Canada - English - Health Canada
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Ranitidine Tablets USP
150 mg and 300 mg Ranitidine (as Ranitidine Hydrochloride)
- Receptor Antagonist
DATE OF PREPARATION:
50 Mural Street, Units 1 & 2
January 27, 2009
Richmond Hill, Ontario
Control # 127275
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Table of Contents
PART I: HEALTH PROFESSIONAL INFORMATION....................................................... 3
SUMMARY PRODUCT INFORMATION.............................................................................. 3
INDICATIONS AND CLINICAL USE ................................................................................... 3
WARNINGS AND PRECAUTIONS ....................................................................................... 4
ADVERSE REACTIONS ......................................................................................................... 5
DRUG INTERACTIONS.......................................................................................................... 6
DOSAGE AND ADMINISTRATION ..................................................................................... 7
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
PART III: CONSUMER INFORMATION............................................................................ 24
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Ranitidine Tablets USP
PART I: HEALTH PROFESSIONAL INFORMATION
SUMMARY PRODUCT INFORMATION
Dosage Form / Strength
Tablet / 150 mg and 300 mg
For a complete listing see Dosage
Forms, Composition and
INDICATIONS AND CLINICAL USE
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
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WARNINGS AND PRECAUTIONS
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.
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.
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).
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.
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
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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
PRECAUTIONS, DOSAGE AND
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
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.
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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
doses of the drug do not inhibit the action of the hepatic cytochrome P
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.
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
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.
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The plasma concentrations of ranitidine are not significantly influenced by the presence of food
in the stomach at the time of oral administrations
(see ACTION AND CLINICAL
Interactions with herbal products have not been established.
Drug-Laboratory Test Interactions
Interactions with laboratory tests have not been established.
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.
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.
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.
For the long-term management of reflux esophagitis, the recommended adult oral dose is 150 mg
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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.
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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
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.
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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
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
-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
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.
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STORAGE AND STABILITY
Store between 15°C - 30°C (59°F - 86°F). Protect from light.
DOSAGE FORMS, COMPOSITION AND PACKAGING
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.
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PART II: SCIENTIFIC INFORMATION
Molecular Formula and mass:
350.87 (as hydrochloride salt)
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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).
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
Ranitidine HCl exists in 2 different polymorphic (crystal)
forms: Form I (mp 134º - 140ºC) and Form II (mp 140º -
1.89 (25ºC), 1.77 (37ºC)
1.5 x 10
@ 315 nm
140º - 144ºC
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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
Arithmetic Mean (CV %)
Ratio of Geometric
88.3 - 106.0
88.0 - 105.3
83.3 - 115.4
Arithmetic means (CV %) only.
is manufactured by GlaxoSmithKline Inc. and was purchased in Canada.
Ranitidine is a potent competitive reversible, selective antagonist of histamine at H
. 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
-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
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.
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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
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
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.
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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.
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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.
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
(TA 1538, TA 98, TA 100 and TA 1537) or in doses of 9 mg/plate
(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
WP67. Ranitidine was not mutagenic at a
concentration of 2 mg/mL in
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
(TA 1535) but not in
(TA 1537) or in
(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,
. Effects of cimetidine and ranitidine on
hepatic drug metabolism. Clin. Pharmacol. Ther. 1982; 31: 297-300.
Brogden RN, Carmine AA,
. 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;
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,
. 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
. 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
. Drug metabolism by rat and human
hepatic microsomes in response to interaction with H
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,
. 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,
. 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,
. 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
IMPORTANT: PLEASE READ
PART III: CONSUMER INFORMATION
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.
ABOUT THIS MEDICATION
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:
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
WARNINGS AND PRECAUTIONS
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
INTERACTIONS WITH THIS MEDICATION
Drugs that may interact with this medicine:
Non-steroidal anti-inflammatory drugs
If you have any concerns regarding drug interactions please
consult your pharmacist or physician.
PROPER USE OF THIS MEDICATION
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):
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
Post-operative peptic ulcer:
150 mg twice daily.
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
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.
SIDE EFFECTS AND WHAT TO DO ABOUT THEM
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.
HOW TO STORE IT
Store between 15-30ºC (59-86ºF). Protect from light.
REPORTING SUSPECTED SIDE EFFECTS
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: email@example.com
By regular mail:
Canadian Adverse Drug Reaction Monitoring Program
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
SERIOUS SIDE EFFECTS, HOW OFTEN THEY HAPPEN
AND WHAT TO DO ABOUT THEM
Talk with your
Symptom / effect
Sleepiness or lack of sleep
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
(including chest pain,
coughing, fever, rash,
swelling, hives, and low