Famotidine Omega -(Without Preservative) Product Monograph

INDICATIONS AND CLINICAL USE

Famotidine is indicated in the treatment of the following conditions where a controlled reduction of gastric secretion is required:

1. 1. Treatment of acute duodenal ulcer;
2. 2. Prophylactic use in duodenal ulcer;
3. 3. Treatment of acute benign gastric ulcer;
4. 4.

   Treatment of pathological hypersecretory conditions (e.g., Zollinger-Ellison

   Syndrome);

5. 5. Treatment of gastroesophageal reflux disease (GERD);
6. 6. Maintenance of remission of patients with GERD.

Famotidine injection is indicated in some hospitalized patients with pathological hypersecretory conditions or intractable ulcers, or as an alternative to the oral dosage form for short-term use in patients who are unable to take oral medication.

CONTRAINDICATIONS

Hypersensitivity to any component of this medication. Cross sensitivity in this class of compounds has been observed. Therefore, famotidine should not be administered to patients with a history of hypersensitivity to other H₂-receptor antagonists.

PRECAUTIONS

Patients with Moderate or Severe Renal Insufficiency

Since CNS adverse effects have been reported in patients with moderate and severe renal insufficiency, longer intervals between doses or lower doses may need to be used in patients with moderate (creatinine clearance 30 - 50 mL/min) or severe (creatinine clearance < 30 mL/min) renal insufficiency to adjust for the longer elimination half-life of famotidine (see HUMAN PHARMACOLOGY, Pharmacokinetics and DOSAGE AND ADMINISTRATION).

Drug Interactions

Studies with famotidine in man, in animal models, and in vitro have shown no significant interference with the disposition of compounds metabolized by the hepatic microsomal enzymes, e.g., cytochrome P450 system. Compounds tested in man have included warfarin, theophylline, phenytoin, diazepam, aminopyrine and antipyrine. Indocyanine green as an index of hepatic blood flow and/or hepatic drug extraction has been tested and no significant effects have been found. In addition, studies with famotidine have shown no augmentation of expected blood alcohol levels resulting from alcohol ingestion.

Use in Gastric Ulcer

Gastric malignancy should be excluded prior to initiation of therapy of gastric ulcer with famotidine. Symptomatic response of gastric ulcer to therapy with famotidine does not preclude the presence of gastric malignancy.

Use in Pregnancy

Reproductive studies have been performed in rats and rabbits at oral doses of up to 2000 and 500 mg/kg/day, respectively (approximately 2500 and 625 times the maximum recommended human dose, respectively), and have revealed no evidence of impaired fertility or harm to the fetus due to famotidine. There are, however, no adequate or well-controlled studies in pregnant women.

Since the safe use of famotidine in pregnant women has not been established, the benefits of treatment with famotidine should be weighed against potential risks.

Nursing Mothers

Famotidine is detectable in human milk. Nursing mothers should either stop this drug or should stop nursing.

Pediatric Use

Safety and effectiveness in children have not been established.

Use in Elderly Patients

No dosage adjustment is required based on age (see HUMAN PHARMACOLOGY, Pharmacokinetics). This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Dosage adjustments in the case of moderate or severe renal impairment is necessary (see PRECAUTIONS, Patients with Moderate or Severe Renal Insufficiency and DOSAGE AND ADMINISTRATION, Dosage Adjustment for Patients with Moderate or Severe Renal Insufficiency).

ADVERSE REACTIONS

Famotidine is usually well tolerated; most adverse reactions have been mild and transient. The adverse reactions listed below have been reported during clinical trials in 2333 patients. In those controlled clinical trials in which famotidine was compared to placebo, the overall incidence of adverse experiences in the group which received famotidine 40 mg at bedtime, was similar to the placebo group. No antiandrogenic or other adverse hormonal effects have been observed.

The following adverse reactions have been reported at a rate greater than 1% in patients on therapy with famotidine in controlled clinical trials, and may be causally related to the drug: headache (4.6 %), dizziness (1.2 %), constipation (1.2 %) and diarrhea (1.6 %).

Other reactions have been reported in clinical trials but occurred under circumstances where a causal relationship could not be established. However, in these rarely reported events, that possibility cannot be excluded. Therefore, these observations are listed to serve as alerting information to physicians.

