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  • CLASSES

    H2 Antagonists

    DEA CLASS

    OTC, Rx

    DESCRIPTION

    Oral/parenteral histamine type 2-receptor antagonist. Less likely to interact with other drugs. Used for gastrointestinal disorders such as gastric or duodenal ulcer, gastroesophageal reflux disease, and pathological hypersecretory conditions.

    COMMON BRAND NAMES

    Heartburn Relief, Pepcid, Pepcid AC, Pepcid AC Maximum Strength

    HOW SUPPLIED

    Famotidine/Heartburn Relief/Pepcid/Pepcid AC/Pepcid AC Maximum Strength Oral Tab: 10mg, 20mg, 40mg
    Famotidine/Pepcid Intravenous Inj Sol: 1mL, 10mg, 20mg, 50mL
    Famotidine/Pepcid Oral Pwd F/Recon: 5mL, 40mg

    DOSAGE & INDICATIONS

    For self-medication of pyrosis (heartburn), acid dyspepsia (acid indigestion), or sour stomach, either for prophylaxis or for symptomatic relief.
    For maximum strength prevention or relief of symptoms.
    Oral dosage (OTC product, e.g., Maximum Strength Pepcid AC or equivalent)
    Adults, Adolescents, and Children >= 12 years

    Maximum non-prescription dosage. Patients should not take for more than 2 weeks without consulting a physician.
    -Prevention: 20 mg PO; take 10 minutes to 1 hour prior to eating a meal which is expected to cause symptoms. Maximum daily dose is 40 mg/day.
    -Treatment: 20 PO single dose. May repeat. Maximum daily dose is 40 mg/day.

    Children < 12 years

    Do not self-medicate.

    Oral dosage (OTC product, e.g., Pepcid AC or equivalent)
    Adults, Adolescents, and Children >= 12 years

    Non-prescription dosage. Patients should not take for more than 2 weeks without consulting a physician.
    -Prevention: 10 mg PO; take 15 minutes to 1 hour prior to eating a meal that is expected to cause symptoms. Maximum daily dose is 20 mg/day.
    -Treatment: 10 PO single dose. May repeat. Maximum daily dose is 20 mg/day.

    Children < 12 years

    Do not self-medicate. Use only if advised by a qualified health care prescriber.

    For the treatment of gastroesophageal reflux disease (GERD) or esophagitis associated with gastroesophageal reflux disease (GERD).
    Oral dosage
    Adults

    20 mg PO twice daily for up to 6 weeks. If esophagitis has developed, a dose of 20—40 mg PO twice daily for up to 12 weeks is recommended.

    Adolescents and Children

    The suggested starting dose is 0.5 mg/kg PO twice daily up to 40 mg PO twice daily. Maintenance dose and duration of therapy have not been determined in this age group. Individualize treatment duration and dose based on clinical response and/or pH determination (gastric or esophageal) and endoscopy. Doses up to 2 mg/kg/day PO have been used for GERD with or without esophagitis including erosions and ulcerations.

    Infants 3 months to < 1 year

    0.5 mg/kg PO twice daily for up to 8 weeks in addition to conservative measures such as thickened feedings.

    Infants < 3 months

    0.5 mg/kg PO once daily of the oral suspension for up to 8 weeks in addition to conservative measures such as thickened feedings.

    Intravenous dosage
    Children

    Pharmacokinetic and pharmacodynamic data support an initial dosage of 0.5 mg/kg IV every 8—12 hours.

    For the treatment of peptic ulcer disease (duodenal ulcer or gastric ulcer).
    NOTE: For dosing in patients with gastric or duodenal ulcers due to H. pylori, see “H. pylori eradication” indication.
    For acute treatment.
    Oral dosage
    Adults

    40 mg PO once daily at bedtime. Most duodenal ulcer patients heal within 4 weeks and full-dose therapy is rarely needed for longer than 6—8 weeks.

    Adolescents and Children

    The suggested starting dose is 0.5 mg/kg/day PO at bedtime or 0.25 mg/kg PO twice daily. Individualize treatment duration and dose based on clinical response and/or pH determination (gastric or esophageal) and endoscopy. Doses up to 1 mg/kg/day PO have been used. In 1 small study, a treatment duration of 8 weeks was effective for the treatment of gastric or duodenal ulcer. Maximum dosage is 40 mg/day.

    Intravenous dosage
    Adults

    20 mg IV every 12 hours.

    Children

    1—2 mg/kg/day IV given in 1—2 divided doses has been used. Pharmacokinetic and pharmacodynamic data support an initial dosage of 0.5 mg/kg IV every 8—12 hours. Maximum dosage is 40 mg/day.

    For maintenance therapy of duodenal ulcer after the initial treatment phase has been completed.
    Oral dosage
    Adults

    20 mg PO once daily at bedtime.

    For Helicobacter pylori (H. pylori) eradication in the treatment of patients with duodenal ulcer disease (active or a history of duodenal ulcer), gastric ulcer†, dyspepsia†, or gastric mucosa associated lymphoid tissue (MALT) lymphoma†.
    Oral dosage
    Adults

    20 mg PO twice daily or 40 mg PO once daily at bedtime with bismuth subsalicylate (525 mg 4 times daily), metronidazole (250 mg 4 times daily), and tetracycline (500 mg 4 times daily) for 10 to 14 days. Continue famotidine at this dosage for an additional 2 to 4 weeks after the discontinuation of the antibiotic therapy to ensure appropriate healing of the active ulcer. This drug combination is expected to result in eradication of H. pylori in 75% to 90% of patients. Famotidine is not effective as a single agent for eradication. Quadruple regimens that include an H2-blocker as an anti-secretory agent are FDA-approved, but are associated with lower compliance and efficacy rates than other recommended regimens. An H2-blocker should not be substituted for a proton pump inhibitor (PPI) in any current H. pylori treatment regimen unless the patient cannot tolerate a PPI. The American College of Gastroenterology (ACG) recommends 10 to 14 days of a triple-drug regimen containing a proton pump inhibitor (PPI), clarithromycin, and either amoxicillin or metronidazole ; a duration of 14 days is recommended as first line therapy in the 2006 global updates from the Maastricht III Consensus Report. A large body of data exist to support the importance of eradication as the first line treatment of gastric MALT lymphoma. Following H. pylori eradication, long term tumor regression is observed in 60% to 90% of patients. NOTE: In populations where H. pylori infection is common (10% or more), patients presenting with non-ulcer dyspepsia should be tested for H. pylori; those found to be H. pylori positive should be started on combination eradication therapy.

    For pathologic GI hypersecretory conditions such as Zollinger-Ellison syndrome, systemic mastocytosis, or multiple endocrine adenoma syndrome.
    Oral dosage
    Adults

    20 mg PO every 6 hours, initially. May titrate. Maximum: 160 mg PO every 6 hours per the manufacturer. Clinically, adjust to patient response. Doses as high as 200 mg PO every 6 hours have been reported.

    Intravenous dosage
    Adults

    20 mg IV every 6 hours when oral therapy is not feasible; higher doses may be needed and therapy should be individualized based on patient response.

    For NSAID-induced ulcer prophylaxis†.
    Oral dosage
    Adults

    40 mg PO twice daily. Data from clinical trials note that only higher doses of H2-blockers are effective at reducing risk for gastric ulceration from NSAIDs. In one trial, patients receiving a NSAID for either rheumatoid arthritis or osteoarthritis were given famotidine 20 mg PO twice daily, famotidine 40 mg PO twice daily, or placebo for 24 weeks. The cumulative incidence of gastric ulcer was significantly reduced by famotidine 40 mg but not the lower dose compared to placebo. The cumulative incidence of duodenal ulcer was significantly reduced by both famotidine doses relative to placebo.

