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₂-receptor Antagonists

Histamine H ₂-receptor Antagonists (Systemic)

This monograph includes information on the following:

1) Cimetidine
2) Famotidine
3) Nizatidine
4) Ranitidine

VA CLASSIFICATION
Cimetidine
Primary: GA301
Secondary: DE890

Famotidine
Primary: GA301

Nizatidine
Primary: GA301

Ranitidine
Primary: GA301


Commonly used brand name(s): Acid Control²; Act²; Alti-Ranitidine⁴; Apo-Cimetidine¹; Apo-Famotidine²; Apo-Nizatidine³; Apo-Ranitidine⁴; Axid³; Axid AR³; Dyspep HB²; Gen-Cimetidine¹; Gen-Famotidine²; Gen-Ranitidine⁴; Maalox H2 Acid Controller²; Mylanta AR Acid Reducer²; Novo-Cimetine¹; Novo-Famotidine²; Novo-Ranitidine⁴; Nu-Cimet¹; Nu-Famotidine²; Nu-Ranit⁴; PMS-Cimetidine¹; Pepcid²; Pepcid AC²; Pepcid AC Acid Controller²; Pepcid I.V.²; Pepcid RPD²; Peptol¹; Tagamet¹; Tagamet HB¹; Tagamet HB 200¹; Ulcidine²; Ulcidine-HB²; Zantac⁴; Zantac 75⁴; Zantac EFFERdose Granules⁴; Zantac EFFERdose Tablets⁴.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Histamine H ₂-receptor antagonist—All drugs in this monograph are used as histamine H ₂-receptor antagonists

Antiulcer agent— All drugs in this monograph are used as antiulcer agents

Gastric acid secretion inhibitor— All drugs in this monograph are used as gastric acid secretion inhibitors.

Urticaria therapy adjunct— Cimetidine.;

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Ulcer, duodenal (prophylaxis and treatment)—Histamine H ₂-receptor antagonists are indicated in the short-term treatment of active duodenal ulcer. They are also indicated (at reduced dosage) in the prevention of duodenal ulcer recurrence in selected patients. ^{{01} {07} {102} {127} {130} {142} {147} {148} {152} {153} {165}}

Ulcer, gastric (treatment)—Cimetidine, famotidine, nizatidine, and ranitidine are indicated in the short-term treatment of active benign gastric ulcer. ^{{01} {102} {127} {130} {146} {149} {154} {165} {174} {210}}

Ulcer, gastric (prophylaxis)—Cimetidine ^{232} and ranitidine are indicated (at reduced dosage) in the prevention of gastric ulcer recurrence after the healing of acute ulcers. ^{219}

Heartburn, acid indigestion, and sour stomach associated with hyperacidity (prophylaxis and treatment)—Nonprescription strengths of the histamine H ₂-receptor antagonists cimetidine ^{222}, famotidine ^{217}, and ranitidine ^{218} are indicated for relief of symptoms associated with hyperacidity, including heartburn, acid indigestion, and sour stomach. ^{216} Nonprescription strengths of cimetidine ^{222}, famotidine ^{217}, nizatidine ^{227}, and ranitidine ^{228} are also indicated in prevention of hyperacidity symptoms brought on by the consumption of food or beverages. ^{216}

Hypersecretory conditions, gastric (treatment)
Zollinger-Ellison syndrome (treatment)
Mastocytosis, systemic (treatment) or
Adenoma, multiple endocrine (treatment)—Cimetidine ^{130}, famotidine ^{{01} {143}}, [nizatidine]¹ , and ranitidine ^{102} are indicated in the treatment of pathological gastric hypersecretion associated with Zollinger-Ellison syndrome (alone or as part of multiple endocrine neoplasia Type-1), systemic mastocytosis, and multiple endocrine adenoma.

Gastroesophageal reflux disease [GERD] (treatment)—Cimetidine ^{{130} {175}}, famotidine ^{{01} {144}}, nizatidine ^{1 {165}}, and ranitidine ^{{102} {173}} are indicated in the treatment of acute gastroesophageal reflux disease, which may or may not cause erosive or ulcerative esophagitis ^{207}.

[Pancreatic insufficiency (treatment adjunct)]¹—Cimetidine is used to enhance pancreatic replacement by reducing peptic acid deactivation and to enhance the efficacy of orally administered pancreatic enzymes in patients with pancreatic insufficiency by reducing the secretion of hydrochloric acid. However, the efficacy of cimetidine in acute pancreatitis has not been established, and some studies have demonstrated that cimetidine may increase and prolong hyperamylasemia. ^{{02} {06}}

Bleeding, upper gastrointestinal (treatment)—Cimetidine ^{{221} {232}}, [ famotidine]^1{47}{145}, and [ranitidine] are used to treat upper gastrointestinal bleeding secondary to gastric ulcer, duodenal ulcer, or hemorrhagic gastritis.

