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  • CLASSES

    H2 Antagonists

    DEA CLASS

    Rx, OTC

    DESCRIPTION

    Oral and parenteral H2-receptor antagonist
    Used for gastrointestinal disorders such as peptic ulcer and gastroesophageal reflux disease
    More potent histamine antagonist than cimetidine; less affinity for CYP450 enzymes

    COMMON BRAND NAMES

    Acid Reducer, Ranitidine, Taladine, Wal-Zan, Zantac, Zantac 150, Zantac 75

    HOW SUPPLIED

    Acid Reducer/Ranitidine/Ranitidine Hydrochloride/Wal-Zan/Zantac/Zantac 150/Zantac 75 Oral Tab: 75mg, 150mg, 300mg
    Ranitidine Hydrochloride/Taladine Oral Cap: 150mg, 300mg
    Ranitidine Hydrochloride/Zantac Intramuscular Inj Sol: 1mL, 25mg
    Ranitidine Hydrochloride/Zantac Intravenous Inj Sol: 1mL, 25mg
    Ranitidine Hydrochloride/Zantac Oral Sol: 1mL, 15mg

    DOSAGE & INDICATIONS

    For the self-medication of non-ulcer dyspepsia (acid indigestion), pyrosis (heartburn), and sour stomach.
    For prophylaxis.
    Oral dosage - OTC product
    Adults and Adolescents

    75 to 150 mg PO immediately before eating or up to 60 minutes before consuming food and beverages that may cause heartburn. Tablets can be taken up to twice daily (maximum daily dose of 300 mg PO). Patients should not take for more than 2 weeks without consulting a physician.

    Children < 12 years

    OTC use is not recommended unless advised by a qualified health care prescriber.

    For treatment.
    Oral dosage - OTC product
    Adults and Adolescents

    75 to 150 mg PO once or twice daily. Patients should not take for more than 2 weeks without consulting a physician.

    Children < 12 years

    OTC use is not recommended unless advised by a qualified health care prescriber.

    For the treatment of gastroesophageal reflux disease (GERD).
    NOTE: While ranitidine may be effective in patients with less severe GERD, proton pump inhibitors (PPIs) offer more rapid symptom relief and better healing.
    For short-term treatment (acute healing phase).
    Oral dosage
    Adults and Adolescents

    150 mg PO twice daily. Symptomatic relief usually occurs within 24 hours after starting therapy. Although higher doses of ranitidine have been studied (300 mg PO twice daily), doubling the standard dose not improve efficacy; if a standard dose is not effective, consider alternate therapy (e.g., PPI).

    Infants and Children

    5 to 10 mg/kg/day PO, administered in 2 or 3 divided doses. Continue therapy for 6 to 8 weeks if improvement in symptoms is noted.

    For maintenance treatment† (relapse prevention).
    Oral dosage
    Adults and Adolescents

    150 mg PO twice daily. The American College of Gastroenterology recommends that treatment be continued for as long as necessary to control symptoms and prevent complications.

    For the treatment of erosive esophagitis.
    For endoscopically diagnosed erosive esophagitis.
    Oral dosage
    Adults and Adolescents

    150 mg PO 4 times per day for up to 12 weeks. Symptomatic relief may begin within 24 hours of initiation of treatment.

    Infants and Children

    5 to 10 mg/kg/day PO, administered in 2 or 3 divided doses.

    To maintain healing in erosive esophagitis after the initial treatment phase is complete.
    Oral dosage
    Adults and Adolescents

    150 mg PO twice daily. NOTE: Single doses administered prior to bedtime (i.e., 300 mg PO at bedtime) have been less effective than 150 mg PO twice daily. Placebo-controlled studies have been carried out for 48 weeks.

    Infants and Children

    Specific guidelines have not been established.

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

    Initially, 150 mg PO twice daily; however, larger doses are usually necessary; in some patients, more frequent dosing may be necessary. Maximum dose for this condition is 6 g/day PO, administered in divided doses. Continue as long as clinically indicated.

    Intravenous or Intramuscular dosage
    Adults and Adolescents

    50 mg IV (intermittent infusion) or IM every 6 to 8 hours; however, larger doses may be necessary. In general, do not exceed 400 mg/day IV, administered in divided doses.

    Continuous Intravenous infusion dosage
    Adults and Adolescents

    For patients with Zollinger-Ellison syndrome, begin infusion at 1 mg/kg/hour. After 4 hours, if the measured gastric acid output is greater than 10 mEq/hour or the patient is symptomatic, adjust the dose upward in 0.5 mg/kg/hour increments, and remeasure the acid output. Dosages up to 2.5 mg/kg/hour or infusion rates up to 220 mg/hour have been used.

    For the treatment of peptic ulcer disease (duodenal ulcer or gastric ulcer) or gastritis†.
    NOTE: For dosing in patients with gastric or duodenal ulcers due to H. pylori, see “H. pylori eradication” indication.
    NOTE: If gastritis or ulceration is due to NSAID therapy, every effort should be made to discontinue the NSAID.
    For short-term treatment of active benign gastric ulcer, active duodenal ulcer or gastritis†.
    Oral dosage
    Adults and Adolescents

    150 mg PO twice daily or 300 mg PO once daily after the evening meal or at bedtime. Most duodenal ulcers heal within 4 weeks, most gastric ulcers heal within 6 weeks. Per the manufacturer, many foreign trials have shown that 100 mg PO twice daily has been as effective as 150 mg PO twice daily for duodenal ulcer. Safety of therapy beyond 8 weeks for uncomplicated duodenal ulcer or beyond 6 weeks for benign gastric ulcer has not been assessed. If follow-up maintenance therapy is indicated, see dosage below.

    Infants and Children

    2 to 4 mg/kg PO twice daily. Maximum dosage for active treatment is 300 mg/day PO.

