- Aseptically dilute the required dose of Famotidine Injection in 100 mL of one of the following solutions:
- 5% Dextrose for Injection
- 0.9% Sodium Chloride Injection
- 10% Dextrose for Injection
- Lactated Ringer's Injection
- Gently invert the bag 4 to 5 times. Avoid shaking.
- Before administration, inspect the bag for particulate matter and discoloration. Discard the bag if particulate and/or discoloration are observed.
Storage of Diluted Product:
Use the diluted product immediately. Alternatively, refrigerate between 2° and 8°C (36° and 46°F) and use within 48 hours.
Risk Summary
Available data with H2-receptor antagonists, including famotidine, in pregnant women over decades of use have not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Reproductive studies have been performed in rats and rabbits at intravenous doses of up to 200 mg/kg/day, with no obvious adverse developmental effects (see Data). Famotidine Injection contains benzyl alcohol as a preservative [see How Supplied/Storage and Handling (16)]. Because benzyl alcohol is rapidly metabolized by a pregnant female, benzyl alcohol exposure in the fetus is unlikely.
The 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 2,000 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.
Risk Summary
There are limited data available on the presence of famotidine in human breast milk following oral administration. There were no effects on the breastfed infant. There are no data on famotidine effects on milk production. Famotidine Injection contains benzyl alcohol as a preservative. Because benzyl alcohol is rapidly metabolized by a lactating female, benzyl alcohol exposure in the breastfed neonate is unlikely.
The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Famotidine Injection and any potential adverse effects on the breastfed child from famotidine or from the underlying maternal condition.
Peptic Ulcer Disease
The safety and effectiveness of Famotidine Injection have been established in pediatric patients 1 year to less than 17 years of age for the treatment of peptic ulcer disease in hospitalized patients or as an alternative to oral famotidine. Use of Famotidine Injection in this age group is supported by evidence from adequate and well-controlled studies of oral famotidine in adults with additional pharmacokinetic and pharmacodynamic data in pediatric patients 1 year to less than 17 years of age [see Dosage and Administration (2.2) and Clinical Pharmacology (12.2, 12.3)].
A safe and effective dosage has not been established in pediatric patients 1 year to less than 17 years of age with renal impairment for the treatment of peptic ulcer disease.
The safety and effectiveness of Famotidine Injection for the treatment of peptic ulcer disease in pediatric patients less than 1 year of age have not been established.
Other Conditions
The safety and effectiveness of Famotidine Injection for the treatment of symptomatic nonerosive GERD, erosive esophagitis due to GERD, pathological hypersecretory conditions and reduction of the risk of DU recurrence have not been established in pediatric patients.
Risk of Benzyl Alcohol Toxicity in Neonates
Famotidine Injection is not approved for use in neonates. Serious adverse reactions, including fatal reactions, of new onset or worsening metabolic acidosis that progressed to neurotoxicity, and in some cases gasping syndrome, have been reported in low-birth weight neonates and preterm neonates who received benzyl alcohol (BA)-containing drugs intravenously. Gasping syndrome is a life-threatening condition in neonates caused by BA toxicity that is characterized by new onset or worsening metabolic acidosis with gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and kidney failure, hypotension, bradycardia, and gasping respirations followed by death. In reported cases, BA in amounts of 99 to 234 mg/kg/day produced blood BA levels of 6.6 to 14.9 mg/dL, but the minimum amount of BA at which gasping syndrome may occur in neonates is not known (Famotidine Injection contains 3.6 mg of BA per mL) [see Warnings and Precautions (5.3)].
Adults
Famotidine inhibited basal and nocturnal gastric secretion, as well as secretion stimulated by food and pentagastrin. After intravenous administration, the maximum effect was achieved within 30 minutes. Single intravenous doses of 20 mg inhibited nocturnal secretion for a period of 10 to 12 hours.
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 central nervous system (CNS), cardiovascular, respiratory or endocrine systems were not noted. Also, no antiandrogenic effects were noted. Serum hormone levels, including prolactin, cortisol, thyroxine (T4), and testosterone, were not altered after treatment with famotidine.
Pediatric Patients
Pharmacodynamics of famotidine were evaluated in five pediatric patients 2 to 13 years of age using the sigmoid Emax model. These data suggest that the relationship between serum concentration of famotidine and gastric acid suppression is similar to that observed in one study of adults (Table 4).
