CIMETIDINE (Generic for TAGAMET HB)

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

Route-Specific Administration

Oral Administration
-All oral dosage forms: May be administered without regard to meals. May administer with food, water, or milk to minimize gastric irritation.
Oral Liquid Formulations
-Measure with calibrated oral syringe or cup prior to administration to give an accurate dosage.
-The oral solution (60 mg/ml) contains 2.8% alcohol.



Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
-Administer via the intramuscular or intravenous routes.
-Multidose vials of cimetidine contain benzyl alcohol as a preservative and should NOT be used to prepare neonatal doses.
Intravenous Administration
General
-Compatible solutions for intravenous (IV) dilution include D5W, D10W, NS, lactated ringers, or 5% sodium bicarbonate.
-Storage of diluted injection: Diluted solutions are stable for up to 48 hours at room temperature.

Intermittent IV injection
-Must be diluted before intravenous use. Do NOT use prefilled syringes for IV injection.
-Do not administer any dosage > 300 mg via IV injection-see intermittent IV infusion.
-Dilute to a maximum of 15 mg/ml (300 mg/20 ml) using non-preserved NS or other compatible IV solution.
-Inject slowly over a period of not less than 5 minutes. Do not inject rapidly; cardiac arrhythmias or hypotension may develop.

Intermittent IV infusion
-Dilute to a maximum concentration of 6 mg/ml (300 mg/50 ml) using D5W, NS, or other compatible IV solution.
-If using ADD-Vantage vials, dilute in ADD-Vantage containers containing 50 or 100 ml of NS or D5W.
-Prediluted cimetidine infusions are also available.
-Infuse dosage over 15-30 minutes.


Continuous IV infusion
-Dilute to a maximum concentration of 6 mg/ml (up to 900 mg for adults) in 100-1000 ml of a compatible IV solution.
-For IV infusion volumes less than 250 ml, a controlled infusion pump is recommended.
-Adjust rate/hour according to individual patient dosage requirements.
-Dilutions are intended to complete over 24 hours.

Intramuscular Administration
-No dilution is necessary for intramuscular (IM) administration.
-Prefilled syringes are available for IM use only.
-Inject into a large muscle. Aspirate prior to injection to avoid injection into a blood vessel.

Mild to severe headache occurred in 2.1% of adult patients who received cimetidine 800 mg/day (n = 2225) and 3.5% of patients who received 1600 mg/day (n = 924) compared with 2.3% of patients who received placebo (n = 1897) in clinical trials. Dizziness and drowsiness, most cases mild, were reported in approximately 1% of patients who received cimetidine at usual doses in clinical trials. Mental confusion, agitation, psychosis, depression, anxiety, hallucinations, disorientation, have been reported mostly in severely ill patients. These central nervous system adverse effects usually developed within 2-3 days after starting and resolved within 3-4 days of stopping cimetidine therapy.

Rare cases of thrombocytopenia (3 cases per million patients) and decreased white blood counts such as neutropenia and leukopenia (1 case per 100,000 patients) or agranulocytosis (3 cases per million patients) have been reported with cimetidine therapy. Some cases have recurred on rechallenge. Pancytopenia, aplastic anemia, and immune hemolytic anemia have also been reported rarely.

Gynecomastia has been reported in patients who received cimetidine therapy for longer than 1 month. Gynecomastia occurred in approximately 4% of adult patients with pathological hypersecretory conditions and in 0.3% to 1% of patients with other conditions in clinical trials. Galactorrhea and hyperprolactinemia have been reported in patients taking cimetidine; in some cases, a switch to an alternate H2-blocker resolved the symptoms.

Dose-related elevated hepatic enzymes (e.g., increased transaminase levels) have been reported with cimetidine therapy; however, most transaminase level elevations did not worsen with continued therapy and returned to normal by the end of therapy. Cholestatic (cholestasis) or mixed cholestatic hepatocellular effects and pancreatitis have also occurred rarely, most cases reversible. There has been 1 report of biopsy proven periportal hepatic fibrosis. Rarely, fatal hepatic injury has been reported with H2-receptor antagonist use.

Rash (unspecified) and rarely reversible alopecia occurred with cimetidine therapy. Very rarely, generalized skin reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, exfoliative dermatitis, and generalized exfoliative erythroderma have been reported with H2-receptor antagonist use.