    Intermittent Intravenous or Intramuscular dosage
    Adults and Adolescents

    50 mg IV or IM every 6 to 8 hours.

    Infants and Children

    2 to 4 mg/kg/day IV divided and administered every 6 to 8 hours, up to a maximum dose of 50 mg IV every 6 to 8 hours.

    Continuous Intravenous infusion dosage
    Adults and Adolescents

    6.25 mg/hour via continuous IV infusion (i.e., total daily dosage will equal 150 mg/24 hours).

    For maintenance therapy after treatment phase is complete.
    Oral dosage
    Adults and Adolescents

    150 mg PO once daily at bedtime. No placebo-controlled studies have lasted for longer than 1 year.

    Infants and Children

    2 to 4 mg/kg/day PO, administered once daily at bedtime. Maximum maintenance dosage 150 mg/day PO.

    For Helicobacter pylori (H. pylori) eradication† in the treatment of patients with peptic ulcer disease, dyspepsia, or gastric mucosa associated lymphoid tissue (MALT) lymphoma†.
    NOTE: The American College of Gastroenterology (ACG) recommends 10—14 days of a triple-drug regimen containing a proton pump inhibitor (PPI), clarithromycin, and either amoxicillin or metronidazole; the same combination for 14 days continues to be recommended as first line therapy in the 2006 global updates from the Maastricht III Consensus Report.
    NOTE: Ranitidine is not effective as a single agent for the eradication of H. pylori. 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 PPI in any current H. pylori treatment regimen unless the patient cannot tolerate a PPI.
    NOTE: In populations where H. pylori infection is common (>= 10%), 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 (also see Helidac monograph).
    NOTE: A large body of data exist to support the importance of H. pylori eradication as the first line treatment of gastric MALT lymphoma. Following H. pylori eradication, long term tumor regression is observed in 60—90% of patients.
    Oral dosage
    Adults and Adolescents

    150 mg PO twice daily or 300 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 ranitidine 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.

    For acid aspiration prophylaxis† prior to anesthesia.
    NOTE: Routine use of H2-blockers prior to surgery to decrease the risks of pulmonary aspiration in patients who have no apparent increased risk for pulmonary aspiration is not recommended. Consult current practice guidelines.
    Oral dosage
    Adults

    150 mg PO 3 hours before anesthesia induction has been shown to be effective in improving gastric fluid properties.

    Intravenous or Intramuscular dosage
    Adults and Adolescents

    50 mg IV 60 minutes prior to induction of anesthesia.

    Children

    1 to 2 mg/kg IM 2 hours prior to induction of anesthesia.

    For NSAID-induced ulcer prophylaxis†.
    Oral dosage
    Adults

    A placebo-controlled, double blind study of 263 patients with either rheumatoid arthritis or osteoarthritis, 150 mg PO twice daily reduced the incidence of duodenal ulceration but not gastric ulceration. Efficacy was determined by endoscopy.

    For stress gastritis prophylaxis† in critically-ill patients.
    NOTE: The 2008 Surviving Sepsis Campaign guidelines recommend H2-blockers or proton pump inhibitors be used in patients with sepsis or septic shock to prevent gastritis.
    Intermittent Intravenous dosage
    Adults and Adolescents

    50 mg IV every 8 hours.

    Infants and Children

    2 to 4 mg/kg/day IV in divided doses every 6 to 8 hours. In a prospective study of 45 critically ill patients (median age: 3 years; range: 2 weeks to 22 years), a dosage of at least 3 mg/kg/day IV given in divided doses was required in most children to maintain gastric pH 4 or higher. Dosages of up to 1.5 mg/kg IV every 6 hours have been used.

    Premature and term neonates

    Per the manufacturer, a dose of 2 mg/kg IV every 12 to 24 hours is sufficient to increase the gastric pH higher than 4 for 15 hours in neonates receiving ECMO. Alternatively, up to 5 mg/kg/day IV, administered in divided doses every 8 hours, has been used.

    Continuous Intravenous infusion dosage
    Adults and Adolescents

    6.25 mg/hour via continuous IV infusion (i.e., total daily dosage will equal 150 mg/24 hours).

    Infants and Children

    In a study of critically ill children, 0.45 mg/kg IV bolus load followed by 0.15 mg/kg/hour (3.6 mg/kg/day) continuous IV infusion maintained ranitidine concentrations sufficient to keep gastric pH higher than 4. The authors recommend monitoring of gastric pH and adjusting the dose when necessary.Premature and Term Neonates: 2 mg/kg continuous IV infusion in patients receiving ECMO has been effective.

    Premature and Term Neonates

    2 mg/kg continuous IV infusion in patients receiving ECMO has been effective.

    For the treatment of acute, severe urticaria† or angioedema† associated with systemic symptoms in combination with an H1-blocker.
    For the prevention of urticaria† and other histamine-mediated reactions† to specific types of chemotherapy (e.g., paclitaxel).
    Intravenous dosage (intermittent IV infusion)
    Adults

    50 mg IV, appropriately diluted, in combination with an H1-blocker (e.g., diphenhydramine) and dexamethasone, administered 30 minutes prior to the initiation of the chemotherapy agent.

    Intravenous dosage
    Adults

    50 mg IV (appropriately diluted), in combination with an H1-blocker (e.g., diphenhydramine).

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    300 mg/day PO or 200 mg/day IV for most indications; up to 6 grams/day PO or 220 mg/hr continuous IV for pathologic hypersecretory conditions.

    Elderly

    300 mg/day PO or 200 mg/day IV for most indications; up to 6 grams/day PO or 220 mg/hr continuous IV for pathologic hypersecretory conditions.

    Adolescents

    300 mg/day PO or 200 mg/day IV for most indications; up to 6 grams/day PO or 220 mg/hr continuous IV for pathologic hypersecretory conditions.

