PHL-Ranitidine Product Monograph

INDICATIONS

phl-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:

C 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;

C the prophylaxis of GI haemorrhage from stress ulceration in seriously ill patients;

C the prophylaxis of recurrent haemorrhage from bleeding ulcers;

C the prevention of Acid Aspiration Syndrome from general anaesthesia in patients considered to be at risk for this, including obstetrical patients in labour, and obese patients

C the prophylaxis and maintenance treatment of duodenal or benign gastric ulcer in patients with a history of recurrent ulceration.

CONTRAINDICATIONS

phl-RANITIDINE tablets is contraindicated for patients known to have hypersensitivity to ranitidine.

WARNINGS

Gastric Ulcer

Treatment with a histamine H₂-antagonist may mask symptoms associated with carcinoma of the stomach and, therefore, may delay diagnosis of that condition. Accordingly, where gastric ulcer is suspected the possibility of malignancy should be excluded before therapy with ranitidine hydrochloride is instituted.

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.

Use in Patients with a History of Acute Porphyria

Rare clinical reports suggest that ranitidine may precipitate acute porphyric attacks. Therefore, ranitidine should be avoided in patients with a history of acute porphyria.

Use in Pregnancy and Nursing Mothers

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 foetus. 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 foetus.

Ranitidine is secreted in breast milk in lactating mothers but the clinical significance of this has not been fully evaluated.

Children

Experience with ranitidine products in children is limited. It has, however, been used successfully in children aged 8 to 18 years in oral doses up to 150 mg twice daily.

PRECAUTIONS

Use in Impaired Renal Function

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 undergoing chronic ambulatory peritoneal dialysis or chronic hemodialysis, a single oral dose of 150 mg ranitidine should be taken immediately after dialysis.

Interaction with Other Drugs

Although ranitidine has been reported to bind weakly to cytochrome P₄₅₀ in vitro, recommended doses of the drug do not inhibit the action of the hepatic cytochrome P₄₅₀-linked oxygenase enzymes.

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 distribution). As well, sporadic cases of drug interactions have been reported in elderly patients involving both hypoglycaemic drugs and theophylline. The significance of these reports cannot be determined at present, as controlled clinical trials with theophylline and ranitidine have not shown interaction.

If high doses (two grams) of sucralfate are 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.

Use in the Elderly

Since malignancy is more common in the elderly, particular consideration must be given to this before therapy with ranitidine is instituted. Elderly patients receiving non-steroidal anti-inflammatory drugs concomitantly with ranitidine should be closely supervised.

As with all medication in the elderly, when prescribing ranitidine, consideration should be given to the patient’s concurrent drug therapy. Sporadic cases of drug interaction have been reported in elderly patients involving both hypoglycaemic drugs and theophylline. The significance of these reports cannot be determined at present, as controlled clinical trials with theophylline and ranitidine have not shown interaction. Elderly patients may be at increased risk for confusional states and depression.

ADVERSE REACTIONS

The following adverse reactions have been reported as events in clinical trials or in the routine management of patients treated with ranitidine hydrochloride. A cause and effect relationship to the drug is not always established.

Central Nervous System: headache, sometimes severe; malaise; dizziness; somnolence; insomnia;

vertigo; and reversible blurred vision suggestive of a change in accommodation. Isolated cases of reversible mental confusion, agitation, depression, hallucinations have been reported, predominantly in severely ill elderly patients.

Cardiovascular: Isolated reports of tachycardia, bradycardia, premature ventricular beats, AV block have been noted. Asystole has been reported in very few individuals with and without predisposing conditions following IV administration and has not been reported following oral administration of ranitidine. (See Precautions, Dosage and Administration)

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

Hepatic: In normal volunteers, transient and reversible SGPT and SGOT values were increased to at least twice the pretreatment levels in 6 of 12 subjects receiving ranitidine 100 mg 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 hepatocanalicularor 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.

Musculoskeletal: Rare reports of arthralgia and myalgia.

Haematologic: Blood count changes (leukopenia, thrombocytopenia) have occurred in a few patients. These are usually reversible. Rare cases of agranulocytosis or pancytopenia, sometimes with marrow hypoplasia or aplasia have been reported.

Endocrine: No clinically significant interference with endocrine or gonadal function has been reported. There have been a few reports of breast symptoms in men taking ranitidine.

Dermatologic: Rash, including cases suggestive of mild erythema multiforme.

