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Ranitidine Tablets USP

150 mg and 300 mg Ranitidine (as Ranitidine Hydrochloride)

Histamine H


- Receptor Antagonist



50 Mural Street, Units 1 & 2

January 27, 2009

Richmond Hill, Ontario

L4B 1E4

Control # 127275

Page 2 of 25

Table of Contents

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

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

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

CONTRAINDICATIONS......................................................................................................... 3

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

ADVERSE REACTIONS ......................................................................................................... 5

DRUG INTERACTIONS.......................................................................................................... 6

DOSAGE AND ADMINISTRATION ..................................................................................... 7

OVERDOSAGE........................................................................................................................ 8

ACTION AND CLINICAL PHARMACOLOGY.................................................................... 9

STORAGE AND STABILITY ............................................................................................... 11

DOSAGE FORMS, COMPOSITION AND PACKAGING................................................... 11

PART II: SCIENTIFIC INFORMATION ............................................................................. 12

PHARMACEUTICAL INFORMATION ............................................................................... 12

CLINICAL TRIALS................................................................................................................ 13

DETAILED PHARMACOLOGY………………………………………………………… 14

TOXICOLOGY ....................................................................................................................... 16

REFERENCES........................................................................................................................ 21

PART III: CONSUMER INFORMATION............................................................................ 24

Page 3 of 25


Ranitidine Tablets USP



Route of


Dosage Form / Strength

Clinically Relevant

Nonmedicinal Ingredients*


Tablet / 150 mg and 300 mg


For a complete listing see Dosage

Forms, Composition and

Packaging section.


NU-RANIT (ranitidine) is 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 anesthesia in patients considered to

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

In addition, NU-RANIT is indicated for the prophylaxis and maintenance treatment of duodenal

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


NU-RANIT (ranitidine) is contraindicated for patients known to have hypersensitivity to


Page 4 of 25


Endocrine and Metabolism

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

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

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 NU-RANIT

(ranitidine) is instituted.


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

(plasma creatinine concentration greater than 300 μmol/L); a recommended daily dose of oral

ranitidine in such patients should be 150 mg.

Special Populations

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 H2 receptor antagonists versus those who had stopped

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

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

induced impaired fertility or harm to the fetus. 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.

Pediatrics (< 18 years of age):

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


Geriatrics (>65 years of age):

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


Page 5 of 25

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 hypoglycemic 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.


Adverse Drug Reaction Overview

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 is

not always established.


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




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, and hallucinations have been reported, predominantly in

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

reported rarely.


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

alopecia have been reported.


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

There have been a few reports of breast symptoms in men taking ranitidine.


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


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.

Page 6 of 25


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 qid intravenously

for seven days, and in 4 of 24 subjects receiving 50 mg qid 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.


Rare reports of arthralgia and myalgia.


Very rare cases of acute interstitial nephritis have been reported.


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.



Although ranitidine has been reported to bind weakly to cytochrome P

in vitro

, recommended

doses of the drug do not inhibit the action of the hepatic cytochrome P

-linked oxygenase

enzymes. However, there have been isolated reports of drug interactions which suggest that

ranitidine may affect the bioavailability of certain drugs (e.g., ketoconazole) by some mechanism

as yet unidentified (e.g., a pH dependent effect on absorption or a change in volume of


As well, sporadic cases of drug interactions have been reported in elderly patients involving both

hypoglycemic 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.

Drug-Drug Interactions

If high doses (two grams) of sucralfate are co-administered 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.

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.

Page 7 of 25

Drug-Food Interactions

The plasma concentrations of ranitidine are not significantly influenced by the presence of food

in the stomach at the time of oral administrations



Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.


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.

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.

Page 8 of 25

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 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 haemorrhage from stress ulceration in seriously ill patients or prophylaxis of

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

by intravenous ranitidine

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


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.


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.

Page 9 of 25


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



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

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.

In respect of both 24 hour acidity and nocturnal acid output, 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


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 oral 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, oral ranitidine did not influence plasma levels of the

following hormones - cortisol, testosterone, oestrogens, 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.

Page 10 of 25


Bioavailability of oral ranitidine is approximately 50%. Serum protein binding of ranitidine in

man is in the range 10 to 19%. The elimination half-life is approximately 3 hours. The principal

route of excretion is the urine (40% recovery of free and metabolized drug in 24 hours).

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 rapidly absorbed after oral administration, peak plasma concentrations being

achieved within 2 to 3 hours. These plasma concentrations are not significantly influenced by

the presence of food in the stomach at the time of the oral administration or by regular doses of


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 1.5 to 3 hours.

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.


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.


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 is 1.4 L/kg.

Special Populations and Conditions

Hepatic Insufficiency:

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.