    Children

    4 mg/kg/day PO or IV for most indications, not to exceed 300 mg/day PO for active treatment or 150 mg/day PO for maintenance treatment of peptic ulcer disease; not to exceed doses of 200 mg/day IV; 5—10 mg/kg/day PO has been used for GERD/erosive esophagitis treatment.

    Infants

    4 mg/kg/day PO or IV for most indications; 5—10 mg/kg/day PO has been used for GERD/erosive esophagitis treatment.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    In patients with compensated cirrhosis, there are minor but clinically insignificant alterations in ranitidine half-life and clearance. It appears that no dosage adjustment is needed in patients with hepatic impairment.

    Renal Impairment

    CrCl >= 50 ml/min: No dosage adjustment needed.
    CrCl < 50 ml/min: Reduce recommended dose by 50% (or extend dosing interval). For example, the manufacturer recommends a dosage of 150 mg PO every 24 hours or 50 mg IV every 18—24 hours for adults. Depending upon the patient's condition, the PO or IV dosage may be cautiously increased to every 12 hours if required.
     
    Intermittent Hemodialysis
    Ranitidine is removed to some degree by hemodialysis. The patient's normal dosage schedule based on CrCl should be adjusted, when possible, so that the timing of a regularly scheduled dose coincides with the end of a hemodialysis session.

    ADMINISTRATION

    Oral Administration

    All oral dosage forms: May be administered without regard to meals. May administer with food, water, or milk to minimize gastric irritation.

    Oral Liquid Formulations

    Oral Solution (Syrup): Measure with calibrated oral syringe or cup prior to administration to give an accurate dosage. Alternatively, ranitidine oral solution may be administered via feeding tube in patients requiring enteral feeding. In vitro stability analysis demonstrates that > 90% of ranitidine syrup is recovered at 24 hours after mixing with eight different enteral feedings. No interaction with food was noted, thus, no medication administration changes are necessary.

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit; undiluted ranitidine tends to exhibit a yellow color that may intensify over time that does not adversely affect potency.
    Administer via the intramuscular (IM) or intravenous (IV) routes.
    Compatible solutions for dilution include D5W, D10W, NS, lactated ringers, or 5% sodium bicarbonate.
    Pharmacy bulk vial package is only available for preparing admixtures; the pre-mixed infusion bags are only for slow IV infusion administration.
    Storage of diluted injection: Diluted solutions are stable for up to 48 hours at room temperature.

    Intravenous Administration

    IV Push
    Dilute to a maximum of 2.5 mg/ml (50 mg/20 ml) using non-preserved NS or other compatible IV solution.
    Inject at a rate no greater than 4 ml/minute (i.e., 50 mg/20 ml dose should be pushed over 5 minutes).
     
    Intermittent IV infusion
    Dilute to a maximum of 0.5 mg/ml using D5W, NS, or other compatible IV solution. Infuse over 15—20 minutes (5—7 ml/minute).
    Pre-mixed ready-to-use infusion bags are available as 1 mg/ml ranitidine (i.e., 50 mg/50 ml). Premixed ready-to-use bags are for slow IV administration only; infuse over 15—20 minutes.
     
    Continuous 24-hour IV infusion
    For adults, dilute 150 mg in 250 ml of D5W or NS or another compatible solution. The diluted solution is stable for up to 48 hours at room temperature. Infuse over 24 hours at a rate of 6.25 mg/hr or as specified by physician. For Zollinger-Ellison patients, dilute in D5W or NS or another compatible solution up to a maximum concentration of 2.5 mg/ml.
    Use a controlled-rate infusion device.
    Alternatively, the dosage may be added to a compatible TPN solution for administration over 24 hours.

    Intramuscular Administration

    No dilution necessary.
    Inject into a large muscle mass. Aspirate prior to injection to avoid injection into a blood vessel.

    STORAGE

    Generic:
    - Protect from light
    - Store at room temperature (between 59 to 86 degrees F)
    - Store in a dry place
    Acid Reducer:
    - Avoid excessive heat (above 104 degrees F)
    - Avoid excessive humidity
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Ranitidine:
    - Avoid excessive heat (above 104 degrees F)
    - Avoid excessive humidity
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Taladine:
    - Protect from light
    - Store at room temperature (between 59 to 86 degrees F)
    - Store in a dry place
    Wal-Zan:
    - Avoid excessive heat (above 104 degrees F)
    - Avoid excessive humidity
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Zantac:
    - Do not freeze
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Zantac 150:
    - Avoid excessive heat (above 104 degrees F)
    - Avoid excessive humidity
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Zantac 75:
    - Avoid excessive heat (above 104 degrees F)
    - Avoid excessive humidity
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Zantac EFFERdose:
    - Store between 36 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Because false positive tests for urine protein may occur with MULTISTIX during ranitidine therapy, testing with sulfosalicylic acid is recommended.
     
    H2 blockers can be used in combination with certain antibiotics to eradicate Helicobacter pylori.[33113] When ranitidine 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

    Ranitidine is contraindicated in any patient hypersensitive to the drug or its components. Cross-sensitivity in this class of compounds has been observed, so ranitidine 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

    Symptomatic response to therapy with ranitidine does not preclude the presence of gastric cancer. In the patient who is self-medicating with OTC ranitidine formulations, the continuation of heartburn, acid indigestion, or dyspepsia beyond 2 weeks signals the need to consult a health-care professional for evaluation.

    Infection

    Symptomatic response to therapy with ranitidine does not preclude the presence of H. pylori infection. Ranitidine 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.