    For stress gastritis prophylaxis† in critically-ill patients.
    Intermittent intravenous dosage
    Adults

    20 mg IV every 12 hours. This dosage adequately maintains intragastric pH above 4.0.

    Continuous IV infusion dosage
    Adults and Adolescents

    Give 10 mg as a single IV initially, follow with an infusion of 1.7 mg/hour IV by continuous infusion (i.e., total daily dosage of 40 mg/day). At least 1 study has verified that this dosage adequately maintains intragastric pH above 4.0.

    For acid aspiration prophylaxis† prior to anesthesia.
    Intravenous dosage
    Adults

    20 mg IV in the morning prior to surgery, prior to induction of anesthesia. According to guidelines of the American Society of Anesthesiologists, routine preoperative use is NOT recommended in patients who have no apparent increased risk for pulmonary aspiration.

    Oral dosage
    Adults

    20 mg PO as a single dose given 3 hours prior to the time of surgery, prior to induction of anesthesia. Alternatively, 40 mg PO has been given the night prior to elective surgery. According to guidelines of the American Society of Anesthesiologists, routine preoperative use is NOT recommended in patients who have no apparent increased risk for pulmonary aspiration.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    40 mg/day PO or IV for active duodenal or benign gastric ulcer; 20 mg/day PO for ulcer maintenance; 40 mg/day PO for GERD; 80 mg/day PO for esophagitis; doses may go as high as 640 mg/day or 800 mg/day (rare) PO or 80 mg/day IV for hypersecretory conditions such as Zollinger-Ellison; 40 mg/day PO for self-medication (OTC).

    Geriatric

    40 mg/day PO or IV for active duodenal or benign gastric ulcer healing; 20 mg/day PO for ulcer maintenance; 40 mg/day PO for GERD; 80 mg/day PO for esophagitis; doses may go as high as 640 mg/day or 800 mg/day (rare) PO or 80 mg/day IV for hypersecretory conditions such as Zollinger-Ellison; 40 mg/day PO for self-medication (OTC).

    Adolescents

    40 mg/day PO or IV for active duodenal or benign gastric ulcer healing; 20 mg/day PO for ulcer maintenance; 40 mg/day PO for GERD; 80 mg/day PO for esophagitis; 40 mg/day PO for self-medication (OTC).

    Children

    12 years: 2 mg/kg/day PO, usually not to exceed 40 mg/day PO or IV for active duodenal or benign gastric ulcer healing; 40 mg/day PO for GERD; 80 mg/day PO for esophagitis; 40 mg/day PO for self-medication (OTC).
    < 12 years: 2 mg/kg/day PO, usually not to exceed 40 mg/day PO or IV for active duodenal or benign gastric ulcer healing; 40 mg/day PO for GERD; 80 mg/day PO for esophagitis; do not self-medicate (OTC).

    Infants

    3 months to < 1 year: 1 mg/kg/day PO.
    < 3 months: 0.5 mg/kg/day PO.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    No dosage adjustment needed, unless decreased renal elimination is also present.

    Renal Impairment

    CrCl >= 50 mL/min: no dosage adjustment needed.
    CrCl < 50 mL/min: reduce recommended dose by 50% (or extend dosing interval to 36—48 hours according to clinical response and degree of renal impairment).

    ADMINISTRATION

    Oral Administration

    May be administered without regard to meals.

    Oral Solid Formulations

    Tablets: May administer with food, water, or milk to minimize gastric irritation.
    Orally disintegrating tablets: No water is needed for administration. Instruct patients to open the tablet blister pack with dry hands, place the tablet on the tongue, allow to disintegrate, then swallow with saliva.

    Oral Liquid Formulations

    Oral suspension:
    Reconstitute by slowly adding 46 mL of purified water. Shake vigorously for 5 to 10 seconds after adding water.
    After reconstitution, each 5 mL contains 40 mg of famotidine.
    Shake suspension well prior to each use. Measure dosage with calibrated device for accuracy.
    Storage of reconstituted suspension: Store at room temperature (15—30 degrees C, 59—86 degrees F) for up to 30 days.

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Intermittent intravenous injection:
    Dilute 20 mg of famotidine injection to a total of 5 or 10 mL with 0.9% Sodium Chloride injection or other compatible solution to give concentrations of 4 or 2 mg/mL, respectively.
    Inject appropriate dose over >= 2 minutes and at a rate <= 10 mg/minute.
     
    Intermittent intravenous (IV) infusion:
    Dilute 20 mg of famotidine in 100 mL of 5% Dextrose injection or 0.9% Sodium Chloride injection or other compatible IV solution to give a final concentration of 0.2 mg/mL.
    Infuse over 15—30 minutes.
    Storage: If not used immediately, store diluted solutions under refrigeration and use within 48 hours of preparation. Although when diluted in common compatible solutions (e.g., 0.9% Sodium Chloride injection, 5% Dextrose injection, Lactated Ringers), famotidine is stable for 7 days at room temperature, the manufacturer warns that there are no data available to confirm sterility under these conditions.
     
    Continuous 24-hour intravenous infusion:
    For adults, dilute 40 mg of famotidine in 250 mL of 5% Dextrose injection or 0.9% Sodium Chloride injection or other compatible solution. The diluted solution is stable for up to 48 hours at room temperature. Infuse over 24 hours at a rate of 11 mL/hr or as specified by physician.
    Use a controlled-rate infusion device.
    Alternatively, the dosage may be added to a compatible TPN solution for administration over 24 hours.
     
    Intermittent intravenous (IV) infusion using premixed infusion in Galaxy containers:
    The premixed infusion container contains famotidine 20 mg per 50 mL 0.9% Sodium Chloride injection.
    Check the container for leaks prior to use by squeezing the bag firmly. If leaks are found, discard solution as sterility may be impaired.
    Do not add supplementary medication.
    Do not use unless solution is clear and seal is intact.
    CAUTION: Do not use plastic containers in series connections. Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is complete.
    Suspend container from eyelet support.
    Remove plastic protector from outlet port at bottom of container.
    Attach administration set. Refer to complete directions accompanying set.
    Infuse over 15—30 minutes.

    STORAGE

    Generic:
    - Avoid excessive heat (above 104 degrees F)
    - Brief exposure to temperatures up to 95 degrees F does not adversely affect product
    - Store at 77 degrees F
    Heartburn Relief:
    - Protect from light
    - Protect from moisture
    - Store between 68 to 77 degrees F
    Pepcid:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Pepcid AC:
    - Protect from light
    - Protect from moisture
    - Store between 68 to 77 degrees F
    Pepcid AC Maximum Strength:
    - Protect from moisture
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    H2 blockers can be used in combination with certain antibiotics to eradicate Helicobacter pylori. When famotidine is used with antimicrobials, clinicians should be cognizant of possible pseudomembranous colitis occurring. Almost all antibacterial agents have been associated with pseudomembranous colitis (antibiotic-associated colitis) which may range in severity from mild to life-threatening. In the colon, overgrowth of Clostridia may exist when normal flora is altered subsequent to antibacterial administration. The toxin produced by Clostridium difficile is a primary cause of pseudomembranous colitis. It is known that systemic use of antibiotics predisposes patients to development of pseudomembranous colitis. Consideration should be given to the diagnosis of pseudomembranous colitis in patients presenting with diarrhea following antibacterial administration. Systemic antibiotics should be prescribed with caution to patients with inflammatory bowel disease such as ulcerative colitis or other GI disease. If diarrhea develops during therapy, the drug should be discontinued. Following diagnosis of pseudomembranous colitis, therapeutic measures should be instituted. In milder cases, the colitis may respond to discontinuation of the offending agent. In moderate to severe cases, fluids and electrolytes, protein supplementation, and treatment with an antibacterial effective against Clostridium difficile may be warranted. Products inhibiting peristalsis are contraindicated in this clinical situation. Practitioners should be aware that antibiotic-associated colitis has been observed to occur over two months or more following discontinuation of systemic antibiotic therapy; a careful medical history should be taken.