Gastrointestinal 8.0 %

Nausea 1.6 %

Vomiting 0.9 %

Anorexia 0.5 %

Abdominal discomfort 0.3 %

Dry mouth 0.2 %

Nervous System/Psychiatric 7.3 %

Insomnia 0.6 %

Somnolence 0.4 %

Anxiety 0.3 %

Paresthesia 0.3 %

Depression 0.2 %

Libido decreased 0.1 %

Respiratory 4.4 %

Bronchospasm <0.1 %

Body as a whole 3.0 %

Fatigue 0.6 %

Asthenia 0.3 %

Fever 0.2 %

Musculoskeletal 1.7 %

Musculoskeletal pain including muscle cramps 0.1 %

Arthralgia 0.1 %

Skin 1.7 %

Pruritus 0.4 % Rash 0.3 %

Alopecia 0.2 %

Flushing 0.2 %

Acne 0.1 %

Dry skin 0.1 %

Cardiovascular 1.0 %

Palpitations 0.2 %

Special Senses 0.9 %

Taste disorder 0.1 %

Tinnitus 0.1 %

Orbital Edema <0.1 %

Urogenital 0.9 %

The adverse reactions reported for famotidine tablets may also occur with famotidine injection. In addition, transient irritation at the injection site has been observed with famotidine injection.

The following additional adverse reactions have been reported since the drug was marketed: urticaria, liver enzymes abnormalities, cholestatic jaundice, anaphylaxis, angioedema. Toxic epidermal necrolysis has been reported very rarely with H₂ receptor antagonists. As with other H₂-receptor antagonists, cases of bradycarida, A-V block and other arrhythmias have been reported rarely in patients treated with famotidine.

The following adverse reactions have been reported; however, a causal relationship to therapy with famotidine has not been established: agitation, confusion, hallucinations, grand mal seizures, rare cases of impotence, thrombocytopenia, pancytopenia, leukopenia and agranulocytosis.

Gynecomastia has been reported rarely. In most cases that were followed up, it was reversible after discontinuing treatment.

Laboratory Abnormalities

Laboratory parameters may be affected during treatment with famotidine, but the changes are usually not considered serious. Among the laboratory changes that were reported during clinical trials were increases in AST, ALT, BUN, and serum creatinine. These changes were rarely of clinical significance.

Only three patients had to be discontinued from therapy because of laboratory adverse experiences, however laboratory abnormalities were present at baseline.

SYMPTOMS AND TREATMENT OF OVERDOSAGE

There is no experience to date with deliberate overdosage. Doses of up to 800 mg/day have been employed in patients with pathological hypersecretory conditions with no serious adverse effects. In the event of overdosage, treatment should be symptomatic and supportive. Unabsorbed material should be removed from the gastrointestinal tract, the patient should be monitored, and supportive therapy should be employed.

The oral LD₅₀ of famotidine in male and female rats and mice was > 5000 mg/kg.

DOSAGE AND ADMINISTRATION

DUODENAL ULCER

Acute Therapy

The recommended adult oral dosage of famotidine for acute duodenal ulcer is 40 mg once a day at bedtime. Treatment should be given for 4 - 8 weeks, but the duration of treatment may be shortened if healing can be documented. Healing occurs within 4 weeks in most cases of duodenal ulcer.

Maintenance Therapy

For the prevention of recurrence of duodenal ulcer, it is recommended that therapy with famotidine be continued with a dose of 20 mg once a day at bedtime, for a duration of up to 6 - 12 months depending on the severity of the condition.

BENIGN GASTRIC ULCER

Acute Therapy

The recommended adult oral dosage for acute benign gastric ulcer is 40 mg once a day at bedtime. Treatment should be given for 4 to 8 weeks, but the duration of treatment may be shortened if healing can be documented.

PATHOLOGICAL HYPERSECRETORY CONDITIONS (SUCH AS ZOLLINGER-ELLISON SYNDROME)

The dosage of famotidine in patients with pathological hypersecretory conditions varies with the individual patient. The recommended adult oral starting dose for pathological hypersecretory conditions is 20 mg every six hours. In some patients, a higher starting dose may be required. Doses should be adjusted to individual patient needs and should continue as long as clinically indicated. Doses up to 800 mg/day have been administered to some patients with severe Zollinger-Ellison syndrome.