Other: Rare cases of hypersensitivity reactions (including chest pain, bronchospasm, fever, rash, eosinophilia, anaphylaxis, urticaria, angioneurotic edema, hypotension) and small increases in serum creatinine have occasionally occurred after a single dose. Acute pancreatitis has been reported rarely.

SYMPTOMS AND TREATMENT OF OVERDOSAGE

There is no experience to date with deliberate overdosage. The usual measures to remove unabsorbed drug from the gastrointestinal tract (including activated charcoal or syrup of ipecac), clinical monitoring and supportive therapy should be employed. Also, if need be, the drug can be removed from the plasma by haemodialysis.

DOSAGE AND ADMINISTRATION

phl-RANITIDINE (Ranitidine Tablets USP) - 150 mg and 300 mg

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 oesophagitis:

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 oesophagitis, the recommended adult oral dose is

150 mg twice daily.

Post-operative peptic ulcer: 150 mg twice daily, taken in the morning and before retiring.

Pathological hypersecretory conditions (Zollinger-Ellison Syndrome): 150 mg three times daily may be administered initially. In some patients, it may be necessary to administer 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.

Alternatively, parenteral ranitidine may be indicated. 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 commences.

DOSAGE FOR THE ELDERLY

For all conditions listed above, the drug dosage for the elderly who are seriously ill should start at the lowest recommended dose and be adjusted as necessary with close supervision.

.HCl O

(CH₃)₂NCH ₂ CH₂SCH₂CH₂NHCNHCH ₃

CHNO 2 PHARMACEUTICAL INFORMATION

DRUG SUBSTANCE

Proper name: ranitidine hydrochloride

Chemical name: (N-{2-[({5-[(Dimethylamino)-methyl]-2-furanyl}-

methyl)thio]ethyl}-N’ -methyl-2-nitro-1,

1-ethenediamine, hydrochloride.

Structural formula:

Empirical formula: C₁₃H₂₂N₄O₃S HCl

Molecular weight: 350.87 (as hydrochloride salt)

Description: Ranitidine hydrochloride is a white to pale yellow, crystalline powder. At room temperature, ranitidine hydrochloride is very soluble in water, moderately soluble in methanol and ethanol and sparingly soluble in chloroform. The pH of an aqueous solution of ranitidine is 4.5 to 6.0.

COMPOSITION

phl-RANITIDINE (Ranitidine Tablets USP)

150 mg: Each tablet contains 150 mg of ranitidine as the hydrochloride.

Tablets also contain the following excipients: microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, castor oil, carnauba wax, hydroxymethylcellulose, and titanium dioxide.

300 mg: Each tablet contains 300 mg of ranitidine as the hydrochloride.

Tablets also contain the following excipients: microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, castor oil, carnauba wax, hydroxymethylcellulose, and titanium dioxide.

STABILITY AND STORAGE RECOMMENDATIONS

Store at controlled room temperature 15 - 30°C. Protect from light and moisture.

AVAILABILITY OF DOSAGE FORMS

phl-RANITIDINE (Ranitidine Tablets USP) 150 mg tablet is a round white, biconvex, film-coated tablet imprinted with “P” and 150 on one side and blank on the other. phl-RANITIDINE 150 mg strength is supplied in bottles of 60, 100, 500 and 1000 tablets. The 60 and 100 count bottles have child-resistant caps. phl-RANITIDINE (Ranitidine Tablets USP) 150 mg tablet is also available in cartons of 10 tablets (1 push-through blister card of 10 tablets) and 30 tablets (3 push-through blister cards of 10 tablets each). This product is dispensed by prescription only.

phl-RANITIDINE (Ranitidine Tablets USP) 300 mg tablet is a capsule-shaped, white, convex, film-coated tablet imprinted with “P” and 300 on one side and blank on the other. phl-RANITIDINE

300 mg strength is supplied in bottles of 30, 100 and 500 tablets. The 30 and 100 count bottles have child-resistant caps. phl-RANITIDINE (Ranitidine Tablets USP) 300 mg tablet is also available in cartons of 10 tablets (1 push-through blister card of 10 tablets) and 30 tablets (3 push-through blister cards of 10 tablets each). This product is dispensed by prescription only.

