famotidine 20 MG in 2 ML Injection
Generic Name: FAMOTIDINE
Brand Name: Famotidine
- Substance Name(s):
- FAMOTIDINE
DRUG INTERACTIONS
Drug Interactions No drug interactions have been identified.
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 include warfarin, theophylline, phenytoin, diazepam, aminopyrine and antipyrine.
Indocyanine green as an index of hepatic drug extraction has been tested and no significant effects have been found.
OVERDOSAGE
The adverse reactions in overdose cases are similar to the adverse reactions encountered in normal clinical experience (see ADVERSE REACTIONS ).
Oral doses of up to 640 mg/day have been given to adult 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 intravenous LD50 of famotidine for mice and rats ranged from 254 to 563 mg/kg and the minimum lethal single I.V.
dose in dogs was approximately 300 mg/kg.
Signs of acute intoxication in I.V.
treated dogs were emesis, restlessness, pallor of mucous membranes or redness of mouth and ears, hypotension, tachycardia and collapse.
The oral LD50 of famotidine in male and female rats and mice was greater than 3000 mg/kg and the minimum lethal acute oral dose in dogs exceeded 2000 mg/kg.
Famotidine did not produce overt effects at high oral doses in mice, rats, cats, and dogs, but induced significant anorexia and growth depression in rabbits starting with 200 mg/kg/day orally.
DESCRIPTION
The active ingredient in famotidine injection, USP is a histamine H2-receptor antagonist.
Famotidine is N’-(aminosulfonyl)-3-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]propanimidamide.
The empirical formula of famotidine is C8H15N7O2S3 and its molecular weight is 337.43.
Its structural formula is: 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.
Famotidine injection, USP is supplied as a sterile concentrated solution for intravenous injection.
Each mL of the solution contains 10 mg of famotidine and the following inactive ingredients: L-aspartic acid 4 mg, mannitol 20 mg, and Water for Injection q.s.
1 mL.
The multidose injection also contains benzyl alcohol 0.9% added as preservative.
Chemical Structure
CLINICAL STUDIES
Clinical Studies The majority of clinical study experience involved oral administration of famotidine tablets, and is provided herein for reference.
Duodenal Ulcer In a U.S.
multicenter, double-blind study in outpatients with endoscopically confirmed duodenal ulcer, orally administered famotidine was compared to placebo.
As shown in Table 1 , 70% of patients treated with famotidine 40 mg h.s.
were healed by week 4.
Table 1: Outpatients with Endoscopically Confirmed Healed Duodenal Ulcers Famotidine 40 mg h.s.
(N=89) Famotidine 20 mg b.i.d.
(N=84) Placebo h.s.
(N=97) Week 2 Statistically significantly different than placebo (p<0.001)32% 38% 17% Week 4 70% 67% 31% Patients not healed by week 4 were continued in the study.
By week 8, 83% of patients treated with famotidine had healed versus 45% of patients treated with placebo.
The incidence of ulcer healing with famotidine was significantly higher than with placebo at each time point based on proportion of endoscopically confirmed healed ulcers.
In this study, time to relief of daytime and nocturnal pain was significantly shorter for patients receiving famotidine than for patients receiving placebo; patients receiving famotidine also took less antacid than the patients receiving placebo.
Long-Term Maintenance Treatment of Duodenal Ulcers Famotidine, 20 mg p.o.
h.s.
was compared to placebo h.s.
as maintenance therapy in two double-blind, multicenter studies of patients with endoscopically confirmed healed duodenal ulcers.
In the U.S.
study the observed ulcer incidence within 12 months in patients treated with placebo was 2.4 times greater than in the patients treated with famotidine.
The 89 patients treated with famotidine had a cumulative observed ulcer incidence of 23.4% compared to an observed ulcer incidence of 56.6% in the 89 patients receiving placebo (p<0.01).
These results were confirmed in an international study where the cumulative observed ulcer incidence within 12 months in the 307 patients treated with famotidine was 35.7%, compared to an incidence of 75.5% in the 325 patients treated with placebo (p<0.01).