Gastric acid suppression with H2-receptor antagonists has been associated with an increased risk of infection in pediatric patients. A causal relationship between the use of cimetidine and infection, such as pneumonia, has not been established; however, several studies have assessed the risk of infection with another H2-receptor antagonist. A study in premature neonates (gestational age 24 to 32 weeks) found a statistically significantly increased risk of overall infection (37.4% vs 9.8%, p less than 0.001), including sepsis, pneumonia, and urinary tract infection, in neonates receiving an H2-blocker; there was also a significantly higher risk of developing necrotizing enterocolitis (9.8% vs 1.6%, p = 0.003) and a significantly higher mortality rate (9.9% vs 1.6%, p = 0.003). One study in previously healthy infants and young children found an increased risk in community-acquired pneumonia (12% vs. 2%, p is less than .05) and acute gastroenteritis (47% vs. 20%, p is less than .05) in patients receiving gastric acid inhibitors compared to controls. Another study in critically ill pediatric patients (n = 60) did not find an increased incidence of ventilator-associated pneumonia in patients receiving acid-suppression therapy compared to those not receiving treatment. Until more is known about the relationship between acid-suppression and pneumonia, clinicians are encouraged to carefully select patients before empirically initiating acid-suppressive therapy with H2-blockers or proton pump inhibitors (PPIs). Increasing evidence in adults suggests a link between acid-suppression therapy and respiratory infection, specifically pneumonia. Several mechanisms have been proposed to account for this association, including the disruption of gastric pH as a barrier against pathogenic colonization of the gastrointestinal tract and as a stimulant of the cough reflex that allows for the clearing of infectious agents from the respiratory tract. Finally, the fact that acid-suppressive therapy may impair white blood cell function, which in turn may lead to a depressed immune response to an infection, is listed among possible mechanisms.

Atrioventricular heart block (AV block), bradycardia, and sinus tachycardia have been reported rarely with H2-receptor antagonist use. Additionally, hypotension and cardiac arrhythmias have occurred rarely following rapid IV bolus administration of cimetidine.

Reversible arthralgia and myalgia have occurred rarely with cimetidine use. Some patients with pre-existing arthritis have reported increased joint symptoms that were alleviated with a cimetidine dosage reduction. Cases of polymyositis have also been reported rarely.

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

Fever and allergic reactions (e.g., anaphylactoid reactions, hypersensitivity vasculitis) have been rarely reported with cimetidine therapy. Resolution of these adverse events occurred when therapy was stopped.

Increased plasma creatinine, slight and possibly related to the dose, has been reported with cimetidine use and does not appear to signify a deterioration in renal function. Interstitial nephritis and urinary retention have occurred with cimetidine therapy rarely. Resolution of these adverse events occurred when therapy was stopped.

Diarrhea, most cases mild, has been reported in approximately 1% of adult patients who received cimetidine at usual doses in clinical trials.

Long-term (e.g., generally >= 2-3 years) treatment with acid-suppressing agents, such as cimetidine, can lead to malabsorption of vitamin B12 (cyanocobalamin). In a large case-controlled study, adult patients with and without an incident diagnosis of vitamin B12 deficiency (n = 25,956 and 184,199, respectively) were compared, and a correlation between vitamin B12 deficiency and gastric acid-suppression therapy was found. Receipt of >= 2 years of a proton pump inhibitor or H2-receptor antagonist was associated with an increased risk for vitamin B12 deficiency. The precise risk in pediatric patients has not been defined. It may be prudent to monitor patients for signs of pernicious anemia. Neurological manifestations of pernicious anemia can occur in the absence of hematologic changes.

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.

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 (less than 1 month of age) after the administration of parenteral solutions containing the preservative benzyl alcohol at dosages more than 99 mg/kg/day. The minimum amount of benzyl alcohol to cause toxicity is unknown. Therefore, use preservative-free cimetidine injectable formulations in neonates.

Symptomatic response to therapy with cimetidine does not preclude the presence of H. pylori infection. H2-blockers, as single agents, will not eradicate H. pylori infection, if present. In patients with concomitant immunosuppression, decreased gastric acidity, including that produced by acid-suppressing agents such as cimetidine, may increase the possibility of a hyperinfection of strongyloidiasis.

Cimetidine should be used cautiously in patients with hepatic disease, because cimetidine clearance may be reduced. Reduced doses of cimetidine may be considered for patients with severe hepatic disease. Various types of reversible confusional states have been attributed to cimetidine. While decreased clearance would seem to predispose patients to adverse reactions, hepatic disease has not been shown conclusively to increase the risk for central nervous system reactions. Cimetidine also 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 renal impairment or renal failure, because cimetidine clearance can be reduced and metabolites can accumulate. Reduced doses of cimetidine are recommended in patients with significant renal impairment. Very low weight premature newborns may require lowered dosages and/or increased dosing intervals due to immature renal function. Various types of reversible confusional states have been attributed to cimetidine. While decreased clearance would seem to predispose patients to adverse reactions, renal impairment has not been shown conclusively to increase the risk for central nervous system reactions.