PHARMACOLOGY

Animal Pharmacology

Ranitidine is a potent competitive, reversible, selective antagonist of histamine at H₂-receptors in vitro and in vivo. Thus, ranitidine antagonised the actions of histamine at H₂-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 pA₂ value of 7.2. In concentrations 1,000 times greater than those required to block H₂-receptors, it failed to block either

H₁-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 H₂-receptors in the stomach in vivo is the pharmacological action of ranitidine with greatest immediate clinical relevance. Ranitidine inhibits gastric secretion induced by various secretagogues in both the rat and dog.

In the conscious dog with a Heidenhain pouch, ranitidine given orally or intravenously antagonised gastric acid secretion induced by histamine, pentagastrin and bethanechol. Ranitidine was 5 to 10 times more active than cimetidine. However, both ranitidine and cimetidine had similar time curves of action. Ranitidine also inhibited the gastric secretory response to food in the conscious fistulated dog.

Ranitidine inhibited acid secretion in the perfused stomach of the anaesthetised rat, and aspirin-induced gastric lesion formation in the conscious rat, both in the presence and absence of excess hydrochloric acid. Measurements of the ration 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 co-administered with the following CNS modulating preparations; codeine, hexobarbitone, ethyl alcohol, chlordiazepoxide, chlorpromazine, imipramine, %-methyldopa, reserpine, apomorphine or pentylenetetrazol, did not alter the pharmacological effects of either preparation.

At a dose level 45 times the antisecretory ED₅₀, 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 nor of any electrocardiographic abnormality.

Long-term toxicity studies have shown that ranitidine does not possess antiandrogenic activity nor does it displace dihydrotestosterone from the androgen binding sites.

Metoclopramide, atropine and 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. Ranitidine reduced the frequency of aspirin- and indomethacin-induced gastric erosions.

The antinociceptive action of aspirin was reduced after ranitidine treatment. Ranitidine, unlike cimetidine, does not inhibit the hepatic mixed function oxygenase system.

Spectral interaction studies have shown that whilst cimetidine binds strongly to cytochrome P₄₅₀, ranitidine has only weak affinity for this enzyme. Cimetidine is known to impair the metabolism of pentobarbitone and warfarin. In doses of up to 166 mg/kg in the rat, ranitidine had no effect on the pentobarbitone sleeping time or the pharmacokinetics and pharmacodynamics of warfarin.

Metabolism, Distribution and Excretion

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

(mouse, rat, rabbit and dog) using radio-labelled drug. The drug was rapidly absorbed after oral administration. In the mouse, rat and rabbit between 30% and 60% of the administered radioactivity was excreted in the urine, the remainder being recovered in the faeces.

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 unmetabolized 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 foetuses showed that small amounts of radioactivity were present in the uveal tract of the foetal eye in both species, in the gall bladder and intestine of the rabbit foetus and in the bladder of the rat foetus. Radioactivity was also detected in the salivary and mammary glands of the maternal rat and at very low concentration, in the milk.

Human Pharmacokinetics

Serum concentrations necessary to inhibit 50% of stimulated gastric acid secretion are estimated to be 36 to 94 ng/mL. Following a single oral dose of 150 mg, serum concentrations of ranitidine are in this range for up to 12 hours. There is a relationship between plasma concentrations of ranitidine and suppression of gastric acid production but wide interindividual variability exists.

Ranitidine is 50% absorbed after oral administration compared to and 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.

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

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.

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

H₂-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.

Clinical Trials

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).

TOXICOLOGY

Toxicology, Impairment of Fertility, Carcinogenesis, and Mutagenesis

Ranitidine hydrochloride has been subjected to exhaustive toxicological testing which has demonstrated the lack of any specific target organ or any special risk associated with its clinical use.

Acute Toxicity Studies

In mice and rats, the intravenous LD₅₀ 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 long-term toxicity and carcinogenicity studies, very high doses of ranitidine were given daily to mice (up to 2000 mg/kg/day) throughout their normal life-span, and to dogs (up to 450 mg/kg/day) for periods 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_max) 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 is a natural phenomena in aging rats and chronic administration of a wide variety of drugs has been known to contribute to this process. Therefore, it is unlikely that the pharmacologic concentrations of ranitidine administered to these rats contributed to this natural process.

In the six-week and six-month oral studies in the dog (100 mg/kg/day) loose faeces 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 faeces, salivation and vomiting were observed in the 54-week dog study.

