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  • CLASSES

    H2 Antagonists

    DEA CLASS

    Rx

    DESCRIPTION

    Oral histamine type 2-receptor antagonist
    Used for gastroesophageal reflux disease (GERD), short-term and maintenance treatment of duodenal ulcer, and short-term treatment of active benign gastric ulcer
    For GERD, proton pump inhibitors (PPIs) are considered to be more effective than H2-blockers

    COMMON BRAND NAMES

    Axid

    HOW SUPPLIED

    Axid Oral Sol: 1mL, 15mg
    Axid/Nizatidine Oral Cap: 150mg, 300mg

    DOSAGE & INDICATIONS

    For self-medication of pyrosis (heartburn), acid dyspepsia (acid indigestion), or sour stomach.
    Oral dosage
    Adults, Adolescents, and Children >= 12 years

    To prevent heartburn, take 75 mg PO immediately before or up to 60 minutes before consuming food or beverages that are known to cause symptoms. For treatment, take 75 mg PO once or twice daily. Maximum dosage is 150 mg/day PO. Patients should not take for more than 2 weeks without consulting a physician.

    For the treatment of gastroesophageal reflux disease (GERD), including endoscopically diagnosed esophagitis (erosive and ulcerative esophagitis) and GERD-associated pyrosis (heartburn).
    Oral dosage (capsules)
    Adults

    150 mg PO twice daily for up to 12 weeks.

    Children† and Adolescents† 12 to 17 years

    150 mg PO twice daily for up to 8 weeks.[53019] Alternatively, 5 mg/kg/dose PO twice daily is recommended by the American Academy of Pediatrics (AAP); however, a maximum dosage is not specified.[55232] While nizatidine may be effective in patients with less severe GERD, proton pump inhibitors (PPIs) offer more rapid symptom relief and better healing.[26115]

    Infants† and Children† 1 to 11 years

    5 mg/kg/dose PO twice daily is recommended by the American Academy of Pediatrics (AAP).[55232] Doses of 2.5 to 10 mg/kg/dose PO twice daily have also been reported.[53019] [53036] [55232] In an open-label, multiple-dose, randomized, parallel-group, multicenter study, patients (aged 5 days to 18 years, n = 210) were randomized to receive either of 2 dose levels (2.5 or 5 mg/kg/dose twice daily) for 8 weeks; no clear superiority between doses was observed.[53019] In a separate placebo controlled study, patients (aged 6 months to 8 years, n = 24) with mild to moderate reflux esophagitis received 10 mg/kg/dose PO twice daily for 8 weeks or a matching placebo. Nizatidine therapy was associated with statistically significant improvement in symptoms, reduced esophageal acid exposure, and healed esophagitis.[53036] While nizatidine may be effective in patients with less severe GERD, proton pump inhibitors (PPIs) offer more rapid symptom relief and better healing.[26115]

    Oral dosage (15 mg/mL solution)
    Adults

    150 mg PO twice daily for up to 12 weeks.

    Children and Adolescents 12 to 17 years

    150 mg PO twice daily for up to 8 weeks.[50745] [53019] Alternatively, 5 mg/kg/dose PO twice daily is recommended by the American Academy of Pediatrics (AAP); however, a maximum dosage is not specified.[55232] While nizatidine may be effective in patients with less severe GERD, proton pump inhibitors (PPIs) offer more rapid symptom relief and better healing.[26115]

    Infants† and Children† 1 to 11 years

    5 mg/kg/dose PO twice daily is recommended by the American Academy of Pediatrics (AAP). Doses of 2.5 to 10 mg/kg/dose PO twice daily have also been reported. In an open-label, multiple-dose, randomized, parallel-group, multicenter study, patients (aged 5 days to 18 years, n = 210) were randomized to receive either of 2 dose levels (2.5 or 5 mg/kg/dose twice daily) for 8 weeks; no clear superiority between doses was observed. In a separate placebo controlled study, patients (aged 6 months to 8 years, n = 24) with mild to moderate reflux esophagitis received 10 mg/kg/dose PO twice daily for 8 weeks or a matching placebo. Nizatidine therapy was associated with statistically significant improvement in symptoms, reduced esophageal acid exposure, and healed esophagitis. While nizatidine may be effective in patients with less severe GERD, proton pump inhibitors (PPIs) offer more rapid symptom relief and better healing.

