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  • CLASSES

    H2 Antagonists

    DEA CLASS

    Rx, OTC

    DESCRIPTION

    Oral/parenteral histamine type 2-receptor antagonist.
    Used for gastrointestinal disorders such as peptic ulcer and gastroesophageal reflux disease (GERD)
    Exhibits many clinically significant drug interactions due to inhibition of CYP450 enzymes.

    COMMON BRAND NAMES

    Acid Reducer, Major Acid Reducer, Tagamet, Tagamet HB

    HOW SUPPLIED

    Acid Reducer/Cimetidine/Major Acid Reducer/Tagamet/Tagamet HB Oral Tab: 200mg, 300mg, 400mg, 800mg
    Cimetidine/Cimetidine Hydrochloride Oral Sol: 5mL, 300mg

    DOSAGE & INDICATIONS

    For the treatment of gastroesophageal reflux disease (GERD) or esophagitis associated with gastroesophageal reflux disease (GERD).
    Oral dosage
    Adults and Adolescents 16 years and older

    800 mg PO twice daily or 400 mg PO four times per day for 12 weeks. While cimetidine may be effective in patients with less severe GERD, proton pump inhibitors (PPIs) offer more rapid symptom relief and better healing.

    Children and Adolescents 1 to 15 years

    20 to 40 mg/kg/day PO in divided doses every 6 hours. A typical starting dose is 10 mg/kg/dose PO four times daily (before meals and at bedtime) given for 8 to 12 weeks. While cimetidine may be effective in patients with less severe GERD, proton pump inhibitors (PPIs) offer more rapid symptom relief and better healing.

    Infants†

    20 to 40 mg/kg/day PO in divided doses four times per day. A typical starting dose is 10 mg/kg/dose PO four times daily (before meals and at bedtime), given for 8 to 12 weeks. While cimetidine may be effective in patients with less severe GERD, proton pump inhibitors (PPIs) offer more rapid symptom relief and better healing.

    Premature and Term Neonates†

    10 mg/kg/day PO given in divided doses every 6 to 12 hours most commonly used; doses up to 20 mg/kg/day have been reported. Lower doses (e.g., 4 mg/kg/dose given every 12 hours or longer) have been used in very low weight premature infants. While cimetidine may be effective in patients with less severe GERD, proton pump inhibitors (PPIs) offer more rapid symptom relief and better healing.

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

    To prevent heartburn, take 200 mg PO right before or any time up to 30 minutes before food or beverages that are known to cause symptoms. For treatment of heartburn, take up to 200 mg PO twice daily. Maximum daily dose is 400 mg/day. Patients should not take for more than 2 weeks without consulting a physician.

    Neonates, Infants, and Children less than 12 years

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

    For the treatment of peptic ulcer disease (duodenal ulcer or gastric ulcer).
    For acute treatment.
    Oral dosage
    Adults and Adolescents 16 years and older

    800 mg PO once daily at bedtime, or 400 mg PO twice daily or 300 mg PO four times per day with meals and at bedtime for 8 to 12 weeks. The American College of Gastroenterology supports a maximum duration of 12 weeks for the treatment of gastric ulcers.

    Children and Adolescents 1 to 15 years

    20 to 40 mg/kg/day PO in divided doses every 6 hours.

    Intravenous dosage (intermittent IV injection or intermittent IV infusion)
    Adults and Adolescents 16 years and older

    300 mg IV, appropriately diluted, every 6 hours for active treatment. Alternatively, may give 37.5 mg/hour (i.e., 900 mg/day) by continuous IV infusion. Several studies have verified that cimetidine 37.5 mg/hour (i.e., 900 mg/day) adequately maintains intragastric pH above 4. For patients requiring a more rapid elevation of gastric pH, the continuous infusion may be preceded by a 150 mg loading dose.

    Children and Adolescents 1 to 15 years

    20 to 40 mg/kg/day IV in divided doses every 6 hours for active treatment.

    Intramuscular dosage
    Adults and Adolescents 16 years and older

    300 mg IM every 6 hours for active treatment.

    Children and Adolescents 1 to 15 years

    20 to 40 mg/kg/day IM divided and given every 6 hours for active treatment.

    For maintenance therapy of refractory duodenal ulcer or gastric ulcer in patients with peptic ulcer disease.
    Oral dosage
    Adults and Adolescents 16 years and older

    400 mg PO once daily at bedtime. No firm data are available to guide decisions regarding duration of therapy. The American College of Gastroenterology supports maintenance therapy for up to 3 years or more if the underlying cause cannot be reversed (e.g. H. pylori cured or NSAIDs discontinued). Shorter treatment courses are recommended if the indication is for a symptomatic recurrence of an uncomplicated ulcer.

    For the treatment of pathological hypersecretory conditions including Zollinger-Ellison syndrome, systemic mastocytosis, and multiple endocrine adenoma syndrome.
    Oral dosage
    Adults

    300 mg PO four times per day with meals and at bedtime. Do not exceed 2400 mg/day PO.

    Intravenous dosage (intermittent IV injection)
    Adults

    300 mg IV, appropriately diluted, given over not less than 5 minutes every 6 hours. If increased dosage is necessary, give 300 mg doses more frequently, up to a maximum daily dose of 2400 mg.

    Intravenous dosage (continuous IV infusion)
    Adults

    50 mg/hour (1200 mg/day) by continuous IV infusion. Alternatively, give 150 mg as a single IV bolus dose initially, followed with an infusion of cimetidine 37.5 mg/hour (i.e., 900 mg/day), and adjust dosage as indicated. In studies of patients with these conditions, the mean infused dose of cimetidine was 160 mg/hr with a range of 40 to 600 mg/hour to keep the intragastric acid secretion at 10 mEq/hr or less.

    Adolescents 16 years and older

    150 mg as a single IV bolus dose initially, followed with an infusion of cimetidine 37.5 mg/hour (i.e., 900 mg/day), and adjust dosage indicated. In studies of patients with these conditions, the mean infused dose of cimetidine was 160 mg/hour with a range of 40 to 600 mg/hour IV infusion to keep the intragastric acid secretion at 10 mEq/hour or less.

    For the treatment of upper GI bleeding or acute gastritis.
    Intravenous dosage (continuous IV infusion)
    Adults and Adolescents >= 16 years

    37.5 mg/hour (i.e., 900 mg/day) by continuous infusion. NOTE: Several studies have verified that cimetidine 37.5 mg/hour (i.e., 900 mg/day) adequately maintains intragastric pH above 4.

    For stress gastritis prophylaxis or active treatment of stress ulceration in critically-ill patients.
    Intravenous dosage (continuous IV infusion)
    Adults and Adolescents 16 years and older

    50 mg/hour (1200 mg/day) by continuous IV infusion. Alternatively, give 150 mg as a single IV bolus dose initially, followed with an infusion of cimetidine 37.5 mg/hour (i.e., 900 mg/day). This dosage adequately maintains intragastric pH above 4.0. If the patient has a CrCl < 30ml/min, the hourly continuous infusion rate should be reduced by 50% (i.e.,: not to exceed 25 mg/hr or 600 mg/day).

    Infants†, Children and Adolescents 15 years and younger

    20 to 40 mg/kg/day IV in divided doses 4 to 6 times per day.

    Premature and Term Neonates†

    10 mg/kg/day IV given in divided doses every 6 to 12 hours most commonly used; doses up to 20 mg/kg/day have been reported. Lower doses (e.g., 4 mg/kg/dose IV given every 12 hours or longer) have been used in very low weight premature infants.

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

    300 mg PO single dose, 1.5 to 2 hours prior to surgery, before induction. According to guidelines of the American Society of Anesthesiologists, routine preoperative use is NOT recommended in patients who have no apparent increased risk for pulmonary aspiration. However, some guidelines recommend an H2-receptor antagonist (PO or IV) for all women presenting for cesarean delivery.

    Intravenous dosage (intermittent IV injection or infusion)
    Adults

    300 mg IV single dose, 1 hour prior to surgery, before induction. According to guidelines of the American Society of Anesthesiologists, routine preoperative use is NOT recommended in patients who have no apparent increased risk for pulmonary aspiration. However, some guidelines recommend an H2-receptor antagonist (PO or IV) for all women presenting for cesarean delivery.

    For NSAID-induced ulcer prophylaxis†.
    Oral dosage
    Adults

    Several oral doses of cimetidine were assessed in a study of the ability of cimetidine to prevent gastric mucosal hemorrhage induced by a single 1296 mg oral dose of aspirin. The authors concluded that a single 200 mg or 400 mg oral dose of cimetidine administered at the time of the aspirin dose was successful in preventing endoscopically visible gastric mucosal damage.

    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

    300 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 (intermittent IV injection or infusion)
    Adults

    300 mg IV (appropriately diluted), in combination with an H1-blocker.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    1200 mg/day PO for most indications, 1600 mg/day PO for GERD. Up to 2400 mg/day PO for pathologic hypersecretory conditions.

    Geriatric

    1200 mg/day PO for most indications, 1600 mg/day PO for GERD. Up to 2400 mg/day PO for pathologic hypersecretory conditions.

    Adolescents

    < 16 years: 40 mg/kg/day PO for most indications; data are limited.
    >= 16 years: 1200 mg/day PO or IV for most indications. 1600 mg/day PO for GERD. Up to 2400 mg/day PO for pathologic hypersecretory conditions.

    Children

    40 mg/kg/day PO or IV for most indications; data are limited.

    Infants

    40 mg/kg/day PO or IV; data are limited.

    Neonates

    20 mg/kg/day PO or IV; data are limited.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Recommendations vary with the degree of hepatic impairment exhibited by the patient, but no quantitative recommendations are available. In general, consider a decreased dosage for those patients with severe hepatic disease (e.g., Child-Pugh grade C cirrhosis).

    Renal Impairment

    CrCl 30 mL/min and higher: No specific recommendations are available.
    CrCl less than 30 mL/min: The manufacturer recommends an adult dosage of 300 mg every 12 hours, PO or IV (intermittently), which reflects an approximate 50% reduction in daily usual dose. The hourly adult continuous infusion rate should be reduced by 50% (i.e.,: not to exceed 25 mg/hour or 600 mg/day in adults). Patients being treated for stress gastritis prophylaxis should receive half the recommended dose. Specific pediatric dose adjustment recommendations are not available. Dosing frequency for intermittent doses may be increased to every 8 hours if necessary, although the lowest frequency of dosing should be used, while assuring adequate patient response, as cimetidine accumulates in renal failure.
     
    Intermittent Hemodialysis
    Cimetidine 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 intermittent dose coincides with the end of a hemodialysis session.

    ADMINISTRATION

    For storage information, see the specific production information within the How Supplied section.

    Oral Administration

    May be administered without regard to meals. Administer with food, water, or milk to minimize gastric irritation.
    Do not administer concomitantly with antacids.

    Injectable Administration

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

    Intravenous Administration

    IV Push
    NOTE: Must be diluted before use. Do not use prefilled syringes for IV injection.
    Do not administer any dosage > 300 mg via IV injection—see intermittent infusion.
    Dilute to a maximum of 15 mg/mL using 0.9% Sodium Chloride for injection or other compatible IV solution.
    Inject over a period of not less than 5 minutes. Do not inject rapidly; cardiac arrhythmias or hypotension may develop.
     
    Intermittent IV infusion
    Dilute dosage, not to exceed 300 mg, to a maximum of 6 mg/mL using 5% Dextrose for injection or other compatible IV solution.
    If using ADD-Vantage vials, dilute in ADD-Vantage containers containing 50 or 100 mL of 0.9% Sodium Chloride for injection or 5% Dextrose for injection.
    Infuse dosage over 15—20 minutes.
    The diluted infusion is stable for 48 hours at room temperature.
     
    Continuous IV infusion
    Dilute up to 900 mg of cimetidine in 100—1000 mL of a compatible solution.
    For IV infusion volumes less than 250 mL, a controlled infusion pump is recommended.
    Adjust rate/hour according to individual patient dosage requirements.
    The diluted infusion is stable for 48 hours at room temperature.

    Intramuscular Administration

    No dilution necessary.
    Prefilled syringes are available. DO NOT USE PREFILLED SYRINGES FOR IV INJECTION.
    Inject into a large muscle. Aspirate prior to injection to avoid injection into a blood vessel.

    STORAGE

    Generic:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Acid Reducer:
    - Store between 68 to 77 degrees F
    Major Acid Reducer:
    - Store between 68 to 77 degrees F
    Tagamet:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Tagamet HB:
    - Store between 68 to 77 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

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

    Benzyl alcohol hypersensitivity, H2-blocker hypersensitivity

    Cimetidine is contraindicated in any patient hypersensitive to the drug or its components. Cross-sensitivity in this class of compounds has been observed, so cimetidine 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. Cimetidine injection multidose vials contain benzyl alcohol as a preservative and should be avoided in patients with benzyl alcohol hypersensitivity.

    Intravenous administration

    There have been rare instances of cardiac arrhythmias and hypotension following the rapid intravenous administration of cimetidine by intravenous bolus. Cimetidine should be diluted and infused at recommended rates as directed by package labeling.

    Gastric cancer

    Symptomatic response to therapy with cimetidine 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.

    Infection

    Symptomatic response to therapy with cimetidine does not preclude the presence of H. pylori infection. Cimetidine 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.

    Hepatic disease, renal failure, renal impairment

    Cimetidine non-selectively inhibits the hepatic cytochrome P450 oxidative enzymes system and many drug interactions have been described when cimetidine was added to, or discontinued from an established drug regimen. The clinician should review potential drug interactions prior to prescribing cimetidine. Cimetidine should be used cautiously in patients with hepatic disease such as cirrhosis, or in those with renal impairment or renal failure, because cimetidine clearance can be reduced. Reduced doses of cimetidine are recommended in patients with renal impairment; further dose reduction may be necessary if liver impairment is also present. Various types of reversible confusional states have been attributed to cimetidine. While decreased clearance would seem to predispose patients to adverse reactions, hepatic disease and/or renal disease have not been shown conclusively to increase the risk for central nervous system reactions.

    Pregnancy

    Self-medication with cimetidine during pregnancy is not recommended; pregnant patients should see their health care professional for a proper diagnosis and for treatment recommendations. Animal studies have not demonstrated a risk to the fetus but there are no adequate studies in pregnant women. Epidemiological evidence based on the use of cimetidine during the first trimester of human gestation does not suggest an increase in fetal malformations compared to the normal population. Risk versus benefit should be considered prior to use. Cimetidine is known to cross the placenta. Unlike other H2-blockers, cimetidine pharmacologically exhibits some weak anti-androgenic activity, and conflicting data from animal studies exist regarding anti-androgenic effects. 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 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. Cimetidine has been used in limited circumstances at term to prevent acid aspiration during labor; some guidelines recommend an H2-blocker (oral or intravenous) for all women presenting for cesarean delivery.

    Breast-feeding

    Cimetidine is secreted into breast milk, usually in concentrations that exceed maternal plasma concentrations. Cimetidine is not usually recommended for use during lactation by the manufacturer. However, in the absence of reported adverse events in infants, the use of cimetidine is usually considered compatible with breast-feeding. Although also excreted in breast milk, other H2-blockers might be considered alternatives due to the fact that they do not typically have anti-androgenic actions, and would not inhibit infant hepatic enzyme activity should the infant be prescribed an interacting medication. Galactorrhea and hyperprolactinemia have been reported in patients taking cimetidine. Of all H2-blockers, famotidine is excreted least in breast milk.

    Neonates

    Cimetidine oral solution contains 2.8% alcohol, which should be considered in the dosing of infants and young children. Cimetidine injection multidose vials contain benzyl alcohol as a preservative and should be avoided in neonates. There have been reports of fatal 'gasping syndrome' in neonates (< 1 month of age) after the administration of parenteral solutions containing the preservative benzyl alcohol at dosages > 99 mg/kg/day. The minimum amount of benzyl alcohol to cause toxicity is unknown. Therefore, use preservative-free cimetidine injection formulations in neonates.

    Tobacco 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. Patients should avoid smoking while taking cimetidine. 

    Immunosuppression

    Per the manufacturer of cimetidine, patients with immunosuppression may have an increased risk of developing infection from strongyloidiasis during the use of acid-suppressing agents.

