellulose, croscarmellose

sodium, and magnesium stearate. The film-coating suspension contains the

following excipients: hydroxypropyl methylcellulose, titanium dioxide,

polydextrose, polyethylene glycol, and triethyl citrate.

RANTIDINE

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PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name:

Ranitidine Hydrochloride

Chemical name:

N[2[[[5[(Dimethylamino)methyl]-2-furanyl]methyl]thio]ethyl}-N’-

methyl-2-nitro-1, 1-ethenediamine, hydrochloride

Molecular formula: C

SHCl

Molecular mass:

350.87 g/mol (as hydrochloride salt)

Structural formula:

Physicochemical properties: Ranitidine hydrochloride is a white to pale yellow

crystalline powder. At room temperature, ranitidine

hydrochloride is soluble in water, methanol, ethanol and

chloroform (decreasing order).

4.5 - 6.0

pKa:

2.19 ± 0.04

Melting Point:

Form 2 is crystallized from isopropanol – HCl solution and

has a melting point of 141 - 142°C

RANTIDINE

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CLINICAL TRIALS

Comparative Bioavailability Studies

A comparative bioavailability study under fasting conditions was performed on RANITIDINE

(ranitidine hydrochloride) tablets 300 mg against the Canadian Reference Product, Zantac

mg tablets (GlaxoSmithKline Inc.). The study was a blinded, single-dose, randomized, two-way

cross-over, bioequivalence study. The pharmacokinetic data are presented in the table below.

Summary Table of the Comparative Bioavailability Data

Fasted Study (1 x 300 mg tablet)

From Measured Data on Ranitidine

Parameter

Test†

Reference*

% Ratio of

Geometric Means

90% Confidence

Intervals

(ng.h/mL)

4721.2

4837.4 (23.1)

4643.8

4738.8 (20.7)

101.67

94.42-109.48

(ng.h/mL)

4838.0

4953.2 (22.8)

4762.6

4858.5 (20.4)

101.58

94.44-109.26

(ng/mL)

955.0

1019.0 (39.0)

890.8

957.6 (41.7)

107.21

95.06-120.92

3.13 (46.0)

3.28 (30.8)

2.60 (11.8)

2.62 (16.4)

Ranitidine tablets 300 mg (Pro Doc Ltée, Canada)

The reference product, Zantac® 300 mg (GlaxoSmithKline Inc.) was purchased in Canada.

Expressed as the arithmetic mean (% CV) only.

RANTIDINE

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DETAILED PHARMACOLOGY

Animal Pharmacology

Ranitidine is a potent competitive reversible, selective antagonist of histamine at H

-receptors in

vitro and in vivo. Thus, ranitidine antagonised the actions of histamine at H

-receptors in the rat

isolated uterus and in the guinea pig isolated atrium. Ranitidine is not an anticholinergic agent.

On a molar basis, ranitidine is 4 to 5 times more active than cimetidine with a pA

value of 7.2.

In concentrations 1,000 times greater than those required to block H

-receptors, it failed to block

either H

-receptors or muscarinic receptors in the guinea pig isolated ileum. The beta-

adrenoceptor responses of the rat uterus and guinea pig atrium to isoprenaline were also

unaffected by ranitidine.

Blockade of histamine H

-receptors in the stomach in vivo is the pharmacological action of

ranitidine with greatest immediate clinical relevance. Ranitidine inhibits gastric secretion

induced by various secretagogues in both the rat and dog.

In the conscious dog with a Heidenhain pouch, ranitidine given orally or intravenously

antagonised gastric acid secretion induced by histamine, pentagastrin and bethanechol.

Ranitidine was 5 to 10 times more active than cimetidine. However, both ranitidine and

cimetidine had similar time curves of action. Ranitidine also inhibited the gastric secretory

response to food in the conscious fistulated dog.

Ranitidine inhibited acid secretion in the perfused stomach of the anaesthetised rat, and

acetylsalicylic acid-induced gastric lesion formation in the conscious rat, both in the presence

and absence of excess hydrochloric acid. Measurements of the ratio of mucosal blood flow to

acid secretion show that the inhibitory action of ranitidine upon gastric acid secretion cannot be

attributed to changes in blood flow.

There were no behavioural effects in the mouse and rat after oral administration of 800 mg/kg

ranitidine. Cats and dogs dosed with ranitidine 80 mg/kg orally, exhibited no behavioural effects

indicative of an action on the central nervous system, although at this high dose level in the dog

there was an indication of peripheral vasodilation and skin irritation due to released histamine.

Ranitidine, when coadministered with the following CNS modulating preparations; codeine,

hexobarbitone, ethyl alcohol, chlordiazepoxide, chlorpromazine, imipramine, α-methyldopa,

reserpine, apomorphine or pentylenetetrazol, did not alter the pharmacological effects of either

preparation.

