Famotidine indicated in adults for the treatment of:

• active duodenal ulcer (DU).

• active gastric ulcer (GU).

• symptomatic nonerosive gastroesophageal reflux disease (GERD).

• erosive esophagitis due to GERD, diagnosed by biopsy.

• treatment of pathological hypersecretory conditions (e.g., Zollinger-Ellison syndrome, multiple endocrine neoplasias).

• reduction of the risk of duodenal ulcer recurrence.

Famotidine is indicated in pediatric patients 1 year of age and older for the treatment of:

• peptic ulcer disease.

• GERD with or without esophagitis and ulcerations.

Famotidine is indicated in pediatric patients from birth to less than 1 year of age for the treatment of:

• GERD

Recommended Dosage in Adults

The recommended dosage and duration of famotidine in adults with normal renal function is shown in Table 1.

Table 1: Recommended Dosage and Duration of Famotidine for Oral Suspension^a in Adults with

Normal Renal Function

a   After preparation, the concentration of famotidine is 8 mg/mL

b   Both dosages demonstrated effectiveness in clinical trials

c   In clinical trials, the majority of patients healed within 4 weeks. For patients who do not heal after 4     

     weeks, consider an additional 2 to 4 weeks of treatment

d   Longer treatment durations have not been studied in clinical trials

Recommended Dosage in Paediatric Patients

The recommended dosage and duration of famotidine in paediatric patients with normal renal function is shown in Table 2.

Table 2: Recommended Dosage and Duration of Famotidine for Oral Suspension^a in Paediatric Patients with Normal Renal Function

a   After preparation, the concentration of famotidine is 8 mg/mL

b   Treatment duration based on adult recommendations (see Table 1). Individualize the dose and

     duration based upon clinical response and/or pH determinations (gastric or esophageal) and    

     endoscopy.

c   Use conservative measures (e.g., thickened feedings) concurrently

d   After 4 weeks of treatment re-evaluate the patient. Consider an additional 4 weeks of treatment if

     treatment benefit outweighs potential risks.

Recommended Dosage in Adults with Renal Impairment

Recommended dosage adjustments for adults with moderate to severe renal impairment (creatinine

clearance less than 60 mL/min) by indication are shown in Table 3. Use the lowest effective dosage.

A safe and effective dosage has not been established in paediatric patients with renal impairment.

Table 3: Recommended Maximum Dosage of Famotidine for Oral Suspension in Adults with

Moderate and Severe Renal Impairment

a Dosage adjustments for renal impairment are provided for both dosing regimens (20 mg twice daily and 40 mg twice daily) which showed effectiveness for the treatment of erosive esophagitis in clinical trials

b The dosage required to treat pathological hypersecretory conditions may exceed the maximum dosage evaluated in patients with impaired renal function. The risk for increased adverse reactions in renally impaired patients treated with famotidine for pathological hypersecretory conditions is unknown.

Special populations

Paediatric Use

Peptic Ulcer Disease and GERD With or Without Esophagitis and Ulcerations

Paediatric Patients One Year to Less than 17 Years of Age

The safety and effectiveness of famotidine for oral suspension have been established in paediatric patients 1 year to less than 17 years of age for the treatment of peptic ulcer disease and GERD with or without esophagitis and ulcerations. Use of famotidine in this age group is supported by evidence from adequate and well-controlled studies of famotidine in adults with additional pharmacokinetic and pharmacodynamic data in paediatric patients 1 year to less than 17 years of age [see Posology and method of administration (4.2), Pharmacological properties (5.1, 5.2)]. The safety and effectiveness of famotidine for oral suspension for the treatment of peptic ulcer disease in paediatric patients less than one year of age have not been established.

GERD

Paediatric Patients Less Than One Year of Age

The safety and effectiveness of famotidine for oral suspension have been established in paediatric patients from birth to less than 1 year of age for the treatment of GERD. The use of famotidine this is age group is supported by evidence from adequate and well-controlled studies of famotidine in adults and with supportive data in paediatric patients from birth to less than 1 year of age [see Posology and method of administration (4.2), Pharmacological properties (5.1, 5.2)].

Other Conditions

The safety and effectiveness for the treatment of pathological hypersecretory conditions and reduction of risk of duodenal ulcer recurrence have not been established in paediatric patients.

A safe and effective dosage has not been established in paediatric patients with renal impairment.

Geriatric Use

Of the 1442 famotidine-treated patients in clinical studies, approximately 10% were 65 and older. In

these studies, no overall differences in safety or effectiveness were observed between elderly and

younger patients. In post marketing experience, CNS adverse reactions have been reported in elderly

patients with and without renal impairment receiving famotidine [see Warnings and Precautions (4.4)].