    Geriatric

    Reversible confusional states have been observed on occasion with cimetidine therapy, predominantly, but not exclusively, in severely ill patients. Advancing age (50 years and older) and preexisting liver or renal impairment appear to be contributing factors. Because geriatric patients are more likely to have renal impairment or other organ dysfunction, care should be taken in dose selection. In some patients, these confusional states have been mild and have not required discontinuation of cimetidine therapy. In cases where discontinuation was judged necessary, the condition usually cleared with 3 to 4 days of drug discontinuation.[50741] [50762] 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 expert panel also recommends dose reduction of H2-antagonists in geriatric patients with a creatinine clearance less than 50 mL/minute due to the potential for mental status changes.[63923] The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to the OBRA guidelines, cimetidine has a higher incidence of medication interactions than other H2-antagonists and should be avoided in the older adult. In addition, cimetidine has anticholinergic properties which may be problematic in the elderly.[60742]

    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 / 0-1.0
    toxic epidermal necrolysis / Delayed / 0-1.0
    exfoliative dermatitis / Delayed / 0-1.0
    erythema multiforme / Delayed / 0-1.0
    Stevens-Johnson syndrome / Delayed / 0-1.0
    AV block / Early / 0-1.0
    bradycardia / Rapid / 0-1.0
    vasculitis / Delayed / 0-1.0
    anaphylactoid reactions / Rapid / 0-1.0
    interstitial nephritis / Delayed / 0-1.0
    agranulocytosis / Delayed / 0-0.1
    hemolytic anemia / Delayed / Incidence not known
    aplastic anemia / Delayed / Incidence not known
    pancytopenia / Delayed / Incidence not known
    atrophic gastritis / Delayed / Incidence not known

    Moderate

    neutropenia / Delayed / 0-1.0
    leukopenia / Delayed / 0-1.0
    cholestasis / Delayed / 0-1.0
    hypotension / Rapid / 0-1.0
    sinus tachycardia / Rapid / 0-1.0
    urinary retention / Early / 0-1.0
    thrombocytopenia / Delayed / 0-0.1
    hallucinations / Early / Incidence not known
    psychosis / Early / Incidence not known
    confusion / Early / Incidence not known
    depression / Delayed / Incidence not known
    galactorrhea / Delayed / Incidence not known
    hyperprolactinemia / Delayed / Incidence not known
    impotence (erectile dysfunction) / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    vitamin B12 deficiency / Delayed / Incidence not known
    pernicious anemia / Delayed / Incidence not known

    Mild

    gynecomastia / Delayed / 0.3-4.0
    headache / Early / 2.1-3.5
    dizziness / Early / 1.0-1.0
    drowsiness / Early / 1.0-1.0
    alopecia / Delayed / 0-1.0
    infection / Delayed / 0-1.0
    arthralgia / Delayed / 0-1.0
    myalgia / Early / 0-1.0
    fever / Early / 0-1.0
    diarrhea / Early / 1.0-1.0
    anxiety / Delayed / Incidence not known
    agitation / Early / Incidence not known
    rash / Early / Incidence not known