At a dose level 45 times the antisecretory ED

, intravenous infusion of ranitidine had no effect

on the heart rate, blood pressure or electrocardiogram of the anaesthetised dog. The respiratory

system was unaffected by ranitidine after oral doses in the mouse, rat, rabbit, cat and dog and

after intravenous doses in the dog.

In the conscious dog, ranitidine had no appreciable effect on blood pressure or heart rate when

administered orally at 10 mg/kg. There were short-lived falls in diastolic blood pressure after an

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Page 16 of 28

intravenous dose of 10 mg/kg, 370 times the antisecretory dose level. There was no evidence of

arrhythmia nor of any electrocardiographic abnormality.

Long-term toxicity studies have shown that ranitidine does not possess antiandrogenic activity

nor does it displace dihydrotestosterone from the androgen binding sites.

Metoclopramide, atropine and acetylsalicylic acid in the rat produced no change in the

antisecretory activity of ranitidine.

The effect of ranitidine on anti-inflammatory drugs was varied. There was no effect on the anti-

inflammatory action of prednisolone, but the anti-inflammatory action of indomethacin was

enhanced. Administration of ranitidine reduced the frequency of acetylsalicylic acid- and

indomethacin-induced gastric erosions. The antinociceptive action of acetylsalicylic acid was

reduced after ranitidine treatment.

Ranitidine, unlike cimetidine, does not inhibit the hepatic mixed function oxygenase system.

Spectral interaction studies have shown that whilst cimetidine binds strongly to cytochrome P

ranitidine has only weak affinity for this enzyme. Cimetidine is known to impair the metabolism

of pentobarbitone and warfarin. In doses of up to 166 mg/kg in the rat, ranitidine had no effect on

the pentobarbitone sleeping time or the pharmacokinetics and pharmacodynamics of warfarin.

Metabolism, Distribution and Excretion

The metabolism of ranitidine hydrochloride has been studied in four species of laboratory animal

(mouse, rat, rabbit and dog) using radio-labelled drug. The drug was rapidly absorbed after oral

administration. In the mouse, rat and rabbit between 30% and 60% of the administered

radioactivity was excreted in the urine, the remainder being recovered in the feces.

In the mouse 47% was excreted in the urine within 24 hours. In the rat, N-demethylation of

ranitidine was the major route of metabolism. 30% of the administered dose was excreted in the

urine as unchanged drug, up to 14% as desmethylranitidine, 3-6% as the N-oxide and 4% as the

S-oxide. In rat bile the major radioactive components were ranitidine and an unidentified

metabolite known as "Fast-Running Metabolite" (FRM) which is thought to be a charge transfer

complex of ranitidine with bile pigments.

In the rabbit, sulphoxidation of ranitidine was the major route of metabolism, 18% of the

administered dose being excreted in the urine as unmetabolised ranitidine, 8% as S-oxide, 2-4%

as the N-oxide, and 2-4% as desmethylranitidine.

In the dog up to 70% of the administered dose was excreted in the first 24 hours. About 40% of

the drug was excreted in the urine as unchanged ranitidine and up to 30% as the N-oxide, N-

oxidation being the main route of metabolism of ranitidine in the dog. The N-oxide was also the

major radioactive component present in dog bile together with small amounts of unchanged

ranitidine and FRM.

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In the rat, rabbit and dog, less than 10.1% of ranitidine in plasma is protein bound. Within one to

seven days of administration of radio-labelled drug in the rat and dog over 99% of the

radioactivity was cleared from the body. In common with many drugs, radioactivity persisted in

the uveal tract of these two species, the half-life in the dog uveal tract being of the order of

6 months. Ranitidine and its S-oxide have greater affinity for melanin than the desmethyl

metabolite; the N-oxide is bound only to a small extent.

The placental transfer of radioactive ranitidine and its metabolites has been studied in the

pregnant rat and rabbit. Whole body autoradiography of rat and rabbit fetuses showed that small

amounts of radioactivity were present in the uveal tract of the fetal eye in both species, in the gall

bladder and intestine of the rabbit fetus and in the bladder of the rat fetus. Radioactivity was also

detected in the salivary and mammary glands of the maternal rat and at very low concentration,

in the milk.

Human Pharmacokinetics

Serum concentrations necessary to inhibit 50% of stimulated gastric acid secretion are estimated

to be 36 to 94 ng/mL. Following a single oral dose of 150 mg, serum concentrations of ranitidine

are in this range for up to 12 hours. There is a relationship between plasma concentrations of

ranitidine and suppression of gastric acid production but wide interindividual variability exists.

Ranitidine is 50% absorbed after oral administration compared to an IV injection with mean peak

levels of 440 to 545 ng/mL occurring two to three hours after a 150 mg dose. The elimination

half-life is 2 to 3 hours.

