Dosing

Duodenal Ulcer
Active Duodenal Ulcer: Clinical studies have indicated that suppression of nocturnal acid is the most important factor in duodenal ulcer healing .. Therefore, there is no apparent rationale, except for familiarity with use, for treating with anything other than a once-daily at bedtime dosage regimen (h.s.).
In a U.S. dose-ranging study of 400 mg h.s., 800 mg h.s. and 1600 mg h.s., a continuous dose response relationship for ulcer healing was demonstrated.
However, 800 mg h.s. is the dose of choice for most patients, as it provides a high healing rate (the difference between 800 mg h.s. and 1600 mg h.s. being small), maximal pain relief, a decreased potential for drug interactions (see Precaution and maximal patient convenience. Patients unhealed at 4 weeks, or those with persistent symptoms, have been shown to benefit from 2 to 4 weeks of continued therapy.
It has been shown that patients who both have an endoscopically demonstrated ulcer larger than 1.0 cm and are also heavy smokers (i.e., smoke one pack of cigarettes or more per day) are more difficult to heal. There is some evidence which suggests that more rapid healing can be achieved in this subpopulation with (cimetidine) 1600 mg at bedtime. While early pain relief with either 800 mg h.s. or 1600 mg h.s. is equivalent in all patients, 1600 mg h.s. provides an appropriate alternative when it is important to ensure healing within 4 weeks for this subpopulation. Alternatively, approximately 94% of all patients will also heal in 8 weeks with (cimetidine) 800 mg h.s.
Other (cimetidine) regimens in the U.S. which have been shown to be effective are: 300 mg four times daily, with meals and at bedtime, the original regimen with which U.S. physicians have the most experience, and 400 mg twice daily, in the morning and at bedtime
Concomitant antacids should be given as needed for relief of pain. However, simultaneous administration of (cimetidine) and antacids is not recommended, since antacids have been reported to interfere with the absorption of (cimetidine).
While healing with (cimetidine) often occurs during the first week or two, treatment should be continued for 4 to 6 weeks unless healing has been demonstrated by endoscopic examination.
Maintenance Therapy for Duodenal Ulcer: In those patients requiring maintenance therapy, the recommended adult oral dose is 400 mg at bedtime.
Active Benign Gastric Ulcer
The recommended adult oral dosage for short-term treatment of active benign gastric ulcer is 800 mg h.s., or 300 mg four times a day with meals and at bedtime. Controlled clinical studies were limited to 6 weeks of treatment . 800 mg h.s. is the preferred regimen for most patients based upon convenience and reduced potential for drug interactions.
Symptomatic response to (cimetidine) does not preclude the presence of a gastric malignancy. It is important to follow gastric ulcer patients to assure rapid progress to complete healing.
Erosive Gastroesophageal Reflux Disease (GERD)
The recommended adult oral dosage for the treatment of erosive esophagitis that has been diagnosed by endoscopy is 1600 mg daily in divided doses (800 mg b.i.d. or 400 mg q.i.d.) for 12 weeks. The use of (cimetidine) beyond 12 weeks has not been established.
Prevention of Upper Gastrointestinal Bleeding
The recommended adult dosing regimen is continuous I.V. infusion of 50 mg/hour. Patients with creatinine clearance less than 30 cc/min. should receive half the recommended dose. Treatment beyond 7 days has not been studied.
Pathological Hypersecretory Conditions
(such as Zollinger-Ellison Syndrome)
Recommended adult oral dosage: 300 mg four times a day with meals and at bedtime. In some patients it may be necessary to administer higher doses more frequently. Doses should be adjusted to individual patient needs, but should not usually exceed 2400 mg per day and should continue as long as clinically indicated.

Use

In hospitalized patients with pathological hypersecretory conditions or intractable ulcers, or in patients who are unable to take oral medication, cimetidine may be administered parenterally.
The doses and regimen for parenteral administration in patients with GERD have not been established.
All parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.
 
