Similar to other H2-antagonists, famotidine causes infrequent adverse reactions. In controlled clinical trials, the incidence of adverse reactions in patients who received famotidine 40 mg at bedtime was similar to that in the placebo group. The following reactions have occurred in greater than 1% of patients and may be causally related to the drug: headache (4.7%), dizziness (1.3%), constipation (1.2%), and diarrhea (1.7%). Other gastrointestinal adverse events reported in clinical trials or post approval include: cholestasis with jaundice, hepatitis, hepatic enzyme abnormalities, vomiting, nausea, abdominal discomfort, anorexia, dysgeusia (reported as taste disorder), and xerostomia. The relationship between these events and famotidine therapy has been unclear in many cases.[44392]

Reversible mental status changes, including agitation, confusion, delirium, hallucinations, hostility, paranoia, depression, insomnia, and disorientation have been reported rarely following famotidine therapy. Anxiety, libido decrease, paresthesias, and drowsiness have also been reported.[44392] A review of central nervous system reactions to H2-antagonists revealed that the incidence varies widely depending on the specific report, and that no single H2-antagonist is more likely to induce CNS reactions than another.[23494] Central nervous system reactions are more likely to occur in elderly patients and/or those with renal impairment. Seizures have been rarely reported in patients with renal impairment. Additionally, in a clinical study of famotidine in 35 infants < 1 year of age with GERD symptoms, agitation was reported in 5 patients that resolved when famotidine was discontinued.[44392]

Few cases of toxic epidermal necrolysis and Stevens-Johnson syndrome have been reported with famotidine therapy. Anaphylactoid reactions have also been reported. Additional hypersensitivity and dermatological reactions reported for famotidine in clinical trials or post approval include: orbital or facial edema, angioedema, urticaria, rash (unspecified), conjunctivitis, alopecia, acne vulgaris, pruritus, xerosis, and flushing. The relationship between these events and famotidine therapy has been unclear in many cases.[44392]

Increasing evidence suggests a link between acid-suppression therapy and respiratory infection, specifically pneumonia (community- and hospital-acquired). Several mechanisms have been proposed to account for this association. One such mechanism states that gastric pH serves as a barrier against pathogenic colonization of the gastrointestinal tract. An increase in gastric pH allows for bacterial and viral invasion which, in theory, can precipitate respiratory infections.[32661] Another proposed mechanism accounts for the role that gastric acid may have on stimulating the cough reflex that allows for the clearing of infectious agents from the respiratory tract. Finally, the fact that acid-suppressive therapy may impair white blood cell function, which in turn may lead to a depressed immune response to an infection, is listed among possible mechanisms.[35601] Regardless of the mechanism, the use of H₂-blockers [32661] and/or PPIs [35601] has been associated with the development of pneumonia. Data from a large epidemiological trial, including 364,683 individuals who developed 5551 first occurrences of community-acquired pneumonia (CAP), suggest an increased risk of developing CAP among users of acid-suppressive therapy compared to those who stopped therapy. After adjusting for confounders, the adjusted relative risk (RR) for CAP among PPI users compared to those who stopped therapy was 1.89 (95% CI, 1.36—2.62). Likewise, users of H₂-blockers had an adjusted RR of 1.63 (95% CI, 1.07—2.48) compared to those who stopped therapy.[32661] In a second large cohort trial, including 63,878 hospital admissions, acid-suppressive therapy was ordered in 52% (83% PPI and 23% H₂- blocker, with some patients exposed to both) of new admissions. Hospital-acquired pneumonia occurred in 2,219 admissions (3.5%) with a higher incidence recorded among acid-suppressive therapy exposed patients compared to non-exposed patients. A subset analysis found a statistically significant association between PPI use (OR, 1.3; 95% CI, 1.1—1.4) and pneumonia. A non-significant association was found with H₂-blockers (OR, 1.2; 95% CI, 0.98—1.4); however, the lack of significance was attributed to the studies lack of power to detect significance for an OR of less than 1.3.[35601] Until more is known about the relationship between acid-suppression and pneumonia, clinicians are encouraged to carefully select patients before empirically initiating acid-suppressive therapy with H₂-blockers or PPIs. A causal relationship between the use of famotidine and pneumonia has not been established.