Page 11 of 25


Store between 15°C - 30°C (59°F - 86°F). Protect from light.



In addition to ranitidine hydrochloride, each film–coated tablet contains the non–medicinal

ingredients: microcrystalline cellulose, hydroxypropyl methylcellulose, polydextrose, titanium

dioxide, magnesium stearate, colloidal silicon dioxide, vanillin and carnauba wax.

Availability of Dosage Forms

NU-RANIT (Ranitidine tablets USP) 150 mg: Each round, white to off-white, biconvex, film–

coated tablet engraved APO on one side and RAN over 150 on the other side. Each tablet

contains 150 mg of ranitidine (as the hydrochloride). Available in bottles of 60, 100 and 500

tablets and in unit dose packages of 60 and 100.

NU-RANIT (Ranitidine tablets USP) 300 mg: Each capsule–shaped, white to off-white,

biconvex, film–coated tablet engraved APO on one side and RAN 300 on the other side. Each

tablet contains 300 mg of ranitidine (as the hydrochloride). Available in bottles of 30, 100 and

500 tablets and in unit dose packages of 30 and 100.

Page 12 of 25



Drug Substance

Proper Name:

Ranitidine hydrochloride

Chemical Names:



-[2-[[[5-(dimethylamino) methyl]-2-furanyl]-

methyl] thio]ethyl]-


-methyl-2-nitro-, monohydrochloride


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


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


-[2-[[[5-[(Dimethylamino) methyl]-furan-2-yl]methyl]-







Molecular Formula and mass:


350.87 (as hydrochloride salt)

Structural Formula:

Page 13 of 25


In 6 clinical trials examining the healing of duodenal ulcers in 1500 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).

Physical Description:

Ranitidine hydrochloride is a white to pale yellow,

crystalline, practically odorless powder. It is sensitive to

light and moisture, and melts at about 140C, with



It is very soluble in water, moderately soluble in alcohol,

and sparingly soluble in chloroform.

pH of 1% w/v Aqueous Solution:

4.5 to 6.0

pH Solubility Profile:

Ranitidine hydrochloride is freely soluble (>1 gram/mL)

over the physiological pH range from 1 to 7.5, including

purified water


Ranitidine HCl exists in 2 different polymorphic (crystal)

forms: Form I (mp 134º - 140ºC) and Form II (mp 140º -



Molar Absorptivity:

Melting Point:

1.89 (25ºC), 1.77 (37ºC)

1.5 x 10

litre mol

@ 315 nm

140º - 144ºC

Page 14 of 25

Comparative Bioavailability Studies

A randomized, single dose, double-blinded, 2-way crossover comparative bioavailability study,

conducted under fasting conditions was performed on 18 healthy male volunteers. The rate and

extent of absorption of ranitidine was measured and compared following a single oral dose

(1 x 300 mg tablet) of

Zantac® (ranitidine hydrochloride) and Apo-Ranitidine (ranitidine

hydrochloride). The results from measured data are summarized in the following table:

Summary Table of the Comparative Bioavailability Data


(A single 300 mg dose: 1 x 300 mg tablet)

From Measured Data/Fasting Conditions

Geometric Mean

Arithmetic Mean (CV %)


Apo–Ranitidine (Apotex

Inc.) (Canada)




Ratio of Geometric

Means (%)

90% Confidence

Interval (%)




7318.0 (20)


7585.3 (21)


88.3 - 106.0




7564.1 (20)


7877.4 (20)


88.0 - 105.3




1567.2 (30)


1604.7 (30)


83.3 - 115.4


2.77 (35)

2.44 (28)


2.94 (8)

3.22 (11)

Arithmetic means (CV %) only.


is manufactured by GlaxoSmithKline Inc. and was purchased in Canada.


Animal Pharmacology

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




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.

Page 15 of 25

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 aspirin-

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


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

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

arrhythmia or 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 aspirin 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 aspirin- and indomethacin-

induced gastric erosions. The antinociceptive action of aspirin was reduced after ranitidine


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

Page 16 of 25

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 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.

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.


Toxicology, Impairment of Fertility, Carcinogenesis, and Mutagenesis

Ranitidine 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.

Page 17 of 25

Acute Toxicity Studies

In mice and rats, the intravenous LD

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

1000 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.

Long-Term Toxicity Studies

In the tong-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 2000 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 are 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


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.

Page 18 of 25

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

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 was 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 haematopoietic 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 haematopoietic 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 haematology, clinical chemistry or


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, defecation, 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. 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


Page 19 of 25

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 tumorigenic effect of

ranitidine in any other tissue.


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


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



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

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.

Page 20 of 25

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

(10mM) and sodium nitrite (40mM) was mutagenic in

S. typhimurium

(TA 1535) but not in



(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 15mM 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.