In isolated cases, dogs passed red-stained faeces 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 faeces were seen, suggesting that any relationship to ranitidine is unlikely. Post-mortem examination of the dogs revealed no ranitidine-induced changes in the alimentary tract.

One dog had marginally raised levels of plasma alanine aminotransferase and alkaline phosphatase during the six-week study. This same dog also showed some necrotic foci in the liver. Small lesions of focal necrosis and fibrosis were also seen in one piece of liver from one female dog treated with

100 mg/kg for six months. No other differences were detected by light and electron microscopic examination of the treated and control livers. Since the focal lesions were seen in only one dog and were restricted to one piece of liver, it suggests that they were not caused by ranitidine.

Muscular tremors, an inability to stand, and rapid respiration were seen on occasion in dogs treated with 225 mg/kg/day in the 54-week study. The prevalence of these observations was increased when the dose was increased to a toxic level of 450 mg/kg/day. One dog died: no specific pathological changes or reason for the death was discovered.

Changes in the colour or granularity of the tapetum lucidum of the eye were detected in three dogs receiving the highest dose of ranitidine (450 mg/kg/day) during the 54-week study. In one dog this change was considered to be related to treatment. The change, a pallor of the tapetum, was reversible. No changes were seen with light or electron microscopic examination of the eye. The changes in the tapetum are of no clinical significance in humans since (i) humans do not have a tapetum lucidum and (ii) the changes were only seen at toxic pharmacological concentrations of ranitidine.

The mean serum glutamic pyruvic transaminase values for dogs treated at 450 mg/kg/day were significantly greater, albeit marginally, than the control values. These enzyme increases were not accompanied by any histological changes.

Studies in which ranitidine was administered parenterally were performed. No sign of specific local irritation attributable to ranitidine was detected. In the rat, no biochemical or histopathological changes were observed at intravenous dose levels as high as 20 mg/kg. Specifically, no significant changes were found in the veins or subcutis. Mild lesions in some muscle samples were observed:

usually, the cells were basophilic and smaller than normal; and the nuclei were swollen, more numerous, and sometimes had migrated to the centre of the cell.

In the rabbit, slight infiltration of the pannicular muscle by mononuclear cells were noted. This minor subcutaneous reaction was uncommon and showed no group related distribution. There was no apparent difference in irritance between ranitidine injection and placebo injection. In the rat, intravenous ranitidine at dose levels of 5.0 and 10.0 mg/kg daily for 15 days and 28 days produced no treatment related changes of biological importance in the 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 urinalysis.

No changes were observed in the eyes of the dogs (specifically the tapetum lucidum) receiving ranitidine in doses up to 30 mg/kg twice daily for 15 days. At intravenous doses above 1.25 mg/kg, ranitidine injection produced immediate and transient reactions in the beagle dog. The following reactions were typically produced by the administration of 1.25 mg/kg: bloodshot eyes, closing and watering of eyes, defaecation, diarrhoea, 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 effect.

A total of 2,297 foetuses from rats treated with ranitidine were examined. There was no evidence that ranitidine is a rat teratogen. Cleft palates occurred in foetuses from both treatment groups, however, there were significantly more in the control rat population.

A total of 944 foetuses from rabbits treated with ranitidine were examined; no drug-related adverse effects or abnormalities in the foetuses 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 foetuses weighed significantly less than foetuses of untreated controls. In addition, 12.4% of ranitidine-exposed foetuses 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 foetal toxicity.

In the subsequent study, no evidence of maternal or foetal 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.

Mutagenesis

Ranitidine is not mutagenic at doses as great as 30 mg/plate in the Ames assay utilizing Salmonella typhimurium (TA 1538, TA 98, TA 100, and TA 1537) or in doses of 9 mg/plate utilizing

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

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

S. typhimurium TA 1535 and at 9 mg/plate in E. coli WP67. Ranitidine was not mutagenic at a concentration of 2 mg/mL in E. coli or S. typhimurium in the more sensitive Oral Solution microtitre fluctuation assay method. This weak direct mutagenic effect is of no clinical significance; the magnitudes of ranitidine concentration used in these assays are thousands of times greater than that attained therapeutically in human plasma.

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 nitrate (40mM) was mutagenic in S. typhimurium (TA 1535) but not in S. typhimurium

(TA 1537) or in E. coli (WP67 or WP2 uvrA). This positive result is attributable to the presence of a nitrosonitrolic acid derivative AH 23729, which was mutagenic. When the sodium nitrate 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.

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