    Neonates†

    2.5 to 5 mg/kg/dose PO twice daily for 8 weeks has been studied for GERD in an open-label, multiple-dose, randomized, parallel-group, multicenter study. Patients (aged 5 days to 18 years, n = 210) were randomized to receive either of 2 dose levels (2.5 or 5 mg/kg/dose twice daily) for 8 weeks; no clear superiority between doses was observed. Neonatal data were not reported separately. While nizatidine may be effective in patients with less severe GERD, proton pump inhibitors (PPIs) offer more rapid symptom relief and better healing.

    For the treatment of duodenal ulcer.
    For an active ulcer.
    Oral dosage (capsules or 15 mg/mL solution)
    Adults

    300 mg PO at bedtime, or 150 mg PO every 12 hours, for 8 weeks. In most patients, ulcers heal within 4 weeks.

    For maintenance therapy after the ulcer has healed.
    Oral dosage (capsules or 15 mg/mL solution)
    Adults

    150 mg PO at bedtime. Treatment beyond 1 year has not been evaluated.

    For the treatment of an active benign gastric ulcer.
    Oral dosage (capsules or 15 mg/mL solution)
    Adults

    300 mg PO daily, administered once daily at bedtime or as 150 mg every 12 hours, for 8 weeks. Prior to treatment, care should be taken to exclude the possibility of malignant gastric ulceration.

    For use in acid aspiration prophylaxis† prior to anesthesia.
    Oral dosage (capsules or 15 mg/ml solution)
    Adults

    300 mg the night before or the morning of surgery, prior to induction of anesthesia.

    For stress gastritis prophylaxis† in critically-ill patients.
    Oral dosage (capsules or 15 mg/ml solution)
    Adults

    150—300 mg PO once daily.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    300 mg/day PO.

    Geriatric

    300 mg/day PO.

    Adolescents

    300 mg/day PO.

    Children

    12 years and older: 300 mg/day PO.
    1 to 11 years: 10 to 20 mg/kg/day PO has been studied.

    Infants

    6 months and older: 10 to 20 mg/kg/day PO has been studied.
    1 to 5 months: 10 mg/kg/day PO has been studied.

    Neonates

    10 mg/kg/day PO has been studied.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    The manufacturer states that in patients with compensated cirrhosis, there are minor but clinically insignificant alterations in nizatidine half-life and clearance. Specific dosage adjustments have not been recommended.

    Renal Impairment

    The following is based on adult recommendations from the manufacturer:
    CrCl > 50 ml/min: No dosage adjustment needed.
    CrCl 20—50 ml/min: For patients receiving treatment for active duodenal ulcer, GERD, or benign gastric ulcer, decrease the dose to 150 mg PO once daily; for patients receiving maintenance therapy, decrease the dose to 150 mg PO every other day.
    CrCl < 20 ml/min: For patients receiving treatment for active duodenal ulcer, GERD, or benign gastric ulcer, decrease the dose to 150 mg PO every other day; for patients receiving maintenance therapy, decrease the dose to 150 mg PO once every 3 days.
    Specific dosage adjustments for pediatric patients with renal impairment are not available.
     
    Intermittent Hemodialysis
    The ability of hemodialysis to remove nizatidine from the body has not been conclusively demonstrated; however, due to the drug's large volume of distribution, nizatidine is not expected to be efficiently removed from the body by this method.

    ADMINISTRATION

    Oral Administration

    All oral dosage forms: May be administered without regard to meals. Administer with food, water, or milk to minimize gastric irritation.
    For non-prescription occasional dosing, if a meal or beverage is known to cause heartburn (pyrosis), may administer 30—60 minutes prior to consuming such food or beverage. Administer with a full glass of water.

    Oral Liquid Formulations

    Oral solution: Administer using a calibrated measuring device to assure accurate dosage.

    STORAGE

    Axid:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Axid AR:
    - 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 nizatidine is used with antimicrobials, clinicians should be cognizant of possible pseudomembranous colitis. 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

    Nizatidine is contraindicated in any patient hypersensitive to the drug or its components. Cross-sensitivity in this class of compounds has been observed, so nizatidine 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. Patients who are self-medicating with nizatidine OTC (Axid AR) should not use nizatidine if they have an allergy to nizatidine or other acid reducers.

    Dysphagia, gastric cancer

    Symptomatic response to therapy with nizatidine 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 who are self-medicating with nizatidine (Axid AR) should seek professional health care provider advice prior to using nizatidine if they are having pain or difficulty while swallowing (dysphagia), vomiting with blood, or have bloody or black stools.