    Hepatic disease

    Because ranitidine is metabolized in the liver, caution should be observed in patients with hepatic disease. Nevertheless, studies in patients with hepatic dysfunction (compensated cirrhosis) indicate that there are minor, but clinically insignificant, alterations in ranitidine half-life, distribution, clearance, and bioavailability. In addition, elevated SGPT (AST) has been observed with IV H2-antagonists administered at greater-than-recommended dosages for 5 days or longer. Monitoring liver enzymes daily, from day 5 to the end of IV therapy, is recommended for patients receiving IV ranitidine at dosages >= 100 mg 4 times daily for periods of 5 days or longer.

    Renal disease, renal failure, renal impairment

    Ranitidine should be used cautiously in those patients with renal disease, specifically in those with renal impairment or renal failure. Accumulation of ranitidine can occur. Ranitidine dosage should be reduced in patients with creatinine clearances of less than 50 ml/min.

    Children, infants, neonates, premature neonates

    The safety and efficacy of ranitidine have been established in children and infants from 1 month to 16 years of age for most indications. Dosages and efficacy have not been established for hypersecretory conditions or the maintenance of healing of erosive esophagitis in pediatric patients. Ranitidine has been used successfully in critically ill children and infants for the purpose of stress-ulcer or acid-reflux prophylaxis (see Dosage). There is limited information on ranitidine use in neonates. Ranitidine elimination is decreased in premature neonates compared to term neonates; dosage adjustment is required in this population (see Dosage). Self-medication (i.e., OTC use) in children under the age of 12 years is not recommended.

    Pregnancy

    Ranitidine is classified in FDA pregnancy risk category B. Animal studies have not demonstrated a risk to the fetus but there are no adequate studies in pregnant women. Ranitidine does cross the placenta; mean fetal:maternal ratios are approximately 0.9 after IV administration versus 0.4 for oral dosages. Human epidemiological evidence has not suggested an association between the drug and congenital defects in first trimester exposure.  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. In general, experts consider ranitidine a preferred H2 blocker when one is necessary in pregnancy, due to more documented data of efficacy and safety in the pregnant population versus other agents. 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. Limited use of single dosages of ranitidine for reducing gastric acid during labor and prior to obstetric delivery, including caesarian section, have not been noted to adversely affect labor or neonatal outcomes.

    Breast-feeding

    The manufacturer recommends that caution be used with administering ranitidine to women who are breast-feeding their infants. Ranitidine is excreted into human breast milk. Milk concentrations increase with time after the administration of a maternal oral dose. Mean maternal milk:plasma ratios at 2 and 6 hours after a single oral dose are 1.9 and 6.7, respectively, although higher concentrations have also been reported. In a single-patient study, maternal milk:plasma ratios at 1.5 hours, 5.5 hours, and 12 hours after a ranitidine 150 mg dose were 6.81, 8.44, and 23.77, respectively. Prior to measuring milk and serum concentrations, the patient had previously received 5 doses of 150 mg ranitidine given every 12 hours. The pre-dose milk:plasma concentration was 18.73. Because it appears that milk concentrations are highest approximately 12 hours after a dose, the authors recommend mothers consider nursing within 2 hours after taking ranitidine, if possible. The effect of ranitidine or the resultant decrease in gastric acidity on the nursing infant is not known. However, the American Academy of Pediatrics has considered the use of cimetidine, a related agent that is also excreted into breast milk, to be usually compatible with breast-feeding due to a lack of reported adverse effects in nursing infants. Most experts consider H-2 blockers to be of low-risk to the nursing infant. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Porphyria

    Rare reports have suggested that ranitidine may precipitate acute porphyric attacks in patients with acute porphyria. It is recommended that ranitidine be avoided in these patients.

    Tobacco smoking

    Tobacco smoking appears to contribute to an increased risk of developing peptic ulcer disease (PUD) and may also impair ulcer healing or increase the risk of ulcer recurrence. Encourage patients taking ranitidine to discontinue tobacco smoking if diagnosed with PUD.

    Bradycardia, cardiac disease

    Rarely, bradycardia has been reported with the rapid intravenous administration of ranitidine injection. In most cases, bradycardia was observed in patients with factors predisposing to cardiac rhythm disturbances. When administering ranitidine injection, the recommended rates of administration should not be exceeded; caution is warranted in elderly patients as well as patients with underlining cardiac disease.

    Geriatric

    No special precautions have been advised for geriatric patients vs younger adults, but some older patients may exhibit decreased renal function. Accumulation of ranitidine can occur unless dosage is adjusted according to the degree of renal impairment. Critically ill, elderly patients have been noted in some uncontrolled studies to be more likely to exhibit central nervous system (CNS) reactions to the H-2 blockers. In addition, elderly patients may be more likely to experience a reduction in heart rate during the rapid administration of ranitidine injection. 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. In addition, ranitidine has anticholinergic properties which may be problematic in the elderly.

    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

    pancreatitis / Delayed / Incidence not known
    hemolytic anemia / Delayed / Incidence not known
    aplastic anemia / Delayed / Incidence not known
    agranulocytosis / Delayed / Incidence not known
    pancytopenia / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    angioedema / Rapid / Incidence not known
    interstitial nephritis / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    bronchospasm / Rapid / Incidence not known
    vasculitis / Delayed / Incidence not known
    bradycardia / Rapid / Incidence not known
    AV block / Early / Incidence not known
    atrophic gastritis / Delayed / Incidence not known

    Moderate

    constipation / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    neutropenia / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    leukopenia / Delayed / Incidence not known
    depression / Delayed / Incidence not known
    confusion / Early / Incidence not known
    blurred vision / Early / Incidence not known
    hallucinations / Early / Incidence not known
    impotence (erectile dysfunction) / Delayed / Incidence not known
    galactorrhea / Delayed / Incidence not known
    eosinophilia / Delayed / Incidence not known
    sinus tachycardia / Rapid / Incidence not known
    premature ventricular contractions (PVCs) / Early / Incidence not known
    vitamin B12 deficiency / Delayed / Incidence not known
    pernicious anemia / Delayed / Incidence not known