Short-term treatment of active duodenal ulcers and benign gastric ulcers; maintenance therapy of duodenal ulcer; treatment of gastric hypersecretory states; treatment of gastroesophageal reflux disease (GERD)

Adverse Reactions

1% to 10%:
Central nervous system: Headache (2% to 4%), dizziness (1%), somnolence (1%), agitation
Endocrine & metabolic: Gynecomastia (<1% to 4%)
Gastrointestinal: Diarrhea (1%)
Frequency not defined:
Cardiovascular: AV block, bradycardia, hypotension, tachycardia, vasculitis
Central nervous system: Confusion, fever
Dermatologic: Alopecia, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, rash
Endocrine & metabolic: Edema of the breasts, sexual ability decreased
Gastrointestinal: Nausea, pancreatitis, vomiting
Hematologic: Agranulocytosis, aplastic anemia, hemolytic anemia (immune-based), neutropenia, pancytopenia, thrombocytopenia
Hepatic: ALT increased, AST increased, hepatic fibrosis (case report)
Neuromuscular & skeletal: Arthralgia, myalgia, polymyositis
Renal: Creatinine increased, interstitial nephritis
Miscellaneous: Anaphylaxis, pneumonia (causal relationship not established)

Contraindications

Hypersensitivity to cimetidine, any component of the formulation, or other H2 antagonists

Warnings / Precautions Drug

Concerns related to adverse effects:
• Confusion: Reversible confusional states, usually clearing within 3-4 days after discontinuation, have been linked to use. Increased age (>50 years) and renal or hepatic impairment are thought to be associated.
Disease-related concerns:
• Gastric malignancy: Relief of symptoms does not preclude the presence of a gastric malignancy.
• Hepatic impairment: Use with caution in patients with hepatic impairment; dosage adjustment recommended.
• Renal impairment: Use with caution in patients with renal impairment; dosage adjustment recommended.
Concurrent drug therapy issues:
• Drugs metabolized through P450 system: Dosage should be adjusted in patients receiving drugs metabolized through the P450 system.
Special populations:
• Elderly: May be inappropriate in this age group due to risk of confusion and other CNS effects (Beers Criteria).
Other warnings/precautions:
• OTC labeling: Should not be taken by individuals experiencing painful swallowing, vomiting with blood, or bloody or black stools; medical attention should be sought. A healthcare provider should be consulted prior to use when pain in the stomach, shoulder, arms or neck is present; if heartburn has occurred for >3 months; or if unexplained weight loss, or nausea and vomiting occur. Frequent wheezing, shortness of breath, lightheadedness, or sweating, especially with chest pain or heartburn, should also be reported. Consultation of a healthcare provider should occur by patients if also taking theophylline, phenytoin, or warfarin; if heartburn or stomach pain continues or worsens; or if use is required for >14 days. OTC cimetidine is not approved for use in patients <12 years of age.
Metabolism/Transport Effects
Substrate of P-glycoprotein; Inhibits CYP1A2 (moderate), 2C9 (weak), 2C19 (moderate), 2D6 (moderate), 2E1 (weak), 3A4 (moderate)