The major route of elimination is renal. After IV administration of 150 mg 3H-ranitidine, 98% of

the dose was recovered, including 5% in feces and 93% in urine, of which 70% was unchanged

parent drug. After oral administration of 150 mg 3-H ranitidine, 96% of the dose was recovered,

26% in the feces and 70% in urine of which 35% was unchanged parent drug. Less than 3% of

the dose is excreted in bile. Renal clearance is approximately 500 mL/min, which exceeds

glomerular filtration indicating net renal tubular secretion.

Ranitidine is absorbed very rapidly after an intramuscular injection. Mean peak levels of

576 ng/mL occur within 15 minutes or less following a 50 mg intramuscular dose. Absorption

from intramuscular sites is virtually complete, with a bioavailability of 90% to 100% compared

with intravenous administration.

The principal route of excretion is the urine, with approximately 30% of the orally-administered

dose collected in the urine as unchanged drug in 24 hours. Renal clearance is about 530 mL/min,

indicating active tubular excretion, with a total clearance of 760 mL/min. The volume of

distribution ranges from 96 to 142 L.

Studies in patients with hepatic dysfunction (compensated cirrhosis) indicate that there are

minor, but clinically insignificant alterations in ranitidine half-life, distribution, clearance and

bioavailability.

RANTIDINE

Page 18 of 28

Serum protein binding averages 15%.

The gastric antisecretory activity of ranitidine metabolites has been examined. In man, both the

principal metabolite in the urine, the N-oxide (4% of the dose) and the S-oxide (1%) possess

weak H

-receptor blocking activity but desmethylranitidine (1%) is only 4 times less potent than

ranitidine in the rat and half as potent as ranitidine in the dog.

Patients Over 50 years of age

In patients over 50 years of age, half-life is prolonged (3 to 4 hours) and clearance is reduced,

consistent with the age-related 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.

Clinical Trials

In 6 clinical trials examining the healing of duodenal ulcers in 1,500 patients, a dose of 300 mg

daily for 4 weeks was found to have an 83% healing rate; however, increasing the dose to

300 mg twice daily gave significantly better results (92% healed at 4 weeks; p<0.001).

TOXICOLOGY

Toxicology, Impairment of Fertility, Carcinogenesis, and Mutagenesis

Ranitidine hydrochloride has been subjected to exhaustive toxicological testing which has

demonstrated the lack of any specific target organ or any special risk associated with its clinical

use.

Non-clinical data revealed no special hazard for humans based on conventional studies of safety

pharmacology, repeated-dose toxicity, genotoxicity, carcinogenic potential and toxicity to

reproduction and development.

Acute Toxicity Studies

In mice and rats, the intravenous LD

is of the order of 75 mg/kg, whereas orally, even doses of

1,000 mg/kg are not lethal. In dogs, the oral minimum lethal dose is 450 mg/kg/day. High single

doses of ranitidine (up to 80 mg/kg orally) show only minimal and reversible signs of toxicity,

some of which are related to transitory histamine releases.

RANTIDINE

Page 19 of 28

Long-Term Toxicity Studies

In the long-term toxicity and carcinogenicity studies, very high doses of ranitidine were given

daily to mice (up to 2000 mg/kg/day) throughout their normal life-span, and to dogs (up to

450 mg/kg/day) for periods of up to one year.

These doses produced massive plasma ranitidine concentrations far in excess of those found in

human patients receiving ranitidine at the recommended therapeutic dose. For example, in the

dogs, peak plasma concentrations were in excess of 115 µg/mL and in mice basal plasma levels

were in the range of 4-9 µg/mL. In man, after oral administration of 150 mg ranitidine, the mean

peak plasma concentration (C

) was between 360 and 650 ng/mL.

In the rat, doses as high as 2,000 mg/kg/day were well tolerated, the only morphological change

seen was the increased incidence of accumulations of foamy alveolar macrophages in the lungs.

The accumulations of these cells is a natural phenomena in aging rats and chronic administration

of a wide variety of drugs has been known to contribute to this process. Therefore, it is unlikely

that the pharmacologic concentrations of ranitidine administered to these rats contributed to this

natural process.

In the six-week and six-month oral studies in the dog (100 mg/kg/day) loose feces were

occasionally detected, while in the six-month study loose stools were accompanied on eight

occasions by mucus-like material and sometimes by blood, mostly from one dog. Loose feces,

salivation and vomiting were observed in the 54-week dog study.

In isolated cases, dogs passed red-stained feces which occasionally tested positive for occult

blood. When the dose level was increased from 100 mg/kg/day to 225 - 450 mg/kg/day, no

further red-stained feces were seen, suggesting that any relationship to ranitidine is unlikely.