Famotidine is known to be substantially excreted by the kidney, and the risk of adverse reactions to

famotidine for oral suspension may be greater in elderly patients, particularly those with impaired renal

function [see Use in Specific Populations (renal impairment)].

In general, use the lowest effective dose of famotidine for oral suspension for an elderly patient and

monitor renal function [see Posology and method of administration (4.2)].

Renal Impairment

CNS adverse reactions and prolonged QT intervals have been reported in patients with moderate and severe renal impairment [see Warnings and Precautions (4.4)]. The clearance of famotidine is reduced in adults with moderate and severe renal impairment compared to adults with normal renal function [see  Pharmacological properties (5.2)]. No dosage adjustment is needed in adults with mild renal impairment (creatinine clearance greater than or equal to 60 mL/minute). Dosage reduction is recommended in adults with moderate or severe renal impairment (creatinine clearance less than 60 mL/minute) [see Posology and method of administration (4.2)]. Data are not available to establish a safe and effective dosage in paediatric patients with renal impairment.

Method of administration

Preparation of Constituted Suspension

Prior to dispensing, constitute famotidine by slowly adding 46 ml of Purified water to the bottle. Shake vigorously for the 5 to 10 seconds immediately after adding the water. The constituted suspension contains 40 mg of famotidine per 5 ml, and should be a smooth, mobile, off-white, and homogeneous suspension.

Administration

·       Shake the bottle of constituted suspension vigorously for 5 to 10 seconds prior to each use.

·       Take famotidine once daily before bedtime or twice daily in the morning and before bedtime.

·       Famotidine may be taken with or without food

·       Famotidine may be given with antacids (famotidine should be administered 1-2 hours before taking an antacid).

·       Store the constituted suspension at 25°C (77°F). Protect from freezing. Discard unused constituted suspension after 30 days.

Central Nervous System Adverse Reactions

Central nervous system (CNS) adverse reactions, including confusion, delirium, hallucinations, disorientation, agitation, seizures and lethargy, have been reported in elderly patients and patients with moderate and severe renal impairment treated with famotidine. Since famotidine blood levels are higher in patients with renal impairment than in patients with normal renal function dosage adjustments are recommended in patients with renal impairment.

Concurrent Gastric Malignancy

In adults, symptomatic response to therapy with famotidine does not preclude the presence of gastric malignancy. Consider evaluation for gastric malignancy in adult patients who have a suboptimal response or an early symptomatic relapse after completing treatment with famotidine for oral suspension.

Renal impairment

Since famotidine is excreted primarily by the kidney, caution should be observed in patients with

impaired renal function. A reduction in daily dosage should be considered if creatinine clearance falls

below 30 ml/min [see Posology and method of administration (4.2)].

In case of long-term treatment with high dosage, monitoring of blood count and liver function is

recommended.

Drugs Dependent on Gastric pH for Absorption

Famotidine can reduce the absorption of other drugs, due to its effect on reducing intragastric acidity,

leading to loss of efficacy of the concomitant drug.

Concomitant administration of famotidine for oral suspension with dasatinib, delavirdine mesylate,

cefditoren, and fosamprenavir is not recommended.

See the prescribing information for other drugs dependent on gastric pH for absorption for administration instructions, including atazanavir, erlotinib, ketoconazole, itraconazole, ledipasvir/ sofosbuvir, nilotinib, and rilpivirine.

The administration of probenecid can delay the elimination of famotidine. Concomitant use of

probenecid and famotidine should be avoided.

Antacids may decrease the absorption of famotidine and lead to lower plasma concentrations of

famotidine. Famotidine should therefore be taken 1 - 2 hours before the application of an antacid.

The concomitant use of sucralfate should be avoided within two hours of the famotidine dose.

The concomitant use of Calcium carbonate and famotidine should be avoided.

Tizanidine (CYP1A2 Substrate)

Although not studied clinically, famotidine is considered a weak CYP1A2 inhibitor and may lead to

substantial increases in blood concentrations of tizanidine, a CYP1A2 substrate. Avoid concomitant use

with famotidine for oral suspension. If concomitant use is necessary, monitor for hypotension, bradycardia or excessive drowsiness. Refer to the full prescribing information for tizanidine.

Pregnancy

Pregnancy Category C

Risk Summary

Available data with H₂ -receptor antagonists, including famotidine, in pregnant women are insufficient to establish a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes.

In animal reproduction studies, no adverse development effects were observed with oral administration of famotidine at doses up to approximately 243 and 122 times, respectively, the recommended human dose of 80 mg per day for the treatment of erosive esophagitis (see Data).