Interactions

Alfentanil: Cimetidine may increase the serum concentration of Alfentanil. Risk C: Monitor therapy
Amiodarone: Cimetidine may increase the serum concentration of Amiodarone. Management: Consider alternatives to cimetidine. If this combination cannot be avoided, monitor for increased amiodarone concentrations/effects with cimetidine initiation/dose increase or decreased concentrations/effects with cimetidine discontinuation/dose decrease. Risk D: Consider therapy modification
Anticonvulsants (Hydantoin): Cimetidine may enhance the adverse/toxic effect of Anticonvulsants (Hydantoin). Cimetidine may increase the serum concentration of Anticonvulsants (Hydantoin). Management: Consider using an alternative H2-antagonist to avoid this interaction. Monitor for toxic effects of hydantoin anticonvulsants if cimetidine is initiated/dose increased. Exceptions: Ethotoin. Risk D: Consider therapy modification
Atazanavir: H2-Antagonists may decrease the absorption of Atazanavir. Management: Specific dose limitations and administration guidelines exist; consult full interaction monograph or atazanavir prescribing information. Risk D: Consider therapy modification
Benzodiazepines (metabolized by oxidation): Cimetidine may decrease the metabolism of Benzodiazepines (metabolized by oxidation). Risk C: Monitor therapy
Bromazepam: Cimetidine may increase the serum concentration of Bromazepam. Management: Consider use of bromazepam with an H2-antagonist that is not a potent CYP inhibitor (e.g., ranitidine) or alternatively, consider use of cimetidine with a benzodiazepine that does not undergo oxidative metabolism (e.g., lorazepam). Risk D: Consider therapy modification
Budesonide (Systemic, Oral Inhalation): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Budesonide (Systemic, Oral Inhalation). Management: Consider reducing the oral budesonide dose when used together with a CYP3A4 inhibitor. This interaction is likely less severe with orally inhaled budesonide. Monitor patients closely for signs/symptoms of corticosteroid excess. Risk D: Consider therapy modification
Calcium Channel Blockers: Cimetidine may decrease the metabolism of Calcium Channel Blockers. Exceptions: AmLODIPine; Clevidipine; NiCARdipine. Risk D: Consider therapy modification
CarBAMazepine: Cimetidine may increase the serum concentration of CarBAMazepine. The serum carbamazepine concentration might return to normal within one week of starting cimetidine. Risk C: Monitor therapy
Carmustine: Cimetidine may enhance the myelosuppressive effect of Carmustine. Management: Consider alternatives to cimetidine in patients receiving carmustine. If the combination cannot be avoided, monitor for enhanced carmustine myelotoxicity. Risk D: Consider therapy modification
Carvedilol: Cimetidine may increase the serum concentration of Carvedilol. Risk C: Monitor therapy
Cefditoren: H2-Antagonists may decrease the serum concentration of Cefditoren. Management: Concomitant use of cefditoren with H2-antagonists and antacids is not recommended. Consider alternative methods to control acid reflux (eg, diet modification) or alternative antimicrobial therapy if use of H2-antagonists can not be avoided. Risk D: Consider therapy modification
Cefpodoxime: H2-Antagonists may decrease the absorption of Cefpodoxime. Separate oral doses by at least 2 hours. Risk C: Monitor therapy
Cefuroxime: H2-Antagonists may decrease the absorption of Cefuroxime. Separate oral doses by at least 2 hours. Risk C: Monitor therapy
Cisapride: Cimetidine may increase the serum concentration of Cisapride. Management: Consider alternatives to cimetidine. If this combination cannot be avoided, monitor for toxic effects of cisapride if cimetidine is initiated/dose increased, or decreased efficacy if cimetidine is discontinued/dose decreased. Risk D: Consider therapy modification
Clopidogrel: CYP2C19 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Clopidogrel. Risk X: Avoid combination
CloZAPine: Cimetidine may increase the serum concentration of CloZAPine. Management: Consider use of an alternative H2 antagonist. Monitor for increased toxic effects of clozapine if cimetidine is initiated/dose increased, or decreased effects if cimetidine is discontinued/dose decreased. Risk D: Consider therapy modification
Colchicine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Colchicine. Management: Reduce colchicine dose as directed when using with a moderate CYP3A4 inhibitor, and increase monitoring for colchicine-related toxicity. Use extra caution in patients with impaired renal and/or hepatic function. Risk D: Consider therapy modification
CYP1A2 Substrates: CYP1A2 Inhibitors (Moderate) may decrease the metabolism of CYP1A2 Substrates. Risk C: Monitor therapy
CYP2C19 Substrates: CYP2C19 Inhibitors (Moderate) may decrease the metabolism of CYP2C19 Substrates. Risk C: Monitor therapy
CYP2D6 Substrates: CYP2D6 Inhibitors (Moderate) may decrease the metabolism of CYP2D6 Substrates. Exceptions: Tamoxifen. Risk C: Monitor therapy
CYP3A4 Substrates: CYP3A4 Inhibitors (Moderate) may decrease the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
Dasatinib: H2-Antagonists may decrease the absorption of Dasatinib. Risk D: Consider therapy modification
Delavirdine: H2-Antagonists may decrease the serum concentration of Delavirdine. Management: Chronic therapy with H2-antagonists should be avoided in patients who are being treated with delavirdine. The clinical significance of short-term H2-antagonist therapy with delavirdine is uncertain, but such therapy should be undertaken with caution. Risk X: Avoid combination
Dexmethylphenidate: H2-Antagonists may increase the absorption of Dexmethylphenidate. Specifically, H2-antagonists may interfere with the normal release of drug from the extended-release capsules (Focalin XR brand), which could result in both increased absorption (early) and decreased delayed absorption. Risk C: Monitor therapy
Dofetilide: Cimetidine may increase the serum concentration of Dofetilide. This is likely via inhibition of dofetilide renal tubular secretion (primarily) and inhibition of dofetilide metabolism. Risk X: Avoid combination
Epirubicin: Cimetidine may increase the serum concentration of Epirubicin. Risk X: Avoid combination
Eplerenone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Eplerenone. Management: A lower starting dose of eplerenone (25 mg once daily for adults) is recommended in patients with hypertension who are also taking drugs that are moderate inhibitors of CYP3A4. Risk D: Consider therapy modification
Erlotinib: H2-Antagonists may decrease the serum concentration of Erlotinib. Management: Avoid H2-antagonists in patients receiving erlotinib when possible. If concomitant treatment cannot be avoided, erlotinib should be dosed once daily, 10 hours after and at least 2 hours before H2-antagonist dosing. Risk D: Consider therapy modification
Everolimus: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Everolimus. Management: Everolimus dose reductions are required for patients being treated for subependymal giant cell astrocytoma or renal cell carcinoma. See prescribing information for specific dose adjustment and monitoring recommendations. Risk D: Consider therapy modification