    Mild

    headache / Early / 6.0-7.7
    nausea / Early / 4.1-4.1
    dizziness / Early / 2.6-2.6
    infection / Delayed / 2.6-2.6
    diarrhea / Early / 2.1-2.1
    abdominal pain / Early / 2.1-2.1
    vomiting / Early / 1.5-1.5
    asthenia / Delayed / 1.5-1.5
    cough / Delayed / 1.5-1.5
    paranoia / Early / Incidence not known
    drowsiness / Early / Incidence not known
    vertigo / Early / Incidence not known
    malaise / Early / Incidence not known
    insomnia / Early / Incidence not known
    agitation / Early / Incidence not known
    gynecomastia / Delayed / Incidence not known
    libido decrease / Delayed / Incidence not known
    arthralgia / Delayed / Incidence not known
    fever / Early / Incidence not known
    rash (unspecified) / Early / Incidence not known
    alopecia / Delayed / Incidence not known
    myalgia / Early / Incidence not known
    injection site reaction / Rapid / Incidence not known
    pruritus / Rapid / 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.
    Acetohexamide: (Moderate) Ranitidine has been shown to affect the pharmacokinetics of some oral sulfonylureas. Patients receiving sulfonylureas should be observed for evidence of altered glycemic response when ranitidine is instituted or discontinued. The mechanism of this interaction may involve either increasing the absorption or decreasing the clearance of the sulfonylurea. Asymptomatic hypoglycemia has been observed as a result of this interaction. It is unclear at this time if famotidine or nizatidine interact with oral sulfonylureas.
    Adefovir: (Moderate) Adefovir is eliminated renally by a combination of glomerular filtration and active tubular secretion; coadministration of adefovir with drugs that reduce renal function or compete for active tubular secretion, such as ranitidine may decrease adefovir elimination by competing for common renal tubular transport systems; therefore increasing serum concentrations of either adefovir and/or ranitidine may occur.
    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; Pioglitazone: (Minor) Concentrations of pioglitazone may be decreased with concomitant use of ranitidine. The effect of capistration on the systemic exposure of pioglitazone was determined in a drug-drug interaction study. Coadministration of pioglitazone 45 mg once daily with ranitidine 150 mg twice daily for 4 days resulted in a 13% and 16% reduction in pioglitazone AUC and Cmax, respectively. Close monitoring of blood glucose is recommended; dosage adjustments in pioglitazone may be needed.
    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.
    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.
    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.
    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.
    Chlorpropamide: (Moderate) Ranitidine has been shown to affect the pharmacokinetics of some oral sulfonylureas. Patients receiving sulfonylureas should be observed for evidence of altered glycemic response when ranitidine is instituted or discontinued. The mechanism of this interaction may involve either increasing the absorption or decreasing the clearance of the sulfonylurea. Asymptomatic hypoglycemia has been observed as a result of this interaction. It is unclear at this time if famotidine or nizatidine interact with oral sulfonylureas.
    Cyclosporine: (Minor) Although data are conflicting, cautious use of ranitidine and cyclosporine is warranted; cyclosporine can cause nephrotoxicity, and ranitidine is substantially excreted by the kidney. The risk of toxic reactions to ranitidine may be greater in patients with impaired renal function; ranitidine dose reduction is needed for renal impairment.
    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.
    Darunavir: (Minor) No change in darunavir concentrations was observed when coadministered with ranitidine. Darunavir can be coadministered with H2-blockers without any dosage adjustments.
    Darunavir; Cobicistat: (Minor) No change in darunavir concentrations was observed when coadministered with ranitidine. Darunavir can be coadministered with H2-blockers without any dosage adjustments.
    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 ranitidine may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of ranitidine for at least 12 hours before and at least 4 hours after administering rilpivirine.
    Donepezil; Memantine: (Minor) Memantine is excreted in part by renal tubular secretion. Competition of memantine for excretion with other drugs that are also eliminated by tubular secretion, such as ranitidine, could result in elevated serum concentrations of one or both drugs.
    Eliglustat: (Major) In poor CYP2D6 metabolizers (PMs), coadministration of ranitidine and eliglustat is not recommended. Ranitidine is a weak CYP3A inhibitor; eliglustat is a CYP3A and CYP2D6 substrate. Because CYP3A plays a significant role in the metabolism of eliglustat in CYP2D6 PMs, coadministration with CYP3A inhibitors may increase eliglustat exposure and the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias) in these patients.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Coadministration with ranitidine may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of ranitidine for at least 12 hours before and at least 4 hours after administering rilpivirine.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Moderate) Coadministration with ranitidine may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of ranitidine for at least 12 hours before and at least 4 hours after administering rilpivirine.
    Entecavir: (Moderate) Both entecavir and ranitidine are secreted by active tubular secretion. In theory, coadministration of entecavir with ranitidine may increase the serum concentrations of either drug due to competition for the drug elimination pathway. The manufacturer of entecavir recommends monitoring for adverse effects when these drugs are coadministered.
    Erlotinib: (Major) If concomitant use of erlotinib with ranitidine is necessary, administer ranitidine 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 ranitidine 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.
    Flibanserin: (Moderate) The concomitant use of flibanserin and multiple weak CYP3A4 inhibitors, including ranitidine, may increase flibanserin concentrations, which may increase the risk of flibanserin-induced adverse reactions. Therefore, patients should be monitored for hypotension, syncope, somnolence, or other adverse reactions, and the risks of combination therapy with multiple weak CYP3A4 inhibitors and flibanserin should be discussed with the patient.
    Fluvastatin: (Moderate) Concomitant administration of ranitidine with fluvastatin can decrease fluvastatin clearance by 18 to 23%, and increase AUC by 24 to 33%.
    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 ranitidine; this also applies to products containing ranitidine such as ranitidine bismuth citrate. If coadministration is necessary, give gefitinib 6 hours after the last dose or 6 hours before the next dose of ranitidine. 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%.