Atrophic gastritis, a precursor for gastric cancer, has been associated with prolonged acid suppression with high dose H2-blockers like famotidine in patients who are H. pylori positive. A 'test and treat' approach for baseline H. pylori infections is recommended for patients with reflux esophagitis on long term acid suppression therapy. Treatment of baseline infection decreases inflammation and may reverse corpus gastritis.[33113]

Cardiovascular adverse events reported for famotidine in clinical trials or post approval include: arrhythmia exacerbation, AV block, and palpitations. The relationship between these events and famotidine therapy has been unclear in many cases. In addition, QT prolongation has been reported in patients with impaired renal function whose dose/dosing interval of famotidine may not have been adjusted appropriately.[44392]

Hematological adverse events have been reported for famotidine in clinical trials or post approval and include few cases of agranulocytosis, pancytopenia, leukopenia, and thrombocytopenia. The relationship between these events and famotidine therapy has been unclear in many cases.[44392]

Miscellaneous adverse events reported for famotidine in clinical trials or post-marketing include: fever, asthenia, fatigue, lethargy, rhabdomyolysis, musculoskeletal pain including muscle cramps, arthralgia, bronchospasm, interstitial pneumonia, and tinnitus. In addition, few cases of impotence (erectile dysfunction) and gynecomastia have been reported; however, in controlled clinical trials, the incidences were not greater than those seen with placebo. The relationship between these events and famotidine therapy has been unclear in many cases.[44392]

Long-term (e.g., generally > 3 years) treatment with acid-suppressing agents can lead to malabsorption of vitamin B12 (cyanocobalamin). One large case-controlled study compared patients with and without an incident diagnosis of vitamin B12 deficiency (n = 25,956 and 184,199, respectively). A correlation was demonstrated between vitamin B12 deficiency and gastric acid-suppression therapy. Patients receiving >= 2 years of a proton pump inhibitor (PPI)(OR, 1.65 [95% CI, 1.58—1.73]) or >= 2 years of a H₂-receptor antagonist (OR, 1.25 [95% CI, 1.17—1.34]) were associated with having an increased risk for vitamin B12 deficiency. A dose-dependant relationship was evident, as daily doses > 1.5 PPI pills/day were more strongly associated with vitamin B12 deficiency (OR, 1.95 [95% CI, 1.77—2.15]) compared to daily doses < 0.75 pills/day (OR, 1.63 [95% CI, 1.48—1.78]; p = 0.007 for interaction).[56553] The possibility of cyanocobalamin deficiency and pernicious anemia should be considered if clinical symptoms are observed. Neurological manifestations of pernicious anemia can occur in the absence of hematologic changes.

Famotidine is contraindicated in any patient hypersensitive to the drug or with other H2-blocker hypersensitivity.[50742]

Symptomatic response to therapy with famotidine does not preclude the presence of gastric cancer. Patients who have a suboptimal response or early symptomatic relapse after completing therapy should consider evaluation for gastric malignancy.[50742] In the patient who is self-medicating with nonprescription (OTC) formulations, the continuation of heartburn, acid indigestion, or dyspepsia beyond 2 weeks signals the need to consult a health care professional for evaluation.[44392] [51488]

Symptomatic response to therapy with famotidine does not preclude the presence of H. pylori infection. H2-blockers, as single agents, will not eradicate H. pylori infection, if present.[63136]

Famotidine should be used cautiously in patients with renal impairment or renal failure as there is a close relationship between the drug's elimination half-life and creatinine clearance. Dosages of famotidine should be adjusted in patients with moderate or severe renal impairment. Central nervous system (CNS) adverse reactions, including confusion, delirium, hallucinations, disorientation, agitation, seizures, and lethargy, have been reported in older adults and patients with moderate and severe renal impairment treated with famotidine; in some cases, the dosages were not adjusted as recommended for renal impairment.[50742]