Table 4: Pharmacodynamics of Famotidine Using the Sigmoid Emax Model
|
| EC50(ng/mL) a |
| Pediatric Patients
| 26 ± 13
|
| Data from one study
| |
| a) Healthy adult subjects
| 26.5 ± 10.3
|
| b) Adult patients with upper GI bleeding
| 18.7 ± 10.8
|
Five published studies (Table 5) examined the effect of famotidine on gastric pH and duration of acid suppression in pediatric patients. While each study had a different design, acid suppression data over time are summarized as follows:
Table 5: Effect of Intravenous Famotidine on Gastric pH and Duration of Acid Suppression in Pediatric Patients 1 to 15 Years of Age
|
|
|
| Dosage Regimen | Number of Patients | Effect on Gastric Acida | Patient Age Range |
| 0.3 mg/kg, single-dose
| 6
| gastric pH >3.5 for 8.7 ± 4.7b hours
| 2 to 7 years
|
| 0.5 mg/kg, single-dose
| 9
| a >2 pH unit increase above baseline ingastric pH for >8 hours
| 2 to 13 years
|
| 0.5 mg/kg twice daily
| 4
| gastric pH >5 for 13.5 ± 1.8b hours
| 6 to 15 years
|
Distribution
Fifteen to 20% of famotidine in plasma is protein bound.
Elimination
Metabolism
Famotidine undergoes minimal first-pass metabolism. Sixty-five to 70% of an intravenous dose are 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 to 3.5 hours. Famotidine is eliminated by renal (65 to 70%) and metabolic (30 to 35%) routes. Renal clearance is 250 to 450 mL/minutes, indicating some tubular excretion.
Specific Populations
Pediatric Patients
Table 6 presents pharmacokinetic data for famotidine administered intravenously. Areas under the curve (AUCs) are normalized to a 0.5 mg/kg intravenous dose for pediatric patients 1 to 15 years of age and compared with an extrapolated 40 mg intravenous dose in adults. Extrapolation is based on results obtained with a 20 mg intravenous adult dose). The pharmacokinetic parameters for pediatric patients, aged 1 year to 15 years, are comparable to those obtained for adults.
Table 6: Pharmacokinetic Parametersa of Intravenous Famotidine In Pediatric Patients 1 Year to 15 Years of Age and Adults
|
|
|
|
Age
(N=number of patients) | Area Under the
Curve (AUC)
(ng-hr/mL) | Total Clearance
(Cl)
(L/hr/kg) | Volume of
Distribution (Vd)
(L/kg) | Elimination
Half-Life
(T1/2)
(hours) |
| 1 to 11 years (N=20)
| 1089 ± 834
| 0.54 ± 0.34
| 2.07 ± 1.49
| 3.38 ± 2.6
|
| 11 to 15 years (N=6)
| 1140 ± 320
| 0.48 ± 0.14
| 1.5 ± 0.4
| 2.3 ± 0.4
|
Adults
(N=16)
| 1726b | 0.39 ± 0.14
| 1.3 ± 0.2
| 2.83 ± 0.99
|
Geriatric Patients
In elderly patients, there are no clinically significant age-related changes in the pharmacokinetics of famotidine. However, in elderly patients with decreased renal function, the clearance of the drug may be decreased [see Use in Specific Populations (8.5)].
Patients with Renal Impairment
In adult patients with severe renal impairment (creatinine clearance less than 30 mL/min), 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 Dosage and Administration (2.3) and Use in Specific Populations (8.6)].
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 eight healthy subjects, the serum AUC0-10h of famotidine increased from 424 to 768 ng•hr/mL and the maximum serum concentration (Cmax) 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 [see Drug Interaction (7.2)]
Central Nervous System (CNS) Adverse Reactions
Advise elderly patients and those with moderate and severe renal impairment of the risk of CNS adverse reactions, including confusion, delirium, hallucinations, disorientation, agitation, seizures, and lethargy [see Warnings and Precautions (5.1)]. Report symptoms immediately to a healthcare provider.
QT Interval Prolongation
Advise patients with moderate and severe renal impairment of the risk of QT interval prolongation [see Use in Specific Populations (8.6)]. Report new cardiac symptoms, such as palpitations, fainting and dizziness or lightheadedness, immediately to a healthcare provider.
Risk of Benzyl Alcohol Toxicity in Neonates
Inform caregivers that serious adverse reactions, including fatal reactions, have been reported in neonates who received drugs containing benzyl alcohol intravenously. Inform the healthcare provider if neurologic, hematologic or cardiac adverse reactions occur [see Warnings and Precautions (5.3)].
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