Gastric Ulcer In both a U.S.
and an international multicenter, double-blind study in patients with endoscopically confirmed active benign gastric ulcer, orally administered famotidine, 40 mg h.s., was compared to placebo h.s.
Antacids were permitted during the studies, but consumption was not significantly different between the famotidine and placebo groups.
As shown in Table 2 , the incidence of ulcer healing (dropouts counted as unhealed) with famotidine was statistically significantly better than placebo at weeks 6 and 8 in the U.S.
study, and at weeks 4, 6 and 8 in the international study, based on the number of ulcers that healed, confirmed by endoscopy.
Table 2: Patients with Endoscopically Confirmed Healed Gastric Ulcers U.S.
Study International Study Famotidine 40 mg h.s.
(N=74) Placebo h.s.
(N=75) Famotidine 40 mg h.s.
(N=149) Placebo h.s.
(N=145) Week 4 45% 39% Statistically significantly better than placebo (p≤0.01)47% 31% Week 6 66% 44% 65% 46% Week 8 Statistically significantly better than placebo (p≤0.05)78% 64% 80% 54% Time to complete relief of daytime and nighttime pain was statistically significantly shorter for patients receiving famotidine than for patients receiving placebo; however, in neither study was there a statistically significant difference in the proportion of patients whose pain was relieved by the end of the study (week 8).
Gastroesophageal Reflux Disease (GERD) Orally administered famotidine was compared to placebo in a U.S.
study that enrolled patients with symptoms of GERD and without endoscopic evidence of erosion or ulceration of the esophagus.
Famotidine 20 mg b.i.d.
was statistically significantly superior to 40 mg h.s.
and to placebo in providing a successful symptomatic outcome, defined as moderate or excellent improvement of symptoms ( Table 3 ).
Table 3: % Successful Symptomatic Outcome Famotidine 20 mg b.i.d.
(N=154) Famotidine 40 mg h.s.
(N=149) Placebo (N=73) Week 6 82p≤0.01 vs Placebo 69 62 By two weeks of treatment, symptomatic success was observed in a greater percentage of patients taking famotidine 20 mg b.i.d.
compared to placebo (p≤0.01).
Symptomatic improvement and healing of endoscopically verified erosion and ulceration were studied in two additional trials.
Healing was defined as complete resolution of all erosions or ulcerations visible with endoscopy.
The U.S.
study comparing famotidine 40 mg p.o.
b.i.d.
to placebo and famotidine 20 mg p.o.
b.i.d., showed a significantly greater percentage of healing for famotidine 40 mg b.i.d.
at weeks 6 and 12 ( Table 4 ).
Table 4: % Endoscopic Healing – U.S.
Study Famotidine 40 mg b.i.d.
(N=127) Famotidine 20 mg b.i.d.
(N=125) Placebo (N=66) Week 6 48p≤0.01 vs Placebo , p≤0.01 vs Famotidine 20 mg b.i.d.
32 18 Week 12 69 , p≤0.05 vs Famotidine 20 mg b.i.d.
54 29 As compared to placebo, patients who received famotidine had faster relief of daytime and nighttime heartburn and a greater percentage of patients experienced complete relief of nighttime heartburn.
These differences were statistically significant.
In the international study, when famotidine 40 mg p.o.
b.i.d.
was compared to ranitidine 150 mg p.o.
b.i.d., a statistically significantly greater percentage of healing was observed with famotidine 40 mg b.i.d.
at week 12 ( Table 5 ).
There was, however, no significant difference among treatments in symptom relief.
Table 5: % Endoscopic Healing – International Study Famotidine 40 mg b.i.d.
(N=175) Famotidine 20 mg b.i.d.
(N=93) Ranitidine 150 mg b.i.d.
(N=172) Week 6 48 52 42 Week 12 71p≤0.05 vs Ranitidine 150 mg b.i.d.