    Glimepiride: (Moderate) Ranitidine has been shown to affect the pharmacokinetics of some oral sulfonylureas. Patients receiving sulfonylureas should be observed for evidence of altered glycemic response when ranitidine is instituted or discontinued. The mechanism of this interaction may involve either increasing the absorption or decreasing the clearance of the sulfonylurea. Asymptomatic hypoglycemia has been observed as a result of this interaction. It is unclear at this time if famotidine or nizatidine interact with oral sulfonylureas.
    Glimepiride; Pioglitazone: (Moderate) Ranitidine has been shown to affect the pharmacokinetics of some oral sulfonylureas. Patients receiving sulfonylureas should be observed for evidence of altered glycemic response when ranitidine is instituted or discontinued. The mechanism of this interaction may involve either increasing the absorption or decreasing the clearance of the sulfonylurea. Asymptomatic hypoglycemia has been observed as a result of this interaction. It is unclear at this time if famotidine or nizatidine interact with oral sulfonylureas. (Minor) Concentrations of pioglitazone may be decreased with concomitant use of ranitidine. The effect of capistration on the systemic exposure of pioglitazone was determined in a drug-drug interaction study. Coadministration of pioglitazone 45 mg once daily with ranitidine 150 mg twice daily for 4 days resulted in a 13% and 16% reduction in pioglitazone AUC and Cmax, respectively. Close monitoring of blood glucose is recommended; dosage adjustments in pioglitazone may be needed.
    Glimepiride; Rosiglitazone: (Moderate) Ranitidine has been shown to affect the pharmacokinetics of some oral sulfonylureas. Patients receiving sulfonylureas should be observed for evidence of altered glycemic response when ranitidine is instituted or discontinued. The mechanism of this interaction may involve either increasing the absorption or decreasing the clearance of the sulfonylurea. Asymptomatic hypoglycemia has been observed as a result of this interaction. It is unclear at this time if famotidine or nizatidine interact with oral sulfonylureas.
    Glipizide: (Moderate) Ranitidine has been shown to affect the pharmacokinetics of some oral sulfonylureas. Patients receiving sulfonylureas should be observed for evidence of altered glycemic response when ranitidine is instituted or discontinued. The mechanism of this interaction may involve either increasing the absorption or decreasing the clearance of the sulfonylurea. Asymptomatic hypoglycemia has been observed as a result of this interaction. It is unclear at this time if famotidine or nizatidine interact with oral sulfonylureas.
    Glipizide; Metformin: (Moderate) Ranitidine has been shown to affect the pharmacokinetics of some oral sulfonylureas. Patients receiving sulfonylureas should be observed for evidence of altered glycemic response when ranitidine is instituted or discontinued. The mechanism of this interaction may involve either increasing the absorption or decreasing the clearance of the sulfonylurea. Asymptomatic hypoglycemia has been observed as a result of this interaction. It is unclear at this time if famotidine or nizatidine interact with oral sulfonylureas.
    Glyburide: (Moderate) Ranitidine has been shown to affect the pharmacokinetics of some oral sulfonylureas. Patients receiving sulfonylureas should be observed for evidence of altered glycemic response when ranitidine is instituted or discontinued. The mechanism of this interaction may involve either increasing the absorption or decreasing the clearance of the sulfonylurea. Asymptomatic hypoglycemia has been observed as a result of this interaction. It is unclear at this time if famotidine or nizatidine interact with oral sulfonylureas.
    Glyburide; Metformin: (Moderate) Ranitidine has been shown to affect the pharmacokinetics of some oral sulfonylureas. Patients receiving sulfonylureas should be observed for evidence of altered glycemic response when ranitidine is instituted or discontinued. The mechanism of this interaction may involve either increasing the absorption or decreasing the clearance of the sulfonylurea. Asymptomatic hypoglycemia has been observed as a result of this interaction. It is unclear at this time if famotidine or nizatidine interact with oral sulfonylureas.
    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 ranitidine and lamotrigine may decrease ranitidine clearance, resulting in increased plasma concentrations and the potential for ranitidine-related adverse events. Lamotrigine is an inhibitor of renal tubular secretion via organic cationic transporter 2 (OCT2) proteins, and ranitidine 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.
    Lomefloxacin: (Minor) The renal tubular secretion of lomefloxacin has been shown to be decreased by ranitidine, and is probably due to competition for renal tubular secretion.
    Lomitapide: (Major) Concomitant use of lomitapide and ranitidine may significantly increase the serum concentration of lomitapide. Therefore, the lomitapide dose should not exceed 30 mg/day PO during concurrent use. Ranitidine is a weak CYP3A4 inhibitor; the exposure to lomitapide is increased by approximately 2-fold in the presence of weak CYP3A4 inhibitors.
    Loperamide: (Moderate) Due to the risk for adverse effects, caution is advised when administering loperamide with ranitidine. Taking these drugs together may increase the serum concentration of loperamide. If these drugs are used together, monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest).
    Loperamide; Simethicone: (Moderate) Due to the risk for adverse effects, caution is advised when administering loperamide with ranitidine. Taking these drugs together may increase the serum concentration of loperamide. If these drugs are used together, monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest).
    Lumacaftor; Ivacaftor: (Moderate) Lumacaftor; ivacaftor may alter the systemic exposure of ranitidine. If used together, ranitidine may require a dosage adjustment to obtain the desired therapeutic effect.
    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.
    Memantine: (Minor) Memantine is excreted in part by renal tubular secretion. Competition of memantine for excretion with other drugs that are also eliminated by tubular secretion, such as ranitidine, could result in elevated serum concentrations of one or both drugs.
    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; Pioglitazone: (Minor) Concentrations of pioglitazone may be decreased with concomitant use of ranitidine. The effect of capistration on the systemic exposure of pioglitazone was determined in a drug-drug interaction study. Coadministration of pioglitazone 45 mg once daily with ranitidine 150 mg twice daily for 4 days resulted in a 13% and 16% reduction in pioglitazone AUC and Cmax, respectively. Close monitoring of blood glucose is recommended; dosage adjustments in pioglitazone may be needed.