Symptomatic response to therapy with cimetidine does not preclude the presence of gastric cancer. There have been rare reports of transient healing of gastric ulcers despite subsequently documented malignancy. In the patient who is self-medicating with nonprescription (OTC) formulations, the continuation of heartburn, acid indigestion, or dyspepsia beyond 2 weeks signals the need to consult a health care professional for evaluation.

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

Rare instances of cardiac arrhythmias and hypotension have been reported following the rapid administration of cimetidine by intravenous (IV) bolus. When administering cimeditine intravenously, recommended rates of administration should not be exceeded; caution may be warranted in patients with underlying serious cardiac disease or with critical conditions, who might be more susceptible to these rare events.

Chronic use of gastric acid-suppressing agents should be used cautiously and with monitoring in patients who are prone to vitamin B12 deficiency. Daily treatment with a gastric acid-suppressing medication, such as cimetidine, over a long period of time (e.g., generally 2 to 3 years or more) has been associated with malabsorption of cyanocobalamin in adults. Consider the possibility of cyanocobalamin deficiency if clinical symptoms are observed.

Description: Cimetidine is an oral and parenteral histamine type 2-receptor antagonist used in the treatment of various gastrointestinal (GI) disorders such as peptic ulcer and gastroesophageal reflux disease (GERD). The actions and indications for cimetidine differ little from other H2-receptor antagonists; however, cimetidine is a known inhibitor of many of the isoenzymes of the hepatic CYP450 enzyme system. Thus, it exhibits many clinically significant drug interactions with other medications. Cimetidine is used mainly for treating GI disorders, although it can be beneficial for other conditions. Over-the-counter oral formulations are available for the prophylaxis and treatment of heartburn and acid indigestion in adolescent and adult patients 12 years of age and older. However, for the symptomatic acute and chronic treatment of GERD, proton pump inhibitors (PPIs) are considered to be more effective than H2-receptor antagonists. Formal data regarding the use of cimetidine in pediatric patients are limited. Cimetidine therapy cannot usually be recommended for pediatric patients less than 16 years of age, but the FDA-approved labeling gives suggested dosage ranges for younger pediatric patients. Other H2-antagonists may be preferred in young children and infants. Infants as young as neonates have received cimetidine therapy off-label.

For the treatment of gastroesophageal reflux disease (GERD) or esophagitis associated with erosive gastroesophageal reflux disease (GERD):
Oral dosage:
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.
Infants*: 20 to 40 mg/kg/day PO in divided doses 4 times per day. A typical starting dose is 10 mg/kg/dose PO 4 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.
Children and Adolescents <= 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 4 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.
Adolescents >= 16 years: 800 mg PO twice daily or 400 mg PO 4 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.

For the self-medication of pyrosis (heartburn), acid dyspepsia (acid indigestion), or sour stomach:
Oral dosage:
Children < 12 years: Do not self-medicate. Use only if advised by qualified health care prescriber.
Children and Adolescents >= 12 years: 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.

For the treatment of peptic ulcer disease (duodenal ulcer or gastric ulcer) or gastritis*:
Oral dosage:
Children and Adolescents <= 15 years: 20 to 40 mg/kg/day PO in divided doses every 6 hours for active ulcer treatment.
Adolescents >= 16 years: 800 mg PO once daily at bedtime, or 400 mg PO twice daily or 300 mg PO 4 times per day with meals and at bedtime for 8 to 12 weeks are all acceptable regimens for active treatment. The American College of Gastroenterology supports a maximum duration of 12 weeks for the treatment of gastric ulcers. If maintenance therapy is indicated, dose is 400 mg PO once daily at bedtime. No firm data are available to guide decisions regarding duration of maintenance 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 infection cured or NSAIDs discontinued). Shorter treatment courses are recommended if the indication is for a symptomatic recurrence of an uncomplicated ulcer.
Intravenous dosage (intermittent IV injection or intermittent IV infusion):
Children and Adolescents <= 15 years: 20 to 40 mg/kg/day IV in divided doses every 6 hours for active treatment.
Adolescents >= 16 years: 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.
Intramuscular dosage:
Children and Adolescents <= 15 years: 20 to 40 mg/kg/day IM divided and given every 6 hours for active treatment.
Adolescents >= 16 years: 300 mg IM every 6 hours for active treatment.

For the treatment of pathological hypersecretory conditions including Zollinger-Ellison syndrome, systemic mastocytosis, and multiple endocrine adenoma syndrome:
Intravenous dosage (continuous IV infusion):
Adolescents >= 16 years of age: 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 stress gastritis prophylaxis or active treatment of stress ulceration in critically-ill patients:
Intravenous dosage:
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.
Infants*, Children and Adolescents <= 15 years: 20 to 40 mg/kg/day IV in divided doses 4 to 6 times per day.
Adolescents >= 16 years: 50 mg/hour (1,200 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. If the patient has a CrCl less than 30 mL/minute, the hourly continuous infusion rate should be reduced by 50% (i.e., not to exceed 25 mg/hour or 600 mg/day).