    Infection

    Symptomatic response to therapy with nizatidine does not preclude the presence of H. pylori infection. Nizatidine therapy does not appear to interfere with the sensitivity of gastric urease biopsy or urea breath-tests for the detection of H. pylori in most patients. H2-blockers, as single agents, will not eradicate H. pylori infection, if present.

    Pregnancy

    Self-medication of nizatidine during pregnancy is not recommended; pregnant patients should see their health care professional for a proper diagnosis and for treatment recommendations. However, according to the American Gastroenterologist Association, the relatively smaller amount of data available from animal and human studies with nizatidine as compared with other H2-blockers makes the choice of another agent prudent. Risk versus benefit should be considered prior to use. Data from animal studies of nizatidine with high doses (300 times the recommended human dose) report more abortions, lower fetal weight, and fewer live fetuses than non-exposed offspring. In 2009, a population-based observational cohort study explored a possible link between gastric acid-suppressive therapy 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 disease. 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 the 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 is necessary before further conclusions can be drawn from this data.

    Breast-feeding

    According to the manufacturer, because nizatidine is excreted into breast milk, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Animal studies have documented transient growth depression in immature animals receiving nizatidine via breast milk. However, studies conducted in lactating women have shown that 0.1% of the administered oral dose of nizatidine is secreted in human milk in proportion to plasma concentrations ; therefore, minimal drug exposure to a breast-feeding infant is expected. Alternative therapies for consideration include antacids and other H2 blockers. In newborns, an H2-antagonist with more extensive use, such as cimetidine or famotidine, may be preferred over nizatidine.

    Children, infants, neonates

    The safety and efficacy of nizatidine have not been established in neonates, infants, and children <= 12 years for most indications. Dosages and efficacy have not been established for pathologic hypersecretory conditions. Self-medication (i.e., OTC) of nizatidine in children under the age of 12 years is not recommended.

    Renal failure, renal impairment

    Nizatidine should be used with caution in patients with renal impairment or renal failure because the drug is eliminated via glomerular filtration. Nizatidine can be prescribed to patients with renal impairment if appropriate dosage reductions are made.

    Tobacco smoking

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

    Geriatric

    No overall differences in safety or effectiveness were observed between geriatric subjects vs. younger subjects in clinical studies of nizatidine. Nizatidine is substantially excreted by the kidney and dose reduction may be necessary if renal impairment is present; monitoring of renal function in the geriatric patient may be useful. 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. 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.

    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 / 0-1.0
    exfoliative dermatitis / Delayed / 0-1.0
    vasculitis / Delayed / 0-1.0
    ventricular tachycardia / Early / 0-1.0
    anaphylactoid reactions / Rapid / 0-1.0
    bronchospasm / Rapid / 0-1.0
    laryngeal edema / Rapid / 0-1.0
    serum sickness / Delayed / 0-1.0
    atrophic gastritis / Delayed / Incidence not known

    Moderate

    chest pain (unspecified) / Early / 2.3-2.3
    confusion / Early / 0-1.0
    amblyopia / Delayed / 1.0-1.0
    impotence (erectile dysfunction) / Delayed / 0-1.0
    thrombocytopenia / Delayed / 0-1.0
    hyperuricemia / Delayed / 0-1.0
    eosinophilia / Delayed / 0-1.0
    cholestasis / Delayed / 0-1.0
    hepatitis / Delayed / 0-1.0
    elevated hepatic enzymes / Delayed / 0-1.0
    jaundice / Delayed / 0-1.0
    anemia / Delayed / 0.2-0.2
    vitamin B12 deficiency / Delayed / Incidence not known
    pernicious anemia / Delayed / Incidence not known

    Mild

    headache / Early / 16.6-16.6
    rhinitis / Early / 9.8-9.8
    dizziness / Early / 4.6-4.6
    sinusitis / Delayed / 2.4-2.4
    drowsiness / Early / 1.9-1.9
    anxiety / Delayed / 1.8-1.8
    infection / Delayed / 1.7-1.7
    pruritus / Rapid / 1.7-1.7
    myalgia / Early / 1.7-1.7
    xerostomia / Early / 1.4-1.4
    rash / Early / 0-1.0
    purpura / Delayed / 0-1.0
    gynecomastia / Delayed / 0-1.0
    urticaria / Rapid / 0.5-0.5
    irritability / Delayed / 5.0
    nasal congestion / Early / 5.0
    pharyngitis / Delayed / 3.3
    cough / Delayed / 5.0
    vomiting / Early / 5.0
    diarrhea / Early / 5.0
    fever / Early / 5.0