    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.
    Midazolam: (Moderate) Although conflicting data exist regarding an interaction between ranitidine and midazolam, it may be prudent to monitor patients taking both ranitidine and midazolam for increased sedation. The manufacturer of ranitidine warns that the absorption of midazolam may be increased in patients taking ranitidine due to alterations in pH.
    Midodrine: (Minor) Although the exact mechanism is uncertain, midodrine may be excreted by the same base-secreting pathway of the kidneys responsible for secretion of other basic drugs like ranitidine. By this pathway, midodrine may potentially interact with ranitidine; however, no drug interactions of this kind have been reported.
    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.
    Nicardipine: (Moderate) Ranitidine may increase nicardipine AUC by inhibiting hepatic metabolism of nicardipine. Clinicians should be alert for exaggerated nicardipine effects if ranitidine is added to the regimen.
    Nifedipine: (Moderate) Cimetidine can increase nifedipine exposure by inhibiting hepatic metabolism of nifedipine. Ranitidine has been shown to have a similar, but lesser, effect on nifedipine pharmacokinetics. Clinicians should be alert for exaggerated nifedipine effects if ranitidine is coadministered.
    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.
    Pioglitazone: (Minor) Concentrations of pioglitazone may be decreased with concomitant use of ranitidine. The effect of capistration on the systemic exposure of pioglitazone was determined in a drug-drug interaction study. Coadministration of pioglitazone 45 mg once daily with ranitidine 150 mg twice daily for 4 days resulted in a 13% and 16% reduction in pioglitazone AUC and Cmax, respectively. Close monitoring of blood glucose is recommended; dosage adjustments in pioglitazone may be needed.
    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.
    Pramipexole: (Moderate) Population pharmacokinetics suggest that coadministration of drugs secreted by the cationic transport system, such as ranitidine, decreases the clearance of pramipexole by about 20 percent. An increase in pramipexole levels secondary to the use of ranitidine, may result in an increased risk of somnolence, postural hypotension, or other clinically significant events.
    Procainamide: (Moderate) When ranitidine is used in doses more than 300 mg/day, such as those used in the treatment of Zollinger-Ellison syndrome, the renal tubular secretion of procainamide is inhibited; procainamide clearance is reduced leading to elevated procainamide and N-acetyl-procainamide plasma concentrations. It may be prudent to monitor patients for procainamide toxicity if procainamide and high doses of ranitidine are coadministered.
    Propantheline: (Minor) Propantheline bromide increases the bioavailability of ranitidine when the drugs are administered concomitantly. Propantheline bromide is believed to delay gastric emptying, increase transit time, and thereby increase the peak plasma concentration of ranitidine.
    Ranolazine: (Moderate) Coadminister ranolazine and ranitidine with caution. Ranitidine 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 ranitidine dose may be necessary.
    Rilpivirine: (Moderate) Coadministration with ranitidine may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of ranitidine 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.
    Risperidone: (Moderate) Although dosage adjustments are not necessary, patients receiving concurrent treatment with risperidone and ranitidine should be monitored for risperidone-induced side effects or extrapyramidal symptoms. Pharmacokinetic data indicate that increased exposure to risperidone and its active metabolite occurs during use of ranitidine. This interaction is thought to be the result of inhibition of CYP3A4, one of the isoenzymes responsible for the metabolism of risperidone.
    Saquinavir: (Minor) The coadministration of saquinavir and ranitidine increases saquinavir plasma concentrations. However, the increase is not thought to be clinically relevant. No dose adjustment of saquinavir is recommended; no dosage information regarding the use of saquinavir enhanced or 'boosted' with ritonavir is available.
    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 ranitidine decreases the geometric mean sonidegib steady-state AUC (0-24 hours) value by 34%.
    Sulfonylureas: (Moderate) Ranitidine has been shown to affect the pharmacokinetics of some oral sulfonylureas. Patients receiving sulfonylureas should be observed for evidence of altered glycemic response when ranitidine is instituted or discontinued. The mechanism of this interaction may involve either increasing the absorption or decreasing the clearance of the sulfonylurea. Asymptomatic hypoglycemia has been observed as a result of this interaction. It is unclear at this time if famotidine or nizatidine interact with oral sulfonylureas.
    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.
    Tolazamide: (Moderate) Ranitidine has been shown to affect the pharmacokinetics of some oral sulfonylureas. Patients receiving sulfonylureas should be observed for evidence of altered glycemic response when ranitidine is instituted or discontinued. The mechanism of this interaction may involve either increasing the absorption or decreasing the clearance of the sulfonylurea. Asymptomatic hypoglycemia has been observed as a result of this interaction. It is unclear at this time if famotidine or nizatidine interact with oral sulfonylureas.
    Tolbutamide: (Moderate) Ranitidine has been shown to affect the pharmacokinetics of some oral sulfonylureas. Patients receiving sulfonylureas should be observed for evidence of altered glycemic response when ranitidine is instituted or discontinued. The mechanism of this interaction may involve either increasing the absorption or decreasing the clearance of the sulfonylurea. Asymptomatic hypoglycemia has been observed as a result of this interaction. It is unclear at this time if famotidine or nizatidine interact with oral sulfonylureas.
    Triazolam: (Moderate) Ranitidine may increase the plasma concentrations of oral triazolam when administered concurrently.
    Trospium: (Moderate) Both trospium and ranitidine are eliminated by active renal tubular secretion; coadministration has the potential to increase serum concentrations of trospium or ranitidine due to competition for the drug elimination pathway. Careful patient monitoring and dosage adjustment of trospium and/or ranitidine is recommended.
    Vandetanib: (Minor) Use caution if coadministration of vandetanib with ranitidine is necessary, due to a possible increase in ranitidine-related adverse reactions. Ranitidine mostly (70%) undergoes non-hepatic elimination; however, it is also 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