Post-mortem examination of the dogs revealed no ranitidine-induced changes in the alimentary

tract.

One dog had marginally raised levels of plasma alanine aminotransferase and alkaline

phosphatase during the six-week study. This same dog also showed some necrotic foci in the

liver. Small lesions of focal necrosis and fibrosis were also seen in one piece of liver from one

female dog treated with 100 mg/kg for six months. No other differences were detected by light

and electron microscopic examination of the treated and control livers. Since the focal lesions

were seen in only one dog and were restricted to one piece of liver, it suggests that they were not

caused by ranitidine.

Muscular tremors, an inability to stand, and rapid respiration were seen on occasion in dogs

treated with 225 mg/kg/day in the 54-week study. The prevalence of these observations was

increased when the dose was increased to a toxic level of 450 mg/kg/day. One dog died: no

specific pathological changes or reason for the death was discovered.

Changes in the colour or granularity of the tapetum lucidum of the eye were detected in three

dogs receiving the highest dose of ranitidine (450 mg/kg/day) during the 54-week study. In one

RANTIDINE

Page 20 of 28

dog this change was considered to be related to treatment. The change, a pallor of the tapetum,

was reversible. No changes were seen with light or electron microscopic examination of the eye.

The changes in the tapetum are of no clinical significance in humans since (i) humans do not

have a tapetum lucidum and (ii) the changes were only seen at toxic pharmacological

concentrations of ranitidine.

The mean serum glutamic pyruvic transaminase values for dogs treated at 450 mg/kg/day were

significantly greater, albeit marginally, than the control values. These enzyme increases were not

accompanied by any histological changes.

Studies in which ranitidine was administered parenterally were performed. No sign of specific

local irritation attributable to ranitidine was detected. In the rat, no biochemical or

histopathological changes were observed at intravenous dose levels as high as 20 mg/kg.

Specifically, no significant changes were found in the veins or subcutis. Mild lesions in some

muscle samples were observed: usually, the cells were basophilic and smaller than normal; and

the nuclei were swollen, more numerous, and sometimes had migrated to the centre of the cell.

In the rabbit, slight infiltration of the pannicular muscle by mononuclear cells were noted. This

minor subcutaneous reaction was uncommon and showed no group related distribution. There

was no apparent difference in irritance between ranitidine injection and placebo injection. In the

rat, intravenous ranitidine at dose levels of 5.0 and 10.0 mg/kg daily for 15 days and 28 days

produced no treatment related changes of biological importance in the hematopoietic system.

In Beagle dogs, intravenous ranitidine injection in doses up to 10 mg/kg/day for 28 and 42 days,

produced no drug-related change in circulating erythrocytes or leukocytes and had no adverse

effects on the hematopoietic system. No dose related changes were seen in electrocardiograms of

Beagle dogs receiving up to 10 mg/kg ranitidine by intravenous injection. At dosage levels of up

to 30 mg/kg, administered twice daily to Beagle dogs for 14 or 15 days, intravenous ranitidine

injection produced no changes of biological significance in hematology, clinical chemistry or

urinalysis.

No changes were observed in the eyes of dogs (specifically the tapetum lucidum) receiving

ranitidine in doses up to 30 mg/kg twice daily for 15 days. At intravenous doses above

1.25 mg/kg, ranitidine injection produced immediate and transient reactions in the Beagle dog.

The following reactions were typically produced by the administration of 1.25 mg/kg: bloodshot

eyes, closing and watering of eyes, defaecation, diarrhea, erythema, flatus, licking of lips,

running nose, salivation, subdued behaviour, swallowing, tachycardia, and trembling. The range

and severity of the effects was aggravated by increased dosage.

Reproduction Studies (Impairment of Fertility)

Reproduction studies were carried out in the rat and rabbit.

RANTIDINE

Page 21 of 28

Rats were exposed to ranitidine before and during mating, throughout pregnancy, lactation and

during the weaning period. No effects on the reproductive process were seen and there was no

evidence of an anti-androgenic effect.

A total of 2,297 fetuses from rats treated with ranitidine were examined. There was no evidence

that ranitidine is a rat teratogen. Cleft palates occurred in fetuses from both treatment groups,

however, there were significantly more in the control rat population.

A total of 944 fetuses from rabbits treated with ranitidine were examined; no drug-related

adverse events or abnormalities in the fetuses were observed.

Rabbits receiving a bolus intravenous injection of ranitidine (10 mg/kg) once daily on gestation

days 7-16 exhibited a reduction in weight gain. Their fetuses weighed significantly less than

fetuses of untreated controls. In addition, 12.4% of ranitidine-exposed fetuses had cleft palates.

Reanalysis of this and a companion study performed to assess reproducibility demonstrated a

lack of data reproducibility. Therefore, the effects observed in the first trial are aberrant, and

should not form the basis for maternal or fetal toxicity.