68 60 Pathological Hypersecretory Conditions (e.g., Zollinger-Ellison Syndrome, Multiple Endocrine Adenomas) In studies of patients with pathological hypersecretory conditions such as Zollinger-Ellison Syndrome with or without multiple endocrine adenomas, famotidine significantly inhibited gastric acid secretion and controlled associated symptoms.
Orally administered doses from 20 to 160 mg q 6 h maintained basal acid secretion below 10 mEq/hr; initial doses were titrated to the individual patient need and subsequent adjustments were necessary with time in some patients.
Famotidine was well tolerated at these high dose levels for prolonged periods (greater than 12 months) in eight patients, and there were no cases reported of gynecomastia, increased prolactin levels, or impotence which were considered to be due to the drug.
HOW SUPPLIED
FOR INTRAVENOUS USE ONLY Famotidine injection, USP 10 mg per 1 mL, is a non-preserved, clear, colorless solution and is supplied as follows: NDC 0069-0121-02, 25 × 2 mL single-dose vials Famotidine injection, USP 10 mg per 1 mL, is a clear, colorless solution and is supplied as follows: NDC 0069-0125-02, 10 × 4 mL multi-dose vials NDC 0069-0126-02, 10 × 20 mL multi-dose vials Storage Store famotidine injection, USP at 2° to 8°C (36° to 46°F).
If solution freezes, bring to room temperature; allow sufficient time to solubilize all the components.
Protect from light.
Retain in carton until time of use.
Although diluted famotidine injection, USP has been shown to be physically and chemically stable for 7 days at room temperature, there are no data on the maintenance of sterility after dilution.
Therefore, it is recommended that if not used immediately after preparation, diluted solutions of famotidine injection, USP should be refrigerated and used within 48 hours (see DOSAGE AND ADMINISTRATION ).
GERIATRIC USE
Geriatric Use Of the 4,966 subjects in clinical studies who were treated with famotidine, 488 subjects (9.8%) were 65 and older, and 88 subjects (1.7%) were greater than 75 years of age.
No overall differences in safety or effectiveness were observed between these subjects and younger subjects.
However, greater sensitivity of some older patients cannot be ruled out.
No dosage adjustment is required based on age (see CLINICAL PHARMACOLOGY IN ADULTS, 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 adjustment 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 ).
INDICATIONS AND USAGE
Famotidine injection, USP supplied as a concentrated solution for intravenous injection, is intended for intravenous use only.
Famotidine injection, USP is indicated in some hospitalized patients with pathological hypersecretory conditions or intractable ulcers, or as an alternative to the oral dosage forms for short term use in patients who are unable to take oral medication for the following conditions: Short term treatment of active duodenal ulcer.
Most adult patients heal within 4 weeks; there is rarely reason to use famotidine at full dosage for longer than 6 to 8 weeks.
Studies have not assessed the safety of famotidine in uncomplicated active duodenal ulcer for periods of more than eight weeks.
Maintenance therapy for duodenal ulcer patients at reduced dosage after healing of an active ulcer.
Controlled studies in adults have not extended beyond one year.
Short term treatment of active benign gastric ulcer.
Most adult patients heal within 6 weeks.
Studies have not assessed the safety or efficacy of famotidine in uncomplicated active benign gastric ulcer for periods of more than 8 weeks.
Short term treatment of gastroesophageal reflux disease (GERD).
Famotidine is indicated for short term treatment of patients with symptoms of GERD (see CLINICAL PHARMACOLOGY IN ADULTS, Clinical Studies ).
Famotidine is also indicated for the short term treatment of esophagitis due to GERD including erosive or ulcerative disease diagnosed by endoscopy (see CLINICAL PHARMACOLOGY IN ADULTS, Clinical Studies ).
5.
Treatment of pathological hypersecretory conditions (e.g., Zollinger-Ellison Syndrome, multiple endocrine adenomas) (see CLINICAL PHARMACOLOGY IN ADULTS, Clinical Studies ).
PEDIATRIC USE
Pediatric Patients <1 year of age Use of famotidine in pediatric patients <1 year of age is supported by evidence from adequate and well-controlled studies of famotidine in adults, and by the following studies in pediatric patients <1 year of age.