GASTROESOPHAGEAL REFLUX DISEASE

The recommended dosage for the symptomatic relief of gastroesophageal reflux disease is 20 mg of famotidine twice a day.

For the treatment of esophageal erosion or ulceration associated with gastroesophageal reflux disease, the recommended dosage is 40 mg of famotidine twice a day.

For the maintenance of remission of patients with GERD, the recommended dosage is 20 mg of famotidine twice a day.

Intravenous Administration

In some hospitalized patients with pathological hypersecretory conditions or intractable ulcers, or in patients who are unable to take oral medication, famotidine injection may be administered. The recommended dosage is 20 mg every 12 hours.

Intravenous injection therapy should be changed to oral treatment as soon as the acute situation is under control.

N

H₂N

NH₂

CH₂SCH₂CH₂C N

S

C

H₂N

NSO₂NH₂ Concomitant Use with Antacids

Antacids may be given concomitantly if needed.

Dosage Adjustment for Patients with Moderate or Severe Renal Insufficiency

In patients with moderate (creatinine clearance 30 -50 mL/min) or severe (creatinine clearance <30 mL/min) renal insufficiency, the elimination half-life of famotidine is increased. For patients with severe renal insufficiency, it may exceed 20 hours, reaching approximately 24 hours in anuric patients. Since CNS adverse reactions have been reported in patients with moderate and severe renal insufficiency, to avoid excess accumulation of the drug in patients with moderate and renal insufficiency, the dose of famotidine should be reduced to half the dose or the dosing interval may be prolonged to 36 - 48 hours as indicated by the patient’s clinical response.

In patients with advanced renal insufficiency, i.e., with a creatinine clearance less than 10 mL/min., the elimination half-life of famotidine may exceed 20 hours reaching approximately 24 hours in anuric patients.

To avoid excess accumulation of the drug, the dosing interval of famotidine may be prolonged to 36 - 48 hours as indicated by the patient’s clinical response.

PHARMACEUTICAL INFORMATION

I. DRUG SUBSTANCE

Proper name: Famotidine

Chemical name: N’-(aminosulfonyl)-3-[[[2-[(diaminomethylene)amino]-4-thiazolyl] methyl]thio]Propanimidamide.

Empirical formula: C₈H₁₅N₇O₂S₃

Structural

formula:

Molecular weight: 337.44

Description: Famotidine is a white to pale yellow crystalline compound that is freely soluble in glacial acetic acid, slightly soluble in methanol, very slightly soluble in water and practically insoluble in ethanol.

II. COMPOSITION

Each mL of the solution for intravenous injection contains 10 mg of famotidine and the following non-medicinal ingredients: L-aspartic acid 4 mg, mannitol 20 mg, and Water for Injection, q.s., 1 mL. Sodium hydroxide and/or hydrochloric acid may have been added to adjust pH. The multidose injection also contains benzyl alcohol 0.9 % added as preservative. III. STABILITY AND STORAGE RECOMMENDATIONS

Store between 2 and 8°C. Protect from light. Do not freeze.

The 2 mL presentation is for single-use only and unused portions should be discarded.

The 4 mL and 20 mL multi dose presentations should be discarded 28 days after initial puncture.

IV. DILUTION FOR INFUSION

Dilution of Famotidine injection for Infusion

Famotidine

injection

Solution

Volume

compatible

Final

Volume

Finale

Concentration

Rate of Infusion

2 mL 3 mL 5 mL 4 mg/mL Not less than 2 minutes

2 mL 8 mL 10 mL 2 mg/mL Not less than 2 minutes

2 mL 100 mL 102 mL 0.196 mg/mL 15 - 30 minutes

NOTE: As with all parenteral drug products, intravenous admixtures should be inspected visually for clarity, particulate matter, precipitate, discolouration and leakage prior to administration, whenever solution and container permit. Solutions showing haziness, particulate matter, precipitate, discolouration or leakage should not be used. Discard unused portion.