    H2-blocker hypersensitivity

    Famotidine is contraindicated in any patient hypersensitive to the drug or its components. Cross-sensitivity in this class of compounds has been observed, so famotidine should be administered with caution to patients with a history of H2-blocker hypersensitivity. An incidence of cross-reactivity among this class of agents is not currently available.

    Gastric cancer, GI bleeding

    Symptomatic response to therapy with famotidine does not preclude the presence of gastric cancer. In the patient who is self-medicating with OTC formulations, the continuation of heartburn, acid indigestion, or dyspepsia beyond 2 weeks signals the need to consult a health-care professional for evaluation. Patients using the the OTC famotidine products should seek immediate medical advice if any sign of GI bleeding (e.g., blood in vomit, stools) or difficult or painful swallowing (dysphagia) becomes evident.

    Infection

    Symptomatic response to therapy with famotidine does not preclude the presence of H. pylori infection. Famotidine therapy does not appear to interfere with the sensitivity of gastric urease biopsy. It is controversial whether H2-blockers interfere with urea breath-tests for the detection of H. pylori; many laboratories recommend holding these drugs for 24—48 hours prior to testing. H2-blockers, as single agents, will not eradicate H. pylori infection.

    Hepatic disease, QT prolongation, renal disease, renal failure, renal impairment

    Famotidine should be used cautiously in patients with hepatic disease, renal impairment or renal failure (renal disease), because the drug can accumulate, causing toxicity. There is a close relationship between the drug's elimination half-life and creatinine clearance. Dosages of famotidine should be adjusted in patients with a creatinine clearance of < 50 ml/min. Rarely, QT prolongation or central nervous system (CNS) reactions have been reported in patients with impaired renal function whose dose/dosing interval of famotidine may not have been adjusted appropriately. Use famotidine with caution in patients with renal impairment and other conditions that may increase the risk of QT prolongation.

    Children, infants, neonates

    Famotidine should not be used for self-medication in neonates, infants, or children younger than 12 years of age unless directed by a clinician.

    Breast-feeding

    According to the manufacturer, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Famotidine is secreted into breast milk. However, of all the H2-blockers, famotidine is excreted least in breast milk. Famotidine is also FDA-approved for use in infants and is used in newborns at doses that are higher than those excreted in breast milk. The American Academy of Pediatrics (AAP) considers the use of cimetidine, a related agent, to be usually compatible with breast-feeding due to a lack of reported adverse effects in nursing infants. In general, H2-blockers are considered to be low-risk for use while breast-feeding based on available data.

    Pregnancy

    Famotidine is classified in FDA pregnancy category B. Animal studies have revealed no evidence of fetal toxicity or teratogenicity. However, there is less animal and human studies data for famotidine as compared with other H2-blockers. The choice of another agent (e.g., ranitidine) may be prudent. In 2009, a population-based observational cohort study explored a possible link between gastric acid suppressive therapy (e.g., H2 blockers) during pregnancy and a diagnosis of allergic disease or a prescription for asthma or allergy medications in the exposed child. Among the cohort (n = 585,716), 1% of children exposed to gastric acid suppressive drugs in pregnancy received a diagnosis of allergic diease. For developing allergy or asthma, an increased OR of 1.43 and 1.51, respectively, were observed regardless of drug used, time of exposure during pregnancy, and maternal history of disease. Proposed possible mechanisms for a link include: (1) exposure to increased amounts of allergens could cause sensitization to digestion-labile antigens in the fetus; (2) the maternal Th2 cytokine pattern could promote an allergy prone phenotype in the fetus; (3) maternal allergen specific immunoglobulin could cross the placenta and sensitize fetal immune cells to food and airborne allergens. Study limitations were present and confirmation of results are necessary before further conclusions can be drawn from this data. Risk versus benefit should be considered prior to use. Self-medication during pregnancy is not recommended; pregnant patients should see their health care professional for a proper diagnosis and for treatment recommendations.

    Tobacco smoking

    Patients taking famotidine should avoid smoking. Tobacco smoking appears to contribute to an increased risk of developing peptic ulcer disease and may also impair ulcer healing or increase the risk of ulcer recurrence.

    Phenylketonuria

    Pepcid AC (famotidine) Chewable Tablets contain phenylalanine 1.4 mg/tablet and should be used cautiously in patients with phenylketonuria.

    Geriatric

    No special precautions have been advised for geriatric patients, but some older patients may exhibit decreased renal function. Dosage adjustments are necessary with reduced renal function. If critically ill, the elderly have been noted in some uncontrolled studies to be more likely to exhibit central nervous system (CNS) reactions to the H2-blockers. According to the Beers Criteria, H-2 receptor antagonists are considered potentially inappropriate medications (PIMs) in geriatric patients with the following disease states or symptoms and should be avoided in these patient populations: dementia/cognitive impairment (possibility of drug-induced adverse CNS effects) or delirium/high risk of delirium (potential for new-onset or worsening delirium). The Beers expert panel also recommends reducing the dose of H-2 antagonists in geriatric patients with a creatinine clearance less than 50 mL/minute due to the potential for mental status changes. 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 H-2 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 used for longer than 12 weeks, clinical rationale for continued need and/or documentation should support an underlying chronic disease (e.g., GERD) or risk factors (e.g., chronic NSAID 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.

    Vitamin B12 deficiency

    Daily treatment with gastric acid-suppressing medication such as nizatidine over a long period of time (e.g., generally > 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 ofvitamin B12 deficiency. A correlation was demonstrated between vitamin B12 deficiency and gastric acid-suppression therapy of > 2 years duration [i.e., proton pump inhibitor (PPI), H2-receptor antagonist]. In addition, a dose-dependant relationship was evident, as larger daily pill counts were more strongly associated with vitamin B12 deficiency. The possibility of cyanocobalamin deficiency should, therefore, be considered if clinical symptoms are observed.

    ADVERSE REACTIONS

    Severe

    seizures / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    angioedema / Rapid / Incidence not known
    atrophic gastritis / Delayed / Incidence not known
    arrhythmia exacerbation / Early / Incidence not known
    AV block / Early / Incidence not known
    agranulocytosis / Delayed / Incidence not known
    pancytopenia / Delayed / Incidence not known
    bronchospasm / Rapid / Incidence not known
    rhabdomyolysis / Delayed / Incidence not known

    Moderate

    constipation / Delayed / 1.2-1.2
    jaundice / Delayed / Incidence not known
    cholestasis / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    delirium / Early / Incidence not known
    depression / Delayed / Incidence not known
    confusion / Early / Incidence not known
    hallucinations / Early / Incidence not known
    edema / Delayed / Incidence not known
    conjunctivitis / Delayed / Incidence not known
    palpitations / Early / Incidence not known
    QT prolongation / Rapid / Incidence not known
    leukopenia / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    impotence (erectile dysfunction) / Delayed / Incidence not known
    vitamin B12 deficiency / Delayed / Incidence not known
    pernicious anemia / Delayed / Incidence not known