Two pharmacokinetic studies in pediatric patients 3 months to 1 year of age is similar to that seen in older pediatric patients (1 to 15 years of age) and adults.
In contrast, pediatric patients 0 to 3 months of age had famotidine clearance values that were 2- to 4-fold less than those in older pediatric patients and adults.
These studies also show that the mean bioavailability in pediatric patients <1 year of age after oral dosing is similar to older pediatric patients and adults.
Pharmacodynamic data in pediatric patients 0 to 3 months of age suggest that the duration of acid suppression is longer compared with older pediatric patients, consistent with the longer famotidine half-life in pediatric patients 0 to 3 months of age.
(See CLINICAL PHARMACOLOGY IN PEDIATRIC PATIENTS, Pharmacokinetics and Pharmacodynamics ).
In a double-blind, randomized, treatment-withdrawal study, 35 pediatric patients <1 year of age who were diagnosed as having gastroesophageal reflux disease were treated for up to 4 weeks with famotidine oral suspension (0.5 mg/kg/dose or 1 mg/kg/dose).
Although an intravenous famotidine formulation was available, no patients were treated with intravenous famotidine in this study.
Also, caregivers were instructed to provide conservative treatment including thickened feedings.
Enrolled patients were diagnosed primarily by history of vomiting (spitting up) and irritability (fussiness).
The famotidine dosing regimen was once daily for patients <3 months of age and twice daily for patients ≥3 months of age.
After 4 weeks of treatment, patients were randomly withdrawn from the treatment and followed an additional 4 weeks for adverse events and symptomatology.
Patients were evaluated for vomiting (spitting up), irritability (fussiness) and global assessments of improvement.
The study patients ranged in age at entry from 1.3 to 10.5 months (mean 5.6 ± 2.9 months), 57% were female, 91% were white and 6% were black.
Most patients (27/35) continued into the treatment withdrawal phase of the study.
Two patients discontinued famotidine due to adverse events.
Most patients improved during the initial treatment phase of the study.
Results of the treatment withdrawal phase were difficult to interpret because of small numbers of patients.
Of the 35 patients enrolled in the study, agitation was observed in 5 patients on famotidine that resolved when the medication was discontinued; agitation was not observed in patients on placebo (see ADVERSE REACTIONS, Pediatric Patients ).
These studies suggest that a starting dose of 0.5 mg/kg/dose of famotidine oral suspension may be of benefit for the treatment of GERD for up to 4 weeks once daily in patients <3 months of age and twice daily in patients 3 months to <1 year of age; the safety and benefit of famotidine treatment beyond 4 weeks have not been established.
Famotidine should be considered for the treatment of GERD only if conservative measures (e.g., thickened feedings) are used concurrently and if the potential benefit outweighs the risk.
PREGNANCY
Pregnancy Pregnancy Category B 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 I.V.
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 (250 times the usual human dose) 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.
NUSRING MOTHERS
Nursing Mothers Studies performed in lactating rats have shown that famotidine is secreted into breast milk.
Transient growth depression was observed in young rats suckling from mothers treated with maternotoxic doses of at least 600 times the usual human dose.
Famotidine is detectable in human milk.
Because of the potential for serious adverse reactions in nursing infants from famotidine, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
DOSAGE AND ADMINISTRATION
In some hospitalized patients with pathological hypersecretory conditions or intractable ulcers, or in patients who are unable to take oral medication, famotidine injection, USP may be administered until oral therapy can be instituted.
The recommended dosage for famotidine injection, USP in adult patients is 20 mg intravenously q 12 h.
The doses and regimen for parenteral administration in patients with GERD have not been established.
Dosage for Pediatric Patients <1 year of age Gastroesophageal Reflux Disease (GERD) See PRECAUTIONS, Pediatric Patients <1 year of age .