    DRUG INTERACTIONS

    Abarelix: (Minor) In the absence of relevant data and as a precaution, drugs that cause hyperprolactinemia, such as cimetidine, should not be administered concomitantly with abarelix, as hyperprolactinemia downregulates the number of pituitary gonadotropin-releasing hormone receptors.
    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.
    Acetaminophen; Aspirin, ASA; Caffeine: (Minor) Inhibitors of CYP1A2, such as cimetidine, may inhibit the hepatic oxidative metabolism of caffeine. In patients who complain of caffeine-related side effects caffeine dosage or intake may need to be reduced.
    Acetaminophen; Caffeine: (Minor) Inhibitors of CYP1A2, such as cimetidine, may inhibit the hepatic oxidative metabolism of caffeine. In patients who complain of caffeine-related side effects caffeine dosage or intake may need to be reduced.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with cimetidine may alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of dihydrocodeine until stable drug effects are achieved. Discontinuation of cimetidine could alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If cimetidine is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Cimetidine is a weak inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase dihydrocodeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy. (Minor) Inhibitors of CYP1A2, such as cimetidine, may inhibit the hepatic oxidative metabolism of caffeine. In patients who complain of caffeine-related side effects caffeine dosage or intake may need to be reduced.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Minor) Inhibitors of CYP1A2, such as cimetidine, may inhibit the hepatic oxidative metabolism of caffeine. In patients who complain of caffeine-related side effects caffeine dosage or intake may need to be reduced.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Minor) Inhibitors of CYP1A2, such as cimetidine, may inhibit the hepatic oxidative metabolism of caffeine. In patients who complain of caffeine-related side effects caffeine dosage or intake may need to be reduced.
    Acetaminophen; Codeine: (Minor) Cimetidine may inhibit the conversion of codeine to morphine, codeine's active metabolite, via the CYP2D6 hepatic isoenzyme and therefore may decrease the ability for codeine to produce analgesic effect.
    Acetaminophen; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of cimetidine is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like cimetidine can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If cimetidine is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Acetaminophen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of cimetidine is necessary. If cimetidine is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a weak inhibitor like cimetidine can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If cimetidine is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    Acetaminophen; Propoxyphene: (Minor) Propoxyphene is a substrate and cimetidine is an inhibitor of CYP2D6. When used in high doses, cimetidine has decreased the metabolism of certain opiate agonists leading to increased opiate concentrations and opiate toxicity in some patients. The clinical significance of the interaction is not well-established.
    Acetohexamide: (Moderate) Cimetidine has been shown to affect the pharmacokinetics of some oral sulfonylureas. Patients receiving sulfonylureas should be observed for evidence of altered glycemic response when cimetidine 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.
    Acyclovir: (Minor) Cimetidine may cause a reduction in the clearance of acyclovir. The clinical significance of these pharmacokinetic interactions is unknown; however, no dosage adjustments are recommended for patients with normal renal function.
    Adefovir: (Moderate) Adefovir is eliminated renally by a combination of glomerular filtration and active tubular secretion; coadministration of adefovir dipivoxil with drugs that reduce renal function or compete for active tubular secretion, such as cimetidine, may decrease adefovir elimination by competing for common renal tubular transport systems, thereby increasing serum concentrations of adefovir and/or cimetidine. Coadministration of these drugs has not been studied, but caution is warranted.
    Albendazole: (Moderate) Cimetidine administration with albendazole has been reported to increase albendazole bioavailability. Concentrations of albendazole sulfoxide were increased in bile and cystic fluid about 2 fold in patients with hydatid cyst disease treated with cimetidine 10 mg per kg per day concomitantly with albendazole compared to administration of albendazole alone. More data are needed to elucidate the clinical consequence of this interaction.
    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.
    Alfentanil: (Minor) Cimetidine is an inhibitor of CYP3A4 and thus, reduces the clearance of alfentanil and may prolong the duration of action of alfentanil. Smaller alfentanil doses will be needed if prolonged alfentanil administration is used. Monitor patients for adverse effects of alfentanil, such as hypotension, nausea, itching, and respiratory depression.
    Alfuzosin: (Moderate) Alfuzosin is extensively metabolized by hepatic enzymes. Administration of of cimetidine, an inhibitor of hepatic cytochrome P450, with alfuzosin may increase the serum concentration of alfuzosin.
    Alogliptin; Metformin: (Moderate) Use with caution, as cimetidine inhibits renal elimination of metformin. Consider alternatives to cimetidine. Increased metformin exposure due to use of cimetidine may lead to gastrointestinal complaints, altered glycemic control, and a potential for an increased risk for lactic acidosis. If it is medically necessary to use cimetidine, carefully monitor. Metformin dose reduction may be needed. An interaction between metformin and oral cimetidine has been observed in normal healthy volunteers in both single- and multiple-dose drug interaction studies. Cimetidine caused a 60% increase in peak metformin concentrations and a 40% increase in metformin exposure (AUC). Cimetidine inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]).
    Alprazolam: (Major) Avoid coadministration of alprazolam and cimetidine due to the potential for elevated alprazolam concentrations, which may cause prolonged sedation and respiratory depression. If coadministration is necessary, consider reducing the dose of alprazolam as clinically appropriate and monitor for an increase in alprazolam-related adverse reactions. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with cimetidine, as these benzodiazepines are not oxidatively metabolized. Alprazolam is a CYP3A4 substrate and cimetidine is a weak CYP3A4 inhibitor. Coadministration with cimetidine increased alprazolam maximum concentration by 82%, decreased clearance by 42%, and increased half-life by 16%.
    Altretamine: (Minor) Cimetidine, a known inhibitor of the cytochrome P-450 enzyme system, can decrease the hepatic metabolism of altretamine, which could result in delayed elimination and increased blood concentrations.
    Amiodarone: (Moderate) Cimetidine may decrease the CYP3A4 metabolism of amiodarone, potentially resulting in increased plasma concentrations of amiodarone and the active metabolite.
    Amitriptyline: (Moderate) Cimetidine can inhibit the hepatic clearance of some tricyclic antidepressants that undergo oxidative metabolism, including amitriptyline. Choose an alternate H2-blocker when possible; alternatively, observe patients closely for TCA-induced side effects or toxicity if the concurrent use of cimetidine is unavoidable.
    Amlodipine; Atorvastatin: (Major) Because HMG-CoA reductase inhibitors may theoretically blunt adrenal and/or gonadal steroid production by interfering with cholesterol synthesis, the manufacturer recommends caution with concomitant administration of drugs that may decrease the concentrations or activity of endogenous hormones, such as cimetidine. It has also been reported that cimetidine could potentially increase the serum concentrations of HMG-CoA reductase inhibitors via the inhibition of the hepatic isoenzymes. Cimetidine does not alter the pharmacokinetics of atorvastatin, cerivastatin, or pravastatin. Clinical evidence of pharmacokinetic interactions with lovastatin and simvastatin is not available.
    Amlodipine; Celecoxib: (Minor) Since celecoxib is metabolized by cytochrome P450 2C9, concurrent administration with cimetidine, which can inhibit this enzyme, may result in increased levels of celecoxib. The clinical significance of this interaction has not been established.
    Amoxapine: (Moderate) Cimetidine can inhibit the systemic clearance of drugs that undergo oxidative metabolism, such as amoxapine, resulting in increased plasma levels of the antidepressant. Patients should be monitored for amoxapine-related side effects and toxicity if cimetidine is added; when possible, choose an alternative H2-blocker for treatment.
    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.
    Amprenavir: (Moderate) Amprenavir may inhibit the metabolism of medications that are metabolized via CYP3A4. Although drug interaction studies have not been conducted, the serum concentrations of cimetidine may be increased with concomitant administration of amprenavir. Theoretically, cimetidine may increase the serum concentration of amprenavir.
    Anagrelide: (Moderate) Anagrelide is partially metabolized by CYP1A2. Coadministration of anagrelide with drugs that inhibit CYP1A2, such as cimetidine, could theoretically decrease the elimination of anagrelide and increase the risk of side effects or toxicity. Patients should be monitored for increased adverse effects if these drugs are coadministered.
    Aripiprazole: (Moderate) Because aripiprazole is metabolized by CYP3A4 and CYP2D6, the manufacturer recommends that the oral aripiprazole dose be reduced to one-quarter (25%) of the usual dose in patients receiving inhibitors of both CYP3A4 and CYP2D6 such as cimetidine. Alternate H2-antagonist therapy that may not interact should be considered. Adult patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. If these agents are used in combination, the patient should be carefully monitored for aripiprazole-related adverse reactions. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP3A4 and CYP2D6 inhibitor.
    Armodafinil: (Moderate) Armodafinil is partially metabolized by CYP3A4/5 isoenzymes. Interactions with potent inhibitors of CYP3A4 such as cimetidine are possible. However, because armodafinil is itself an inducer of the CYP3A4 isoenzyme, drug interactions due to CYP3A4 inhibition by other medications may be complex and difficult to predict. Observation of the patient for increased effects from armodafinil may be needed.
    Artemether; Lumefantrine: (Moderate) Cimetidine is an inhibitor and artemether a substrate of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased artemether concentrations. Concomitant use warrants caution due to the potential for increased side effects. (Moderate) Cimetidine is an inhibitor and lumefantrine a substrate of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased lumefantrine concentrations. Concomitant use warrants caution due to the potential for increased side effects, including increased potentiation of QT prolongation.
    Aspirin, ASA; Butalbital; Caffeine: (Minor) Inhibitors of CYP1A2, such as cimetidine, may inhibit the hepatic oxidative metabolism of caffeine. In patients who complain of caffeine-related side effects caffeine dosage or intake may need to be reduced.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Minor) Cimetidine may inhibit the conversion of codeine to morphine, codeine's active metabolite, via the CYP2D6 hepatic isoenzyme and therefore may decrease the ability for codeine to produce analgesic effect. (Minor) Inhibitors of CYP1A2, such as cimetidine, may inhibit the hepatic oxidative metabolism of caffeine. In patients who complain of caffeine-related side effects caffeine dosage or intake may need to be reduced.
    Aspirin, ASA; Caffeine: (Minor) Inhibitors of CYP1A2, such as cimetidine, may inhibit the hepatic oxidative metabolism of caffeine. In patients who complain of caffeine-related side effects caffeine dosage or intake may need to be reduced.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with cimetidine may alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of dihydrocodeine until stable drug effects are achieved. Discontinuation of cimetidine could alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If cimetidine is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Cimetidine is a weak inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase dihydrocodeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy. (Minor) Inhibitors of CYP1A2, such as cimetidine, may inhibit the hepatic oxidative metabolism of caffeine. In patients who complain of caffeine-related side effects caffeine dosage or intake may need to be reduced.
    Aspirin, ASA; Caffeine; Orphenadrine: (Minor) Inhibitors of CYP1A2, such as cimetidine, may inhibit the hepatic oxidative metabolism of caffeine. In patients who complain of caffeine-related side effects caffeine dosage or intake may need to be reduced.
    Aspirin, ASA; Carisoprodol: (Minor) Carisoprodol is extensively metabolized and is a significant substrate of CYP2C19 isoenzymes. Theoretically, CY2C19 inhibitors, such as cimetidine, could increase carisoprodol plasma levels, with potential for enhanced CNS depressant effects.
    Aspirin, ASA; Carisoprodol; Codeine: (Minor) Carisoprodol is extensively metabolized and is a significant substrate of CYP2C19 isoenzymes. Theoretically, CY2C19 inhibitors, such as cimetidine, could increase carisoprodol plasma levels, with potential for enhanced CNS depressant effects. (Minor) Cimetidine may inhibit the conversion of codeine to morphine, codeine's active metabolite, via the CYP2D6 hepatic isoenzyme and therefore may decrease the ability for codeine to produce analgesic effect.
    Aspirin, ASA; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of cimetidine is necessary. If cimetidine is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a weak inhibitor like cimetidine can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If cimetidine is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    Aspirin, ASA; Pravastatin: (Major) Because HMG-CoA reductase inhibitors may theoretically blunt adrenal and/or gonadal steroid production by interfering with cholesterol synthesis, the manufacturer recommends caution with concomitant administration of drugs that may decrease the concentrations or activity of endogenous hormones, such as cimetidine. It has also been reported that cimetidine could potentially increase the serum concentrations of HMG-CoA reductase inhibitors via the inhibition of the hepatic isoenzymes. Cimetidine does not alter the pharmacokinetics of atorvastatin, cerivastatin, or pravastatin. Clinical evidence of pharmacokinetic interactions with lovastatin and simvastatin is not available.
    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.
    Atomoxetine: (Moderate) Atomoxetine is primarily a substrate for the cytochrome P450 isozyme CYP2D6. A dosage adjustment of atomoxetine may be needed in normal populations (also known as extensive metabolizers) when atomoxetine is administered with inhibitors of the CYP2D6 enzyme, such as cimetidine. In vitro studies suggest that coadministration of CYP2D6 inhibitors to poor metabolizers will not further increase the plasma concentrations of atomoxetine.
    Atorvastatin: (Major) Because HMG-CoA reductase inhibitors may theoretically blunt adrenal and/or gonadal steroid production by interfering with cholesterol synthesis, the manufacturer recommends caution with concomitant administration of drugs that may decrease the concentrations or activity of endogenous hormones, such as cimetidine. It has also been reported that cimetidine could potentially increase the serum concentrations of HMG-CoA reductase inhibitors via the inhibition of the hepatic isoenzymes. Cimetidine does not alter the pharmacokinetics of atorvastatin, cerivastatin, or pravastatin. Clinical evidence of pharmacokinetic interactions with lovastatin and simvastatin is not available.
    Atorvastatin; Ezetimibe: (Major) Because HMG-CoA reductase inhibitors may theoretically blunt adrenal and/or gonadal steroid production by interfering with cholesterol synthesis, the manufacturer recommends caution with concomitant administration of drugs that may decrease the concentrations or activity of endogenous hormones, such as cimetidine. It has also been reported that cimetidine could potentially increase the serum concentrations of HMG-CoA reductase inhibitors via the inhibition of the hepatic isoenzymes. Cimetidine does not alter the pharmacokinetics of atorvastatin, cerivastatin, or pravastatin. Clinical evidence of pharmacokinetic interactions with lovastatin and simvastatin is not available.
    Azelastine: (Minor) The mean Cmax and AUC of azelastine may be increased when coadministered with cimetidine. Theoretically, systemic exposure of nasally administered azelastine may be increased by coadministration with cimetidine, although an interaction has not been documented.
    Azelastine; Fluticasone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together. (Minor) The mean Cmax and AUC of azelastine may be increased when coadministered with cimetidine. Theoretically, systemic exposure of nasally administered azelastine may be increased by coadministration with cimetidine, although an interaction has not been documented.
    Beclomethasone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Coadministration of ergotamine with inhibitors of CYP3A4, such as cimetidine, may potentially increase the risk of ergot toxicity. Coadministration should be done cautiously, and avoided when possible.
    Belzutifan: (Moderate) Monitor for anemia and hypoxia if concomitant use of cimetidine with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and cimetidine is a CYP2C19 inhibitor.
    Bendamustine: (Major) Consider the use of an alternative therapy if cimetidine treatment is needed in patients receiving bendamustine. Cimetidine may increase bendamustine exposure, which may increase the risk of adverse reactions (e.g., myelosuppression, infection, hepatotoxicity). Bendamustine is a CYP1A2 substrate and cimetidine is a CYP1A2 inhibitor.
    Benzhydrocodone; Acetaminophen: (Moderate) Concurrent use of benzhydrocodone with cimetidine may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Consider a dose reduction of benzhydrocodone until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. Discontinuation of cimetidine in a patient taking benzhydrocodone may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. If cimetidine is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a substrate for CYP3A4 and CYP2D6. Cimetidine is an inhibitor of CYP3A4 and CYP2D6.
    Betamethasone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    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 Subcitrate Potassium; Metronidazole; Tetracycline: (Moderate) Cimetidine is an enzyme inhibitor that can decrease the hepatic metabolism of metronidazole. As a result, elimination can be delayed and serum metronidazole concentrations can increase. The sequelae of this interaction are unclear, although prolonged administration of metronidazole has been associated with seizures. If possible, cimetidine should not be used during metronidazole therapy.
    Bismuth Subsalicylate: (Minor) H2-blockers may increase the systemic absorption of bismuth from bismuth-containing compounds like bismuth subsalicylate.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Cimetidine is an enzyme inhibitor that can decrease the hepatic metabolism of metronidazole. As a result, elimination can be delayed and serum metronidazole concentrations can increase. The sequelae of this interaction are unclear, although prolonged administration of metronidazole has been associated with seizures. If possible, cimetidine should not be used during metronidazole therapy. (Minor) H2-blockers may increase the systemic absorption of bismuth from bismuth-containing compounds like bismuth subsalicylate.
    Boceprevir: (Moderate) Close clinical monitoring is advised when administering cimetidine with boceprevir due to an increased potential for boceprevir-related adverse events. If cimetidine dose adjustments are made, re-adjust the dose upon completion of boceprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathways of cimetidine and boceprevir. Cimetidine is an inhibitor of the hepatic isoenzyme CYP3A4; boceprevir is metabolized by this isoenzyme. When used in combination, the plasma concentrations of boceprevir may be elevated.
    Bortezomib: (Minor) Agents that inhibit cytochrome P450 3A4 may increase the exposure to bortezomib and increase the risk for toxicity; however, bortezomib is also metabolized by other CYP isoenzymes. Therefore, the clinical significance of concurrent administration of bortezomib with cimetidine is not known.
    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.
    Brimonidine; Timolol: (Moderate) Monitor for an increased incidence of timolol-related adverse effects if cimetidine and timolol are used concomitantly. Coadministration of cimetidine and timolol may result in increased plasma concentrations of timolol. Cimetidine is a CYP2D6 inhibitor. Timolol is a CYP2D6 substrate.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of cimetidine is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like cimetidine can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If cimetidine is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of cimetidine is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like cimetidine can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If cimetidine is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Budesonide: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together. (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) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together. (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) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together. (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.
    Bupivacaine; Lidocaine: (Moderate) Concomitant use of systemic lidocaine and cimetidine may increase lidocaine plasma concentrations. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP1A2 and CYP3A4 substrate; cimetidine inhibits both of these isoenzymes. Concomitant use of lidocaine with a weak CYP1A2 and CYP3A4 inhibitor has reportedly increased lidocaine plasma concentrations by 24% to 75%.
    Buprenorphine: (Minor) Since the metabolism of buprenorphine is mediated by the CYP3A4 isozyme, co-administration of drugs that inhibit CYP3A4, such as cimetidine, may cause decreased clearance of buprenorphine. Thus, there is a potential for excessive buprenorphine-related side effects.
    Buprenorphine; Naloxone: (Minor) Since the metabolism of buprenorphine is mediated by the CYP3A4 isozyme, co-administration of drugs that inhibit CYP3A4, such as cimetidine, may cause decreased clearance of buprenorphine. Thus, there is a potential for excessive buprenorphine-related side effects.
    Bupropion: (Moderate) Cimetidine has resulted in increased plasma concentrations of the active metabolites, threohydrobupropion and erythrobupropion, but the clinical significance is not known.
    Bupropion; Naltrexone: (Moderate) Cimetidine has resulted in increased plasma concentrations of the active metabolites, threohydrobupropion and erythrobupropion, but the clinical significance is not known.
    Buspirone: (Moderate) CYP3A4 inhibitors, such as cimetidine, may decrease systemic clearance of buspirone leading to increased or prolonged effects. If buspirone is to be administered concurrently with significant CYP3A4 inhibitors, a low dose of buspirone is recommended initially.
    Butalbital; Acetaminophen; Caffeine: (Minor) Inhibitors of CYP1A2, such as cimetidine, may inhibit the hepatic oxidative metabolism of caffeine. In patients who complain of caffeine-related side effects caffeine dosage or intake may need to be reduced.
    Butalbital; Acetaminophen; Caffeine; Codeine: (Minor) Cimetidine may inhibit the conversion of codeine to morphine, codeine's active metabolite, via the CYP2D6 hepatic isoenzyme and therefore may decrease the ability for codeine to produce analgesic effect. (Minor) Inhibitors of CYP1A2, such as cimetidine, may inhibit the hepatic oxidative metabolism of caffeine. In patients who complain of caffeine-related side effects caffeine dosage or intake may need to be reduced.
    Cabotegravir; Rilpivirine: (Moderate) Coadministration with cimetidine may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of H2 receptor antagonist for at least 12 hours before and at least 4 hours after administering rilpivirine.
    Caffeine: (Minor) Inhibitors of CYP1A2, such as cimetidine, may inhibit the hepatic oxidative metabolism of caffeine. In patients who complain of caffeine-related side effects caffeine dosage or intake may need to be reduced.
    Caffeine; Sodium Benzoate: (Minor) Inhibitors of CYP1A2, such as cimetidine, may inhibit the hepatic oxidative metabolism of caffeine. In patients who complain of caffeine-related side effects caffeine dosage or intake may need to be reduced.
    Calcium Carbonate; Risedronate: (Major) Use of H2-blockers with delayed-release risedronate tablets (Atelvia) is not recommended. Co-administration of drugs that raise stomach pH increases risedronate bioavailability due to faster release of the drug from the enteric coated tablet. This interaction does not apply to risedronate immediate-release tablets.
    Canagliflozin; Metformin: (Moderate) Use with caution, as cimetidine inhibits renal elimination of metformin. Consider alternatives to cimetidine. Increased metformin exposure due to use of cimetidine may lead to gastrointestinal complaints, altered glycemic control, and a potential for an increased risk for lactic acidosis. If it is medically necessary to use cimetidine, carefully monitor. Metformin dose reduction may be needed. An interaction between metformin and oral cimetidine has been observed in normal healthy volunteers in both single- and multiple-dose drug interaction studies. Cimetidine caused a 60% increase in peak metformin concentrations and a 40% increase in metformin exposure (AUC). Cimetidine inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]).
    Carbamazepine: (Major) Carbamazepine is metabolized by the hepatic isoenzyme CYP3A4. Drugs known to inhibit CYP3A4, such as cimetidine, may decrease carbamazepine metabolism and increase carbamazepine plasma concentrations. Serum carbamazepine concentrations should be monitored closely during coadministration; reduce carbamazepine doses may be necessary.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of cimetidine is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like cimetidine can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If cimetidine is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of cimetidine is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like cimetidine can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If cimetidine is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Carisoprodol: (Minor) Carisoprodol is extensively metabolized and is a significant substrate of CYP2C19 isoenzymes. Theoretically, CY2C19 inhibitors, such as cimetidine, could increase carisoprodol plasma levels, with potential for enhanced CNS depressant effects.