In the subsequent study, no evidence of maternal or fetal toxicity was observed in rabbits dosed

with 100 mg/kg ranitidine orally during days 2-29 of pregnancy. The peak plasma levels of

ranitidine after a 100 mg/kg oral dose are similar to those obtained one minute after a 10 mg/kg

dose administered intravenously (20-25 µg/mL). Therefore, no teratogenic effects of ranitidine

have been demonstrated at doses of 10 mg/kg (IV) and 100 mg/kg (Tablets) in rabbits.

Carcinogenicity Studies

There is no evidence that ranitidine is a carcinogen. Long term toxicity and carcinogenicity

studies have involved the treatment of 600 mice and 636 rats at doses up to 2,000 mg/kg for two

years and 129 weeks respectively and 42 dogs at doses up to 450 mg/kg/day for periods up to

one year. These dose levels are far in excess of those to be used therapeutically in man. None of

these animals had any intestinal metaplasia. There was no evidence of a tumourigenic effect of

ranitidine in any other tissue.

Mutagenesis

Ranitidine is not mutagenic at doses as great as 30 mg/plate in the Ames Assay utilizing

Salmonella typhimurium (TA 1538, TA 98, TA 100 and TA 1537) or in doses of 9 mg/plate

utilizing Escherichia coli (WP2 and WP2 uvrA) with or without activation.

Ranitidine at concentrations of 20-30 mg/plate had a weak direct mutagenic action in

S. typhimurium TA 1535 and at 9 mg/plate in E. coli WP67. Ranitidine was not mutagenic at a

concentration of 2 mg/mL in E. coli or S. typhimurium in the more sensitive Oral Solution

microtitre fluctuation assay method. This weak direct mutagenic effect is of no clinical

significance; the magnitudes of ranitidine concentration used in these assays are thousands of

times greater than that attained therapeutically in human plasma.

RANTIDINE

Page 22 of 28

The principal metabolites of ranitidine in man were not significantly mutagenic. This conclusion

is supported by the following experiment. A test solution obtained by interacting ranitidine

(10 mM) and sodium nitrite (40 mM) was mutagenic in S. typhimurium (TA 1535) but not in

S. typhimurium (TA 1537) or in E. coli (WP67 or WP2 uvrA). This positive result is attributable

to the presence of a nitrosonitrolic acid derivative AH 23729, which was mutagenic. When the

sodium nitrite concentration was reduced to 15 mM or less, the solution was not mutagenic in

any of the test microorganisms. The formation of AH 23729 requires concentrations of nitrous

acid far in excess of those encountered in any probable physiological conditions. The other

nitrosation products were not mutagenic in any of the microorganisms tested. There is no reason,

therefore, for supposing that ranitidine is likely to be mutagenic in animals or man as a

consequence of nitrosation in the stomach.

There is no evidence from long term toxicology, carcinogenicity and mutagenicity studies in

animals to suggest that ranitidine is likely to have any deleterious effects in man when

administered at therapeutic dose levels.

RANTIDINE

Page 23 of 28

REFERENCES

Ashton MG, Holdsworth CD, Ryan FP, Moore M. Healing of gastric ulcers after one,

two, and three months of ranitidine. Br Med J (Clin Res Ed) 1982; 284(6314): 467-468.

Bell JA, Dallas FA, Jenner WN, Martin LE. The metabolism of ranitidine in animals and

man [proceedings]. Biochem Soc Trans 1980; 8(1): 93.

Bories P, Michel H, Duclos B, Beraud JJ, Mirouze J. Use of ranitidine, without mental

confusion, in patients with renal failure. Lancet 1980; 2(8197): 755.

Boyd EJ, Wilson JA, Wormsley KG. Review of ulcer treatment: role of ranitidine. J Clin

Gastroenterology 1983; 5 Suppl 1: 133-141.

Breen KJ, Bury R, Desmond PV, Mahsford ML, Morphette B, Westwood B et al. Effects

of cimetidine and ranitidine on hepatic drug metabolism. Clin Pharmacol Ther 1982;

31(3): 297-300.

Brogden RN, Carmine AA, Heel RC, Speight TM, Avery GS. Ranitidine: a review of its

pharmacology and therapeutic use in peptic ulcer disease and other allied diseases. Drugs

1982; 24(4): 267-303.

Critchlow JF. Comparative efficacy of parenteral histamine H

-antagonists in acid

suppression for the prevention of stress ulceration. Am J Med 1987; 83(6A): 23-28.

Damman HG, Muller P, Simon B. Parenteral ranitidine: onset and duration of action. Br J

Anaesth. 1982; 54(11): 1235-1236.

Danilewitz M, Tim LO, Hirschowitz B. Ranitidine suppression of gastric hypersecretion

resistant to cimetidine. N Engl J Med 1982; 306(1): 20-22.