The studies described in PRECAUTIONS, Pediatric Patients <1 year of age suggest the following starting doses in pediatric patients <1 year of age: Gastroesophageal Reflux Disease (GERD) – 0.5 mg/kg/dose of famotidine oral suspension for the treatment of GERD for up to 8 weeks once daily in patients <3 months of age and 0.5 mg/kg/dose twice daily in patients 3 months to <1 year of age.
Patients should also be receiving conservative measures (e.g., thickened feedings).
The use of intravenous famotidine in pediatric patients <1 year of age with GERD has not been adequately studied.
Dosage for Pediatric Patients 1–16 years of age See PRECAUTIONS, Pediatric Patients 1 to 16 years of age .
The studies described in PRECAUTIONS, Pediatric Patients 1 to 16 years of age suggest that the starting dose in pediatric patients 1 to 16 years of age is 0.25 mg/kg intravenously (injected over a period of not less than two minutes or as a 15-minute infusion) q 12 h up to 40 mg/day.
While published uncontrolled clinical studies suggest effectiveness of famotidine in the treatment of peptic ulcer, data in pediatric patients are insufficient to establish percent response with dose and duration of therapy.
Therefore, treatment duration (initially based on adult duration recommendations) and dose should be individualized based on clinical response and/or gastric pH determination and endoscopy.
Published uncontrolled studies in pediatric patients 1 to 16 years of age have demonstrated gastric acid suppression with doses up to 0.5 mg/kg intravenously q 12 h.
Dosage Adjustments for Patients with Moderate or Severe Renal Insufficiency In adult patients with moderate (creatinine clearance <50 mL/min) or severe (creatinine clearance <10 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 effects have been reported in patients with moderate and severe renal insufficiency, to avoid excess accumulation of the drug in patients with moderate or severe renal insufficiency, the dose of famotidine injection, USP may be reduced to half the dose, or the dosing interval may be prolonged to 36 to 48 hours as indicated by the patient’s clinical response.
Based on the comparison of pharmacokinetic parameters for famotidine in adults and pediatric patients, dosage adjustment in pediatric patients with moderate or severe renal insufficiency should be considered.
Pathological Hypersecretory Conditions (e.g., Zollinger-Ellison Syndrome, Multiple Endocrine Adenomas) The dosage of famotidine in patients with pathological hypersecretory conditions varies with the individual patient.
The recommended adult intravenous dose is 20 mg q 12 h.
Doses should be adjusted to individual patient needs and should continue as long as clinically indicated.
In some patients, a higher starting dose may be required.
Oral doses up to 160 mg q 6 h have been administered to some adult patients with severe Zollinger-Ellison Syndrome.
To prepare famotidine intravenous solutions, aseptically dilute 2 mL of famotidine injection, USP (solution containing 10 mg/mL) with 0.9% Sodium Chloride Injection or other compatible intravenous solution (see Stability, Famotidine Injection, USP ) to a total volume of either 5 mL or 10 mL and inject over a period of not less than 2 minutes.
To prepare famotidine intravenous infusion solutions, aseptically dilute 2 mL of famotidine injection, USP with 100 mL of 5% dextrose or other compatible solution (see Stability, Famotidine Injection, USP ), and infuse over a 15 to 30 minute period.
Concomitant Use of Antacids Antacids may be given concomitantly if needed.
Stability Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.
Famotidine Injection, USP When added to or diluted with most commonly used intravenous solutions, e.g., Water for Injection, 0.9% Sodium Chloride Injection, 5% and 10% Dextrose Injection, or Lactated Ringer’s Injection, diluted famotidine injection, USP is physically and chemically stable (i.e., maintains at least 90% of initial potency) for 7 days at room temperature—see HOW SUPPLIED, Storage .
When added to or diluted with Sodium Bicarbonate Injection, 5%, famotidine injection, USP at a concentration of 0.2 mg/mL (the recommended concentration of famotidine intravenous infusion solutions) is physically and chemically stable (i.e., maintains at least 90% of initial potency) for 7 days at room temperature—see HOW SUPPLIED, Storage .
However, a precipitate may form at higher concentrations of famotidine injection, USP (>0.2 mg/mL) in Sodium Bicarbonate Injection, 5%.