The estimated background risk for major birth defects and miscarriage for the indicated population is

unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the

U.S. general population, the background risk of major birth defects and miscarriage in clinically

recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Animal Data

Reproductive studies have been performed in rats and rabbits at oral doses of up to 2000 and 500 mg

/kg/day, respectively, and in both species at intravenous doses of up to 200 mg/kg/day, and have revealed no significant evidence of impaired fertility or harm to the fetus due to famotidine. While no direct fetotoxic effects have been observed, sporadic abortions occurring only in mothers displaying marked decreased food intake were seen in some rabbits at oral doses of 200 mg/kg/day (about 49 times the recommended human dose of 80 mg per day, based on body surface area) or higher. There are, however, no adequate or well-controlled studies in pregnant women. Because animal reproductive studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Lactation

Risk Summary

There are limited data available on the presence of famotidine in human breast milk. There were no

effects on the breastfed infant. There are no data on famotidine effects on milk production. Famotidine is present in the milk of lactating rats (see Data).

The developmental and health benefits of breastfeeding should be considered along with the mother's

clinical need for famotidine and any potential adverse effects on the breastfed child from famotidine for

oral suspension or from the underlying maternal condition.

Data

Animal Data

Transient growth depression was observed in young rats suckling from mothers treated with maternotoxic doses of famotidine at least 600 times the usual human dose.

None known

a.    Summary of the safety profile

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in

the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of famotidine for oral suspension has been established based on adequate and well controlled

studies of another oral famotidine product. The following is a summary of the adverse reactions reported in those studies.

Oral famotidine was studied in 7 US and international placebo- and active-controlled trials in

approximately 2500 patients. A total of 1442 patients were treated with famotidine, including 302 treated with 40 mg twice daily, 456 treated with 20 mg twice daily, 461 treated with 40 mg once daily, and 396 treated with 20 mg once daily. The population was 17 to 91 years old, fairly well distributed between sex and race; however, the predominant race was Caucasian.

b.   Tabulated summary of adverse reactions

c. Paediatric Population

Peptic Ulcer Disease and GERD With or Without Esophagitis and Ulcerations

Paediatric Patients One Year to Less than 17 Years of Age

The safety and effectiveness of famotidine for oral suspension have been established in paediatric patients 1 year to less than 17 years of age for the treatment of peptic ulcer disease and GERD with or without esophagitis and ulcerations. Use of famotidine in this age group is supported by evidence from adequate and well-controlled studies of famotidine in adults with additional pharmacokinetic and pharmacodynamic data in paediatric patients 1 year to less than 17 years of age [Posology and method of administration (4.2), Pharmacological properties (5.1, 5.2)]. The safety and effectiveness of famotidine for oral suspension for the treatment of peptic ulcer disease in paediatric patients less than one year of age have not been established.

GERD

Paediatric Patients Less Than One Year of Age

The safety and effectiveness of famotidine for oral suspension have been established in paediatric patients from birth to less than 1 year of age for the treatment of GERD. The use of famotidine this is age group is supported by evidence from adequate and well-controlled studies of famotidine in adults and with supportive data in paediatric patients from birth to less than 1 year of age [see Posology and method of administration (4.2), Pharmacological properties (5.1, 5.2)].

Other Conditions

The safety and effectiveness for the treatment of pathological hypersecretory conditions and reduction of risk of duodenal ulcer recurrence have not been established in paediatric patients.

A safe and effective dosage has not been established in paediatric patients with renal impairment.

d. Geriatric Use

Of the 1442 famotidine-treated patients in clinical studies, approximately 10% were 65 and older. In

these studies, no overall differences in safety or effectiveness were observed between elderly and

younger patients. In post marketing experience, CNS adverse reactions have been reported in elderly

patients with and without renal impairment receiving famotidine [see Warnings and Precautions (4.4)].

Famotidine is known to be substantially excreted by the kidney, and the risk of adverse reactions to

famotidine for oral suspension may be greater in elderly patients, particularly those with impaired renal

function [see Use in Specific Populations (renal impairment)].

In general, use the lowest effective dose of famotidine for oral suspension for an elderly patient and

monitor renal function [see Posology and method of administration (4.2)].

e. Renal Impairment

CNS adverse reactions and prolonged QT intervals have been reported in patients with moderate

and severe renal impairment [see Warnings and Precautions (4.4)]. The clearance of famotidine

is reduced in adults with moderate and severe renal impairment compared to adults with normal

renal function [see Pharmacological properties (5.2)]. No dosage adjustment is needed in adults

with mild renal impairment (creatinine clearance greater than or equal to 60 mL/minute). Dosage

reduction is recommended in adults with moderate or severe renal impairment (creatinine clearance less than 60 mL/minute) [see Posology and method of administration (4.2)]. Data are not available

to establish a safe and effective dosage in paediatric patients with renal impairment.