    Carmustine, BCNU: (Moderate) Use cimetidine and carmustine together with caution; increased myelosuppression (e.g., leukopenia and neutropenia) may occur. Consider using an alternative agent in place of cimetidine.
    Carvedilol: (Moderate) Monitor for an increased incidence of carvedilol-related adverse effects if cimetidine and carvedilol are used concomitantly. Inhibitors of the hepatic CYP450 isozyme CYP2D6 may inhibit the hepatic oxidative metabolism of carvedilol. Cimetidine inhibits several hepatic cytochrome isozymes, including CYP2D6 and has been shown to increase carvedilol steady-state area under the plasma-concentration time curve (AUC) by 30%. Maximum serum concentrations of carvedilol are not increased. The clinical significance of this pharmacokinetic interaction is unclear.
    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.
    Celecoxib: (Minor) Since celecoxib is metabolized by cytochrome P450 2C9, concurrent administration with cimetidine, which can inhibit this enzyme, may result in increased levels of celecoxib. The clinical significance of this interaction has not been established.
    Cetrorelix: (Minor) Drugs that cause hyperprolactinemia, such as cimetidine, should not be administered concomitantly with gonadotropin releasing hormone analogs since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
    Chlordiazepoxide: (Moderate) Cimetidine can inhibit the hepatic clearance of some benzodiazepines that undergo oxidative metabolism, including chlordiazepoxide.
    Chlordiazepoxide; Amitriptyline: (Moderate) Cimetidine can inhibit the hepatic clearance of some benzodiazepines that undergo oxidative metabolism, including chlordiazepoxide. (Moderate) Cimetidine can inhibit the hepatic clearance of some tricyclic antidepressants that undergo oxidative metabolism, including amitriptyline. Choose an alternate H2-blocker when possible; alternatively, observe patients closely for TCA-induced side effects or toxicity if the concurrent use of cimetidine is unavoidable.
    Chlordiazepoxide; Clidinium: (Moderate) Cimetidine can inhibit the hepatic clearance of some benzodiazepines that undergo oxidative metabolism, including chlordiazepoxide.
    Chloroquine: (Major) Avoid concomitant use of chloroquine and cimetidine as cimetidine may inhibit the metabolism of chloroquine, increasing its plasma concentration.
    Chlorpheniramine; Codeine: (Minor) Cimetidine may inhibit the conversion of codeine to morphine, codeine's active metabolite, via the CYP2D6 hepatic isoenzyme and therefore may decrease the ability for codeine to produce analgesic effect.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of dihydrocodeine with cimetidine may alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of dihydrocodeine until stable drug effects are achieved. Discontinuation of cimetidine could alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If cimetidine is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Cimetidine is a weak inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase dihydrocodeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Concomitant use of dihydrocodeine with cimetidine may alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of dihydrocodeine until stable drug effects are achieved. Discontinuation of cimetidine could alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If cimetidine is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Cimetidine is a weak inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase dihydrocodeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of cimetidine is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like cimetidine can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If cimetidine is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Chlorpheniramine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of cimetidine is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like cimetidine can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If cimetidine is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of cimetidine is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like cimetidine can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If cimetidine is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of cimetidine is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like cimetidine can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If cimetidine is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Chlorpromazine: (Minor) Cimetidine has been reported to alter the steady-state plasma concentrations of chlorpromazine. It is possible that cimetidine may also reduce the hepatic metabolism of chlorpromazine. Excessive sedation has been reported in a few case reports. There are limited data supporting the clinical significance of this interaction. Another H-2 blocker may be preferred. Monitor the patient for altered clinical response to therapy or excessive sedation if these drugs are co-administered.
    Chlorpropamide: (Moderate) Cimetidine has been shown to affect the pharmacokinetics of some oral sulfonylureas. Patients receiving sulfonylureas should be observed for evidence of altered glycemic response when cimetidine 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.
    Ciclesonide: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Cilostazol: (Minor) Cilostazol is extensively metabolized by the CYP3A4 hepatic isoenzyme and appears to interact with medications that are potent inhibitors of this enzyme, including cimetidine. When significant CYP3A4 inhibitors are administered concomitantly, the cilostazol adult dosage should be reduced by 50%.
    Cisapride: (Major) Consider alternatives to cimetidine in patients receiving cisapride. Coadministration of cimetidine and cisapride results in increased exposure to cisapride. Serious cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation, torsade de pointes, and QT prolongation have been reported in patients taking cisapride with other drugs that inhibit CYP3A4. In a drug interaction study, cimetidine increased the AUC of cisapride by 45%. Cimetidine is a weak inhibitor of CYP3A4; cisapride is a CYP3A4 substrate.
    Citalopram: (Moderate) The plasma concentration of citalopram, a CYP2C19 substrate, may be increased when administered concurrently with cimetidine, a CYP2C19 inhibitor. Because citalopram causes dose-dependent QT prolongation, the maximum daily dose should not exceed 20 mg per day in patients receiving CYP2C19 inhibitors. In clinical trial subjects, combined administration of cimetidine and citalopram for 8 days resulted in an increase in citalopram AUC and Cmax of 43% and 39%, respectively.
    Clobazam: (Moderate) A dosage reduction of clobazam may be necessary during co-administration of cimetidine. Metabolism of N-desmethylclobazam, the active metabolite of clobazam, occurs primarily through CYP2C19 and cimetidine is an inhibitor of CYP2C19. Extrapolation from pharmacogenomic data indicates that concurrent use of clobazam with moderate or potent inhibitors of CYP2C19 may result in up to a 5-fold increase in exposure to N-desmethylclobazam. Adverse effects, such as sedation, lethargy, ataxia, or insomnia may be potentiated.
    Clofarabine: (Moderate) The concomitant use of clofarabine and cimetidine resulted in decreased clofarabine renal excretion in a preclinical study in rats. Cimetidine is a substrate for OAT3 and OCT2. Monitor for signs of clofarabine toxicity such as gastrointestinal toxicity (e.g., nausea, vomiting, diarrhea, mucosal inflammation), hematologic toxicity, and skin toxicity (e.g. hand and foot syndrome, rash, pruritus) in patients also receiving OAT3 or OCT2 substrates or inhibitors.
    Clomipramine: (Moderate) Cimetidine can inhibit the systemic clearance of tricyclic antidepressants that undergo oxidative metabolism, such as clomipramine, resulting in increased plasma levels of the antidepressant. Patients should be monitored for TCA-related side effects and toxicity if cimetidine is added; when possible, choose an alternative H2-blocker for treatment.
    Clonazepam: (Moderate) Cimetidine can decrease the hepatic oxidative metabolism of clonazepam if administered concomitantly.
    Clopidogrel: (Moderate) Monitor for reduced clopidogrel efficacy during concomitant use of cimetidine. Clopidogrel is primarily metabolized to its active metabolite by CYP2C19; cimetidine is a CYP2C19 inhibitor.
    Clorazepate: (Moderate) Cimetidine can inhibit the hepatic clearance of some benzodiazepines that undergo oxidative metabolism, including clorazepate.
    Clozapine: (Moderate) Caution is advisable during concurrent use of cimetidine and clozapine. Cimetidine is an inhibitor of CYP3A4, CYP2D6, and CYP1A2, the isoenzymes responsible for the metabolism of clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through inhibition of CYP1A2, 2D6, or 3A4 may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with an inhibitor of CYP3A4, CYP2D6, or CYP1A2 should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
    Cobimetinib: (Moderate) If concurrent use of cobimetinib and cimetidine is necessary, use caution and monitor for increased cobimetinib-related adverse effects. Cobimetinib is a CYP3A substrate in vitro, and cimetidine is a weak inhibitor of CYP3A. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7). Simulations showed that predicted steady-state concentrations of cobimetinib at a reduced dose of 20 mg administered concurrently with short-term (less than 14 days) treatment of a moderate CYP3A inhibitor were similar to observed steady-state concentrations of cobimetinib 60 mg alone. The manufacturer of cobimetinib recommends avoiding coadministration with moderate to strong CYP3A inhibitors, and significantly reducing the dose of cobimetinib if coadministration with moderate CYP3A inhibitors cannot be avoided. Guidance is not available regarding concomitant use of cobimetinib with weak CYP3A inhibitors.
    Codeine: (Minor) Cimetidine may inhibit the conversion of codeine to morphine, codeine's active metabolite, via the CYP2D6 hepatic isoenzyme and therefore may decrease the ability for codeine to produce analgesic effect.
    Codeine; Guaifenesin: (Minor) Cimetidine may inhibit the conversion of codeine to morphine, codeine's active metabolite, via the CYP2D6 hepatic isoenzyme and therefore may decrease the ability for codeine to produce analgesic effect.
    Codeine; Guaifenesin; Pseudoephedrine: (Minor) Cimetidine may inhibit the conversion of codeine to morphine, codeine's active metabolite, via the CYP2D6 hepatic isoenzyme and therefore may decrease the ability for codeine to produce analgesic effect.
    Codeine; Phenylephrine; Promethazine: (Minor) Cimetidine may inhibit the conversion of codeine to morphine, codeine's active metabolite, via the CYP2D6 hepatic isoenzyme and therefore may decrease the ability for codeine to produce analgesic effect.
    Codeine; Promethazine: (Minor) Cimetidine may inhibit the conversion of codeine to morphine, codeine's active metabolite, via the CYP2D6 hepatic isoenzyme and therefore may decrease the ability for codeine to produce analgesic effect.
    Corticosteroids: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Cortisone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Cyclosporine: (Moderate) Additive nephrotoxicity can occur if cyclosporine is administered with other nephrotoxic drugs such as cimetidine.
    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 cimetidine 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.
    Dalfampridine: (Moderate) Concurrent treatment with OCT2 inhibitors, such as cimetidine, may cause increased exposure to dalfampridine. Elevated levels of dalfampridine increase the risk of seizures. The potential benefits of taking OCT2 inhibitors concurrently with dalfampridine should be considered against the risk of seizures in these patients. Consider alternatives to cimetidine.
    Dapagliflozin; Metformin: (Moderate) Use with caution, as cimetidine inhibits renal elimination of metformin. Consider alternatives to cimetidine. Increased metformin exposure due to use of cimetidine may lead to gastrointestinal complaints, altered glycemic control, and a potential for an increased risk for lactic acidosis. If it is medically necessary to use cimetidine, carefully monitor. Metformin dose reduction may be needed. An interaction between metformin and oral cimetidine has been observed in normal healthy volunteers in both single- and multiple-dose drug interaction studies. Cimetidine caused a 60% increase in peak metformin concentrations and a 40% increase in metformin exposure (AUC). Cimetidine inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]).
    Darifenacin: (Moderate) The mean Cmax and AUC of darifenacin 30 mg once daily at steady state were 42 percent and 34 percent higher, respectively, in the presence of cimetidine. Monitor patients receiving these two drugs concomitantly for increased anticholinergic effects; dosage adjustments may be necessary.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Concurrent administration of cimetidine with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of paritaprevir, ritonavir, and dasabuvir. Cimetidine is an inhibitor of the hepatic isoenzymes CYP3A4 and CYP2D6; ritonavir is partially metabolized by both of these enzymes. In addition, paritaprevir and dasabuvir (minor) are substrates of CYP3A4. Monitor for adverse events if these drugs are administered together. (Moderate) Concurrent administration of cimetidine with ritonavir may result in elevated plasma concentrations of ritonavir. Cimetidine is an inhibitor of the hepatic isoenzymes CYP3A4 and CYP2D6; ritonavir is partially metabolized by both of these enzymes. Monitor for adverse events if these drugs are administered together.
    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.
    Deflazacort: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Degarelix: (Minor) In the absence of relevant data and as a precaution, drugs that cause hyperprolactinemia, such as cimetidine, should not be administered concomitantly with degarelix, as hyperprolactinemia downregulates the number of pituitary gonadotropin-releasing hormone receptors.
    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.
    Desipramine: (Moderate) Cimetidine can inhibit the systemic clearance of tricyclic antidepressants that undergo oxidative metabolism, such as desipramine, resulting in increased plasma levels of the antidepressant.
    Dexamethasone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Dextromethorphan; Quinidine: (Major) Quinidine concentrations should be monitored closely after cimetidine is added; choose an alternate acid-reducing therapy if possible. Quinidine is eliminated primarily by the CYP3A4 isoenzyme. Cimetidine can inhibit quinidine metabolism and produce quinidine toxicity.
    Diazepam: (Moderate) Cimetidine can inhibit the hepatic clearance of some benzodiazepines that undergo oxidative metabolism, such as diazepam. In some cases, dosage reduction of the interacting drug will be necessary or an alternative to cimetidine should be considered.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of dihydrocodeine with cimetidine may alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of dihydrocodeine until stable drug effects are achieved. Discontinuation of cimetidine could alter dihydrocodeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If cimetidine is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Dihydrocodeine is primarily metabolized by CYP2D6 to dihydromorphine, and by CYP3A4. Cimetidine is a weak inhibitor of CYP3A4 and CYP2D6. CYP3A4 inhibitors may increase dihydrocodeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
    Dihydroergotamine: (Major) Monitor for increased dihydroergotamine-related adverse effects with coadministration of cimetidine. The serum concentration of dihydroergotamine may increase during concurrent use. Cimetidine is a weak CYP3A4 inhibitor; dihydroergotamine is a CYP3A4 substrate.
    Diltiazem: (Moderate) Cimetidine can increase the plasma levels of diltiazem, possibly via inhibition of cytochrome P-450 metabolism. Concurrent cimetidine and diltiazem therapy may require a reduction in diltiazem dosage in some patients; monitor clinical response.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of cimetidine is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like cimetidine can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If cimetidine is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    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.
    Dofetilide: (Contraindicated) Cimetidine is an inhibitor of renal cationic tubular secretion and is contraindicated with dofetilide due to the potential for increased plasma dofetilide concentrations and associated proarrhythmias. Cimetidine (400 mg PO twice daily) coadministered with dofetilide (500 mcg PO twice daily) for 7 days increased dofetilide plasma levels by 58%. Cimetidine, at over-the-counter doses of 100 mg PO twice daily, results in a 13% increase in dofetilide plasma concentrations following a single 500 mcg oral dose. Omeprazole, ranitidine, or antacids (aluminum and magnesium hydroxides) may be used as anti-ulcer therapy alternatives to cimetidine; these agents did not alter dofetilide pharmacokinetics.
    Dolasetron: (Moderate) Coadministration of dolasetron and cimetidine, a nonselective inhibitor of cytochrome P450, increased the blood concentrations of dolasetron's active metabolite by 24%.
    Dolutegravir; Rilpivirine: (Moderate) Coadministration with cimetidine may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of H2 receptor antagonist for at least 12 hours before and at least 4 hours after administering rilpivirine.
    Donepezil; Memantine: (Moderate) 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 cimetidine, could result in elevated serum concentrations of one or both drugs.
    Dorzolamide; Timolol: (Moderate) Monitor for an increased incidence of timolol-related adverse effects if cimetidine and timolol are used concomitantly. Coadministration of cimetidine and timolol may result in increased plasma concentrations of timolol. Cimetidine is a CYP2D6 inhibitor. Timolol is a CYP2D6 substrate.
    Doxepin: (Moderate) Cimetidine can inhibit the systemic clearance of tricyclic antidepressants that undergo oxidative metabolism, such as doxepin, resulting in increased plasma levels of the antidepressant.
    Doxercalciferol: (Moderate) CYP450 enzyme inhibitors, like cimetidine, may inhibit the 25-hydroxylation of doxercalciferol, thereby decreasing the formation of the active metabolite and thus, decreasing efficacy. Patients should be monitored for a decrease in efficacy if CYP450 inhibitors are coadministered with doxercalciferol.
    Doxorubicin: (Major) Cimetidine is a mild inhibitor of CYP2D6 and CYP3A4; doxorubicin is a major CYP2D6 and CYP3A4 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP2D6 and/or CYP3A4, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of cimetidine and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Dronabinol: (Moderate) Use caution if coadministration of dronabinol with cimetidine is necessary, and monitor for an increase in dronabinol-related adverse reactions (e.g., feeling high, dizziness, confusion, somnolence). Dronabinol is a CYP2C9 and 3A4 substrate; cimetidine is a weak inhibitor of CYP3A4. Concomitant use may result in elevated plasma concentrations of dronabinol.
    Dronedarone: (Moderate) Dronedarone is metabolized by CYP3A. Cimetidine is an inhibitor CYP3A4. Concomitant use of dronedarone with cimetidine may also increase dronedarone concentrations. No data exist regarding the appropriate dose adjustment needed to allow safe administration of dronedarone with CYP3A4 inhibitors; therefore, use caution when coadministering dronedarone with CYP3A4 inhibitors such as cimetidine.
    Duloxetine: (Moderate) Use caution during coadministration of duloxetine and cimetidine; duloxetine concentrations may be increased. Duloxetine is a CYP1A2 substrate; cimetidine is a weak CYP1A2 inhibitor.
    Dutasteride: (Moderate) Dutasteride is metabolized by CYP3A4 enzyme. The clearance of dutasteride may be reduced when co-administered with CYP3A4 inhibitors, such as cimetidine.
    Dutasteride; Tamsulosin: (Moderate) Cimetidine is a weak inhibitor of CYP2D6, one of the enzymes responsible for metabolism of tamsulosin. The manufacturer recommends that tamsulosin be used with caution in combination with cimetidine. A study involving 10 healthy volunteers (age range 21 to 40 years) showed that cimetidine administered at the highest recommended dose (400 mg q6h for 6 days) significantly (26%) decreased the clearance of a single tamsulosin 0.4 mg dose. This resulted in a moderate increase in tamsulosin AUC (44%). (Moderate) Dutasteride is metabolized by CYP3A4 enzyme. The clearance of dutasteride may be reduced when co-administered with CYP3A4 inhibitors, such as cimetidine.
    Eliglustat: (Major) In poor CYP2D6 metabolizers (PMs), coadministration of cimetidine and eliglustat is not recommended. In extensive CYP2D6 metabolizers (EM) with mild hepatic impairment, coadministration of these agents requires dosage reduction of eliglustat to 84 mg PO once daily. Cimetidine is a weak CYP3A (and CYP2D6) inhibitor; eliglustat is a CYP3A and CYP2D6 substrate. Coadministration with CYP2D6 and CYP3A inihibitors, such as cimetidine, may increase eliglustat exposure and the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias).
    Eltrombopag: (Moderate) Eltrombopag is metabolized by CYP1A2. The significance of administering inhibitors of CYP1A2, such as cimetidine, on the systemic exposure of eltrombopag has not been established. Monitor patients for signs of eltrombopag toxicity if these drugs are coadministered.
    Elvitegravir: (Moderate) Caution is warranted when elvitegravir is administered with cimetidine as there is a potential for elevated elvitegravir concentrations. Cimetidine is a CYP3A4 and CYP2D6 inhibitor, while elvitegravir is a substrate of CYP3A4.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Caution is warranted when elvitegravir is administered with cimetidine as there is a potential for elevated elvitegravir concentrations. Cimetidine is a CYP3A4 and CYP2D6 inhibitor, while elvitegravir is a substrate of CYP3A4.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is warranted when elvitegravir is administered with cimetidine as there is a potential for elevated elvitegravir concentrations. Cimetidine is a CYP3A4 and CYP2D6 inhibitor, while elvitegravir is a substrate of CYP3A4.
    Empagliflozin; Linagliptin; Metformin: (Moderate) Use with caution, as cimetidine inhibits renal elimination of metformin. Consider alternatives to cimetidine. Increased metformin exposure due to use of cimetidine may lead to gastrointestinal complaints, altered glycemic control, and a potential for an increased risk for lactic acidosis. If it is medically necessary to use cimetidine, carefully monitor. Metformin dose reduction may be needed. An interaction between metformin and oral cimetidine has been observed in normal healthy volunteers in both single- and multiple-dose drug interaction studies. Cimetidine caused a 60% increase in peak metformin concentrations and a 40% increase in metformin exposure (AUC). Cimetidine inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]).
    Empagliflozin; Metformin: (Moderate) Use with caution, as cimetidine inhibits renal elimination of metformin. Consider alternatives to cimetidine. Increased metformin exposure due to use of cimetidine may lead to gastrointestinal complaints, altered glycemic control, and a potential for an increased risk for lactic acidosis. If it is medically necessary to use cimetidine, carefully monitor. Metformin dose reduction may be needed. An interaction between metformin and oral cimetidine has been observed in normal healthy volunteers in both single- and multiple-dose drug interaction studies. Cimetidine caused a 60% increase in peak metformin concentrations and a 40% increase in metformin exposure (AUC). Cimetidine inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]).
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Coadministration with cimetidine may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of H2 receptor antagonist for at least 12 hours before and at least 4 hours after administering rilpivirine.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Moderate) Coadministration with cimetidine may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of H2 receptor antagonist for at least 12 hours before and at least 4 hours after administering rilpivirine.
    Enalapril; Felodipine: (Moderate) Cimetidine is a potent inhibitor of many of the isoenzymes of the hepatic CYP450 oxidative enzyme system and the metabolism of calcium-channel blockers like felodipine is inhibited by cimetidine.
    Encainide: (Major) Encainide is significantly metabolized by CYP2D6 isoenzymes. Caution is recommended when administering encainide with CYP2D6 inhibitors since encainide exhibits a narrow therapeutic range and large increases in serum concentrations may be associated with severe adverse reactions. The half-life of encainide is prolonged in patients given cimetidine (a weak CYP2D6 inhibitor) concurrently resulting in an increase in the AUC of encainide and its metabolites. Close clinical monitoring may be necessary during coadministration of cimetidine. In some cases, dosage changes will be necessary or an alternative to cimetidine should be chosen.
    Entecavir: (Moderate) Both entecavir and cimetidine are secreted by active tubular secretion. In theory, coadministration of entecavir with cimetidine 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.
    Epirubicin: (Major) Discontinue cimetidine during treatment with epirubicin due to the risk of increased epirubicin exposure which may result in an increase of epirubicin-related adverse reactions. Coadministration of cimetidine increased the mean AUC of epirubicin by 50% and decreased its plasma clearance by 30%.
    Ergonovine: (Major) Coadministration of certain ergot alkaloids with inhibitors of CYP3A4, such as cimetidine, may potentially increase the risk of ergot toxicity. Use with extreme caution.
    Ergotamine: (Major) Coadministration of ergotamine with inhibitors of CYP3A4, such as cimetidine, may potentially increase the risk of ergot toxicity. Coadministration should be done cautiously, and avoided when possible.
    Ergotamine; Caffeine: (Major) Coadministration of ergotamine with inhibitors of CYP3A4, such as cimetidine, may potentially increase the risk of ergot toxicity. Coadministration should be done cautiously, and avoided when possible. (Minor) Inhibitors of CYP1A2, such as cimetidine, may inhibit the hepatic oxidative metabolism of caffeine. In patients who complain of caffeine-related side effects caffeine dosage or intake may need to be reduced.