Page 21 of 25


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

two and three months of ranitidine. Br. Med. J. 1982; 284: 467-468.

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

and man. [Abstract] Biochem. Soc. Trans. 1980; 8: 93.

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

confusion in patients with renal failure. [Letter] Lancet 1980; 2: 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. RD, Desmond PV,

et al

. Effects of cimetidine and ranitidine on

hepatic drug metabolism. Clin. Pharmacol. Ther. 1982; 31: 297-300.

Brogden RN, Carmine AA,

et al

. Ranitidine: A review of its pharmacology and

therapeutic use in peptic ulcer disease and other allied diseases. Drugs 1982; 24: 267-


Critchlow JF. Comparative efficacy of parenteral histamine H

-antagonists in acid

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

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

Br. J. Anaesth. 1982; 54: 1235-1236.

Danilewitz M, Ou Tim L, Hirschowitz B. Ranitidine suppression of gastric

hypersecretion resistant to cimetidine. N. Engl. J. Med. 1982; 306: 20-22.

Domschke W, Lux G, Domschke S. Furan H

-antagonist ranitidine inhibits

pentagastric-stimulated gastric secretion stronger than cimetidine. Gastroenterotogy

1980; 79: 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: 446-451.

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

ranitidine in healing NSAID-associated gastric and duodenal ulcers. Br. J. Rheumatol.

1990; 29 (Suppl. 2): 9, A17.

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:


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

17: 873-885.

Page 22 of 25

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

Anaesthesiologica Scand. 1987; 31: 387-390.

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

ranitidine hydrochloride and cimetidine. Curr. Ther. Res. 1980; 28:154-162.

Harris PW, Morison DH, Dunn GL,

et al

. Intramuscular cimetidine and ranitidine as

prophylaxis against gastric aspiration syndrome – a randomized double blind study.

Can. Anaesth. Soc. J. 1984; 31: 599 - 603.

Jensen RT, Collen JM

et al

. Cimetidine-induced impotence and breast changes in

patients with gastric hypersecretory states. N. Engl. J. Med. 1983; 308: 883.

Knodell RG, Holtzman JL, Crankshow DL

et al

. Drug metabolism by rat and human

hepatic microsomes in response to interaction with H

-receptor antagonists.

Gastroenterology 1982; 82: 1007.

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: 181-186.

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

NSAID-associated gastric and duodenal ulcers. Gut 1991; 32: 252-255.

Lebert PA, Mahon WA,

et al

. Ranitidine kinetics and dynamics II. Intravenous dose

studies and comparison with cimetidine. Clin. Pharmacol. Ther. 1981; 30: 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 CJD, Francis RN. Pre-operative ranitidine. Anaesthesia 1983; 38: 324-326.

Misiewicz JJ, Sewing K. (eds.). Proceedings of the First International Symposium on

Ranitidine. Scand. J. Gastroenterol. 1981; 1.6 (Suppl. 69): 1-131.

Misiewicz JJ, Wormsley KG (eds.). The Clinical Use of Ranitidine. The Medicine

Publishing Foundation Symposium Series S, Pembroke House, Oxford, 1982.

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

prolactin secretion. Postgrad. Med. J. 1980; 56: 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,

et al

. Effect of prolonged administration of

ranitidine on pituitary and thyroid hormones, and their response to specific

hypothalamic-releasing factors. Clin. Endocrinol. 1981; 15: 457-462.

Page 23 of 25

Peden NR, Robertson AJ, Boyd EJS,

et al

. Mitogen stimulation of peripheral blood

lymphocytes of duodenal ulcer patients during treatment with cimetidine or ranitidine.

Gut 1982; 23: 398-403.

Riley AJ, Salmon PR (eds.). Ranitidine. Excerpta Medica, Amsterdam, 1982.

Roberts CJC. Clinical Pharmacokinetics of Ranitidine. Clin. Pharmacokin. 1984; 9:


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

of solids in man. Br. J. Clin. Pharmacol. 1982; 13: 252-253.

Wolfe MM. Considerations for selection of parenteral histamine (H


antagonists. Am. J. Med. 1987; 83: 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: 264.

Product Monograph. Zantac

(Ranitidine Hydrochloride) Tablets, Oral Solution and

Injection USP. Date of Revision January 23, 2006, GlaxoSmithKline Inc., Mississauga,


Page 24 of 25




Ranitidine Tablets USP

150 mg and 300 mg

This leaflet is part III of a three-part “Product Monograph”

published when NU-RANIT was approved for sale in Canada

and is designed specifically for Consumers. This leaflet is a

summary and will not tell you everything about NU-RANIT.

Contact your doctor or pharmacist if you have any questions

about the drug.