For the treatment of viral warts:
-for the treatment of molluscum contagiosum*:
Oral dosage:
Children and Adolescents: Nine of 12 children with molluscum contagiosum refractory to traditional therapy responded to treatment with cimetidine 40 mg/kg/day PO given in divided doses. Three children had no new lesions, but persistence of several existing lesions. Treatment was administered for 2 months. Maximum total dosage did not exceed adult dose of 1,200 mg/day PO. Controlled trials are lacking and are needed to establish efficacy.
-for the treatment of common warts (verruca vulgaris*):
Oral dosage:
Children and Adolescents: 30 to 40 mg/kg/day PO divided 3 times per day has been described in case reports. Generally, cimetidine was administered for 2 consecutive months. Responses usually occurred after the first month of treatment. Controlled trials are lacking and are needed to establish efficacy; one placebo-controlled trial inclusive of children and adults failed to show benefit over placebo.

Maximum Dosage Limits:
-Neonates
20 mg/kg/day PO or IV; data are limited.
-Infants
40 mg/kg/day PO or IV; data are limited.
-Children
40 mg/kg/day PO or IV for most indications; data are limited.
-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.

Patients with Hepatic Impairment Dosing
Recommendations vary with the degree of hepatic impairment exhibited by the patient, but no quantitative recommendations are available. A decreased dosage should be considered for those patients with severe hepatic disease (e.g., Child-Pugh grade C cirrhosis).

Patients with Renal Impairment Dosing
CrCl >= 30 ml/min: No specific recommendations are available.
CrCl < 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/hr or 600 mg/day in adults). Patients being treated for stress gastritis prophylaxis should receive half the recommended dose. Pediatric recommendations are not specifically available. Dosing frequency for intermittent dosing 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.

*non-FDA-approved indication

Monograph content under development

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. The drug has no anticholinergic actions. 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 with an H1-receptor antagonist blocks both the initial and delayed histaminic response.

Pharmacokinetics: Cimetidine is administered orally and parenterally. 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 4-5 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. Half-life is roughly 2 hours in adult patients with normal renal function.

Affected cytochrome P450 isoenzymes: 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.


-Route-Specific Pharmacokinetics
Oral Route
Cimetidine is rapidly and completely absorbed in the GI tract, but first-pass metabolism reduces oral bioavailability to 60-70% in adults. The rate but not the extent of absorption can be affected by food. Peak plasma concentrations occur in 45-90 minutes. Approximately 48% of an oral dose of cimetidine is excreted in the urine as the parent compound. The remainder is excreted in the feces.

Intravenous Route
Peak concentrations generally occur within 15 minutes of intermittent intravenous dosing. Blood levels with other infusion rates vary in direct proportion to the infusion rate. Approximately 75% of an IV dose of cimetidine is excreted in the urine as the parent compound. The remainder is excreted in the feces.

Intramuscular Route
Intramuscular administration provides comparatively effective blood concentrations to oral and intravenous routes. Following intramuscular administration of cimetidine, approximately 75% of the drug is recovered from the urine after 24 hours as the parent compound.


-Special Populations
Pediatrics
Neonates
Cimetidine is effectively eliminated via hepatic metabolism as well as renal routes. Following administration of 15-20 mg/kg/day, the half-life ranges from 2.1-3.4 h. The half-life decreases as total body clearance increases. Variabilities in clearance are primarily due to differences in renal development. Premature neonates generally require lower dosing rates and/or increased intervals between doses. Approximately 90% of a dose is recovered in the urine as cimetidine and its metabolites. Accumulation of cimetidine metabolites may occur with prolonged dosing.

Children
In children, the overall clearance of cimetidine is generally higher than that observed in adults; faster clearance is especially observed in the critically ill or children with burns. Increased clearance has also been reported in children with cystic fibrosis. Elimination half-lives for cimetidine, cimetidine sulfoxide, and hydroxymethyl cimetidine of 1.39, 2.6, and 4.7 hours, respectively are observed after a mean dose of cimetidine of 26 +/- 6.6 mg/kg/day administered intravenously over 15 minutes in four divided doses. With doses >= 20 mg/kg/day, children exhibit plasma concentrations maintained at or above 0.5 mcg/ml for a significantly longer period of time when compared with lower daily doses.

Hepatic Impairment
Uncompensated cirrhosis is associated with decreased clearance of cimetidine. Therefore, dosage reductions are recommended in patients with severe hepatic impairment (e.g., Child-Pugh grade C cirrhosis).

Renal Impairment
Renal dysfunction is associated with an increased cimetidine half-life; the half-life is increased to 5 hours in anephric adult patients. Those with renal dysfunction require lower dosing rates and/or increased intervals between doses.