    Erlotinib: (Major) Avoid coadministration of erlotinib with cimetidine if possible due to altered plasma concentrations of erlotinib. If concomitant use is unavoidable, separate dosing is required, as the solubility of erlotinib is pH dependent, decreasing as the pH increases. Erlotinib must be taken 10 hours after the last dose of cimetidine and at least 2 hours before the next dose. Additionally, monitor for erlotinib-related adverse reactions; a dose reduction may be necessary for severe reactions. Coadministration of erlotinib with medications that increase the pH of the upper gastrointestinal tract may decrease the absorption of erlotinib. 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%. Increasing the dose of erlotinib is not likely to compensate for the loss of exposure. Erlotinib is also primarily metabolized by CYP3A4 and to a lesser extent by CYP1A2. Cimetidine is a weak CYP3A4 and CYP1A2 inhibitor.
    Ertugliflozin; Metformin: (Moderate) Use with caution, as cimetidine inhibits renal elimination of metformin. Consider alternatives to cimetidine. Increased metformin exposure due to use of cimetidine may lead to gastrointestinal complaints, altered glycemic control, and a potential for an increased risk for lactic acidosis. If it is medically necessary to use cimetidine, carefully monitor. Metformin dose reduction may be needed. An interaction between metformin and oral cimetidine has been observed in normal healthy volunteers in both single- and multiple-dose drug interaction studies. Cimetidine caused a 60% increase in peak metformin concentrations and a 40% increase in metformin exposure (AUC). Cimetidine inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]).
    Escitalopram: (Moderate) The plasma concentration of escitalopram, a CYP2C19 and CYP3A4 substrate, may be increased when administered concurrently with cimetidine, a CYP2C19 and CYP3A4 inhibitor. If these drugs are used together, monitor for escitalopram-associated adverse reactions.
    Estazolam: (Moderate) Cimetidine is a CYP3A4 inhibitor and may reduce the metabolism of estazolam and increase the potential for benzodiazepine toxicity.
    Estradiol; Progesterone: (Minor) The metabolism of progesterone may be inhibited by cimetidine, an inhibitor of cytochrome P450 3A4 hepatic enzymes.
    Ethanol: (Minor) Some studies have suggested that H2-receptor antagonists inhibit gastric alcohol dehydrogenase and thus decrease the first pass metabolism of alcohol, and some studies have suggested an interaction may not always occur. A meta-analysis evaluating the effects of H2-blockers on blood alcohol concentrations reported that only cimetidine and ranitidine, but not other H2-blockers, caused small elevations in serum alcohol 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.
    Etonogestrel: (Minor) Coadministration of etonogestrel and moderate CYP3A4 inhibitors such as cimetidine may increase the serum concentration of etonogestrel.
    Etonogestrel; Ethinyl Estradiol: (Minor) Coadministration of etonogestrel and moderate CYP3A4 inhibitors such as cimetidine may increase the serum concentration of etonogestrel.
    Ezetimibe; Simvastatin: (Major) Because HMG-CoA reductase inhibitors may theoretically blunt adrenal and/or gonadal steroid production by interfering with cholesterol synthesis, the manufacturer recommends caution with concomitant administration of drugs that may decrease the concentrations or activity of endogenous hormones, such as cimetidine. It has also been reported that cimetidine could potentially increase the serum concentrations of HMG-CoA reductase inhibitors via the inhibition of the hepatic isoenzymes. Cimetidine does not alter the pharmacokinetics of atorvastatin, cerivastatin, or pravastatin. Clinical evidence of pharmacokinetic interactions with lovastatin and simvastatin is not available.
    Fedratinib: (Major) Avoid coadministration of fedratinib with cimetidine as concurrent use may increase fedratinib exposure. Fedratinib is a substrate of both CYP3A4 and CYP2C19; cimetidine is an inhibitor of both CYP3A4 and CYP2C19. The coadministration of fedratinib with agents that are both a CYP3A4 and CYP2C19 inhibitor has not been evaluated.
    Felodipine: (Moderate) Cimetidine is a potent inhibitor of many of the isoenzymes of the hepatic CYP450 oxidative enzyme system and the metabolism of calcium-channel blockers like felodipine is inhibited by cimetidine.
    Fentanyl: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of cimetidine is necessary. If cimetidine is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like cimetidine can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If cimetidine is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
    Finerenone: (Moderate) Monitor serum potassium during initiation or dose adjustment of either finerenone or cimetidine; a finerenone dosage reduction may be necessary. Concomitant use may increase finerenone exposure and the risk of hyperkalemia. Finerenone is a CYP3A substrate and cimetidine is a weak CYP3A inhibitor. Coadministration with another weak CYP3A inhibitor increased overall exposure to finerenone by 21%.
    Flecainide: (Major) Flecainide is significantly metabolized by CYP2D6 isoenzymes. Caution is recommended when administering flecainide with CYP2D6 inhibitors, such as cimetidine; flecainide exhibits a narrow therapeutic range and large increases in serum concentrations may be associated with severe adverse reactions. Close clinical monitoring may be necessary during coadministration with cimetidine. In some cases, dosage changes will be necessary for flecanaide or an alternative to cimetidine should be chosen.
    Flibanserin: (Moderate) The concomitant use of flibanserin and multiple weak CYP3A4 inhibitors, including cimetidine, 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 potential outcomes of combination therapy with multiple weak CYP3A4 inhibitors and flibanserin should be discussed with the patient.
    Floxuridine: (Minor) Data suggest chronic administration of cimetidine with fluorouracil, 5-FU, can increase 5-FU serum concentrations, but it is not clear if this interaction results in increased 5-FU efficacy or toxicity. Patients receiving either 5-FU or floxuridine should be monitored for a possible increased response to 5-FU if cimetidine is used concurrently.
    Fluconazole: (Moderate) It is not clear that cimetidine interacts with fluconazole in any clinically significant way. Significant decreases in the AUC and Cmax of fluconazole were noted following administration of fluconazole 50 mg PO given two hours after a single dose of cimetidine 400 mg PO to six healthy male volunteers. However, fluconazole pharmacokinetics and bioavailability were not affected when fluconazole 200 mg PO as a single dose was given with cimetidine 600 mg to 900 mg IV over a 4-hour period in healthy male volunteers. Cimetidine, due to inhibition of hepaticCYP P450 enzyme system, may also inhibit the metabolism of the systemic azole antifungal agents, but a clinically important interaction has not been established.
    Fludrocortisone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Flunisolide: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Fluorouracil, 5-FU: (Minor) Chronic administration of cimetidine with fluorouracil, 5-FU, can increase 5-FU serum concentrations, but it is not clear if this interaction results in increased 5-FU efficacy or toxicity. Patients receiving either 5-FU should be monitored for a possible increased response to 5-FU if cimetidine is used concurrently.
    Fluoxetine: (Moderate) Although no clinical data are available, it is possible that inhibitors of hepatic enzymes such as cimetidine may decrease the metabolism of fluoxetine. Until more data are available, cimetidine should be used cautiously in patients receiving fluoxetine.
    Flurazepam: (Moderate) Cimetidine can inhibit the hepatic clearance of some benzodiazepines that undergo oxidative metabolism, including flurazepam.
    Fluticasone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Fluticasone; Salmeterol: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Fluticasone; Vilanterol: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Fluvastatin: (Major) Because HMG-CoA reductase inhibitors may theoretically blunt adrenal and/or gonadal steroid production by interfering with cholesterol synthesis, the manufacturer recommends caution with concomitant administration of drugs that may decrease the concentrations or activity of endogenous hormones, such as cimetidine. It has also been reported that cimetidine could potentially increase the serum concentrations of HMG-CoA reductase inhibitors via the inhibition of the hepatic isoenzymes. Cimetidine does not alter the pharmacokinetics of atorvastatin, cerivastatin, or pravastatin. Clinical evidence of pharmacokinetic interactions with lovastatin and simvastatin is not available.
    Fluvoxamine: (Moderate) Cimetidine may inhibit the metabolism of fluvoxamine.
    Fomepizole: (Minor) In healthy volunteers, moderate oral doses of fomepizole significantly reduced the rate of elimination of ethanol by approximately 40%. Similarly, ethanol decreased the rate of elimination of fomepizole by approximately 50%. Both interactions occur via alcohol dehydrogenase inhibition. Although not studied, reciprocal interactions may occur with concomitant use of fomepizole and drugs that increase or inhibit the cytochrome P450 enzyme system, like cimetidine.
    Food: (Moderate) The incidence of marijuana associated adverse effects may change following coadministration with cimetidine. Cimetidine is an inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of marijuana's most psychoactive compound, delta-9-tetrahydrocannabinol (Delta-9-THC). When given concurrently with cimetidine, the amount of Delta-9-THC converted to the active metabolite 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-THC) may be reduced. These changes in Delta-9-THC and 11-OH-THC plasma concentrations may result in an altered marijuana adverse event profile.
    Formoterol; Mometasone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    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.
    Ganirelix: (Minor) In the absence of relevant data and as a precaution, drugs that cause hyperprolactinemia, such as cimetidine, should not be administered concomitantly with gonadotropin releasing hormone analogs since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
    Gefitinib: (Major) Avoid coadministration of cimetidine 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 cimetidine. Gefitinib exposure is affected by gastric pH. Coadministration with high doses of another H2-blocker to maintain gastric pH above 5 decreased gefitinib exposure by 47%.
    Glimepiride: (Moderate) Cimetidine has been shown to affect the pharmacokinetics of some oral sulfonylureas. Patients receiving sulfonylureas should be observed for evidence of altered glycemic response when cimetidine 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; Rosiglitazone: (Moderate) Cimetidine has been shown to affect the pharmacokinetics of some oral sulfonylureas. Patients receiving sulfonylureas should be observed for evidence of altered glycemic response when cimetidine 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) Cimetidine has been shown to affect the pharmacokinetics of some oral sulfonylureas. Patients receiving sulfonylureas should be observed for evidence of altered glycemic response when cimetidine 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) Cimetidine has been shown to affect the pharmacokinetics of some oral sulfonylureas. Patients receiving sulfonylureas should be observed for evidence of altered glycemic response when cimetidine 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. (Moderate) Use with caution, as cimetidine inhibits renal elimination of metformin. Consider alternatives to cimetidine. Increased metformin exposure due to use of cimetidine may lead to gastrointestinal complaints, altered glycemic control, and a potential for an increased risk for lactic acidosis. If it is medically necessary to use cimetidine, carefully monitor. Metformin dose reduction may be needed. An interaction between metformin and oral cimetidine has been observed in normal healthy volunteers in both single- and multiple-dose drug interaction studies. Cimetidine caused a 60% increase in peak metformin concentrations and a 40% increase in metformin exposure (AUC). Cimetidine inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]).
    Glyburide: (Moderate) Cimetidine has been shown to affect the pharmacokinetics of some oral sulfonylureas. Patients receiving sulfonylureas should be observed for evidence of altered glycemic response when cimetidine 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) Cimetidine has been shown to affect the pharmacokinetics of some oral sulfonylureas. Patients receiving sulfonylureas should be observed for evidence of altered glycemic response when cimetidine 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. (Moderate) Use with caution, as cimetidine inhibits renal elimination of metformin. Consider alternatives to cimetidine. Increased metformin exposure due to use of cimetidine may lead to gastrointestinal complaints, altered glycemic control, and a potential for an increased risk for lactic acidosis. If it is medically necessary to use cimetidine, carefully monitor. Metformin dose reduction may be needed. An interaction between metformin and oral cimetidine has been observed in normal healthy volunteers in both single- and multiple-dose drug interaction studies. Cimetidine caused a 60% increase in peak metformin concentrations and a 40% increase in metformin exposure (AUC). Cimetidine inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]).
    Green Tea: (Minor) Some, but not all, green tea products contain caffeine. Inhibitors of the hepatic CYP450 isoenzyme CYP1A2, such as cimetidine, may inhibit the hepatic oxidative metabolism of caffeine. No specific management is recommended except in patients who complain of caffeine-related side effects like nausea, tremor, or palpitations. In such patients, the dosage of caffeine-containing medications or the ingestion of caffeine-containing products may need to be reduced.
    Guaifenesin; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of cimetidine is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like cimetidine can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If cimetidine is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of cimetidine is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like cimetidine can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If cimetidine is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Halofantrine: (Moderate) Drugs which significantly inhibit cytochrome CYP3A4, such as cimetidine, may lead to an inhibition of halofantrine metabolism, placing the patient at risk for halofantrine cardiac toxicity. If concurrent use of halofantrine and a CYP3A4 inhibitor is warranted, it would be prudent to use caution and monitor the ECG periodically
    HMG-CoA reductase inhibitors: (Major) Because HMG-CoA reductase inhibitors may theoretically blunt adrenal and/or gonadal steroid production by interfering with cholesterol synthesis, the manufacturer recommends caution with concomitant administration of drugs that may decrease the concentrations or activity of endogenous hormones, such as cimetidine. It has also been reported that cimetidine could potentially increase the serum concentrations of HMG-CoA reductase inhibitors via the inhibition of the hepatic isoenzymes. Cimetidine does not alter the pharmacokinetics of atorvastatin, cerivastatin, or pravastatin. Clinical evidence of pharmacokinetic interactions with lovastatin and simvastatin is not available.
    Homatropine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of cimetidine is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like cimetidine can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If cimetidine is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydantoins: (Major) Cimetidine inhibits the hepatic metabolism of the following anticonvulsants: fosphenytoin, phenytoin, and possibly ethotoin. Serum concentrations of these drugs may increase and produce clinically undesirable side effects or drug toxicity. Where possible, the use of cimetidine in the presence of these medications should be avoided.
    Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of cimetidine is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like cimetidine can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If cimetidine is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrocodone; Ibuprofen: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of cimetidine is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like cimetidine can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If cimetidine is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrocodone; Phenylephrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of cimetidine is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like cimetidine can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If cimetidine is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of cimetidine is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like cimetidine can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If cimetidine is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of cimetidine is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like cimetidine can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If cimetidine is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of cimetidine is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like cimetidine can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If cimetidine is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
    Hydrocortisone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Hydroxychloroquine: (Moderate) Avoid concomitant use of hydroxychloroquine and cimetidine as cimetidine may inhibit the metabolism of hydroxychloroquine, increasing its plasma concentration. This interaction has been observed on treatment with the structurally similar chloroquine and cannot be ruled out for hydroxychloroquine.
    Ibuprofen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of cimetidine is necessary. If cimetidine is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a weak inhibitor like cimetidine can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If cimetidine is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    Imatinib: (Minor) Imatinib, STI-571 is metabolized by cytochrome P450 3A4, which can be inhibited by cimetidine. During concurrent use, clinicians should be aware of the potential increase risk of imatinib toxicity.
    Imipramine: (Moderate) Cimetidine can inhibit the hepatic clearance of some tricyclic antidepressants that undergo oxidative metabolism, such as imipramine. Choose an alternate H2-blocker when possible; alternatively, observe patients closely for TCA-induced side effects or toxicity if the concurrent use of cimetidine is unavoidable.
    Infigratinib: (Moderate) Separate the administration of infigratinib and H2-receptor antagonists if concomitant use is necessary. Coadministration may decrease infigratinib exposure resulting in decreased efficacy. Administer infigratinib two hours before or ten hours after an H2-receptor antagonist.
    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.
    Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with cimetidine may result in increased serum concentrations of isavuconazonium. Isavuconazole, the active moiety of isavuconazonium, is a sensitive substrate of the hepatic isoenzyme CYP3A4; cimetidine is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
    Isradipine: (Moderate) Cimetidine is a potent inhibitor of many of the isoenzymes of the hepatic CYP450 oxidative enzyme system and may decrease the metabolism of isradipine.
    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.
    Ivabradine: (Moderate) Use caution during coadministration of ivabradine and cimetidine as increased concentrations of ivabradine are possible. Ivabradine is primarily metabolized by CYP3A4; cimetidine inhibits CYP3A4. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
    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.
    Labetalol: (Moderate) Monitor for an increased incidence of labetalol-related adverse effects if cimetidine and labetalol are used concomitantly. Cimetidine increases the oral bioavailability of labetalol, possibly by decreasing first-pass liver metabolism or by increasing the oral absorption of labetalol.
    Lamotrigine: (Minor) Coadministration of cimetidine and lamotrigine may decrease cimetidine clearance, resulting in increased plasma concentrations and the potential for cimetidine-related adverse events. Lamotrigine is an inhibitor of renal tubular secretion via organic cationic transporter 2 (OCT2) proteins, and cimetidine 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.
    Leflunomide: (Moderate) Closely monitor for cimetidine-induced side effects when these drugs are used together. In some patients, a dosage reduction of cimetidine may be required. Following oral administration, leflunomide is metabolized to an active metabolite, teriflunomide, which is responsible for essentially all of leflunomide's in vivo activity. Teriflunomide is an inhibitor of the renal uptake organic anion transporter OAT3. Use of teriflunomide with cimetidine, a substrate of OAT3, may increase cimetidine plasma concentrations.
    Lemborexant: (Major) Limit the dose of lemborexant to a maximum of 5 mg PO once daily if coadministered with cimetidine as concurrent use may increase lemborexant exposure and the risk of adverse effects. Lemborexant is a CYP3A4 substrate; cimetidine is a weak CYP3A4 inhibitor. Consider if an alternative to cimetidine would be appropriate for the patient. Coadministration of lemborexant with a weak CYP3A4 inhibitor is predicted to increase lemborexant exposure by less than 2-fold.
    Levobupivacaine: (Minor) Levobupivacaine is metabolized by CYP3A4 and 1A2. Known inhibitors of either CYP 3A4 or CYP 1A2, such as cimetidine, may result in increased systemic levels of levobupivacaine when given concurrently, with potential for toxicity.
    Levomethadyl: (Moderate) Agents that inhibit hepatic cytochrome P450 3A4, such as cimetidine, may decrease the metabolism of levomethadyl, increase levomethadyl levels, and may precipitate severe arrhythmias including torsade de pointes.
    Lidocaine: (Moderate) Concomitant use of systemic lidocaine and cimetidine may increase lidocaine plasma concentrations. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP1A2 and CYP3A4 substrate; cimetidine inhibits both of these isoenzymes. Concomitant use of lidocaine with a weak CYP1A2 and CYP3A4 inhibitor has reportedly increased lidocaine plasma concentrations by 24% to 75%.
    Lidocaine; Prilocaine: (Moderate) Concomitant use of systemic lidocaine and cimetidine may increase lidocaine plasma concentrations. Monitor for lidocaine toxicity if used together. Lidocaine is a CYP1A2 and CYP3A4 substrate; cimetidine inhibits both of these isoenzymes. Concomitant use of lidocaine with a weak CYP1A2 and CYP3A4 inhibitor has reportedly increased lidocaine plasma concentrations by 24% to 75%.
    Linagliptin; Metformin: (Moderate) Use with caution, as cimetidine inhibits renal elimination of metformin. Consider alternatives to cimetidine. Increased metformin exposure due to use of cimetidine may lead to gastrointestinal complaints, altered glycemic control, and a potential for an increased risk for lactic acidosis. If it is medically necessary to use cimetidine, carefully monitor. Metformin dose reduction may be needed. An interaction between metformin and oral cimetidine has been observed in normal healthy volunteers in both single- and multiple-dose drug interaction studies. Cimetidine caused a 60% increase in peak metformin concentrations and a 40% increase in metformin exposure (AUC). Cimetidine inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]).
    Lithium: (Moderate) Moderate to significant dietary sodium changes, or changes in sodium and fluid intake, may affect lithium excretion. Systemic sodium chloride administration may result in increased lithium excretion and therefore, decreased serum lithium concentrations. In addition, high fluid intake may increase lithium excretion. For patients receiving sodium-containing intravenous fluids, symptom control and lithium concentrations should be carefully monitored. It is recommended that patients taking lithium maintain consistent dietary sodium consumption and adequate fluid intake during the initial stabilization period and throughout lithium treatment. Supplemental oral sodium and fluid should be only be administered under careful medical supervision.
    Lomitapide: (Major) Concomitant use of lomitapide and cimetidine may significantly increase the serum concentration of lomitapide. Therefore, the lomitapide dose should not exceed 30 mg/day PO during concurrent use. Cimetidine is a weak CYP3A4 inhibitor; the exposure to lomitapide is increased by approximately 2-fold in the presence of weak CYP3A4 inhibitors.
    Lomustine, CCNU: (Major) Avoid coadministration of cimetidine and lomustine. Concomitant use of cimetidine and lomustine causes an increase in bone marrow toxicity. The mechanism of this effect is not clear, and may not be related to cimetidine's inhibition of the hepatic CYP450 enzyme system.
    Lonafarnib: (Major) Avoid coadministration of lonafarnib and cimetidine; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. If coadministration is unavoidable, reduce to or continue lonafarnib at a dosage of 115 mg/m2 and closely monitor patients for lonafarnib-related adverse reactions. Resume previous lonafarnib dosage 14 days after discontinuing cimetidine. Lonafarnib is a sensitive CYP3A4 substrate and cimetidine is a weak CYP3A4 inhibitor.
    Loperamide: (Moderate) The plasma concentration of loperamide, a CYP3A4 and CYP2D6 substrate, may be increased when administered concurrently with cimetidine, a minor inhibitor of CYP3A4 and CYP2D6. Consider if an alternative to cimetidine would be suitable for the patient. cimetidine must be used, monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities [i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP) and cardiac arrest]. In a case report, a patient reported ingesting 100 to 250 mg of loperamide with 400 mg of cimetidine daily for several months to simulate the euphoric sensation associated with opioids; this patient presented to the hospital with recurrent syncope and developed TdP requiring electrical cardioversion and the QT interval was significantly prolonged to more than 700 msec.
    Loperamide; Simethicone: (Moderate) The plasma concentration of loperamide, a CYP3A4 and CYP2D6 substrate, may be increased when administered concurrently with cimetidine, a minor inhibitor of CYP3A4 and CYP2D6. Consider if an alternative to cimetidine would be suitable for the patient. cimetidine must be used, monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities [i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP) and cardiac arrest]. In a case report, a patient reported ingesting 100 to 250 mg of loperamide with 400 mg of cimetidine daily for several months to simulate the euphoric sensation associated with opioids; this patient presented to the hospital with recurrent syncope and developed TdP requiring electrical cardioversion and the QT interval was significantly prolonged to more than 700 msec.