Fesoterodine: CYP2D6 Inhibitors may increase serum concentrations of the active metabolite(s) of Fesoterodine. Risk C: Monitor therapy
Fosamprenavir: H2-Antagonists may decrease the serum concentration of Fosamprenavir. Cimetidine may also inhibit the metabolism of the active metabolite amprenavir, making its effects on fosamprenavir/amprenavir concentrations difficult to predict. Risk C: Monitor therapy
Gefitinib: H2-Antagonists may decrease the serum concentration of Gefitinib. Risk C: Monitor therapy
Halofantrine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Halofantrine. Risk D: Consider therapy modification
Indinavir: H2-Antagonists may decrease the serum concentration of Indinavir. Risk C: Monitor therapy
Iron Salts: H2-Antagonists may decrease the absorption of Iron Salts. Exceptions: Ferric Gluconate; Ferumoxytol; Iron Dextran Complex; Iron Sucrose. Risk C: Monitor therapy
Itraconazole: H2-Antagonists may decrease the serum concentration of Itraconazole. Management: When this combination is used, the itraconazole should be administered with a cola beverage (8 ounces). Itraconazole oral suspension may be less sensitive to this interaction. Monitor patient response to itraconazole closely. Risk D: Consider therapy modification
Ketoconazole: H2-Antagonists may decrease the serum concentration of Ketoconazole. Management: Administer oral ketoconazole at least 2 hours prior to use of any H2-receptor antagonist. Monitor patients closely for signs of inadequate clinical response to ketoconazole. Risk D: Consider therapy modification
Ketoconazole (Systemic): H2-Antagonists may decrease the serum concentration of Ketoconazole (Systemic). Management: Administer oral ketoconazole at least 2 hours prior to use of any H2-receptor antagonist. Monitor patients closely for signs of inadequate clinical response to ketoconazole. Risk D: Consider therapy modification
Lurasidone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lurasidone. Risk D: Consider therapy modification
Mesalamine: H2-Antagonists may diminish the therapeutic effect of Mesalamine. Histamine H2-Antagonist-mediated increases in gastrointestinal pH may cause the premature release of mesalamine from specific sustained-release mesalamine products. Management: Consider avoiding concurrent administration of high-dose histamine H2-receptor antagonists with sustained-release mesalamine products. Risk D: Consider therapy modification
MetFORMIN: Cimetidine may increase the serum concentration of MetFORMIN. Risk D: Consider therapy modification
Methylphenidate: H2-Antagonists may increase the absorption of Methylphenidate. Specifically, H2-antagonists may interfere with the normal release of drug from the extended-release capsules (Ritalin LA brand), which could result in both increased absorption (early) and decreased delayed absorption. Risk C: Monitor therapy
Moclobemide: Cimetidine may decrease the metabolism of Moclobemide. Risk D: Consider therapy modification
Nebivolol: CYP2D6 Inhibitors (Moderate) may increase the serum concentration of Nebivolol. Risk C: Monitor therapy
Nelfinavir: H2-Antagonists may decrease the serum concentration of Nelfinavir. Concentrations of the active M8 metabolite may also be reduced. Risk C: Monitor therapy
Nicotine: Cimetidine may increase the serum concentration of Nicotine. Risk C: Monitor therapy
Pentoxifylline: Cimetidine may increase the serum concentration of Pentoxifylline. Risk C: Monitor therapy
P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy
P-glycoprotein/ABCB1 Inhibitors: P-glycoprotein/ABCB1 Substrates may increase the serum concentration of P-glycoprotein/ABCB1 Inhibitors. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy
Pimecrolimus: CYP3A4 Inhibitors (Moderate) may decrease the metabolism of Pimecrolimus. Risk C: Monitor therapy
Posaconazole: H2-Antagonists may decrease the serum concentration of Posaconazole. Management: Avoid concurrent use whenever possible. Monitor patients closely for decreased antifungal effects if this combination is used. Consider using a noninteracting antifungal as appropriate. Risk D: Consider therapy modification
Pramipexole: Cimetidine may increase the serum concentration of Pramipexole. Risk C: Monitor therapy
Praziquantel: Cimetidine may increase the serum concentration of Praziquantel. Risk C: Monitor therapy
Procainamide: Cimetidine may decrease the excretion of Procainamide. Risk D: Consider therapy modification
Propafenone: Cimetidine may increase the serum concentration of Propafenone. Risk C: Monitor therapy
QuiNIDine: Cimetidine may increase the serum concentration of QuiNIDine. Management: Consider alternatives to cimetidine. If the combination cannot be avoided, monitor for increased quinidine concentrations/toxicity with cimetidine initiation/dose increase, or decreased concentrations/effects with cimetidine discontinuation/dose decrease. Risk D: Consider therapy modification
QuiNINE: Cimetidine may increase the serum concentration of QuiNINE. Risk D: Consider therapy modification
Rilpivirine: H2-Antagonists may decrease the serum concentration of Rilpivirine. Management: Administer histamine H2 receptor antagonists at least 12 hours before or 4 hours after rilpivirine. Risk D: Consider therapy modification
Roflumilast: Cimetidine may increase serum concentrations of the active metabolite(s) of Roflumilast. Cimetidine may increase the serum concentration of Roflumilast. Risk C: Monitor therapy
Salmeterol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Salmeterol. Risk C: Monitor therapy
Saquinavir: H2-Antagonists may increase the serum concentration of Saquinavir. Risk C: Monitor therapy
Saxagliptin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Saxagliptin. Risk C: Monitor therapy
Selective Serotonin Reuptake Inhibitors: Cimetidine may decrease the metabolism of Selective Serotonin Reuptake Inhibitors. Risk D: Consider therapy modification
Sulfonylureas: Cimetidine may increase the serum concentration of Sulfonylureas. Risk C: Monitor therapy
Theophylline Derivatives: Cimetidine may decrease the metabolism of Theophylline Derivatives. Exceptions: Dyphylline. Risk D: Consider therapy modification
Thioridazine: CYP2D6 Inhibitors may decrease the metabolism of Thioridazine. Risk X: Avoid combination
Tolvaptan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tolvaptan. Risk X: Avoid combination
Tricyclic Antidepressants: Cimetidine may decrease the metabolism of Tricyclic Antidepressants. Risk C: Monitor therapy
Varenicline: H2-Antagonists may increase the serum concentration of Varenicline. Management: Monitor for increased varenicline adverse effects with concomitant use of cimetidine or other H2-antagonists, particulary in patients with severe renal impairment. International product labeling recommendations vary. Consult appropriate labeling. Risk C: Monitor therapy
Vitamin K Antagonists (eg, warfarin): Cimetidine may enhance the anticoagulant effect of Vitamin K Antagonists. Risk D: Consider therapy modification
Zaleplon: Cimetidine may decrease the metabolism of Zaleplon. Risk D: Consider therapy modification
ZOLMitriptan: Cimetidine may increase the serum concentration of ZOLMitriptan. Risk C: Monitor therapy