    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.
    Amphetamine; Dextroamphetamine Salts: (Moderate) The use of H2-blockers with amphetamine therapy may change the onset of action of amphetamine or dextroamphetamine due to the increase in gastric pH. The time to maximum concentration (Tmax) of these amphetamines is decreased compared to when administered alone, thus increasing stimulant concentrations, which may be of particular significance with extended-release dosage forms. Monitor clinical response and adjust if needed.
    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: (Moderate) Monitor for altered response to budesonide in patients receiving H2-blockers with enteric-coated or extended-release formulations of oral budesonide. 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.
    Budesonide; Formoterol: (Moderate) Monitor for altered response to budesonide in patients receiving H2-blockers with enteric-coated or extended-release formulations of oral budesonide. 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.
    Budesonide; Glycopyrrolate; Formoterol: (Moderate) Monitor for altered response to budesonide in patients receiving H2-blockers with enteric-coated or extended-release formulations of oral budesonide. 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.
    Cabotegravir; Rilpivirine: (Moderate) Coadministration with nizatidine may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of nizatidine for at least 12 hours before and at least 4 hours after administering rilpivirine.
    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.
    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.
    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.
    Dacomitinib: (Moderate) Administer dacomitinib at least 6 hours before or 10 hours after taking nizatidine due to the risk of decreased plasma concentrations of dacomitinib which may impact efficacy. Although the effect of H2-blockers on dacomitinib pharmacokinetics has not been studied, coadministration with a proton pump inhibitor decreased the dacomitinib Cmax and AUC by 51% and 39%, respectively.
    Dasatinib: (Major) Do not administer H2-blockers with dasatinib due to the potential for decreased dasatinib exposure and reduced efficacy. Consider using an antacid if acid suppression therapy is needed. Administer the antacid at least 2 hours prior to or 2 hours after the dose of dasatinib. Concurrent use of an H2-blocker reduced the mean Cmax and AUC of dasatinib by 63% and 61%, respectively.
    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.
    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 nizatidine may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of nizatidine for at least 12 hours before and at least 4 hours after administering rilpivirine.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Coadministration with nizatidine may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of nizatidine for at least 12 hours before and at least 4 hours after administering rilpivirine.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Moderate) Coadministration with nizatidine may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of nizatidine for at least 12 hours before and at least 4 hours after administering rilpivirine.
    Erlotinib: (Major) If concomitant use of erlotinib with nizatidine is necessary, erlotinib must be taken 10 hours after the last dose of nizatidine and at least 2 hours before the next dose. Erlotinib displays pH-dependent solubility with decreased solubility at a higher pH; the increased gastric pH resulting from nizatidine 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. Erlotinib exposure was decreased by 33% and the Cmax by 54% when erlotinib was administered 2 hours after a single dose of an H2-antagonist. When administered at least 10 hours after an evening dose of an H2-antagonist and 2 hours before the morning dose, erlotinib exposure was decreased by 15% and Cmax by 17%.
    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: (Major) Avoid coadministration of nizatidine with gefitinib if possible due to decreased exposure to gefitinib, which may lead to reduced efficacy. If concomitant use is unavoidable, take gefitinib 6 hours after the last dose or 6 hours before the next dose of nizatidine. Gefitinib exposure is affected by gastric pH. Coadministration with high doses of an H2-blocker to maintain gastric pH above 5 decreased gefitinib exposure by 47%.
    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) When administering H2-blockers with the 100 mg itraconazole capsule and 200 mg itraconazole tablet formulations, systemic exposure to itraconazole is decreased. Conversely, exposure to itraconazole is increased when H2-blockers are administered with the 65 mg itraconazole capsule. Administer H2-blockers at least 2 hours before or 2 hours after the 100 mg capsule or 200 mg tablet. Monitor for increased itraconazole-related adverse effects if H2-blockers are administered with itraconazole 65 mg capsules.
    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.
    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.
    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.
    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) Take neratinib at least 2 hours before the next dose of an H2-blocker or 10 hours after the last dose of an H2-blocker due to decreased absorption and systemic exposure of neratinib; the solubility of neratinib decreases with increasing pH of the GI tract. The Cmax and AUC of neratinib were reduced by 57% and 48%, respectively, when administered 2 hours after a daily dose of ranitidine 300 mg. The Cmax and AUC of neratinib were reduced by 44% and 32%, respectively, when administered 2 hours before ranitidine 150 mg twice daily (given approximately 12 hours apart).
    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.
    Octreotide: (Moderate) Coadministration of oral octreotide with H2-blockers may require increased doses of octreotide. Coadministration of oral octreotide with drugs that alter the pH of the upper GI tract, including H2-blockers, may alter the absorption of octreotide and lead to a reduction in bioavailability.
    Pazopanib: (Major) Avoid coadministration of pazopanib with H2-blockers due to decreased absorption of pazopanib, which may decrease efficacy. If concomitant administration with a gastric acid-reducing agent is unavoidable, consider the use of a short-acting antacid in place of an H2-blocker; separate administration of the short-acting antacid and pazopanib by several hours to avoid a reduction in pazopanib exposure. Concomitant use of pazopanib with a proton pump inhibitor decreased pazopanib exposure (AUC and Cmax) by approximately 40%.
    Pexidartinib: (Moderate) Administer pexidartinib 2 hours before or 10 hours after H2-blockers as concurrent administration may reduce pexidartinib exposure. Although the effects of H2-blockers on pexidartinib pharmacokinetics have not been studied, other acid-reducing agents have been shown to decrease pexidartinib exposure by 50%.
    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.
    Rilpivirine: (Moderate) Coadministration with nizatidine may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of nizatidine 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.
    Selpercatinib: (Major) Avoid coadministration of selpercatinib with nizatidine due to the risk of decreased selpercatinib exposure which may reduce its efficacy. If concomitant use is unavoidable, take selpercatinib 2 hours before or 10 hours after administration of nizatidine. Coadministration with acid-reducing agents decreases selpercatinib plasma concentrations; however, no clinically significant differences in the pharmacokinetics of selpercatinib were observed when given under fasting conditions with multiple daily doses of another H2-receptor antagonist given 10 hours prior to and 2 hours after the selpercatinib dose.
    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 nizatidine 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.