    Lopinavir; Ritonavir: (Moderate) Concurrent administration of cimetidine with ritonavir may result in elevated plasma concentrations of ritonavir. Cimetidine is an inhibitor of the hepatic isoenzymes CYP3A4 and CYP2D6; ritonavir is partially metabolized by both of these enzymes. Monitor for adverse events if these drugs are administered together.
    Lovastatin: (Major) Because HMG-CoA reductase inhibitors may theoretically blunt adrenal and/or gonadal steroid production by interfering with cholesterol synthesis, the manufacturer recommends caution with concomitant administration of drugs that may decrease the concentrations or activity of endogenous hormones, such as cimetidine. It has also been reported that cimetidine could potentially increase the serum concentrations of HMG-CoA reductase inhibitors via the inhibition of the hepatic isoenzymes. Cimetidine does not alter the pharmacokinetics of atorvastatin, cerivastatin, or pravastatin. Clinical evidence of pharmacokinetic interactions with lovastatin and simvastatin is not available.
    Lovastatin; Niacin: (Major) Because HMG-CoA reductase inhibitors may theoretically blunt adrenal and/or gonadal steroid production by interfering with cholesterol synthesis, the manufacturer recommends caution with concomitant administration of drugs that may decrease the concentrations or activity of endogenous hormones, such as cimetidine. It has also been reported that cimetidine could potentially increase the serum concentrations of HMG-CoA reductase inhibitors via the inhibition of the hepatic isoenzymes. Cimetidine does not alter the pharmacokinetics of atorvastatin, cerivastatin, or pravastatin. Clinical evidence of pharmacokinetic interactions with lovastatin and simvastatin is not available.
    Lurasidone: (Moderate) Because lurasidone is primarily metabolized by CYP3A4, concurrent use of CYP3A4 inhibitors, such as cimetidine, can theoretically lead to an increased risk of lurasidone-related adverse reactions.
    Maprotiline: (Moderate) Cimetidine can inhibit the systemic clearance of drugs that undergo oxidative metabolism, such as maprotiline, resulting in increased plasma levels of the antidepressant. Patients should be monitored for maprotiline-related side effects and toxicity if cimetidine is added; when possible, choose an alternative H2-blocker for treatment.
    Maraviroc: (Minor) Use caution if coadministration of maraviroc with cimetidine is necessary, due to a possible increase in maraviroc exposure. Maraviroc is a CYP3A substrate and cimetidine is a weak CYP3A4 inhibitor. Monitor for an increase in adverse effects with concomitant use.
    Mebendazole: (Minor) Cimetidine may reduce the metabolism of mebendazole and increase mebendazole serum concentrations. Adverse hematological effects have been observed during concurrent use of cimetidine with high doses or prolonged mebendazole therapy. In a study of 7 patients, cimetidine significantly increased mebendazole concentrations; however, it was not considered to be of therapeutic relevance. In another study of 8 patients, concomitant use of cimetidine and a 30-day mebendazole treatment regimen resulted in a significant increase in mebendazole serum concentrations.
    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.
    Melatonin: (Moderate) Caution should be exercised when melatonin is used in patients on cimetidine, which increases plasma melatonin levels by inhibiting its metabolism. Melatonin is primarily metabolized by CYP1A2, with lesser contributions by CYP1A1, CYP2C9 and CYP2C19. The interaction may increase the potential for sedative and central nervous system (CNS) side effects from melatonin.
    Memantine: (Moderate) 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 cimetidine, could result in elevated serum concentrations of one or both drugs.
    Meperidine: (Minor) Excessive sedation and respiratory depression may occur if meperidine is used with cimetidine. When used in high doses (i.e., more than 600 mg/day), cimetidine has decreased the metabolism of certain opiate agonists leading to increased serum opiate concentrations and toxicity in some patients. In healthy subjects, cimetidine reduced the clearance and volume of distribution of meperidine.
    Meperidine; Promethazine: (Minor) Excessive sedation and respiratory depression may occur if meperidine is used with cimetidine. When used in high doses (i.e., more than 600 mg/day), cimetidine has decreased the metabolism of certain opiate agonists leading to increased serum opiate concentrations and toxicity in some patients. In healthy subjects, cimetidine reduced the clearance and volume of distribution of meperidine.
    Metformin: (Moderate) Use with caution, as cimetidine inhibits renal elimination of metformin. Consider alternatives to cimetidine. Increased metformin exposure due to use of cimetidine may lead to gastrointestinal complaints, altered glycemic control, and a potential for an increased risk for lactic acidosis. If it is medically necessary to use cimetidine, carefully monitor. Metformin dose reduction may be needed. An interaction between metformin and oral cimetidine has been observed in normal healthy volunteers in both single- and multiple-dose drug interaction studies. Cimetidine caused a 60% increase in peak metformin concentrations and a 40% increase in metformin exposure (AUC). Cimetidine inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]).
    Metformin; Repaglinide: (Moderate) Use with caution, as cimetidine inhibits renal elimination of metformin. Consider alternatives to cimetidine. Increased metformin exposure due to use of cimetidine may lead to gastrointestinal complaints, altered glycemic control, and a potential for an increased risk for lactic acidosis. If it is medically necessary to use cimetidine, carefully monitor. Metformin dose reduction may be needed. An interaction between metformin and oral cimetidine has been observed in normal healthy volunteers in both single- and multiple-dose drug interaction studies. Cimetidine caused a 60% increase in peak metformin concentrations and a 40% increase in metformin exposure (AUC). Cimetidine inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]). (Minor) In healthy volunteers, the coadministration of cimetidine with repaglinide did not significantly alter the absorption or disposition of repaglinide. Repaglinide is partly metabolized by CYP3A4. Drugs that inhibit CYP3A4 may increase plasma concentrations of repaglinide. Cimetidine has been shown to be a mild inhibitor of CYP3A4. If these drugs are co-administered, dose adjustment of repaglinide may rarely be necessary. Consider other H2-blockers as alternatives.
    Metformin; Rosiglitazone: (Moderate) Use with caution, as cimetidine inhibits renal elimination of metformin. Consider alternatives to cimetidine. Increased metformin exposure due to use of cimetidine may lead to gastrointestinal complaints, altered glycemic control, and a potential for an increased risk for lactic acidosis. If it is medically necessary to use cimetidine, carefully monitor. Metformin dose reduction may be needed. An interaction between metformin and oral cimetidine has been observed in normal healthy volunteers in both single- and multiple-dose drug interaction studies. Cimetidine caused a 60% increase in peak metformin concentrations and a 40% increase in metformin exposure (AUC). Cimetidine inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]).
    Metformin; Saxagliptin: (Moderate) Use with caution, as cimetidine inhibits renal elimination of metformin. Consider alternatives to cimetidine. Increased metformin exposure due to use of cimetidine may lead to gastrointestinal complaints, altered glycemic control, and a potential for an increased risk for lactic acidosis. If it is medically necessary to use cimetidine, carefully monitor. Metformin dose reduction may be needed. An interaction between metformin and oral cimetidine has been observed in normal healthy volunteers in both single- and multiple-dose drug interaction studies. Cimetidine caused a 60% increase in peak metformin concentrations and a 40% increase in metformin exposure (AUC). Cimetidine inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]).
    Metformin; Sitagliptin: (Moderate) Use with caution, as cimetidine inhibits renal elimination of metformin. Consider alternatives to cimetidine. Increased metformin exposure due to use of cimetidine may lead to gastrointestinal complaints, altered glycemic control, and a potential for an increased risk for lactic acidosis. If it is medically necessary to use cimetidine, carefully monitor. Metformin dose reduction may be needed. An interaction between metformin and oral cimetidine has been observed in normal healthy volunteers in both single- and multiple-dose drug interaction studies. Cimetidine caused a 60% increase in peak metformin concentrations and a 40% increase in metformin exposure (AUC). Cimetidine inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]).
    Methylergonovine: (Major) Cimetidine is a significant CYP3A4 inhibitor. Coadministration of methylergonovine with inhibitors of CYP3A4 may potentially increase the risk of ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects). Coadministration should be done cautiously, and avoided when possible.
    Methylprednisolone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Methysergide: (Major) The risk of ergot toxicity is potentially increased by the use of CYP3A4 inhibitors; such as cimetidine. Coadministration should be done cautiously until further data are available regarding the combination of cimetidine with methysergide.
    Metoprolol: (Moderate) While not reported, clinicians should be alert to exaggerated metoprolol effects if the drug is given with cimetidine. Cimetidine has variable effects on metoprolol pharmacokinetics. Although cimetidine has been shown to increase metoprolol blood levels, no clinical effects on the pharmacodynamics of metoprolol have been demonstrated.
    Metoprolol; Hydrochlorothiazide, HCTZ: (Moderate) While not reported, clinicians should be alert to exaggerated metoprolol effects if the drug is given with cimetidine. Cimetidine has variable effects on metoprolol pharmacokinetics. Although cimetidine has been shown to increase metoprolol blood levels, no clinical effects on the pharmacodynamics of metoprolol have been demonstrated.
    Metronidazole: (Moderate) Cimetidine is an enzyme inhibitor that can decrease the hepatic metabolism of metronidazole. As a result, elimination can be delayed and serum metronidazole concentrations can increase. The sequelae of this interaction are unclear, although prolonged administration of metronidazole has been associated with seizures. If possible, cimetidine should not be used during metronidazole therapy.
    Mexiletine: (Moderate) Cimetidine exerts variable effects on the serum levels of mexiletine, so patients should be monitored closely during concomitant therapy with these two agents.
    Midazolam: (Moderate) Midazolam is metabolized by hepatic isozyme CYP3A4. Inhibitors of this pathway, such as cimetidine, can potentiate the clinical effects of midazolam.
    Midodrine: (Minor) Midodrine may potentially interact with drugs that are actively secreted by the base-secreting system of the kidney, including cimetidine.
    Mirtazapine: (Moderate) In vitro studies have identified mirtazapine as a substrate for several CYP450 isoenzymes including 2D6, 1A2, and 3A4. Cimetidine is an inhibitor of CYP1A2, CYP2D6, and CYP3A4. In a study of 12 healthy subjects, cimetidine 800 mg twice daily increased the AUC of mirtazapine 30 mg/day by more than 50%. It may be necessary to decrease the mirtazapine dosage during co-administration of mirtazapine and cimetidine. Conversely, if cimetidine is discontinued, the dosage of mirtazapine may need to be increased.
    Modafinil: (Moderate) Modafinil is extensively metabolized by the CYP3A4 hepatic isoenzyme. When significant CYP3A4 inhibitors like cimetidine are administered concomitantly with modafinil, the health care professional may need to observe the patient for increased effects from modafinil.
    Mometasone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Moricizine: (Moderate) Cimetidine is a potent inhibitor of many of the isoenzymes of the hepatic CYP450 oxidative enzyme system and may inhibit the hepatic clearance of moricizine.
    Morphine: (Moderate) Concurrent use of morphine and cimetidine may increase the adverse effects of morphine, especially if a large cimetidine dose is used or if the patient is not young and healthy. One patient undergoing hemodialysis experienced confusion and severe respiratory depression when given morphine and cimetidine concurrently. As determined by data obtained from healthy patients, the mean systemic exposure, half-life, volume of distribution, and plasma clearance of morphine were similar after 4 days of pretreatment with either placebo or cimetidine 300 mg every 6 hours by mouth. In another crossover study, the concurrent receipt of cimetidine 600 mg orally and 10 mg morphine intramuscularly by 8 healthy adults led to a more profound depression of the CO2 response and delay in its recovery as compared with only morphine receipt; cimetidine alone had negligible respiratory effects. Also, concomitant administration of morphine and cimetidine has been reported to precipitate apnea, confusion, and muscle twitching in an isolated report. Monitor patients for increased respiratory and CNS depression when receiving both cimetidine and morphine.
    Morphine; Naltrexone: (Moderate) Concurrent use of morphine and cimetidine may increase the adverse effects of morphine, especially if a large cimetidine dose is used or if the patient is not young and healthy. One patient undergoing hemodialysis experienced confusion and severe respiratory depression when given morphine and cimetidine concurrently. As determined by data obtained from healthy patients, the mean systemic exposure, half-life, volume of distribution, and plasma clearance of morphine were similar after 4 days of pretreatment with either placebo or cimetidine 300 mg every 6 hours by mouth. In another crossover study, the concurrent receipt of cimetidine 600 mg orally and 10 mg morphine intramuscularly by 8 healthy adults led to a more profound depression of the CO2 response and delay in its recovery as compared with only morphine receipt; cimetidine alone had negligible respiratory effects. Also, concomitant administration of morphine and cimetidine has been reported to precipitate apnea, confusion, and muscle twitching in an isolated report. Monitor patients for increased respiratory and CNS depression when receiving both cimetidine and morphine.
    Nafarelin: (Minor) Cimetidine causes hyperprolactinemia and should not be administered concomitantly with nafarelin since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.
    Naloxegol: (Minor) Although naloxegol is metabolized primarily by the CYP3A enzyme system, concomitant use with weak CYP3A4 inhibitors, such as cimetidine, is not expected to effect naloxegol concentrations in a clinically significant manner. No dosage adjustments are necessary.
    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; Esomeprazole: (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.
    Nebivolol: (Moderate) Nebivolol is metabolized by CYP2D6 and cimetidine inhibits CYP2D6. The plasma levels of d-nebivolol were increased by 23% with the coadministration of cimetidine 400 mg twice daily. The clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible. If these drugs are coadministered, patients should be monitored for increased toxicity as well as increased therapeutic effect.
    Nebivolol; Valsartan: (Moderate) Nebivolol is metabolized by CYP2D6 and cimetidine inhibits CYP2D6. The plasma levels of d-nebivolol were increased by 23% with the coadministration of cimetidine 400 mg twice daily. The clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible. If these drugs are coadministered, patients should be monitored for increased toxicity as well as increased therapeutic effect.
    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).
    Niacin; Simvastatin: (Major) Because HMG-CoA reductase inhibitors may theoretically blunt adrenal and/or gonadal steroid production by interfering with cholesterol synthesis, the manufacturer recommends caution with concomitant administration of drugs that may decrease the concentrations or activity of endogenous hormones, such as cimetidine. It has also been reported that cimetidine could potentially increase the serum concentrations of HMG-CoA reductase inhibitors via the inhibition of the hepatic isoenzymes. Cimetidine does not alter the pharmacokinetics of atorvastatin, cerivastatin, or pravastatin. Clinical evidence of pharmacokinetic interactions with lovastatin and simvastatin is not available.
    Nicardipine: (Moderate) Cimetidine is a potent inhibitor of many of the isoenzymes of the hepatic CYP450 oxidative enzyme system and has been shown to increase the oral bioavailability of nicardipine. Patients should be monitored closely and lower doses of nicardipine may be considered during concomitant therapy with cimetidine.
    Nifedipine: (Moderate) Cimetidine has been shown to increase the oral bioavailability of dihydropyridines. Cimetidine can potentially affect the disposition of nifedipine due to inhibitory effects on cytochrome P-450 and, therefore, first-pass metabolism of nifedipine, increasing nifedipine bioavailability and serum concentrations. Lower doses of nifedipine may be considered during concomitant therapy with cimetidine.
    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.
    Nimodipine: (Moderate) Cimetidine has been shown to increase the oral bioavailability of nimodipine due to cimetidine's effects on the cytochrome P-450 hepatic enzymes. Lower doses of nimodipine may be necessary in patients receiving cimetidine.
    Nisoldipine: (Moderate) Avoid coadministration of nisoldipine with cimetidine due to increased plasma concentrations of nisoldipine. Coadministration of cimetidine and nisoldipine increased nisoldipine exposure by 30% to 45%. If coadministration is unavoidable, monitor blood pressure closely during concurrent use of these medications. Nisoldipine is a CYP3A4 substrate and cimetidine is a weak CYP3A4 inhibitor.
    Nortriptyline: (Moderate) Cimetidine can inhibit the systemic clearance of tricyclic antidepressants that undergo oxidative metabolism, such as nortriptyline, resulting in increased plasma levels of the antidepressant.
    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.
    Olanzapine: (Minor) Inhibitors of CYP1A2, such as cimetidine, could potentially decrease the elimination of olanzapine.
    Olanzapine; Fluoxetine: (Moderate) Although no clinical data are available, it is possible that inhibitors of hepatic enzymes such as cimetidine may decrease the metabolism of fluoxetine. Until more data are available, cimetidine should be used cautiously in patients receiving fluoxetine. (Minor) Inhibitors of CYP1A2, such as cimetidine, could potentially decrease the elimination of olanzapine.
    Olanzapine; Samidorphan: (Minor) Inhibitors of CYP1A2, such as cimetidine, could potentially decrease the elimination of olanzapine.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Concurrent administration of cimetidine with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of paritaprevir, ritonavir, and dasabuvir. Cimetidine is an inhibitor of the hepatic isoenzymes CYP3A4 and CYP2D6; ritonavir is partially metabolized by both of these enzymes. In addition, paritaprevir and dasabuvir (minor) are substrates of CYP3A4. Monitor for adverse events if these drugs are administered together. (Moderate) Concurrent administration of cimetidine with ritonavir may result in elevated plasma concentrations of ritonavir. Cimetidine is an inhibitor of the hepatic isoenzymes CYP3A4 and CYP2D6; ritonavir is partially metabolized by both of these enzymes. Monitor for adverse events if these drugs are administered together.
    Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of cimetidine is necessary. If cimetidine is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a weak inhibitor like cimetidine can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If cimetidine is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
    Oxymorphone: (Minor) When used in high doses (i.e., > 600 mg/day), cimetidine has decreased the metabolism of certain opiate agonists leading to increased opiate levels and opiate toxicity in some patients. Monitor patients for increased respiratory and CNS depression during coadministration.
    Paroxetine: (Moderate) Cimetidine inhibits cytochrome isoenzymes CYP1A2, CYP2C9, and CYP3A4 while paroxetine is metabolized by isoenzyme CYP2D6. Although one would assume no interaction would occur, several studies have shown that cimetidine can increase paroxetine AUC. While significant adverse effects have not been reported, patients should be monitored carefully for an increased response to paroxetine if cimetidine is coadministered. Dosage adjustments of paroxetine should be based on clinical effect for the individual.
    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%.
    Pentoxifylline: (Moderate) Cimetidine, a known hepatic enzyme inhibitor, can increase pentoxifylline serum concentrations. Patients should be monitored for increased pentoxifylline adverse reactions if cimetidine is added.
    Perphenazine; Amitriptyline: (Moderate) Cimetidine can inhibit the hepatic clearance of some tricyclic antidepressants that undergo oxidative metabolism, including amitriptyline. Choose an alternate H2-blocker when possible; alternatively, observe patients closely for TCA-induced side effects or toxicity if the concurrent use of cimetidine is unavoidable.
    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%.
    Pimozide: (Contraindicated) Because post-marketing surveillance reports have documented QT prolongation and ventricular arrhythmias, including torsade de pointes and death when known and potent inhibitors of CYP3A4 are coadministered with pimozide, the use of cimetidine should be considered contraindicated in patients taking pimozide. Pimozide is metabolized primarily through CYP3A4, and to a lesser extent CYP1A2 and CYP2D6. Cimetidine is an inhibitor of CYP3A4, CYP2D6, and CYP1A2. Elevated pimozide concentrations can lead to QT prolongation, ventricular arrhythmias, and sudden death.
    Pioglitazone; Glimepiride: (Moderate) Cimetidine has been shown to affect the pharmacokinetics of some oral sulfonylureas. Patients receiving sulfonylureas should be observed for evidence of altered glycemic response when cimetidine 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.
    Pioglitazone; Metformin: (Moderate) Use with caution, as cimetidine inhibits renal elimination of metformin. Consider alternatives to cimetidine. Increased metformin exposure due to use of cimetidine may lead to gastrointestinal complaints, altered glycemic control, and a potential for an increased risk for lactic acidosis. If it is medically necessary to use cimetidine, carefully monitor. Metformin dose reduction may be needed. An interaction between metformin and oral cimetidine has been observed in normal healthy volunteers in both single- and multiple-dose drug interaction studies. Cimetidine caused a 60% increase in peak metformin concentrations and a 40% increase in metformin exposure (AUC). Cimetidine inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]).
    Pirfenidone: (Major) Discontinue cimetidine prior to beginning pirfenidone because it may increase exposure to pirfenidone. Cimetidine is a moderate inhibitor of CYP1A2, CYP2C19, and to a lesser extent CYP2D6. Pirfenidone is primarily metabolized by CYP1A2 with minor contributions from CYP2C9, CYP2C19, CYP2D6, and CYP2E1.
    Pitavastatin: (Major) Because HMG-CoA reductase inhibitors may theoretically blunt adrenal and/or gonadal steroid production by interfering with cholesterol synthesis, the manufacturer recommends caution with concomitant administration of drugs that may decrease the concentrations or activity of endogenous hormones, such as cimetidine. It has also been reported that cimetidine could potentially increase the serum concentrations of HMG-CoA reductase inhibitors via the inhibition of the hepatic isoenzymes. Cimetidine does not alter the pharmacokinetics of atorvastatin, cerivastatin, or pravastatin. Clinical evidence of pharmacokinetic interactions with lovastatin and simvastatin is not available.
    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.
    Posaconazole: (Major) The concurrent use of posaconazole immediate-release oral suspension and cimetidine should be avoided, if possible, due to the potential for decreased posaconazole efficacy. If this combination is required, closely monitor for breakthrough fungal infections. When posaconazole oral suspension (200 mg PO daily) was administered with cimetidine (400 mg PO twice daily), the mean reductions in both posaconazole Cmax and AUC were 39%. The administration of posaconazole oral suspension with antacids and H2-blockers other than cimetidine has not resulted in clinically significant adverse events; no dosage adjustments of posaconazole are required when administered concomitantly with antacids or H2-blockers other than cimetidine. The pharmacokinetics of posaconazole delayed-release tablets and oral suspension are not significantly affected by antacids or H2-blockers.
    Pravastatin: (Major) Because HMG-CoA reductase inhibitors may theoretically blunt adrenal and/or gonadal steroid production by interfering with cholesterol synthesis, the manufacturer recommends caution with concomitant administration of drugs that may decrease the concentrations or activity of endogenous hormones, such as cimetidine. It has also been reported that cimetidine could potentially increase the serum concentrations of HMG-CoA reductase inhibitors via the inhibition of the hepatic isoenzymes. Cimetidine does not alter the pharmacokinetics of atorvastatin, cerivastatin, or pravastatin. Clinical evidence of pharmacokinetic interactions with lovastatin and simvastatin is not available.
    Praziquantel: (Moderate) Drugs that inhibit hepatic metabolism via the microsomal CYP450 enzyme system, such as cimetidine, may increase the bioavailability of praziquantel.
    Prednisolone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Prednisone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Procainamide: (Moderate) H2-blockers, such as cimetidine, inhibit the renal tubular secretion of procainamide. Clearance of procainamide is reduced and serum concentrations are increased by cimetidine.
    Progesterone: (Minor) The metabolism of progesterone may be inhibited by cimetidine, an inhibitor of cytochrome P450 3A4 hepatic enzymes.