    Mild

    headache / Early / 4.7-4.7
    diarrhea / Early / 1.7-1.7
    dizziness / Early / 1.3-1.3
    nausea / Early / Incidence not known
    anorexia / Delayed / Incidence not known
    dysgeusia / Early / Incidence not known
    vomiting / Early / Incidence not known
    xerostomia / Early / Incidence not known
    agitation / Early / Incidence not known
    drowsiness / Early / Incidence not known
    paranoia / Early / Incidence not known
    paresthesias / Delayed / Incidence not known
    insomnia / Early / Incidence not known
    anxiety / Delayed / Incidence not known
    libido decrease / Delayed / Incidence not known
    urticaria / Rapid / Incidence not known
    flushing / Rapid / Incidence not known
    xerosis / Delayed / Incidence not known
    pruritus / Rapid / Incidence not known
    acne vulgaris / Delayed / Incidence not known
    rash (unspecified) / Early / Incidence not known
    alopecia / Delayed / Incidence not known
    infection / Delayed / Incidence not known
    muscle cramps / Delayed / Incidence not known
    asthenia / Delayed / Incidence not known
    gynecomastia / Delayed / Incidence not known
    tinnitus / Delayed / Incidence not known
    fever / Early / Incidence not known
    fatigue / Early / Incidence not known
    musculoskeletal pain / Early / Incidence not known
    arthralgia / Delayed / Incidence not known