Animal studies and epidemiologic data during pregnancy suggest famotidine use when necessary is not harmful, even though there are no adequate and well-controlled studies evaluating famotidine use in pregnant patients.[20917] [50742] [51456] [51477] In one such study of human data, exposure to H2-blockers, including famotidine, was not associated with an increased risk for congenital malformations (adjusted OR 1.03, 95% CI: 0.80, 1.32); also, no such association was found when therapeutic pregnancy terminations were included in the analysis (adjusted OR 1.17, 95% CI: 0.93, 1.46). Exposure to H2-blockers was not associated with perinatal mortality, premature delivery, low birth weight, or low Apgar scores.[68907] In animal reproduction studies, no adverse development effects were observed with oral famotidine at doses up to approximately 243 and 122 times, respectively, the recommended human dose of 80 mg/day for the treatment of erosive esophagitis.[50742] [51477] Guidelines recommend a trial of lifestyle modifications as first-line therapy for heartburn and gastroesophageal reflux disease (GERD) during pregnancy, followed by antacids if lifestyle adjustments are ineffective. For ongoing symptoms, H2-blockers such as famotidine can be used. Other medications should be reserved for pregnant patients who fail H2-blocker therapy.[68890] Self-medication with H2-blockers (OTC formulations) during pregnancy is not recommended. Pregnant patients should see their health care professional for a proper diagnosis and for treatment recommendations.[45899] Famotidine has been used in limited circumstances at term to prevent acid aspiration during labor; some guidelines recommend an H2-blocker (PO or IV) for all women presenting for cesarean delivery.[66408]

There are limited data suggesting the presence of famotidine in human breast milk; however, there were no effects on the breastfed infant; experts and guidelines consider use of famotidine compatible with breast-feeding. There are no data on famotidine effects on milk production. Famotidine is present in the milk of lactating rats.[50742] [51477] [45899] [68890] Famotidine is indicated for use in infants and is used in newborns at doses that are higher than those excreted in breast milk.[45876] According to guidelines, if heartburn/gastroesophageal reflux (GERD) symptoms persist after delivery, antacids and sucralfate are safe to use during lactation because they are not concentrated in breast milk. H2-blockers are excreted in breast milk, but cimetidine and famotidine are considered safe for use during lactation and may be used if symptoms persist despite antacid use. Famotidine is preferred in lactation due to the low concentration in breast milk.[68890] [45899]

No special precautions have been advised for famotidine use in geriatric patients, but dosage adjustments are necessary in geriatric patients with reduced renal function. If critically ill, the elderly in some uncontrolled studies have appeared to be more likely to exhibit central nervous system (CNS) reactions to the H2-antagonists.[50742] According to the Beers Criteria, H2-receptor antagonists are considered potentially inappropriate medications (PIMs) in geriatric patients with delirium/high risk of delirium (potential for new-onset or worsening delirium) and should be avoided in this patient population. The Beers panel also recommends dose reduction of H2-antagonists in geriatric patients with a creatinine clearance less than 50 mL/minute due to the potential for mental status changes.[63923] The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to the OBRA guidelines, the indication for use of an H2-antagonist should be based on clinical symptoms and/or endoscopic findings. During use to treat or prevent NSAID-induced gastritis or esophagitis, there should be documentation that analgesics with less GI toxicity than NSAIDs have been tried or were not indicated. If the H2-antagonist is used for longer than 12 weeks, clinical rationale and documentation should support an underlying chronic disease (e.g., GERD) or risk factors (e.g., chronic NSAID use) for continued use. Dosing should be based on renal function. Adverse consequences of medication therapy include new or worsening headaches, confusion, nausea, vomiting, flatulence, dysphagia, abdominal pain, diarrhea, or other GI symptoms.[60742]

Daily treatment with gastric acid-suppressing medication over a long period of time (e.g., generally more than 3 years) may lead to malabsorption of cyanocobalamin and vitamin B12 deficiency. One large case-controlled study compared patients with and without an incident diagnosis of vitamin B12 deficiency. A correlation was demonstrated between vitamin B12 deficiency and gastric acid-suppression therapy with PPIs or H2-blockers of greater than 2 years duration. A dose-dependent relationship was also evident, as larger daily pill counts were more strongly associated with vitamin B12 deficiency.[56553] Consider the possibility of cyanocobalamin deficiency if clinical symptoms are observed.

Famotidine injection multidose vials contain benzyl alcohol as a preservative and should be avoided in neonates. There have been reports of fatal 'gasping syndrome' in neonates (less than 1 month of age) after the administration of parenteral solutions containing the preservative benzyl alcohol at dosages more than 99 mg/kg/day. The minimum amount of benzyl alcohol to cause toxicity is unknown. Therefore, use preservative-free famotidine injectable formulations in neonates.[51456]