Domschke W, Lux G, Domschke S. Furan H

-antagonist ranitidine inhibits pentagastric-

stimulated gastric secretion stronger than cimetidine. Gastroenterology 1980; 79(6):

1267-1271.

Durrant JM, Strunin L. Comparative trial of the effect of ranitidine and cimetidine on

gastric secretion in fasting patients at induction of anaesthesia. Can Anaesth Soc J 1982;

29(5): 446-451.

Ehsanullah RSB, Page MC, Tildesley G, Wood JR. A placebo-controlled study of

ranitidine in healing NSAID-associated gastric and duodenal ulcers. British Society for

Rheumatology, Seventh Annual General Meeting, London, 26-28 September 1990.

RANTIDINE

Page 24 of 28

Freston JW. H

-receptor antagonists and duodenal ulcer recurrence: analysis of efficacy

and commentary on safety, costs and patient selection. Am J Gastroenterol. 1987; 82(12):

1242-1249.

Gaginella TS, Bauman JH. Ranitidine hydrochloride. Drug Intell Clin Pharm 1983;

17(12): 873-885.

Goudsouzian NG, Young ET. The efficacy of ranitidine in children. Acta

Anaesthesiologica Scand 1987; 31(5): 387-390.

Halparin L, Reudy J. Inhibition of pentagastrin-stimulated gastric acid secretion by

ranitidine hydrochloride and cimetidine. Current Therapeutic Research. 1980; 28(2): 154-

162.

Harris PW, Morison DH, Dunn GL, Fargas-Babjak AM, Moudgil Gc, Smedstad KG et al.

Intramuscular cimetidine and ranitidine as prophylaxis against gastric aspiration

syndrome - a randomized double blind study. Can Anaesth Soc J 1984; 31(6): 599 - 603.

Jensen RT, Collen JM, Pandol SJ, Allende HD, Raufman JP, Bissonnette BM et al.

Cimetidine-induced impotence and breast changes in patients with gastric hypersecretory

states. N Engl J Med 1983; 308(15):883.

Knodell RG, Holtzman JL, Crankshaw DL, Steele NM, Stanley LN. Drug metabolism by

rat and human hepatic microsomes in response to interaction with H

-receptor

antagonists. Gastroenterology 1982; 82(1): 84-88.

Konturek SJ, Obtulowicz W, Kwiecien N, Sito E, Mikos K, Olesky J. Comparison of

ranitidine and cimetidine in the inhibition of histamine, sham-feeding and meal-induced

gastric secretion in duodenal ulcer patients. Gut 1980; 21(3): 181-186.

Lancaster-Smith MJ, Jaderberg ME, Jackson DA. Ranitidine in the treatment of non-

steroidal anti-inflammatory drug associated gastric and duodenal ulcers. Gut 1991; 32(3):

252-255.

Lebert PA, Mahon WA, MacLeod SM, Soldin SJ, Fenje P, Vandenberghe HM.

Ranitidine kinetics and dynamics II. Intravenous dose studies and comparison with

cimetidine. Clin Pharmacol The. 1981; 30(4): 545-550.

Leeder JS, Tesoro AM, Bertho-Gebara CE, Macleod SM. Comparative bioavailability of

ranitidine tablets and suspension. Canadian Journal of Hospital Pharmacy 1984; 37(3),

92-94, 106.

Maile CJ, Francis RN. Pre-operative ranitidine. Effect of a single intravenous dose on pH

and volume of gastric aspirate. Anaesthesia 1983; 38(4): 324-326.

RANTIDINE

Page 25 of 28

Misiewicz JJ, Sewing K, editors. Proceedings of the First International Symposium on

Ranitidine. Scand J Gastroenterol 1981; 16 (Suppl. 69): 1-131.

Misiewicz JJ, Wormsley KG, editors. The clinical use of ranitidine. Proceedings of the

Second International Symposium on Ranitidine held at the Barbican Centre, London, UK,

October 1981. 2

International Symposium on Ranitidine; 1981; London, England.

Oxford [Oxfordshire]: Medicine Publishing Foundation; 1982.

Nelis GF, Van de Meene JGC Comparative effect of cimetidine and ranitidine on

prolactin secretion. Postgrad Med J 1980; 56(657): 478-480.

Page M, Lacey L. Ranitidine syrup in the treatment of duodenal ulcer. American Journal

of Gastroenterology. 1987; 82(9),977.

Pasquali R, Corinaldesi R, Miglioli M, Melchionda N, Capelli M, Barbara L. Effect of

prolonged administration of ranitidine on pituitary and thyroid hormones, and their

response to specific hypothalamic-releasing factors. Clin Endocrinol 1981; 15(5): 457-

462.