    DRUG INTERACTIONS

    Acalabrutinib: (Moderate) Separate the administration of acalabrutinib and H2-blockers if these agents are used together; administer acalabrutinib 2 hours before the H2-blocker. Acalabrutinib solubility decreases with increasing pH values; therefore, coadministration may result in decreased acalabrutinib exposure and effectiveness.
    Alendronate: (Moderate) Although the clinical significance has not been determined, the bioavailability of oral alendronate is doubled by concomitant administration of intravenous ranitidine. Investigations have not been undertaken to determine if other H2-antagonists have a similar effect on bioavailability. Patients should be closely monitored when H2-blockers are coadministered as they may affect the bioavailability of alendronate, possibly leading to a higher likelihood of developing adverse effects while taking alendronate.
    Alendronate; Cholecalciferol: (Moderate) Although the clinical significance has not been determined, the bioavailability of oral alendronate is doubled by concomitant administration of intravenous ranitidine. Investigations have not been undertaken to determine if other H2-antagonists have a similar effect on bioavailability. Patients should be closely monitored when H2-blockers are coadministered as they may affect the bioavailability of alendronate, possibly leading to a higher likelihood of developing adverse effects while taking alendronate.
    Alogliptin; Metformin: (Minor) Famotidine may decrease the renal clearance of metformin secondary to competition for renal tubular transport systems. Such an interaction has been observed when cimetidine was administered with metformin. The decrease in renal excretion led to a 40% increase in metformin AUC. Although interactions with cationic drugs remain theoretical (except for cimetidine), caution is warranted when famotidine and metformin are prescribed concurrently. Famotidine may be less likely to interact with metformin versus cimetidine or ranitidine because of less tubular excretion.
    Amphetamine: (Major) It is not recommended to use Adzenys ER (amphetamine) extended-release oral suspension with gastric pH modulators, such as H2-blockers; concomitant use may result in dose-dumping by potentially changing the release profile and exposure to amphetamine. Consider the use of alternative agents.
    Amphetamine; Dextroamphetamine: (Major) It is not recommended to use Adzenys ER (amphetamine) extended-release oral suspension with gastric pH modulators, such as H2-blockers; concomitant use may result in dose-dumping by potentially changing the release profile and exposure to amphetamine. Consider the use of alternative agents.
    Aripiprazole: (Minor) Coadministration of aripiprazole with famotidine decreases aripiprazole's solubility and rate of absorption. The Cmax of aripiprazole and the metabolite dehydroaripiprazole are decreased by 37% and 21%, respectively, and the AUC of aripiprazole and the dehydroaripiprazole metabolite are decreased by 13% and 15%, respectively. This interaction does not appear to cause clinically relevant effects and therefore no dosage adjustments are required.
    Atazanavir: (Major) Coadministration of H2-blockers with atazanavir reduces serum atazanavir concentrations; however, H2-blockers can be used under specific administration restrictions. Although data are insufficient to recommend atazanavir dosing in children < 40 kg receiving concomitant H2-blockers, the same recommendations regarding timing and maximum doses of concomitant H2-blockers should be followed. In treatment-naive patients >= 40 kg, do not exceed an H2- blocker dose equivalent to famotidine 40 mg twice daily, and give atazanavir 300 mg with ritonavir 100 mg once daily with food. Give atazanavir simultaneously with and/or at least 10 hours after the H2- blocker. If a treatment-naive adult or adolescent (>= 40 kg) cannot tolerate ritonavir, do not exceed an H2- blocker dose equivalent to famotidine 20 mg twice daily, and the atazanavir dose should be increased to 400 mg once daily with food given at least 2 hours before or 10 hours after the H2- blocker. Data are insufficent to recommend atazanavir dosing in children or adolescents < 40 kg not receiving ritonavir boosting. In treatment-naive patients on a cobicistat-boosted regimen, cobicistat and atazanavir may be administered without dosage adjustment if given at the same time or a minimum of 10 hours after dosing of the H2-blocker. The H2-blocker dose should not exceed a dose that is comparable to 40 mg/day of famotidine in treatment-naive patients. In treatment-experienced patients >= 40 kg, do not exceed an H2- blocker dose equivalent to famotidine 20 mg twice daily, and give atazanavir 300 mg with ritonavir 100 mg once daily with food. Give atazanavir simultaneously with and/or at least 10 hours after the H2- blocker. In treatment-experienced patients >= 40 kg receiving H2-antagonists and tenofovir, atazanavir should be dosed 400 mg with ritonavir 100 mg once daily with food. In antiretroviral-experienced patients on a cobicistat-boosted regimen, the dosage of cobicistat with atazanavir needs to be increased if administered with H2-blockers; the recommended dose is cobicistat 150 mg/day with atazanavir 400 mg/day and 20 mg/day or less of famotidine or other comparably dosed H2-blocker. Significant reductions in atazanavir serum concentrations may lead to therapeutic failure and the development of HIV resistance. Closely monitor patients for antiretroviral therapeutic failure and resistance development during treatment with an H2- blocker.
    Atazanavir; Cobicistat: (Major) Coadministration of H2-blockers with atazanavir reduces serum atazanavir concentrations; however, H2-blockers can be used under specific administration restrictions. Although data are insufficient to recommend atazanavir dosing in children < 40 kg receiving concomitant H2-blockers, the same recommendations regarding timing and maximum doses of concomitant H2-blockers should be followed. In treatment-naive patients >= 40 kg, do not exceed an H2- blocker dose equivalent to famotidine 40 mg twice daily, and give atazanavir 300 mg with ritonavir 100 mg once daily with food. Give atazanavir simultaneously with and/or at least 10 hours after the H2- blocker. If a treatment-naive adult or adolescent (>= 40 kg) cannot tolerate ritonavir, do not exceed an H2- blocker dose equivalent to famotidine 20 mg twice daily, and the atazanavir dose should be increased to 400 mg once daily with food given at least 2 hours before or 10 hours after the H2- blocker. Data are insufficent to recommend atazanavir dosing in children or adolescents < 40 kg not receiving ritonavir boosting. In treatment-naive patients on a cobicistat-boosted regimen, cobicistat and atazanavir may be administered without dosage adjustment if given at the same time or a minimum of 10 hours after dosing of the H2-blocker. The H2-blocker dose should not exceed a dose that is comparable to 40 mg/day of famotidine in treatment-naive patients. In treatment-experienced patients >= 40 kg, do not exceed an H2- blocker dose equivalent to famotidine 20 mg twice daily, and give atazanavir 300 mg with ritonavir 100 mg once daily with food. Give atazanavir simultaneously with and/or at least 10 hours after the H2- blocker. In treatment-experienced patients >= 40 kg receiving H2-antagonists and tenofovir, atazanavir should be dosed 400 mg with ritonavir 100 mg once daily with food. In antiretroviral-experienced patients on a cobicistat-boosted regimen, the dosage of cobicistat with atazanavir needs to be increased if administered with H2-blockers; the recommended dose is cobicistat 150 mg/day with atazanavir 400 mg/day and 20 mg/day or less of famotidine or other comparably dosed H2-blocker. Significant reductions in atazanavir serum concentrations may lead to therapeutic failure and the development of HIV resistance. Closely monitor patients for antiretroviral therapeutic failure and resistance development during treatment with an H2- blocker.
    Bisacodyl: (Minor) The concomitant use of bisacodyl tablets with H2-blockers can cause the enteric coating of the bisacody tablet to dissolve prematurely, leading to possible gastric irritation or dyspepsia. Avoid H2-blockers within 1 hour before or after the bisacodyl dosage.
    Bismuth Subsalicylate: (Minor) H2-blockers may increase the systemic absorption of bismuth from bismuth-containing compounds like bismuth subsalicylate.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Minor) H2-blockers may increase the systemic absorption of bismuth from bismuth-containing compounds like bismuth subsalicylate.
    Bosutinib: (Moderate) Bosutinib displays pH-dependent aqueous solubility; therefore, concomitant use of bosutinib and H2-blockers may result in decreased plasma exposure of bosutinib. Separate the administration of bosutinib and H2-blockers by more than 2 hours.
    Budesonide: (Major) Enteric-coated budesonide granules (Entocort EC) dissolve at a pH > 5.5. Likewise, the dissolution of the coating of extended-release budesonide tablets (Uceris) is pH dependent. Concomitant use of oral budesonide and antacids, milk, or other drugs that increase gastric pH levels can cause these products to dissolve prematurely, possibly affecting release properties and absorption of the drug in the duodenum. When cimetidine (1 gram/day PO) is administered with an uncoated formulation of oral budesonide, a slight increase in absorption and peak plasma concentrations occur, resulting in significant cortisol suppression. In general, it may be prudent to avoid drugs such as H2-blockers in combination with oral budesonide.
    Budesonide; Formoterol: (Major) Enteric-coated budesonide granules (Entocort EC) dissolve at a pH > 5.5. Likewise, the dissolution of the coating of extended-release budesonide tablets (Uceris) is pH dependent. Concomitant use of oral budesonide and antacids, milk, or other drugs that increase gastric pH levels can cause these products to dissolve prematurely, possibly affecting release properties and absorption of the drug in the duodenum. When cimetidine (1 gram/day PO) is administered with an uncoated formulation of oral budesonide, a slight increase in absorption and peak plasma concentrations occur, resulting in significant cortisol suppression. In general, it may be prudent to avoid drugs such as H2-blockers in combination with oral budesonide.
    Bupivacaine; Lidocaine: (Moderate) Concomitant use of systemic lidocaine and famotidine may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; famotidine inhibits CYP1A2.
    Calcium Carbonate; Risedronate: (Major) Use of H2-blockers with delayed-release risedronate tablets (Atelvia) is not recommended. Co-administration of drugs that raise stomach pH increases risedronate bioavailability due to faster release of the drug from the enteric coated tablet. This interaction does not apply to risedronate immediate-release tablets.
    Canagliflozin; Metformin: (Minor) Famotidine may decrease the renal clearance of metformin secondary to competition for renal tubular transport systems. Such an interaction has been observed when cimetidine was administered with metformin. The decrease in renal excretion led to a 40% increase in metformin AUC. Although interactions with cationic drugs remain theoretical (except for cimetidine), caution is warranted when famotidine and metformin are prescribed concurrently. Famotidine may be less likely to interact with metformin versus cimetidine or ranitidine because of less tubular excretion.
    Cefditoren: (Moderate) Cefditoren pivoxil absorption may be decreased by H2-blockers. Coadministration is not recommended. A reduction in mean Cmax (by 27%) and AUC (by 22%) were seen for oral cefditoren pivoxil (single dose, 400 mg after a meal) when a single intravenous dose of an H2-blocker (famotidine) was given. The clinical significance of this interaction is not known.
    Cefpodoxime: (Moderate) H2-blockers should be avoided during treatment with cefpodoxime. Coadministration could result in antibiotic failure. H2-blockers increase gastric pH. Cefpodoxime proxetil requires low gastric pH for dissolution. While the rate of absorption is not affected, coadministration reduces cefpodoxime AUC, peak plasma concentration (by 42%), and extent of absorption (by 32%).