    Propafenone: (Moderate) Cimetidine is a potent inhibitor of many of the isoenzymes of the hepatic CYP450 oxidative enzyme system and has been shown to increase propafenone serum concentrations by 24%. Close clinical monitoring may be necessary during coadministration of cimetidine with interacting drugs.
    Propoxyphene: (Minor) Propoxyphene is a substrate and cimetidine is an inhibitor of CYP2D6. When used in high doses, cimetidine has decreased the metabolism of certain opiate agonists leading to increased opiate concentrations and opiate toxicity in some patients. The clinical significance of the interaction is not well-established.
    Propranolol: (Moderate) Monitor for an increased incidence of propranolol-related adverse effects if cimetidine and propranolol are used concomitantly. Reduced clearance and increased serum concentrations of propranolol have been reported during concurrent use of cimetidine. Cimetidine is a CYP2D6 inhibitor. Propranolol is a CYP2D6 substrate.
    Propranolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for an increased incidence of propranolol-related adverse effects if cimetidine and propranolol are used concomitantly. Reduced clearance and increased serum concentrations of propranolol have been reported during concurrent use of cimetidine. Cimetidine is a CYP2D6 inhibitor. Propranolol is a CYP2D6 substrate.
    Protriptyline: (Moderate) Cimetidine can inhibit the systemic clearance of tricyclic antidepressants that undergo oxidative metabolism, resulting in increased plasma levels of the antidepressant. Patients should be monitored for TCA-related side effects and toxicity if cimetidine is added.
    Quazepam: (Moderate) Cimetidine can inhibit the hepatic clearance of some benzodiazepines that undergo oxidative metabolism, including quazepam.
    Quetiapine: (Minor) Cimetidine may cause a decrease in quetiapine clearance. Although it is not usually necessary to adjust the dose of quetiapine when cimetidine is coadministered, patients should be monitored for a potential increase in the pharmacologic effects of quetiapine.
    Quinidine: (Major) Quinidine concentrations should be monitored closely after cimetidine is added; choose an alternate acid-reducing therapy if possible. Quinidine is eliminated primarily by the CYP3A4 isoenzyme. Cimetidine can inhibit quinidine metabolism and produce quinidine toxicity.
    Quinine: (Minor) Cimetidine reduced the hepatic clearance of quinine and prolonged its half-life. Peak quinine serum concentrations were not affected. The clinical significance of this pharmacokinetic interaction is unclear.
    Ramelteon: (Major) Caution is recommended during concurrent use of ramelteon and cimetidine. Because ramelteon is metabolized via CYP3A4 and CYP1A2, use with CYP3A4 and CYP1A2 inhibitors, such as cimetidine, may increase exposure to ramelteon and the potential for adverse reactions. Other CYP1A2 inhibitors have been shown to have significant interactions with ramelteon, leading to elevated AUC of ramelteon > 190-fold and Cmax > 70 fold. If cimetidine must be administered with ramelteon, monitor the patient closely for toxicity due to elevated ramelteon serum concentrations. Alternatives to cimetidine may be considered, such as famotidine or nizatidine.
    Ranolazine: (Moderate) Coadminister ranolazine and cimetidine with caution. Cimetidine 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. Cimetidine also is a CYP2D6 and CYP3A4 inhibitor, and ranolazine is a substrate for these enzymes; however, coadministration of cimetidine does not increase the plasma concentrations of ranolazine in healthy volunteers.
    Rasagiline: (Moderate) Monitor for dopaminergic adverse effects during concurrent use of rasagiline and cimetidine. Coadministration may result in increased rasagiline concentrations. A dose reduction of rasagiline may be necessary. Rasagiline is primarily metabolized by CYP1A2; cimetidine is a weak CYP1A2 inhibitor. When administered with a strong CYP1A2 inhibitor, the AUC of rasagiline was increased by 83%.
    Repaglinide: (Minor) In healthy volunteers, the coadministration of cimetidine with repaglinide did not significantly alter the absorption or disposition of repaglinide. Repaglinide is partly metabolized by CYP3A4. Drugs that inhibit CYP3A4 may increase plasma concentrations of repaglinide. Cimetidine has been shown to be a mild inhibitor of CYP3A4. If these drugs are co-administered, dose adjustment of repaglinide may rarely be necessary. Consider other H2-blockers as alternatives.
    Rilpivirine: (Moderate) Coadministration with cimetidine may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of H2 receptor antagonist 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.
    Ritonavir: (Moderate) Concurrent administration of cimetidine with ritonavir may result in elevated plasma concentrations of ritonavir. Cimetidine is an inhibitor of the hepatic isoenzymes CYP3A4 and CYP2D6; ritonavir is partially metabolized by both of these enzymes. Monitor for adverse events if these drugs are administered together.
    Rivaroxaban: (Minor) Coadministration of rivaroxaban and cimetidine may result in increases in rivaroxaban exposure and may increase bleeding risk. Cimetidine is a mild inhibitor of CYP3A4, and rivaroxaban is a substrate of CYP3A4. If these drugs are administered concurrently, monitor the patient for signs and symptoms of bleeding.
    Roflumilast: (Moderate) Coadminister cimetidine and roflumilast cautiously as increased systemic exposure to roflumilast has been demonstrated in pharmacokinetic study. Increased roflumilast-induced adverse reactions may result. Cimetidine is an inhibitor of CYP3A4 and CYP1A2; roflumilast is a CYP3A4 and CYP1A2 substrate. In an open-label crossover study in 16 healthy volunteers, the coadministration of cimetidine (400 mg twice daily for 7 days) with a single oral dose of roflumilast 500 mcg resulted in a 46% and 85% increase in roflumilast Cmax and AUC; and a 4% decrease in Cmax and 27% increase in AUC for the active metabolite roflumilast N-oxide.
    Romidepsin: (Moderate) Romidepsin is a substrate for CYP3A4. Cimetidine is a mild inhibitor of CYP3A4. Concurrent administration of romidepsin with a mild CYP3A4 inhibitor may cause an increase in systemic romidepsin concentrations. Use caution when concomitant administration of these agents is necessary.
    Ropinirole: (Moderate) Coadministration of cimetidine and ropinirole may result in increased ropinirole concentrations. Cimetidine is a weak CYP1A2 inhibitor; ropinirole is a CYP1A2 substrate.
    Ropivacaine: (Major) Known inhibitors of cytochrome P450 1A2, such as cimetidine, may increase the systemic levels of ropivacaine and increase the risk of toxicity when given concurrently.
    Rosuvastatin: (Major) Because HMG-CoA reductase inhibitors may theoretically blunt adrenal and/or gonadal steroid production by interfering with cholesterol synthesis, the manufacturer recommends caution with concomitant administration of drugs that may decrease the concentrations or activity of endogenous hormones, such as cimetidine. It has also been reported that cimetidine could potentially increase the serum concentrations of HMG-CoA reductase inhibitors via the inhibition of the hepatic isoenzymes. Cimetidine does not alter the pharmacokinetics of atorvastatin, cerivastatin, or pravastatin. Clinical evidence of pharmacokinetic interactions with lovastatin and simvastatin is not available.
    Rosuvastatin; Ezetimibe: (Major) Because HMG-CoA reductase inhibitors may theoretically blunt adrenal and/or gonadal steroid production by interfering with cholesterol synthesis, the manufacturer recommends caution with concomitant administration of drugs that may decrease the concentrations or activity of endogenous hormones, such as cimetidine. It has also been reported that cimetidine could potentially increase the serum concentrations of HMG-CoA reductase inhibitors via the inhibition of the hepatic isoenzymes. Cimetidine does not alter the pharmacokinetics of atorvastatin, cerivastatin, or pravastatin. Clinical evidence of pharmacokinetic interactions with lovastatin and simvastatin is not available.
    Ruxolitinib: (Moderate) Ruxolitinib is a CYP3A4 substrate. When used with drugs that are mild or moderate inhibitors of CYP3A4 such as cimetidine, a dose adjustment is not necessary, but monitoring patients for toxicity may be prudent. There was an 8% and 27% increase in the Cmax and AUC of a single dose of ruxolitinib 10 mg, respectively, when the dose was given after a short course of erythromycin 500 mg PO twice daily for 4 days. The change in the pharmacodynamic marker pSTAT3 inhibition was consistent with the increase in exposure.
    Saquinavir: (Moderate) The concurrent use of saquinavir boosted with ritonavir and cimetidine should be avoided if possible due to the potential for life-threatening cardiac arrhythmias such as torsades de pointes (TdP). Cimetidine is an inhibitor of several CYP isoenzymes including CYP3A4; an isoenzyme responsible for the metabolism of saquinavir. Increased plasma concentrations of saquinavir may occur during coadministration; saquinavir boosted with ritonavir has been found to cause dose-dependent QT and PR prolongation. The interaction between saquinavir not boosted with ritonavir and cimetidine has not been found to produce clinically relevant effects, although some patients could experience and increase in adverse effects if saquinavir and cimetidine are coadministered.
    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.
    Segesterone Acetate; Ethinyl Estradiol: (Minor) Coadministration of segesterone and moderate CYP3A4 inhibitors such as cimetidine may increase the serum concentration of segesterone.
    Selpercatinib: (Major) Avoid coadministration of selpercatinib with cimetidine 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 cimetidine. 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.
    Sibutramine: (Moderate) The hepatic CYP450 3A4-mediated metabolism of sibutramine may be inhibited by cimetidine.
    Sildenafil: (Moderate) Use caution in administering cimetidine with sildenafil. Consider if alternative therapy to cimetidine is appropriate for the patient. Cimetidine is a nonspecific CYP inhibitor and is expected to increase sildenafil exposure. Cimetidine (800 mg) caused a 56% increase in plasma sildenafil concentrations when coadministered with sildenafil 50 mg to healthy volunteers. Population clinical trial data also indicate a reduction in sildenafil clearance when the drug is coadministered with cimetidine.
    Simeprevir: (Moderate) Use caution with concurrent use of simeprevir and cimetidine. Cimetidine weakly inhibits CYP3A4 which may increase the plasma concentrations of simeprevir, resulting in adverse effects. The FDA-labeling recommends avoiding moderate and strong CYP3A4 inhibitors.
    Simvastatin: (Major) Because HMG-CoA reductase inhibitors may theoretically blunt adrenal and/or gonadal steroid production by interfering with cholesterol synthesis, the manufacturer recommends caution with concomitant administration of drugs that may decrease the concentrations or activity of endogenous hormones, such as cimetidine. It has also been reported that cimetidine could potentially increase the serum concentrations of HMG-CoA reductase inhibitors via the inhibition of the hepatic isoenzymes. Cimetidine does not alter the pharmacokinetics of atorvastatin, cerivastatin, or pravastatin. Clinical evidence of pharmacokinetic interactions with lovastatin and simvastatin is not available.
    Simvastatin; Sitagliptin: (Major) Because HMG-CoA reductase inhibitors may theoretically blunt adrenal and/or gonadal steroid production by interfering with cholesterol synthesis, the manufacturer recommends caution with concomitant administration of drugs that may decrease the concentrations or activity of endogenous hormones, such as cimetidine. It has also been reported that cimetidine could potentially increase the serum concentrations of HMG-CoA reductase inhibitors via the inhibition of the hepatic isoenzymes. Cimetidine does not alter the pharmacokinetics of atorvastatin, cerivastatin, or pravastatin. Clinical evidence of pharmacokinetic interactions with lovastatin and simvastatin is not available.
    Sirolimus: (Moderate) Coadministration of cimetidine with sirolimus may result in increased sirolimus plasma concentrations increasing the risk for nephrotoxicity. Sirolimus is a CYP3A4 substrate; cimetidine is a CYP3A43 inhibitor.
    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) Use sonidegib and cimetidine together with caution; sonidegib levels and/or exposure may be altered. Cimetidine is a weak CYP3A4 inhibitor and may increase the level of the CYP3A4 substrate, sonidegib, resulting in an increased risk of adverse events, particularly musculoskeletal toxicity. Based on population PK analysis, the concomitant administration of a histamine-2-receptor antagonist such as cimetidine decreases the geometric mean sonidegib steady-state AUC (0-24 hours) value by 34%.
    Sotorasib: (Major) Avoid coadministration of sotorasib and gastric acid-reducing agents, such as H2-receptor antagonists. Coadministration may decrease sotorasib exposure resulting in decreased efficacy. If necessary, sotorasib may be administered 4 hours before or 10 hours after a locally acting antacid. Coadministration with an H2-receptor antagonist decreased sotorasib exposure by 38% under fed conditions.
    Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if cimetidine must be administered. Consider a reduced dose of sufentanil injection with frequent monitoring for respiratory depression and sedation if concurrent use of cimetidine is necessary. If cimetidine is discontinued, consider increasing the sufentanil injection dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Sufentanil is a CYP3A4 substrate, and coadministration with a weak CYP3A4 inhibitor like cimetidine can increase sufentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of sufentanil. If cimetidine is discontinued, sufentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to sufentanil.
    Sulfonylureas: (Moderate) Cimetidine has been shown to affect the pharmacokinetics of some oral sulfonylureas. Patients receiving sulfonylureas should be observed for evidence of altered glycemic response when cimetidine 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.
    Sumatriptan; 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.
    Tacrine: (Moderate) Cimetidine increases the bioavailability and peak plasma concentrations of tacrine secondary to inhibition of the hepatic cytochrome P450 enzyme system, specifically the CYP1A2 isoenzyme.
    Tacrolimus: (Major) Tacrolimus is metabolized via the hepatic cytochrome P-450 system. Drugs that inhibit this enzyme system, including cimetidine, may decrease the metabolism of tacrolimus. Subsequent increased plasma concentrations of tacrolimus may lead to nephrotoxicity.
    Tamsulosin: (Moderate) Cimetidine is a weak inhibitor of CYP2D6, one of the enzymes responsible for metabolism of tamsulosin. The manufacturer recommends that tamsulosin be used with caution in combination with cimetidine. A study involving 10 healthy volunteers (age range 21 to 40 years) showed that cimetidine administered at the highest recommended dose (400 mg q6h for 6 days) significantly (26%) decreased the clearance of a single tamsulosin 0.4 mg dose. This resulted in a moderate increase in tamsulosin AUC (44%).
    Tasimelteon: (Moderate) Caution is recommended during concurrent use of tasimelteon and cimetidine. Because tasimelteon is metabolized via CYP3A4 and CYP1A2, use with CYP3A4 and CYP1A2 inhibitors, such as cimetidine, may increase exposure to tasimelteon and the potential for adverse reactions.
    Telaprevir: (Moderate) Close clinical monitoring is advised when administering cimetidine with telaprevir due to an increased potential for telaprevir-related adverse events. If cimetidine dose adjustments are made, re-adjust the dose upon completion of telaprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathways of cimetidine and telaprevir. Cimetidine is an inhibitor of the hepatic isoenzyme CYP3A4; telaprevir is metabolized by this isoenzyme. When used in combination, the plasma concentrations of telaprevir may be elevated.
    Terbinafine: (Minor) According to the manufacturer, cimetidine decreases the clearance of terbinafine by one-third. Studies were performed in normal volunteers. It is unknown if this interaction would be clinically significant; the exact mechanisms are not known.
    Teriflunomide: (Moderate) Teriflunomide is an inhibitor of the renal uptake organic anion transporter OAT3. Use of teriflunomide with cimetidine, a substrate of OAT3, may increase cimetidine plasma concentrations. Monitor for increased adverse effects from cimetidine, such as dose-related elevations in hepatic enzymes. Adjust the dose of cimetidine as necessary and clinically appropriate.
    Thalidomide: (Moderate) Thalidomide and other agents that slow cardiac conduction such as H2-blockers should be used cautiously due to the potential for additive bradycardia.
    Theophylline, Aminophylline: (Major) Aminophylline is primarily metabolized in the liver by the CYP1A2 isoenzyme. Cimetidine inhibits the CYP1A2 isoenzyme and not only reduces the hepatic metabolism of aminophylline, but a reduction in the renal clearance of theophylline may occur via competition for renal tubular secretion. However, the hepatic-based interaction is more significant. In patients receiving aminophylline, an alternative to cimetidine should be considered when possible. Alternatively, if concomitant therapy is necessary, patients should be monitored closely for increased effects of theophylline and the need for aminophylline dosage adjustments. The Beers criteria recommends that this drug combination be avoided in older adults. (Major) Theophylline is primarily metabolized in the liver by the CYP1A2 isoenzyme. Cimetidine inhibits the CYP1A2 isoenzyme and not only reduces the hepatic metabolism of theophylline, but a reduction in the renal clearance of theophylline may occur via competition for renal tubular secretion. However, the hepatic-based interaction is more significant. In patients receiving theophylline, an alternative to cimetidine should be considered when possible. Alternatively, if concomitant therapy is necessary, patients should be monitored closely for increased effects of theophylline and the need for theophylline dosage adjustments.
    Thioridazine: (Contraindicated) Cimetidine is a moderate inhibitor of CYP2D6 and the use of thioridazine concomitantly with CYP2D6 inhibitors is contraindicated due to the possible risk of QT prolongation and subsequent arrhythmias, or other serious side effects, due to elevated serum concentrations of thioridazine. Consider an alternative to cimetidine for patients taking thioridazine.
    Ticlopidine: (Major) Cimetidine has been shown to reduce the clearance of ticlopidine by 50%. Monitor for increased ticlopidine-related adverse effects during concurrent use.
    Timolol: (Moderate) Monitor for an increased incidence of timolol-related adverse effects if cimetidine and timolol are used concomitantly. Coadministration of cimetidine and timolol may result in increased plasma concentrations of timolol. Cimetidine is a CYP2D6 inhibitor. Timolol is a CYP2D6 substrate.
    Tinidazole: (Major) Coadministration may result in increased tinidazole concentrations. Cimetidine is an enzyme inhibitor that can decrease the hepatic metabolism of tinidazole.
    Tizanidine: (Major) Tizanidine is primarily metabolized by CYP1A2. If possible, avoid the concurrent use of tizanidine with other CYP1A2 inhibitors, such as cimetidine, as concurrent use could lead to substantial increases in tizanidine blood concentrations. If concurrent use cannot be avoided, initiate tizanidine therapy with the 2 mg dose and increase in 2 to 4 mg increments daily based on patient response to therapy. Discontinue tizanidine if hypotension, bradycardia, or excessive drowsiness occur.
    Tocainide: (Moderate) Cimetidine is a potent inhibitor of many of the isoenzymes of the hepatic CYP450 oxidative enzyme system. Tocainide oral bioavailability may be reduced by cimetidine.
    Tolazamide: (Moderate) Cimetidine has been shown to affect the pharmacokinetics of some oral sulfonylureas. Patients receiving sulfonylureas should be observed for evidence of altered glycemic response when cimetidine 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) Cimetidine has been shown to affect the pharmacokinetics of some oral sulfonylureas. Patients receiving sulfonylureas should be observed for evidence of altered glycemic response when cimetidine 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.
    Tolvaptan: (Moderate) Coadministration of tolvaptan and hypertonic saline (e.g., 3% NaCl injection solution) is not recommended. The use of hypertonic sodium chloride in combination with tolvaptan may result in a too rapid correction of hyponatremia and increase the risk of osmotic demyelination (i.e., central pontine myelinolysis).
    Trandolapril; Verapamil: (Moderate) Cimetidine is a potent inhibitor of many of the isoenzymes of the hepatic CYP450 oxidative enzyme system. The metabolism of calcium-channel blockers like verapamil is inhibited by cimetidine.
    Tretinoin, ATRA: (Moderate) Cimetidine may decrease the CYP450 metabolism of systemic tretinoin, ATRA, potentially resulting in increased plasma concentrations of tretinoin, ATRA.
    Triamcinolone: (Moderate) Concomitant use of systemic sodium chloride, especially at high doses, and corticosteroids may result in sodium and fluid retention. Assess sodium chloride intake from all sources, including intake from sodium-containing intravenous fluids and antibiotic admixtures. Carefully monitor sodium concentrations and fluid status if sodium-containing drugs and corticosteroids must be used together.
    Triazolam: (Moderate) Cimetidine can inhibit the hepatic clearance of some benzodiazepines that undergo oxidative metabolism, including triazolam.
    Trimetrexate: (Moderate) Cimetidine can inhibit oxidative hepatic enzymes responsible for metabolizing trimetrexate. Concurrent use can decrease the clearance of trimetrexate and thus increase its plasma levels. Use cimetidine cautiously when they are given together with trimetrexate.
    Trimipramine: (Moderate) Cimetidine can inhibit the systemic clearance of tricyclic antidepressants that undergo oxidative metabolism, such as trimipramine, resulting in increased plasma levels of the antidepressant. Patients should be monitored for TCA-related side effects and toxicity if cimetidine is added; when possible, choose an alternative H2-blocker for treatment.
    Trospium: (Moderate) Both trospium and cimetidine are eliminated by active renal tubular secretion; coadministration has the potential to increase serum concentrations of trospium or cimetidine due to competition for the drug elimination pathway. Careful patient monitoring and dosage adjustment of trospium and/or cimetidine is recommended.
    Ubrogepant: (Major) Limit the initial and second dose of ubrogepant to 50 mg if coadministered with cimetidine. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a CYP3A4 substrate; cimetidine is a weak CYP3A4 inhibitor.
    Ulipristal: (Minor) Ulipristal is a substrate of CYP3A4 and cimetidine is a CYP3A4 inhibitor. Concomitant use may increase the plasma concentration of ulipristal resulting in an increased risk for adverse events.
    Valacyclovir: (Minor) Cimetidine may cause a reduction in the clearance of acyclovir. The clinical significance of these pharmacokinetic interactions is unknown; however, no dosage adjustments are recommended for patients with normal renal function.
    Varenicline: (Minor) Inhibitors of OCT2 (e.g., cimeditine) may increase the exposure of varenicline but these changes may not necessitate a dose adjustment of varenicline as the increase in systemic exposure is not expected to be clinically meaningful. Administration cimetidine (300 mg four times daily), with varenicline (2 mg single dose) to 12 smokers increased the systemic exposure of varenicline by 29% due to a reduction in varenicline renal clearance. In vitro studies demonstrated the active renal secretion of varenicline is mediated by the human organic cation transporter OCT2. Another H2 antagonist may be preferable to cimetidine in patients taking varenicline.
    Vemurafenib: (Moderate) Concomitant use of vemurafenib and cimetidine may result in increased vemurafenib concentrations. Vemurafenib is CYP3A4 substrate and cimetidine is a CYP3A4 inhibitor. Use caution and monitor patients for increased side effects.
    Venlafaxine: (Moderate) The metabolism of venlafaxine may be inhibited to some degree by cimetidine. No dosage adjustments are recommended in normal patients, but caution should be observed in the elderly and in patients with preexisting hypertension and/or hepatic disease or impairment because the results of this interaction can be more pronounced.
    Verapamil: (Moderate) Cimetidine is a potent inhibitor of many of the isoenzymes of the hepatic CYP450 oxidative enzyme system. The metabolism of calcium-channel blockers like verapamil is inhibited by cimetidine.
    Vincristine Liposomal: (Moderate) Cimetidine is a mild CYP3A4 inhibitor, and vincristine is a CYP3A substrate. Coadministration could increase exposure to vincristine; monitor patients for increased side effects if these drugs are given together.
    Vincristine: (Moderate) Cimetidine is a mild CYP3A4 inhibitor, and vincristine is a CYP3A substrate. Coadministration could increase exposure to vincristine; monitor patients for increased side effects if these drugs are given together.
    Vinorelbine: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with cimetidine is necessary. Vinorelbine is a CYP3A4 substrate and cimetidine is a weak CYP3A4 inhibitor.
    Vorapaxar: (Moderate) Use caution during concurrent use of vorapaxar and cimetidine. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with cimetidine, a mild CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
    Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with cimetidine is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Cimetidine is a CYP1A2 and weak CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP1A2/CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
    Zalcitabine, ddC: (Moderate) The renal tubular secretion of zalcitabine, ddC appears to be inhibited by cimetidine. Patients should be closely monitored for signs of toxicity, with a reduction in zalcitabine dose if necessary, when cimetidine is coadministered.
    Zaleplon: (Major) Reduce the initial dose of zaleplon to 5 mg in patients receiving concomitant cimetidine therapy. Coadministration of cimetidine resulted in an 85% increase in the Cmax and AUC of zaleplon in a drug interaction study. Cimetidine inhibits both aldehyde oxidase and CYP3A4, the primary and secondary enzymes, respectively, responsible for zaleplon metabolism.
    Zolmitriptan: (Major) If cimetidine and zolmitriptan are used concomitantly, limit the maximum single dose of zolmitriptan to 2.5 mg and do not exceed 5 mg in any 24 hour peroid. Following the coadministration of cimetidine, the half-life and AUC of zolmitriptan (5 mg PO) and its active metabolite are roughly doubled.