Famotidine solutions are compatible with:

Water for Injection

5% Dextrose Injection

10% Dextrose Injection

Lactated Ringer’s Injection

All diluted admixtures for infusion should be prepared in PVC bags and should be stored between 2 and 8/C, protected from light. Diluted solutions should be used within 24 hours due to the possibility of microbial contamination during preparation.

AVAILABILITY OF DOSAGE FORMS

Famotidine OMEGA, 10 mg per 1 mL, is a clear, colorless solution and is available as a non-preserved unit dose containing 2 mL of injectable solution. Available in 10 x 2 mL vials.

Famotidine OMEGA, 10 mg per 1 mL, is a clear, colorless solution and is available as a preserved multiple dose containing 4 mL of injectable solution. Available in 4 mL vials.

Famotidine OMEGA, 10 mg per 1 mL, is a clear, colorless solution and is available as a preserved multiple dose containing 20 mL of injectable solution. Available in 20 mL vials.

PHARMACOLOGY

I HUMAN PHARMACOLOGY

food.

.

ion.

Other Effects

Pharmacokinetics

excretion.

.

II ANIMAL PHARMACOLOGY

96%.

Mechanism of Action

H₂-receptor antagonist. There was no effect i

H₂-receptors is

retarded.

Absorption and Distribution

effectively cross the blood-brain or placental barrier of rats. It was present in rat milk.

Metabolism and Excretion

inor amounts. Urinary and fecal excretion of radioactivity in rats accounted for 28% and 70%, respectively, of an oral dose, compared to 83% and 17% respectively, of an intravenous dose. About 2.4% of the dose in rats was excreted in the bile. Dogs excreted 45% of an oral dose in the urine, compared to 100% of an intravenous dose.

Effects on Liver Microsomal Drug-Metabolizing Enzymes

Famotidine did not affect pentobarbital or hexobarbital sleeping times and it did not affect ascorbic acid excretion, suggesting that famotidine does not induce drug-metabolizing enzymes. Famotidine caused none of the changes induced by cimetidine on the pharmacokinetics of diazepam, warfarin, and propranolol. Famotidine produced only minimal suppression of aminopyrine and diazepam N-demethylase activity in vitro, and showed little affinity for testosterone hydroxylases of mouse liver in vitro.

Gastrointestinal Effects other than Antisecretory

Famotidine prevented gastric erosions induced in rats by cold restraint, water immersion, pyloric ligation, or drugs such as acetylsalicylic acid, histamine or prednisolone; also duodenal ulcers caused by cysteamine and mepirizole. It also significantly accelerated the healing of the gastric lesions induced by acetic acid and the duodenal ulcers produced by mepirizole.

The antiulcer effect of famotidine plus magnesium and aluminum hydroxides was greater than the sum of the effects of these drugs used separately.

Famotidine inhibited the gastric lesions and hemorrhage resulting from blood removal and histamine injection in anaesthetized rats.

In normal rats, famotidine had no effect on the concentration of gastric mucosal histamine, but it did reduce the levels of cAMP, particularly in response to histamine stimulation.

In anaesthetized cats, famotidine had no effect on the intragastric electropotential when tested at intragastric doses more than ten-fold greater than those required to block gastric secretion maximally.

Cardiorenal Effects

The cardiorenal effects of famotidine were studied in dogs and rats. Ten mg/kg of famotidine administered

dose of 10 mg/kg was without diuretic effect.

Central Nervous System Effects

The effects of famotidine on the central nervous system were studied in squirrels, monkeys, mice, and cats. In monkeys famotidine had a bidirectional effect on lever pressing (avoidance response) causing an increase at the low dose (1.0 mg/kg p.o.) and a small decrease at 9 mg/kg. In mice following intraperitoneal administration of 6 to 150 mg/kg no overt behavioural signs or symptoms of central nervous system activity were observed. In mice famotidine was not active as an antagonist of the CNS actions of TRH, neurotensin, substance P, or amphetamine. Famotidine was free of major or minor tranquillizing, anticonvulsant, anticholinergic, ganglionic blocking, or dopaminergic activity. In cats, famotidine did not affect the EEG or arousal response but did prolong the duration of hippocampal after-discharge. Only 4% of the plasma concentration of the drug was detected in the cerebrospinal fluid.