    Ceftibuten: (Minor) H2-blockers can affect the pharmacokinetics of some orally-administered cephalosporins. The oral bioavailability of ceftibuten was reported to be increased by the administration of 150 mg of ranitidine PO every 12 hours for 3 days, but this interaction is of unknown clinical relevance.
    Cefuroxime: (Major) Avoid the concomitant use of H2-blockers and cefuroxime. Drugs that reduce gastric acidity, such as H2-blockers, can interfere with the oral absorption of cefuroxime axetil and may result in reduced antibiotic efficacy.
    Ceritinib: (Moderate) Use caution if coadministration of ceritinib with H2-blockers is necessary, as the bioavailability of ceritinib may be reduced. Ceritinib displays pH-dependent solubility with decreased solubility at a higher pH, but data are conflicting regarding clinical significance. In healthy subjects, the AUC and Cmax of ceritinib decreased by 76% and 79%, respectively, when a single dose was administered with esomeprazole. However, in a subgroup of patients with NSCLC from a multicenter, open-label clinical trial, the AUC and Cmax of ceritinib decreased by 30% and 25%, respectively, after a single dose was administered with proton pump inhibitors; there was no clinically meaningful effect on ceritinib exposure at steady state.
    Cysteamine: (Major) Monitor white blood cell (WBC) cystine concentration closely when administering delayed-release cysteamine (Procysbi) with H2-blockers. Drugs that increase the gastric pH may cause the premature release of cysteamine from delayed-release capsules, leading to an increase in WBC cystine concentration.
    Dapagliflozin; Metformin: (Minor) Famotidine may decrease the renal clearance of metformin secondary to competition for renal tubular transport systems. Such an interaction has been observed when cimetidine was administered with metformin. The decrease in renal excretion led to a 40% increase in metformin AUC. Although interactions with cationic drugs remain theoretical (except for cimetidine), caution is warranted when famotidine and metformin are prescribed concurrently. Famotidine may be less likely to interact with metformin versus cimetidine or ranitidine because of less tubular excretion.
    Dasatinib: (Severe) Long-term suppression of gastric acid secretion by H2-blockers is likely to decrease the exposure to dasatinib. The concomitant use these agents is not recommended. For example, in a study of 24 healthy subjects, administration of a single 50 mg dose of dasatinib 10 hours after famotidine reduced the AUC and Cmax of dasatinib by 61% and 63%, respectively. Because separating the administration of dasatinib and antacids by at least 2 hours minimizes the interaction, the use of antacids should be considered in place of H2-blockers in patients receiving dasatinib therapy.
    Delavirdine: (Major) Coadministration of delavirdine with H2-blockers results in decreased absorption of delavirdine. Administration of delavirdine and H2-blockers should be separated by at least 1 hour. Chronic use of H2-blockers with delavirdine is not recommended.
    Dexmethylphenidate: (Minor) The effects of gastrointestinal pH alterations on the absorption of extended-release dexmethylphenidate (Focalin XR) have not been studied. Per the manufacturer of extended-release dexmethylphenidate, the modified release characteristics are pH-dependent. It is possible that the administration of H2-blockers or other acid suppressants could alter the release of extended-release dexmethylphenidate, resulting in reduced or increased absorption. Patients receiving an H2-blocker should be monitored for adverse effects and reduced therapeutic efficacy of extended-release dexmethylphenidate.
    Diphenhydramine; Naproxen: (Moderate) The enteric-coated, delayed-release naproxen tablets are designed to dissolve at a pH of 6 or greater. Concomitant use of this particular naproxen product with H--blockers is not recommended due to the gastric pH alteration.
    Dirithromycin: (Minor) The absorption of dirithromycin is slightly enhanced when administered immediately following H2-blockers. The clinical significance of this interaction is unclear.
    Dolutegravir; Rilpivirine: (Moderate) Coadministration with famotidine may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of famotidine for at least 12 hours before and at least 4 hours after administering rilpivirine.
    Empagliflozin; Metformin: (Minor) Famotidine may decrease the renal clearance of metformin secondary to competition for renal tubular transport systems. Such an interaction has been observed when cimetidine was administered with metformin. The decrease in renal excretion led to a 40% increase in metformin AUC. Although interactions with cationic drugs remain theoretical (except for cimetidine), caution is warranted when famotidine and metformin are prescribed concurrently. Famotidine may be less likely to interact with metformin versus cimetidine or ranitidine because of less tubular excretion.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Coadministration with famotidine may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of famotidine for at least 12 hours before and at least 4 hours after administering rilpivirine.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Moderate) Coadministration with famotidine may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of famotidine for at least 12 hours before and at least 4 hours after administering rilpivirine.
    Erlotinib: (Major) If concomitant use of erlotinib with famotidine is necessary, administer famotidine approximately 10 hours before and at least 2 hours after the erlotinib dose. Erlotinib displays pH-dependent solubility with decreased solubility at a higher pH; the increased gastric pH resulting from famotidine therapy may reduce the bioavailability of erlotinib. Increasing the dose of erlotinib without modifying the administration schedule is unlikely to compensate for loss of exposure.
    Esomeprazole; Naproxen: (Moderate) The enteric-coated, delayed-release naproxen tablets are designed to dissolve at a pH of 6 or greater. Concomitant use of this particular naproxen product with H--blockers is not recommended due to the gastric pH alteration.
    Ethanol: (Minor) Some studies have suggested that H2-receptor antagonists inhibit gastric alcohol (ethanol) dehydrogenase and thus decrease the first pass metabolism of ethanol, and some studies have suggested an interaction may not always occur. A meta-analysis evaluating the effects of H2-blockers on blood ethanol concentrations reported that only cimetidine and ranitidine, but not other H2-blockers, caused small elevations in serum ethanol levels. However, it was reported that larger studies were less likely to show an effect and that these elevations were not likely to be clinically relevant.
    Fosamprenavir: (Moderate) The coadministration of fosamprenavir with H2-blockers decreases amprenavir plasma concentrations. Use these drugs together with caution as amprenavir plasma concentrations may be decreased, which could lead to loss of virologic response and possible viral resistance to fosamprenavir.
    Gefitinib: (Moderate) If possible, avoid the concomitant use of gefitinib with famotidine. If coadministration is necessary, give gefitinib 6 hours after the last dose or 6 hours before the next dose of famotidine. Drugs that increase gastric pH may decrease plasma concentrations of gefitinib; coadministration of high doses of ranitidine with sodium bicarbonate (to maintain the gastric pH above 5) to healthy subjects decreased mean gefitinib AUC by 47%.
    Glipizide; Metformin: (Minor) Famotidine may decrease the renal clearance of metformin secondary to competition for renal tubular transport systems. Such an interaction has been observed when cimetidine was administered with metformin. The decrease in renal excretion led to a 40% increase in metformin AUC. Although interactions with cationic drugs remain theoretical (except for cimetidine), caution is warranted when famotidine and metformin are prescribed concurrently. Famotidine may be less likely to interact with metformin versus cimetidine or ranitidine because of less tubular excretion.
    Glyburide; Metformin: (Minor) Famotidine may decrease the renal clearance of metformin secondary to competition for renal tubular transport systems. Such an interaction has been observed when cimetidine was administered with metformin. The decrease in renal excretion led to a 40% increase in metformin AUC. Although interactions with cationic drugs remain theoretical (except for cimetidine), caution is warranted when famotidine and metformin are prescribed concurrently. Famotidine may be less likely to interact with metformin versus cimetidine or ranitidine because of less tubular excretion.
    Iron: (Minor) The bioavailability of oral iron salts is influenced by gastric pH, and the concomitant administration of H2-blockers can decrease iron absorption. The non-heme ferric form of iron needs an acidic intragastric pH to be reduced to ferrous and to be absorbed. Iron salts and polysaccharide-iron complex provide non-heme iron. H2-blockers have long-lasting effects on the secretion of gastric acid and thus, increase the pH of the stomach. The increase in intragastric pH can interfere with the absorption of iron salts.
    Itraconazole: (Moderate) Administer h2-blockers at least 2 hours before or 2 hours after oral itraconazole to minimize the potential for an interaction. Because itraconazole oral bioavailability requires an acidic environment for solubility, its absorption may be decreased with concomitant administration of h2-blockers.
    Ketoconazole: (Major) Ketoconazole requires an acidic pH for absorption. Medications that increase gastric pH or decrease acid output can cause a notable decrease in the bioavailability of ketoconazole. Medications that have this effect are antacids, antimuscarinics, histamine H2-blockers, and proton pump inhibitors (PPIs). Except for antacids, these medications have a prolonged duration of action, and staggering their time of administration with ketoconazole by several hours may not prevent the drug interaction. An alternative imidazole antifungal should be chosen if any of these gastrointestinal medications are required. If these drugs must be coadministered, administer ketoconazole tablets with an acidic beverage and closely monitor for breakthrough infection.
    Lamotrigine: (Minor) Coadministration of famotidine and lamotrigine may decrease famotidine clearance, resulting in increased plasma concentrations and the potential for famotidine-related adverse events. Lamotrigine is an inhibitor of renal tubular secretion via organic cationic transporter 2 (OCT2) proteins, and famotidine is excreted via this route.
    Lansoprazole; Naproxen: (Moderate) The enteric-coated, delayed-release naproxen tablets are designed to dissolve at a pH of 6 or greater. Concomitant use of this particular naproxen product with H--blockers is not recommended due to the gastric pH alteration.
    Ledipasvir; Sofosbuvir: (Major) Solubility of ledipasvir decreases as gastric pH increases; thus, coadministration of ledipasvir; sofosbuvir with H2-blockers may result in lower ledipasvir plasma concentrations. Ledipasvir; sofosbuvir can be administered with H2-blockers if given simultaneously or separated by 12 hours. The H2-blocker dose should not exceed a dose that is comparable to famotidine 40 mg twice daily.
    Lidocaine: (Moderate) Concomitant use of systemic lidocaine and famotidine may increase lidocaine plasma concentrations by decreasing lidocaine clearance and therefore prolonging the elimination half-life. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP3A4 and CYP1A2 substrate; famotidine inhibits CYP1A2.
    Linagliptin; Metformin: (Minor) Famotidine may decrease the renal clearance of metformin secondary to competition for renal tubular transport systems. Such an interaction has been observed when cimetidine was administered with metformin. The decrease in renal excretion led to a 40% increase in metformin AUC. Although interactions with cationic drugs remain theoretical (except for cimetidine), caution is warranted when famotidine and metformin are prescribed concurrently. Famotidine may be less likely to interact with metformin versus cimetidine or ranitidine because of less tubular excretion.