To report any side effect(s):
Saudi Arabia

Other GCC states /other countries

The types of adverse reactions in overdosage of famotidine are similar to the adverse reactions

encountered with use of recommended dosages.

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.

Due to low binding to plasma proteins, famotidine is eliminated by haemodialysis. There is limited

experience on the usefulness of haemodialysis as a treatment for famotidine overdosage.

Pharmacotherapeutic group: Histamine H2 receptor antagonist, ATC code: A02B A03

Pharmacodynamics

Adults

Famotidine inhibited both basal and nocturnal gastric secretion, as well as secretion stimulated by food

and pentagastrin. After oral administration of famotidine, the onset of the antisecretory effect occurred

within one hour; the maximum effect was dose-dependent, occurring within one to three hours. Duration

of inhibition of secretion by doses of 20 mg and 40 mg was 10 to 12 hours.

Single evening oral doses of 20 mg and 40 mg inhibited basal and nocturnal acid secretion in all subjects; mean nocturnal gastric acid secretion was inhibited by 86% and 94%, respectively, for a period of at least 10 hours. The same doses given in the morning suppressed food-stimulated acid

secretion in all subjects. The mean suppression was 76% and 84%, respectively, 3 to 5 hours after

administration, and 25% and 30%, respectively, 8 to 10 hours after administration. In some subjects

who received the 20 mg dose, however, the antisecretory effect was dissipated within 6 to 8 hours.

There was no cumulative effect with repeated doses. The nocturnal intragastric pH was raised by

evening doses of 20 mg and 40 mg of famotidine to mean values of 5.0 and 6.4, respectively. When

famotidine was given after breakfast, the basal daytime interdigestive pH at 3 and 8 hours after 20 mg or

40 mg of famotidine was raised to about 5.

Famotidine had little or no effect on fasting or postprandial serum gastrin levels. Gastric emptying and

exocrine pancreatic function were not affected by famotidine.

In clinical pharmacology studies, systemic effects of famotidine in the CNS, cardiovascular, respiratory

or endocrine systems were not noted. Also, no anti-androgenic effects were noted.

Serum hormone levels, including prolactin, cortisol, thyroxine (T₄), and testosterone, were not altered

after treatment with famotidine.

Paediatric Patients

Pharmacodynamics of famotidine, assessed by gastric pH, were evaluated in 5 paediatric patients 2

years to 13 years of age using the sigmoid E_max model. These data suggest that the relationship between serum concentration of famotidine and gastric acid suppression is similar to that observed in adults (see Table 4).

Table 4: Serum Concentrations of Famotidine Associated with Gastric Acid Reduction in

Famotidine- Treated Paediatric and Adult Patients^a

a Using the Sigmoid E_max model, serum concentrations of famotidine associated with 50% maximum

gastric acid reduction are presented as means ± SD.

In a study examining the effect of famotidine on gastric pH and duration of acid suppression in paediatric patients, four paediatric patients ages 11 to 15 years of age using the oral formulation at a dose of 0.5 mg/kg, maintained a gastric pH above 5 for 13.5 ± 1.8 hours.

Mechanism of action

Famotidine is a competitive inhibitor of histamine-2 (H₂) receptors. The primary clinically important

pharmacologic activity of famotidine is inhibition of gastric secretion. Both the acid concentration and

volume of gastric secretion are suppressed by famotidine, while changes in pepsin secretion are

proportional to volume output.

Oral administration

Absorption

Famotidine is incompletely absorbed. The bioavailability of oral doses is 40 to 45%. Bioavailability

may be slightly increased by food, or slightly decreased by antacids; however, these effects are of no

clinical consequence.

Peak famotidine plasma levels occur in 1 to 3 hours. Plasma levels after multiple dosages are similar to

those after single doses.

Distribution

Fifteen to 20% of famotidine in plasma is protein bound.

Elimination

Metabolism

Famotidine undergoes minimal first-pass metabolism. Twenty-five to 30% of an oral dose was

recovered in the urine as unchanged compound. The only metabolite identified in humans is the

S-oxide.

Excretion

Famotidine has an elimination half-life of 2.5-3.5 hours. Famotidine is eliminated by renal (65 to

70%) and metabolic (30 to 35%) routes. Renal clearance is 250 to 450 mL/minute, indicating

some tubular excretion.