TOXICOLOGY

Acute Toxicity

Species Sex Route LD₅₀ (mg/kg)

Mouse M

F

P.O.^x

P.O.^x

4,684

3,233

Mouse M

F

I.V. (4%)

I.V. (4%)

254

358

Rat M

F

P.O.^x

P.O.^x

4,907

4,049

Rat M

F

I.P.

I.P.

987

814

^x In solution (acidic, 50 - 55°C deionized water).

Subacute and Chronic Toxicity

Famotidine is well tolerated by both rats and dogs at doses of 2 g/kg twice a day orally in subacute studies and at doses up to 1000 or 2000 mg/kg/day for one year in these species. Eosinophilic cytoplasmic granularity of gastric chief cells was seen at a higher incidence in rats given 200 mg/kg/day or more of the compound compared to controls. This is considered as a secondary effect due to the exaggerated pharmacologic activity of the compound at these extremely high dosage levels and is considered of no toxicologic significance. In a 106-week study in rats designed to study the carcinogenic potential of the compound, this gastric change did not progress to hyperplasia or neoplasia. Similarly, mice (given the compound for 92 weeks) showed no evidence of a neoplastic potential. Based on the results from studies performed using pharmacologically-related compounds, this change was fully reversible.

Intravenous administration of famotidine was well tolerated by rats for 13 weeks at dosage levels of up to 20 mg/kg/day and by dogs, except for occasional emesis, at dosage levels of up to 10 mg/kg/day for 5 to 26 weeks.

Reproduction Studies

In studies with rats given oral doses of up to 2000 mg/kg/day or intravenous doses of up to 200 mg/kg/day (approximately 2500 and 250 times the maximum recommended human dose, respectively), fertility and reproductive performance were not affected.

Famotidine given orally to pregnant rats up to 2000 mg/kg/day or intravenously at dosage levels up to 200 mg/kg/day, from Days 7 to 17 of pregnancy did not reveal any evidence of embryolethality or teratogenicity.

Oral administration of famotidine to pregnant rabbits from Days 6 to 18 of pregnancy at dosage levels up to 500 mg/kg/day revealed no evidence of embryolethality or teratogenicity. Mutagenicity

Famotidine was tested in a reverse-mutation test (Ames test) using Salmonella typhimurium and Escherichia coli with and without metabolic activation. No mutagenic potential was seen. These same studies were performed with famotidine/sodium, nitrite reaction mixture and C-nitroso derivatives of famotidine and they were also negative. Famotidine and C-nitroso derivatives of famotidine were tested in the rec-assay using Bacillus subtilis H17 and M45 and the tests were negative for DNA-damaging capacity of the compounds. In in vivo studies in mice, a micronucleus test and a chromosomal aberration test, no evidence of a mutagenic effect was seen.

Carcinogenicity

A 92-week oral carcinogenicity study was conducted in mice at doses of 20, 200 and 2000 mg/kg/day. No evidence of a carcinogenic potential was seen. A 106-week oral carcinogenicity study in rats given doses of 20, 200 and 2000 mg/kg/day did not reveal any carcinogenic potential for famotidine.

Special Studies

The effects of famotidine on the thyroid of rats were evaluated after five weeks of oral administration at doses up to 2000 mg/kg/day. No evidence of treatment-related alterations of serum thyroid hormone levels, thyroid weight or the microscopic appearance were seen after administration of famotidine.

In immunogenicity studies, no effect on the production of IgE antibodies was seen in the sera of mice which were injected, once intraperitoneally, with famotidine alone (up to 2 mg/8 mL/kg) or coupled with either mouse serum albumin or ovalbumin. The sera were used to measure passive cutaneous anaphylaxis in rats which were then challenged with solutions of antigens similar to those antigens used for the initial dose in mice. Similarly, no evidence of an anaphylactic reaction was seen in guinea pigs challenged intravenously with famotidine after initiating doses (three times, subcutaneously, at six-day intervals) of up to 10 mg/mL.

REFERENCES

1. 1.

   Dammann HG, Walter TA, Muller P, Simon B. The role of H₂-antagonists in Zollinger-Ellison Syndrome. Ital

   J Gastroenterol 1984; 16:167-169.