    Mefloquine: (Moderate) H2-blockers may increase plasma concentrations of mefloquine. Patients on chronic mefloquine therapy might be at increased risk of adverse reactions, especially patients with a neurological or psychiatric history. In a small study involving 6 healthy subjects and 6 peptic ulcer patients, cimetidine increased the Cmax and AUC of mefloquine. In the study, the pharmacokinetics of mefloquine were determined after receiving a single oral mefloquine 500 mg dose alone and after 3-days of cimetidine 400 mg PO twice daily. In both healthy subjects and peptic ulcer patients, Cmax was increased 42.4% and 20.5%, respectively. The AUC was increased by 37.5% in both groups. Elimination half-life, total clearance, and volume of distribution were not significantly affected. An increase in adverse reactions was not noted.
    Mesalamine, 5-ASA: (Major) The dissolution of the coating on mesalamine extended-release capsules (Apriso) and the delayed-release tablets (Lialda) is dependent on pH. Avoid coadministration with drugs that raise gastric pH like H2-blockers.
    Metformin: (Minor) Famotidine may decrease the renal clearance of metformin secondary to competition for renal tubular transport systems. Such an interaction has been observed when cimetidine was administered with metformin. The decrease in renal excretion led to a 40% increase in metformin AUC. Although interactions with cationic drugs remain theoretical (except for cimetidine), caution is warranted when famotidine and metformin are prescribed concurrently. Famotidine may be less likely to interact with metformin versus cimetidine or ranitidine because of less tubular excretion.
    Metformin; Pioglitazone: (Minor) Famotidine may decrease the renal clearance of metformin secondary to competition for renal tubular transport systems. Such an interaction has been observed when cimetidine was administered with metformin. The decrease in renal excretion led to a 40% increase in metformin AUC. Although interactions with cationic drugs remain theoretical (except for cimetidine), caution is warranted when famotidine and metformin are prescribed concurrently. Famotidine may be less likely to interact with metformin versus cimetidine or ranitidine because of less tubular excretion.
    Metformin; Repaglinide: (Minor) Famotidine may decrease the renal clearance of metformin secondary to competition for renal tubular transport systems. Such an interaction has been observed when cimetidine was administered with metformin. The decrease in renal excretion led to a 40% increase in metformin AUC. Although interactions with cationic drugs remain theoretical (except for cimetidine), caution is warranted when famotidine and metformin are prescribed concurrently. Famotidine may be less likely to interact with metformin versus cimetidine or ranitidine because of less tubular excretion.
    Metformin; Rosiglitazone: (Minor) Famotidine may decrease the renal clearance of metformin secondary to competition for renal tubular transport systems. Such an interaction has been observed when cimetidine was administered with metformin. The decrease in renal excretion led to a 40% increase in metformin AUC. Although interactions with cationic drugs remain theoretical (except for cimetidine), caution is warranted when famotidine and metformin are prescribed concurrently. Famotidine may be less likely to interact with metformin versus cimetidine or ranitidine because of less tubular excretion.
    Metformin; Saxagliptin: (Minor) Famotidine may decrease the renal clearance of metformin secondary to competition for renal tubular transport systems. Such an interaction has been observed when cimetidine was administered with metformin. The decrease in renal excretion led to a 40% increase in metformin AUC. Although interactions with cationic drugs remain theoretical (except for cimetidine), caution is warranted when famotidine and metformin are prescribed concurrently. Famotidine may be less likely to interact with metformin versus cimetidine or ranitidine because of less tubular excretion.
    Metformin; Sitagliptin: (Minor) Famotidine may decrease the renal clearance of metformin secondary to competition for renal tubular transport systems. Such an interaction has been observed when cimetidine was administered with metformin. The decrease in renal excretion led to a 40% increase in metformin AUC. Although interactions with cationic drugs remain theoretical (except for cimetidine), caution is warranted when famotidine and metformin are prescribed concurrently. Famotidine may be less likely to interact with metformin versus cimetidine or ranitidine because of less tubular excretion.
    Methylphenidate: (Minor) The modified release characteristics of extended-release methylphenidate are pH-dependent. Administration of H2-blockers could alter the release of methylphenidate. Patients receiving extended-release methylphenidate with acid suppressants should be monitored for adverse effects and therapeutic efficacy.
    Naproxen: (Moderate) The enteric-coated, delayed-release naproxen tablets are designed to dissolve at a pH of 6 or greater. Concomitant use of this particular naproxen product with H--blockers is not recommended due to the gastric pH alteration.
    Naproxen; Pseudoephedrine: (Moderate) The enteric-coated, delayed-release naproxen tablets are designed to dissolve at a pH of 6 or greater. Concomitant use of this particular naproxen product with H--blockers is not recommended due to the gastric pH alteration.
    Naproxen; Sumatriptan: (Moderate) The enteric-coated, delayed-release naproxen tablets are designed to dissolve at a pH of 6 or greater. Concomitant use of this particular naproxen product with H--blockers is not recommended due to the gastric pH alteration.
    Neratinib: (Major) Avoid concomitant use of neratinib with H2-blockers due to decreased efficacy of neratinib. Concomitant use with a proton pump inhibitor decreased neratinib exposure by 65%. Concomitant use with other pH lowering agents was not studied, but a decrease in the AUC of neratinib is considered likely.
    Nilotinib: (Moderate) If concomitant use of these agents is necessary, administer the H2-blocker approximately 10 hours before and approximately 2 hours after the nilotinib dose. Nilotinib displays pH-dependent solubility with decreased solubility at a higher pH. The concomitant use of nilotinib and H2-blockers that elevate the gastric pH may reduce the bioavailability of nilotinib. In a study in healthy subjects, there was no significant change in nilotinib pharmacokinetics when a single 400-mg nilotinib dose was given 10 hours after and 2 hours prior to famotidine.
    Pazopanib: (Major) Pazopanib displays pH-dependent solubility with decreased solubility at a higher pH. The concomitant use of pazopanib and H2-blockers, which elevate the gastric pH, may reduce the bioavailability of pazopanib. If a drug is needed to raise the gastric pH, consider use of a short-acting antacid; separate antacid and pazopanib dosing by several hours.
    Polyethylene Glycol; Electrolytes; Bisacodyl: (Minor) The concomitant use of bisacodyl tablets with H2-blockers can cause the enteric coating of the bisacody tablet to dissolve prematurely, leading to possible gastric irritation or dyspepsia. Avoid H2-blockers within 1 hour before or after the bisacodyl dosage.
    Ponatinib: (Major) Ponatinib displays pH-dependent aqueous solubility; therefore, concomitant use of ponatinib and H2-blockers may result in decreased bioavailability and plasma exposure of ponatinib. Avoid concomitant use of ponatinib with H2-blockers unless the benefit outweighs the possible risk of ponatinib underexposure. If the use of both agents is necessary, monitor patients for signs of reduced efficacy.
    Ranolazine: (Moderate) Coadminister ranolazine and famotidine with caution. Famotidine is a substrate of the OCT2 transporter. Dosage reduction for metformin, another OCT2 transporter substrate, is recommended by the manufacturer of ranolazine. Coadministration of metformin and ranolazine 1000 mg twice daily results in increased plasma concentrations of metformin. Doses of metformin do not require reduction if coadministered with ranolazine 500 mg twice daily. Reductions in the famotidine dose may be necessary.
    Rilpivirine: (Moderate) Coadministration with famotidine may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of famotidine for at least 12 hours before and at least 4 hours after administering rilpivirine.
    Risedronate: (Major) Use of H2-blockers with delayed-release risedronate tablets (Atelvia) is not recommended. Co-administration of drugs that raise stomach pH increases risedronate bioavailability due to faster release of the drug from the enteric coated tablet. This interaction does not apply to risedronate immediate-release tablets.
    Secretin: (Major) Discontinue use of H2-blockers at least 2 days before administering secretin. Patients who are receiving H2-blockers at the time of stimulation testing may be hyperresponsive to secretin stimulation, falsely suggesting gastrinoma.
    Sofosbuvir; Velpatasvir: (Major) H2-blockers may be administered simultaneously with or 12 hours apart from velpatasvir. H2-blocker doses should not exceed doses comparable to famotidine 40 mg twice daily. Velpatasvir solubility decreases as pH increases; therefore, drugs that increase gastric pH are expected to decrease the concentrations of velpatasvir, potentially resulting in loss of antiviral efficacy.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) H2-blockers may be administered simultaneously with or 12 hours apart from velpatasvir. H2-blocker doses should not exceed doses comparable to famotidine 40 mg twice daily. Velpatasvir solubility decreases as pH increases; therefore, drugs that increase gastric pH are expected to decrease the concentrations of velpatasvir, potentially resulting in loss of antiviral efficacy.
    Sonidegib: (Moderate) Based on population PK analysis, the concomitant administration of a histamine-2-receptor antagonist such as famotidine decreases the geometric mean sonidegib steady-state AUC (0-24 hours) value by 34%.
    Thalidomide: (Moderate) Thalidomide and other agents that slow cardiac conduction such as H2-blockers should be used cautiously due to the potential for additive bradycardia.
    Theophylline, Aminophylline: (Minor) Aminophylline is a prodrug of theophylline, and is primarily metabolized in the liver by the CYP1A2 isoenzyme. In general, famotidine does not interact with aminophylline and does not affect theophylline levels in most patients. One small study documented a significant decrease in theophylline clearance after therapy with famotidine. Be alert for any evidence of interaction, and monitor the patients aminophylline therapy as per standard of care or if side effects are reported. (Minor) Theophylline is primarily metabolized in the liver by the CYP1A2 isoenzyme. In general, famotidine does not interact with theophylline and does not affect theophylline levels in most patients. One small study documented a significant decrease in theophylline clearance after therapy with famotidine. Be alert for any evidence of interaction, and monitor the patients theophylline therapy as per standard of care or if side effects are reported.
    Tizanidine: (Major) Tizanidine is primarily metabolized by CYP1A2. If possible, avoid the concurrent use of tizanidine with other CYP1A2 inhibitors. Famotidine is a weak CYP1A2 inhibitor. Concurrent use could lead to substantial increases in tizanidine blood concentrations. If concurrent use cannot be avoided, initiate tizanidine therapy with the 2 mg dose and increase in 2 to 4 mg increments daily based on patient response to therapy. Discontinue tizanidine if hypotension, bradycardia, or excessive drowsiness occur.
    Vandetanib: (Minor) Use caution if coadministration of vandetanib with famotidine is necessary, due to a possible increase in famotidine-related adverse reactions. Famotidine is an OCT2 substrate. Coadministration with vandetanib increased the Cmax and AUC of metformin, another OCT2 substrate, by 50% and 74%, respectively.