Peden NR, Robertson AJ, Boyd EJ, Brown RA, Gibbs JH, Potts RC et al. Mitogen

stimulation of peripheral blood lymphocytes of duodenal ulcer patients during treatment

with cimetidine or ranitidine. Gut 1982; 23(5): 398-403.

Riley AJ, Salmon PR editors. Ranitidine: proceedings of an international symposium held

in the context of the Seventh World Congress of Gastroenterology, Stockholm, 17

June

1982. 3

International symposium on Ranitidine and 7

World Congress of

Gastroenterology; 1982; Stockholm, Sweden. Amsterdam: Excerpta Medica; 1982.

Roberts CJ. Clinical pharmacokinetics of ranitidine. Clin Pharmacokin1984; 9(3): 211-

221.

Scarpignato C, Bertaccine G, Zimbara G, Vitulo F. Ranitidine delays gastric emptying of

solids in man. Br J Clin Pharmacol 1982; 13(2): 252-253.

Wolfe MM. Considerations for selection of parenteral histamine (H

)-receptor

antagonists. Am J Med 1987; 83(6A): 82-88.

Yeomans ND, Hanson RG, Smallwood RA, Mihaly GW, Louis WJ. Effect of chronic

ranitidine treatment on secretion of intrinsic factor. Br Med J 1982; 285(6337):264.

Product Monograph for Zantac® (GlaxoSmithKline Inc., Canada), Date of revision:

January 15, 2015, Control Number: 179097.

IMPORTANT: PLEASE READ

RANITIDINE

Page 26 of 28

PART III: CONSUMER INFORMATION

Pr

RANITIDINE

Ranitidine Tablets, USP

150 mg and 300 mg

This leaflet is part III of a three-part "Product Monograph"

published when RANITIDINE was approved for sale in Canada

and is designed specifically for Consumers. This leaflet is a

summary and will not tell you everything about RANITIDINE.

Contact your doctor or pharmacist if you have any questions about

the drug.

ABOUT THIS MEDICATION

What the medication is used for:

RANITIDINE (ranitidine hydrochloride) tablets are used in the

treatment of:

to heal ulcers in the stomach, or the part that it empties into

(the duodenum).

to prevent stomach ulcers which may be caused by medicines

called non-steroidal anti-inflammatory drugs (NSAIDs), often

used to treat arthritis

to prevent ulcers from bleeding

to heal or stop problems caused by acid in the food pipe

(esophagus) or too much acid in the stomach. This can cause

pain or discomfort sometimes known as indigestion or

heartburn

to stop acid coming up from the stomach while under

anaesthetic during an operation

What it does:

RANITIDINE belongs to a group of medicines called H

-receptor

blockers. It works by reducing the amount of acid in your stomach.

When it should not be used:

Don’t take RANITIDINE tablets if you are allergic

(hypersensitive) to ranitidine or any other ingredients of

RANITIDINE (see What the nonmedicinal ingredients are).

What the medicinal ingredient is:

Ranitidine hydrochloride

What the nonmedicinal ingredients are:

Croscarmallose sodium, hypromellose, magnesium stearate,

microcrystalline cellulose, polydextrose, polyethylene glycol,

titanium dioxide, and triethyl citrate.

What dosage forms it comes in:

RANITIDINE is available as tablets, 150 mg and 300 mg.

WARNINGS AND PRECAUTIONS

BEFORE you use RANITIDINE talk to your doctor or pharmacist

if you:

have stomach cancer

have kidney disease, your doctor may lower your dose of

RANITIDINE

have a rare condition called acute porphyria (a blood disease)

have lung disease

are diabetic

have any problems with your immune system

have had stomach ulcers before and you are taking Non-

Steroidal Anti-Inflammatory (NSAID) medicines

are pregnant, planning to become pregnant, breastfeeding or

planning to breastfeed

are taking any other medications including NSAIDs (see

Interactions with this Medication).

Under rare circumstances supervised by the doctor, H2-receptor

antagonists such as RANITIDINE might be used for long periods.

Long term use of H2-receptor antagonists may prevent normal

absorption of vitamin B12 from the diet and could lead to vitamin

B12 deficiency. Talk to your doctor.

INTERACTIONS WITH THIS MEDICATION

Tell your doctor or pharmacist if you‘re taking any other

medicines, if you’ve taken any recently, or if you start taking new

ones. This includes medicines bought without a prescription.

Some medicines can affect how RANITIDINE works or make it

more likely that you’ll have side effects. RANITIDINE can also

affect how some other medicines work.