    Ranitidine is classified in FDA pregnancy risk category B. Animal studies have not demonstrated a risk to the fetus but there are no adequate studies in pregnant women. Ranitidine does cross the placenta; mean fetal:maternal ratios are approximately 0.9 after IV administration versus 0.4 for oral dosages. Human epidemiological evidence has not suggested an association between the drug and congenital defects in first trimester exposure.  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. In general, experts consider ranitidine a preferred H2 blocker when one is necessary in pregnancy, due to more documented data of efficacy and safety in the pregnant population versus other agents. 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. Limited use of single dosages of ranitidine for reducing gastric acid during labor and prior to obstetric delivery, including caesarian section, have not been noted to adversely affect labor or neonatal outcomes.

    The manufacturer recommends that caution be used with administering ranitidine to women who are breast-feeding their infants. Ranitidine is excreted into human breast milk. Milk concentrations increase with time after the administration of a maternal oral dose. Mean maternal milk:plasma ratios at 2 and 6 hours after a single oral dose are 1.9 and 6.7, respectively, although higher concentrations have also been reported. In a single-patient study, maternal milk:plasma ratios at 1.5 hours, 5.5 hours, and 12 hours after a ranitidine 150 mg dose were 6.81, 8.44, and 23.77, respectively. Prior to measuring milk and serum concentrations, the patient had previously received 5 doses of 150 mg ranitidine given every 12 hours. The pre-dose milk:plasma concentration was 18.73. Because it appears that milk concentrations are highest approximately 12 hours after a dose, the authors recommend mothers consider nursing within 2 hours after taking ranitidine, if possible. The effect of ranitidine or the resultant decrease in gastric acidity on the nursing infant is not known. However, the American Academy of Pediatrics has considered the use of cimetidine, a related agent that is also excreted into breast milk, to be usually compatible with breast-feeding due to a lack of reported adverse effects in nursing infants. Most experts consider H-2 blockers to be of low-risk to the nursing infant. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Mechanism of Action: Ranitidine competitively inhibits the binding of histamine to receptors on gastric parietal cells (designated as the H2-receptor), thus reducing basal and nocturnal gastric acid secretion. The drug also decreases the amount of gastric acid released in response to stimuli such as food, caffeine, insulin, betazole, or pentagastrin. Ranitidine reduces the total volume of gastric juice, thereby indirectly decreasing pepsin secretion. Ranitidine has little to no effect on serum gastrin and does not impair intrinsic factor secretion. The drug does not appear to alter gastric motility, gastric emptying, esophageal pressures, biliary secretions, or pancreatic secretions. Ranitidine is not an antimuscarinic anticholinergic. Ranitidine may aid in gastromucosal healing, and it may protect the mucosa from the irritant effects caused by aspirin and nonsteroidal antiinflammatory agents. Other actions of ranitidine include an increase in gastric bacterial flora (e.g., nitrate-reducing organisms). The clinical significance of this effect is not known. H2-blockers, as single agents, do not eradicate H. pylori infection.After bolus ranitidine doses of 100 mg IV or greater, small and transient increases in prolactin serum concentrations have been noted. Ranitidine does not affect serum concentrations or release of gonadotropin, TSH, or GH. Ranitidine may impair the release of vasopressin. Ranitidine has no effect on serum cortisol, aldosterone, androgen, or estrogen levels.In combination with an H1-receptor antagonist, ranitidine can suppress the formation of edema, flare, and pruritus that results from histaminic activity. Human skin mast cells express both H1- and H2-receptors. Stimulation of H2-receptors leads to changes in membrane permeability (activating the cyclic AMP-PKA pathway) causing vasodilation. The resultant dilation develops more slowly and is more sustained, as compared to H1-stimulation. Combination therapy blocks both the initial and delayed histaminic response.

    PHARMACOKINETICS

    Ranitidine is administered either orally or parenterally. It distributes throughout the body fluids and tissues, and can be found in breast milk and CSF. Using inhibition of pentagastrin-induced acid secretion as an indicator, ranitidine's effects persist for 8—12 hours. It ranitidine undergoes partial metabolism (30%) in the liver, and both the unchanged drug and metabolites are excreted in the urine and feces. The half-life is 2—3 hours.
     
    Affected cytochrome P450 isoenzymes and drug transporters: none
    Although ranitidine has been reported to bind weakly to cytochrome P-450 in vitro, recommended doses of the drug do not inhibit the action of the cytochrome P-450 enzyme system. However, there have been isolated reports of drug interactions that suggest that ranitidine may affect the bioavailability of certain drugs by some mechanism as yet unidentified (e.g., a pH-dependent effect on absorption or a change in volume of distribution).
     

    Oral Route

    Due to first-pass elimination, oral bioavailability of ranitidine is about 50—60%. The presence of food in the GI tract does not appear to affect the extent or rate of absorption. 
     
    Following oral administration, roughly 30% of an administered dose is excreted unchanged in the urine. 

    Intravenous Route

    Intramuscular (IM) administration results in a bioavailability of 90—100% compared to intravenous (IV) administration. 
     
    Following IV injection, roughly 70% of ranitidine is recovered in the urine unchanged.

    Intramuscular Route

    Intramuscular (IM) administration of ranitidine results in a bioavailability of 90—100% compared to intravenous (IV) administration.