2. 2.

   Dicenta C, Pierzchala PA, Rhymer AR, Jaffe ME. Outline of clinical studies with a new H₂-antagonist:

   famotidine. Ital J Gastroenterol 1984; 16:181-182.

3. 3. Hayakawa A, Che K, Miyoshi A, Harasawa S, Miwa T, Makabatake T. Properties of famotidine in relation to safety. Ital J Gastroenterol 1984; 16:174-176.
4. 4. Howard JM, Collen MJ, Cherner JA, McArthur KE, Maton PN, Gardner JD, Jensen RT. Famotidine: an effective, potent H₂ antagonist for the therapy of Zollinger-Ellison Syndrome (ZES). Gastroenterology (in Soc. Proc.) 1984; 86:1117.
5. 5.

   Howard JM, Chremos AN, Collen MJ, McArthur KE, Cherner JA, Maton PN, Ciarleglio CA, Cornelius MJ,

   Gardner JD, Jensen RT. Famotidine, a new, potent, long-acting histamine H₂-receptor antagonist: comparison with cimetidine and ranitidine in the treatment of Zollinger-Ellison syndrome. Gastroenterology 1985; 88:1026-1033.

6. 6. Hucker HB, Hutt JE, Chremos AN, Rotmensch H. Disposition and matabolism of famotidine, a potent H₂-receptor blocker, in man. Fed Proc Fed Am Soc Exp Biol (in Soc. Proc.) 1984; 43:655.
7. 7. McCallum RW, Kuljian B, Chremos AN, Tupy-Visich MA, Huber PB. Prolonged gastric antisecretory effect of a novel H₂-receptor inhibitor, MK-208. Gastroenterology (in Soc. Proc.) 1983; 84:1245.
8. 8. Miyoshi A, Muto V, Mori H, Miwa T, Nakazawa S, Ohe K, Hayakawa A. Famotidine: Summary of overall safety from Japanese clinical studies. Ital J Gastroenterol 1984; 16(2):177-178.
9. 9. Muller P, Dammann HG, Schmidt-Gayk H, Lichtwald K, Staiger C, Simon B. Famotidine (MK-208): Duration of action, 24-hour intragastric acidity, antipyrine kinetics and basal hormone levels in man. Gastroenterology (in Soc. Proc.) 1984; 86:1190.
10. 10.

    Ohe K, Miyoshi A, Yachi A, Yabana T, Saton K, Sakita T, Fukutomi H, Mutoh H, Sugata F, Fujita Y, Matsuo

    Y, Mori H, Miwa T, Miwa M, Kubota Y, Watanabe Y, Nakazawa S, Segawa K, Tsukamoto S, Moriga M, Kishi S. Clinical pharmacology of famotidine - effect of famotidine on gastric secretion. Ital J Gastroenterol 1984; 16:169-171.

11. 11. Ryan JR, Vargas R, Mantell G, Chremos AN, McMahon FG, Regel G. The effect of dose size, frequency and timing of famotidine (MK-208) on nocturnal and meal-stimulated gastric secretion. Clin Pharmacol Ther (in Soc. Proc.) 1984; 35:271.
12. 12.

    Ryan R. Clinical pharmacology of famotidine: Summary of data from the United States. Ital J Gastroenterol

    1984; 16:171-174.

13. 13. Shiratori K, Watanabe S, Maruyama M, Kurokawa K, Takeuchi T. Effect of famotidine on gastric secretion, and on 24-hour intragastric pH in duodenal ulcer patients. Gastroenterology (in Soc. Proc.) 1984; 86:1250.
14. 14. Smith JL, Gamal MA, Chremos AN, Graham DY. Effect of an H₂-receptor antagonist, MK-208, on gastric parietal and nonparietal secretion. Gastroenterology (in Soc. Proc.) 1983; 84:1314.
15. 15. Smith JL, Gamal MA, Chremos AN, Graham DY. Famotidine a new H₂-receptor antagonist effect on parietal nonparietal and pepsin secretion in man. Dig Dis Sci 1985; 30:308-312.

OMEGA

Montreal, Canada H3M 3A2