    PREGNANCY AND LACTATION

    Pregnancy

    Self-medication of nizatidine during pregnancy is not recommended; pregnant patients should see their health care professional for a proper diagnosis and for treatment recommendations. However, according to the American Gastroenterologist Association, the relatively smaller amount of data available from animal and human studies with nizatidine as compared with other H2-blockers makes the choice of another agent prudent. Risk versus benefit should be considered prior to use. Data from animal studies of nizatidine with high doses (300 times the recommended human dose) report more abortions, lower fetal weight, and fewer live fetuses than non-exposed offspring. In 2009, a population-based observational cohort study explored a possible link between gastric acid-suppressive therapy 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 disease. 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 the 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 is necessary before further conclusions can be drawn from this data.

    According to the manufacturer, because nizatidine is excreted into breast milk, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Animal studies have documented transient growth depression in immature animals receiving nizatidine via breast milk. However, studies conducted in lactating women have shown that 0.1% of the administered oral dose of nizatidine is secreted in human milk in proportion to plasma concentrations ; therefore, minimal drug exposure to a breast-feeding infant is expected. Alternative therapies for consideration include antacids and other H2 blockers. In newborns, an H2-antagonist with more extensive use, such as cimetidine or famotidine, may be preferred over nizatidine.

    MECHANISM OF ACTION

    Mechanism of Action: Nizatidine competitively inhibits the binding of histamine to the 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. Nizatidine 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. Nizatidine may aid in gastromucosal healing, and it may protect the mucosa from the irritant effects caused by aspirin and nonsteroidal antiinflammatory agents. H2-blockers, as single agents, do not erradicate H. pylori infection.

    PHARMACOKINETICS

    Nizatidine is administered orally.
     
    The drug is roughly 35% protein-bound. Approximately 7% of an oral dose is metabolized in the liver to N2-monodesmethylnizatidine, which has H2-antagonist activity. Approximately 60% of unchanged drug and its metabolites are excreted in the urine and approximately 6% in the feces. Nizatidine is eliminated by both glomerular filtration and active tubular secretion. The elimination half-life is 1 to 2 hours.

    Oral Route

    The bioavailability of nizatidine is about 95% in patients with normal renal function. The presence of food in the GI tract appears to increase the absorption of nizatidine. The drug distribution is unknown.