Drugs that may interact with RANITIDINE include:

procainamide or n-acetylprocainamide (used to treat heart

problems)

warfarin (used to thin the blood)

triazolam (used to treat insomnia)

midazolam (a sedative that may be given just before an

operation)

ketoconazole (used to treat fungal infections)

atazanavir or delaviridine (used to treat HIV)

gefitnib (used to treat lung cancer)

Non-Steroidal Anti-Inflammatory (NSAID) medicines (used

to treat pain and inflammation)

sucralfate (used to treat ulcers). Your doctor may advise that

you take high doses or oral sucralfate (e.g. 2g) at least 2

hours after RANITIDINE administration.

PROPER USE OF THIS MEDICATION

Usual Adult Dose:

Always take RANITIDINE exactly as your doctor has told you to.

Check with your doctor or pharmacist if you’re not sure.

The usual dose is either:

150 mg in the morning and 150 mg in the evening or,

300 mg at bedtime

Your exact dose will depend on your particular stomach

condition. Your doctor will tell you the dose you should take.

Swallow each tablet whole with some water.

IMPORTANT: PLEASE READ

RANITIDINE

Page 27 of 28

Overdose:

If you take too much RANITIDINE, contact your doctor or

pharmacist for advice. If possible, show them the RANITIDINE

pack.

If you think you have taken too much RANITIDINE, contact a

healthcare professional, hospital emergency department or regional

Poison Control Centre immediately, even if there are no

symptoms.

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

Side effects may include:

allergic reactions

skin rash

inflammation of blood vessels (vasculitis)

inflammation of the pancreas (pancreatitis)

inflammation of the liver (hepatitis), sometimes with

yellowing of the whites of the eyes or skin (jaundice)

inflammation in the kidney (interstitial nephritis)

slow, fast or irregular heartbeat

diarrhea, constipation, nausea, vomiting, stomach pain

feeling confused, depressed, or excited, or seeing or hearing

things that are not really there (hallucinations), trouble

sleeping (insomnia); feeling sleepy (somnolence)

joint or muscle pain, malaise, uncontrolled movement

headache, dizziness, blurred vision

unusual hair loss or thinning (alopecia)

unable to get or maintain an erection (impotence)

unusual secretion of breast milk or breast enlargement in men

If you have any concerns about the side effects, tell your doctor, nurse

or pharmacist.

Side effects that may show up in your blood tests:

changes to liver function

low levels of white blood cells

decrease in number of blood platelets (cells that help blood to

clot)

decrease in number of all types of blood cells

small increase in the level of creatinine (a waste product) in your

blood

SERIOUS SIDE EFFECTS, HOW OFTEN THEY HAPPEN

AND WHAT TO DO ABOUT THEM

Symptoms / effects

Talk with your

physician or

pharmacist

Stop taking

drug and

seek

immediate

emergency

medical

attention

Only if

severe

In all

cases

Rare

Hypersensitivity

Reaction

Raised and itchy

rash (hives),

swelling,

sometimes of the

face or mouth

(angioedema),

chest pain,

shortness of

breath,

unexplained fever,

wheezing or

difficulty in

breathing, feeling

faint, especially

when standing up,

collapse

Very Rare

Serious Skin

Reactions

Skin rash, which

may blister, and

look like small

targets (central

dark spots

surrounded by a

paler area, with a

dark ring around

the edge)

Hepatitis

Yellowing of the

skin or whites of

the eyes, dark or

tea coloured urine,

pale coloured

stools/ bowel

movements,

nausea/vomiting,

loss of appetite,

pain, aching or

tenderness on right

side below the ribs

Cardiovascular

Slow, fast or

irregular heartbeat

This is not a complete list of side effects. For any unexpected

effects while taking RANITIDINE, contact your doctor or

pharmacist.

IMPORTANT: PLEASE READ

RANITIDINE

Page 28 of 28

HOW TO STORE IT

Store between 15°C and 30°C. Protect from light and moisture. Do

not store in the bathroom. Keep RANITIDINE out of the reach and

sight of children.

Reporting Side Effects

You can report any suspected side effects associated with the

use of health products to Health Canada by:

Visiting the Web page on Adverse Reaction Reporting

(https://www.canada.ca/en/health-

canada/services/drugs-health-products/medeffect-

canada/adverse-reaction-reporting.html)

for information

on how to report online, by mail or by fax; or

Calling toll-free at 1-866-234-2345.

NOTE: Contact your health professional if you need

information about how to manage your side effects. The

Canada Vigilance Program does not provide medical advice.

MORE INFORMATION

If you want more information about RANITIDINE:

Talk to your healthcare professional

Find the full product monograph that is prepared for

healthcare professionals and includes this Consumer

Information by visiting the Health Canada website

(https://www.canada.ca/en/health-canada.html); or by

contacting Pro Doc Ltée at 1-800-361-8559,

www.prodoc.qc.ca or info@prodoc.qc.ca.

This leaflet was prepared by

Pro Doc Ltée, Laval, Québec, H7L 3W9

Last revised: September 18, 2019

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