    PREGNANCY AND LACTATION

    Pregnancy

    Famotidine is classified in FDA pregnancy category B. Animal studies have revealed no evidence of fetal toxicity or teratogenicity. However, there is less animal and human studies data for famotidine as compared with other H2-blockers. The choice of another agent (e.g., ranitidine) may be prudent. In 2009, a population-based observational cohort study explored a possible link between gastric acid suppressive therapy (e.g., H2 blockers) during pregnancy and a diagnosis of allergic disease or a prescription for asthma or allergy medications in the exposed child. Among the cohort (n = 585,716), 1% of children exposed to gastric acid suppressive drugs in pregnancy received a diagnosis of allergic diease. For developing allergy or asthma, an increased OR of 1.43 and 1.51, respectively, were observed regardless of drug used, time of exposure during pregnancy, and maternal history of disease. Proposed possible mechanisms for a link include: (1) exposure to increased amounts of allergens could cause sensitization to digestion-labile antigens in the fetus; (2) the maternal Th2 cytokine pattern could promote an allergy prone phenotype in the fetus; (3) maternal allergen specific immunoglobulin could cross the placenta and sensitize fetal immune cells to food and airborne allergens. Study limitations were present and confirmation of results are necessary before further conclusions can be drawn from this data. Risk versus benefit should be considered prior to use. Self-medication during pregnancy is not recommended; pregnant patients should see their health care professional for a proper diagnosis and for treatment recommendations.

    According to the manufacturer, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Famotidine is secreted into breast milk. However, of all the H2-blockers, famotidine is excreted least in breast milk. Famotidine is also FDA-approved for use in infants and is used in newborns at doses that are higher than those excreted in breast milk. The American Academy of Pediatrics (AAP) considers the use of cimetidine, a related agent, to be usually compatible with breast-feeding due to a lack of reported adverse effects in nursing infants. In general, H2-blockers are considered to be low-risk for use while breast-feeding based on available data.

    MECHANISM OF ACTION

    Famotidine competitively inhibits the binding of histamine to H2-receptors on the gastric basolateral membrane of parietal cells, reducing basal and nocturnal gastric acid secretions. The drug also decreases the gastric acid response to stimuli such as food, caffeine, insulin, betazole, or pentagastrin. Famotidine reduces the total volume of gastric juice, thus indirectly decreasing pepsin secretion. The drug does not appear to alter gastric motility, gastric emptying, esophageal pressures, biliary secretions, or pancreatic secretions. Famotidine may aid in gastromucosal healing, and it may protect the mucosa from the irritant effects caused by aspirin and nonsteroidal antiinflammatory agents.

    PHARMACOKINETICS

    Famotidine is administered orally and parenterally.
     
    The drug distributes widely throughout the body tissues, although only minimally into CSF. Plasma protein binding is approximately 15—20%. There is no cumulative effect with repeat doses; plasma concentrations after multiple doses are similar to those after single doses. Famotidine undergoes minimal first-pass metabolism. The majority (65—70%) of a famotidine dose is excreted in the urine; 30—35% of the dose is metabolized by the liver. The S-oxide metabolite is the only one identified in humans. Famotidine elimination half-life is 2.5—3.5 hours in adults with normal renal function.

    Oral Route

    Bioavailability of famotidine is approximately 40—45%. Famotidine tablets, oral suspension, and orally disintegrating tablets are bioequivalent. Food may slightly increase and antacids may slightly decrease the bioavailability of famotidine, however, the effects are considered clinically insignificant. The onset of action is usually within 1 hour after oral administration with maximum effects occurring within 1—3 hours depending on the dose. The duration of action is roughly 10—12 hours. Twenty-five to 30% of an oral dose are excreted in urine as unchanged drug. 

    Intravenous Route

    Sixty five to 70% of an intravenous dose of famotidine is excreted in urine as unchanged drug.