    PREGNANCY AND LACTATION

    Pregnancy

    Self-medication with cimetidine during pregnancy is not recommended; pregnant patients should see their health care professional for a proper diagnosis and for treatment recommendations. Animal studies have not demonstrated a risk to the fetus but there are no adequate studies in pregnant women. Epidemiological evidence based on the use of cimetidine during the first trimester of human gestation does not suggest an increase in fetal malformations compared to the normal population. Risk versus benefit should be considered prior to use. Cimetidine is known to cross the placenta. Unlike other H2-blockers, cimetidine pharmacologically exhibits some weak anti-androgenic activity, and conflicting data from animal studies exist regarding anti-androgenic effects. 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 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. Cimetidine has been used in limited circumstances at term to prevent acid aspiration during labor; some guidelines recommend an H2-blocker (oral or intravenous) for all women presenting for cesarean delivery.

    Cimetidine is secreted into breast milk, usually in concentrations that exceed maternal plasma concentrations. Cimetidine is not usually recommended for use during lactation by the manufacturer. However, in the absence of reported adverse events in infants, the use of cimetidine is usually considered compatible with breast-feeding. Although also excreted in breast milk, other H2-blockers might be considered alternatives due to the fact that they do not typically have anti-androgenic actions, and would not inhibit infant hepatic enzyme activity should the infant be prescribed an interacting medication. Galactorrhea and hyperprolactinemia have been reported in patients taking cimetidine. Of all H2-blockers, famotidine is excreted least in breast milk.

    MECHANISM OF ACTION

    Cimetidine blocks the effects of histamine at the receptor located on the basolateral membrane of the parietal cell (designated as the H2-receptor). The result is a reduction of both gastric acid volume and gastric acidity. Cimetidine also decreases the amount of gastric acid released in response to other stimuli including food, caffeine, insulin, betazole, or pentagastrin. Because gastric secretions respond to multiple stimuli, cimetidine does not reduce acid-output as dramatically as the proton-pump inhibiting medications (e.g., omeprazole). Cimetidine does not appear to alter gastric motility, gastric emptying, esophageal pressure, or the secretion rate of the gallbladder or pancreas. Cimetidine also exhibits weak anti-androgenic effects.
     
    In combination with an H1-receptor antagonist, cimetidine 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

    Cimetidine is administered orally and parenterally. The drug distributes throughout body tissues, is found in breast milk, and crosses the placenta. Both oral and parenteral administration provide comparable periods of therapeutically effective blood levels; blood concentrations remain above that required to provide 80% inhibition of basal gastric acid secretion for 4 to 5 hours in adults. Cimetidine is extensively metabolized by oxidative hydroxylation and conjugation predominately to a sulfoxide metabolite. Cimetidine has been shown to inhibit a number of CYP isoenzymes, including 1A2, 2C19, and to a lesser extent 2D6 and 3A4. Approximately 48% of an oral dose of cimetidine and approximately 75% of an IV or IM dose of cimetidine is excreted is recovered from the urine after 24 hours as the parent compound. The remainder is excreted in the feces. The half-life is roughly 2 hours in adult patients with normal renal function.
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP1A2, CYP2C19, CYP2D6, and CYP3A4
    Cimetidine is the classic example of a drug that inhibits cytochrome oxidative hepatic metabolism, and it inhibits this system non-selectively. Cimetidine has been shown to inhibit a number of CYP isoenzymes, including CYP1A2, CYP2C19, and to a lesser extent CYP2D6 and CYP3A4.

    Oral Route

    Cimetidine is rapidly and completely absorbed in the GI tract, but first-pass metabolism reduces oral bioavailability to 60 to 70%. The rate but not the extent of absorption can be affected by food.

    Intravenous Route

    Peak concentrations (Cmax) generally occur within 15 minutes of intermittent intravenous dosing. Blood levels with other infusion rates vary in direct proportion to the infusion rate.

    Intramuscular Route

    Intramuscular administration provides comparatively effective blood concentrations to oral and intravenous routes.