Pregnancy

B
Pregnancy Implications
Teratogenic effects were not observed in animal reproduction studies; therefore, cimetidine is classified as pregnancy category B. Cimetidine crosses the placenta. An increased risk of congenital malformations or adverse events in the newborn has generally not been observed following maternal use of cimetidine during pregnancy. Histamine H2 antagonists have been evaluated for the treatment of gastroesophageal reflux disease (GERD), as well as gastric and duodenal ulcers during pregnancy. Although if needed, cimetidine is not the agent of choice. Histamine H2 antagonists may be used for aspiration prophylaxis prior to cesarean delivery.

Lactation

Enters breast milk/not recommended (AAP rates “compatible”; AAP 2001 update pending)
Breast-Feeding Considerations
Cimetidine is excreted into breast milk. The concentration of cimetidine in maternal serum in comparison to breast milk is highly variable. Breast-feeding is not recommended by the manufacturer. Consider the renal function of the breast-feeding infant.

Mechanism of Action

Competitive inhibition of histamine at H2 receptors of the gastric parietal cells resulting in reduced gastric acid secretion, gastric volume and hydrogen ion concentration reduced

Pharmacodynamics / Kinetics

Onset of action: 1 hour
Duration: 80% reduction in gastric acid secretion for 4-5 hours after 300 mg dose
Distribution: 1.3 L/kg
Protein binding: 20%
Metabolism: Partially hepatic, forms metabolites
Half-life elimination: Neonates: 3.6 hours; Children: 1.4 hours; Adults: 2 hours
Excretion: Primarily urine (48% as unchanged drug); feces (some)