What the medication is used for:

NU-RANIT, also known as ranitidine hydrochloride is used to

treat stomach or intestinal ulcers and prevent their return. It can

relieve discomfort from ulcer pain and the heartburn associated

with acid reflux.

What it does:

NU-RANIT belongs to a group of medicines called H


site antagonists. It acts by blocking histamine receptors that are

present on the cells in the stomach lining thereby reducing the

amount of acid produced by these cells.

When it should not be used:

Do not take NU-RANIT if you have previously had an allergic

reaction to the medicine or any of the non-medicinal ingredients

of the product.

What the medicinal ingredient is:

Ranitidine Hydrochloride

What the important non-medicinal ingredients are:

Microcrystalline cellulose, hydroxypropyl methylcellulose,

polydextrose, titanium dioxide, magnesium stearate, colloidal

silicon dioxide, vanillin and carnauba wax.

What dosage forms it comes in:

Tablets, 150 mg and 300 mg


Before you use NU-RANIT talk to your doctor or pharmacist if:

you have severe decreased renal function

you have lung disease, diabetes or a compromised immune


you are pregnant or breast-feeding.

you are older than 65 years of age, for your doctor to rule

out the possibility of stomach cancer. Also, make sure your

doctor knows if you are taking non-steroidal anti-

inflammatory drugs (NSAIDs).

occurrence of a gastric ulcer is suspected . NU-RANIT can

mask the symptoms of stomach cancer and therefore delay

the diagnosis of this condition.

This medicine should not be used if you have acute porphyria (a

rare blood disorder).

Experience with NU-RANIT in children below 8 years of age is



Drugs that may interact with this medicine:

Non-steroidal anti-inflammatory drugs


Hypoglycemic drugs



If you have any concerns regarding drug interactions please

consult your pharmacist or physician.


Usual Dose:

Duodenal and benign gastric ulcer:

300 mg once daily at

bedtime or 150 mg twice daily. In duodenal ulcers, when more

rapid healing is desired: 300mg twice daily for 4 weeks.

Maintenance treatment: Duodenal and benign gastric ulcer:

150 mg once daily at bedtime.

Duodenal ulcer (smoker):

mg nightly.

Reflux esophagitis:

300 mg once daily at bedtime

or 150 mg twice daily for up to 8 weeks. In patients with

moderate to severe esophagitis, may increase to 150 mg four

times daily.

Post-operative peptic ulcer:

150 mg twice daily.

Zollinger-Ellison Syndrome:

Initially 150 mg three times daily.

Some patients may require more frequent dosing.

NSAID-induced lesions (both ulcers and erosions) and their














Prophylaxis of Acid Aspiration Syndrome:

150 mg the evening

prior to anesthesia or 2 hours prior to anesthesia.

Prophylaxis of hemorrhage from stress ulceration or

prophylaxis of recurrent hemorrhage from bleeding

peptic ulcers:

150mg twice daily for patients on oral feeding.

Elderly patients should start at the lowest recommended dose and

be adjusted as necessary.


If you take more than the prescribed dose please consult your

physician or Emergency room as soon as possible.


Like other medications, NU-RANIT can cause some side effects.

Page 25 of 25

These side effects are most likely to be minor and temporary.

Do not be

alarmed by this list of possible side effects. You may

not experience any of them. If any of these side effects

experienced, do not hesitate to report them to your doctor.












unexpected effects while taking NU-RANIT, contact your

doctor or pharmacist.


Store between 15-30ºC (59-86ºF). Protect from light.


To monitor drug safety, Health Canada collects information on

serious and unexpected effects of drugs. If you suspect you have

had a serious or unexpected reaction to this drug you may notify

Health Canada by:

toll-free telephone: 866-234-2345

toll-free fax 866-678-6789

By email:

By regular mail:

Canadian Adverse Drug Reaction Monitoring Program


Health Canada

Address Locator: 0201C2

Ottawa, ON K1A 1B9

NOTE: Before contacting Health Canada, you should contact

your physician or pharmacist.


For more information, please contact your pharmacist, doctor or

other healthcare professional or the Dispedia Drug Information

Department at: 1-800-667-4708 or visit our website at

This leaflet was prepared by Nu-Pharm Inc., Richmond Hill,

Ontario, L4B 1E4.

Date of Revision: January 27, 2009



Talk with your

doctor or


Symptom / effect



In all




drug and

call your

doctor or








Sleepiness or lack of sleep


Blurred vision

Changes to heart rate

(increase & decrease) and





Pain in the muscles and


Tenderness/ soreness of

the breasts in males

Skin rash, redness of the

skin or hair loss

Allergic reactions

(including chest pain,

coughing, fever, rash,

swelling, hives, and low

blood pressure)

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