Specific Populations

Paediatric Patients

Infants from birth to 12 Months

After a single oral dose administration of 0.5 mg/kg orally in patients from birth to 12 months, the

bioavailability is approximately 42%.

The AUC increased 1.4-fold after single oral dose of 1 mg/kg compared to 0.5 mg/kg and 2.7-fold

after multiple oral doses of 1 mg/kg compared to 0.5 mg/kg.

Plasma clearance is reduced and elimination half-life is prolonged in paediatric patients from birth

to 3 months of age compared to older paediatric patients. Following intravenous administration of

0.5 mg/kg, CL_Total was 0.13 ±0.06 L/hr/kg, 0.21 ± 0.06 L/hr/kg, and 0.49 ± 0.17 L/hr/kg in paediatric patients <1 month of age, <3 months of age, and >3 to 12 months of age, respectively.

Elimination half-life was 10.5 hours, 8.1 hours, and 4.5 hours in paediatric patients <1 month of

age, <3 months of age, and >3 to 12 months of age, respectively.

Patients 11 Years to 15 Years

The mean bioavailability in 8 paediatric patients was 50% compared to adult values of 42% to 49%.

Pharmacokinetic parameters in paediatrics 11 years to 15 years is compared to infants from birth to 12

months in Table 5.

Table 5: Mean Pharmacokinetic Parameters Following a Single Oral Dose of 0.5 mg/kg in Infants and Paediatric Patients

a arithmetic mean ± S.D.

b median

c observed minimum and maximum values

d reported minimum and maximum values

Patients with Renal Impairment

In adult patients with severe renal impairment (creatinine clearance less than 30 mL/minute), the systemic exposure (AUC) of famotidine increased at least 5-fold. In adult patients with moderate renal impairment (creatinine clearance between 30 to 60 mL/minute), the AUC of famotidine increased at least 2-fold [see Posology and method of administration (4.2), Use in Specific Populations (renal impairment)].

Drug Interaction Studies

Human Organic Anion Transporter (OAT) 1 and 3: In vitro studies indicate that famotidine is a substrate for OAT1 and OAT3. Following coadministration of probenecid (1500 mg), an inhibitor of OAT1 and OAT3, with a single oral 20 mg dose of famotidine in 8 healthy subjects, the serum AUC_{0 10h} of famotidine increased from 424 to 768 ng∙hr/mL and the maximum serum concentration (C_max) increased from 73 to 113 ng/mL. Renal clearance, urinary excretion rate and amount of famotidine excreted unchanged in urine were decreased. The clinical relevance of this interaction is unknown.

Multidrug and Toxin Extrusion Protein 1 (MATE-1): An in vitro study showed that famotidine is an

inhibitor of MATE-1.

However, no clinically significant interaction with metformin, a substrate for MATE-1, was observed.

CYP1A2: Famotidine is a weak CYP1A2 inhibitor.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenic potential of famotidine was assessed in a 106-week oral carcinogenicity study in rats and a

92-week oral carcinogenicity study in mice. In the 106-week study in rats and the 92-week study in mice at oral doses of up to 2000 mg/kg/day (approximately 243 and 122 times, respectively, based on body

surface area, the recommended human dose of 80 mg per day for the treatment of erosive esophagitis),

there was no evidence of carcinogenic potential for famotidine.

Famotidine was negative in the microbial mutagen test (Ames test) using Salmonella typhimurium and

Escherichia coli with or without rat liver enzyme activation at concentrations up to 10,000 mcg/plate. In in vivo studies in mice, with a micronucleus test and a chromosomal aberration test, no evidence of a mutagenic effect was observed.

In studies with rats given oral doses of up to 2000 mg/kg/day (approximately 243 times, based on body

surface area, the recommended human dose of 80 mg per day) fertility and reproductive performance were not affected.

Confectioners sugar

Microcrystalline Cellulose/Carboxy methyl Cellulose sodium

Xanthan gum

Sodium benzoate

Methyl Paraben sodium

Citric acid anhydrous

Purified water

Mint flavour

Cherry flavour

Not applicable

Store famotidine dry powder and constituted suspension at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F)

Protect from freezing. Discard unused constituted suspension after 30 days.

Dispense in a USP tight, light-resistant container.

Keep out of reach and sight of children.

Famotidine For Oral Suspension USP, 40 mg/5 mL is a white to off white powder containing 400 mg of Famotidine per 50 mL provided in HDPE bottle for constitution. When constituted as directed, Famotidine for Oral Suspension is a smooth, mobile, off-white homogenous suspension with a flavour containing 40mg of Famotidine per 5 mL.

Pack size: Bottle with the leaflet fixed to the bottle cap..

No special requirements.