Stress-related mucosal damage (prophylaxis and treatment)—[Parenteral ranitidine] is used to prevent and treat and parenteral cimetidine ^{232} is indicated to prevent and used to treat ^{130} upper gastrointestinal, stress-induced ulceration and bleeding, especially in intensive care patients. However, the efficacy of histamine H ₂-receptor antagonists in treating hemorrhage in critically ill patients has not been established. ^{{04} {98} {176}}

[Pneumonitis, aspiration (prophylaxis)]—Cimetidine ^{232}, ranitidine ^{100}, and famotidine ^{{62} {63}} also are used before anesthesia induction for the prophylaxis of aspiration pneumonitis. ^{156}

Arthritis, rheumatoid (treatment adjunct)—[ Cimetidine] and [ranitidine]¹ are used for the relief of gastrointestinal symptoms associated with the use of nonsteroidal anti-inflammatory drugs in the treatment of rheumatoid arthritis. ^{{54} {59} {60} {61} {101} {150} {151}}

[Urticaria, acute (treatment adjunct) ]¹—Cimetidine is used in combination with an antihistamine to treat acute urticaria. ^{{64} {65} {66} {67}}

¹ Not included in Canadian product labeling.

Pharmacology/Pharmacokinetics

Table 1. Pharmacology/Pharmacokinetics

Drug	Absorption * (% oral bioavailability)	Protein binding	Biotransformation	Half-life (elimination)
				With normal renal function (hr)	With reduced creatinine clearance (mL/min: hr)
Cimetidine	Rapid (60–70)	Low (15–20%)	Hepatic (30–40% of oral dose)	Oral: 2.0 Parenteral: 1.6–2.1 † {23} {26}	20–50: 2.9 <20: 3.7 Anephric: 5
Famotidine	Rapid; incomplete (40–45)	Low (15–20%)	Hepatic (minimal first pass metabolism)	Oral/Parenteral: 2.5–3.5	<10: 20 or more
Nizatidine	Rapid {37} (>90)	Moderate (35%)	Hepatic (minimal first pass metabolism) {76}	Oral: 1–2	Anephric: 3.5–11
Ranitidine	Rapid (39–87) {26}	Low (15%)	Hepatic	Oral: 2.5 Parenteral: 2–2.5	Oral—20–30: 8–9 Parenteral—25–35: 4.8

^* Rate of absorption, but not extent, is delayed by food. Younger patients usually have better absorption of cimetidine than elderly patients. Absorption of famotidine and nizatidine is slightly increased by food, while the absorption of ranitidine is not significantly affected by the presence of food.
^† In burn patients with thermal injury ranging from 6 to 80% of the body surface, and with normal renal function, elimination half-life of cimetidine has been found to be significantly reduced.

Table 2. Pharmacology/Pharmacokinetics

Drug	Mean serum concentration resulting in 50% inhibition * (ng/mL)	Time to peak concentration after oral dose (hr)	Time to peak effect (hr)	Duration of action (hr)	Elimination † (% excreted unchanged)
Cimetidine	500	0.75-1.5	Oral: 1–2 {26}	Nocturnal: 6–8 Basal: 4–5	Primarily renal (48% of oral dose; 75% of parenteral dose) ‡
Famotidine	13	1–3	Oral: 1–3 Parenteral: 0.5 {01}	Nocturnal and basal: 10–12 (oral and IV)	Primarily renal (30–35% of oral dose; 65–70% of parenteral dose) {154}
Nizatidine	295	0.5–3	Oral: 0.5–3	Nocturnal: Up to 12 Basal: Up to 8	Primarily renal (60% of oral dose)
Ranitidine	100	2–3	Oral: 1–3 {26}	Nocturnal: 13 Basal: 4	Primarily renal (30% of oral dose; 70% of parenteral dose)

^* Refers to inhibition of pentagastrin-stimulated acid secretion. ^{26}
† Trace amounts of H ₂-receptor antagonists are removable by hemodialysis and peritoneal dialysis.
^‡ In burn patients with thermal injury ranging from 6 to 80% of the body surface, and with normal renal function, total clearance of cimetidine has been found to be significantly increased.


Physicochemical characteristics:
Molecular weight—
    Cimetidine: 252.34
    Famotidine: 337.43
    Nizatidine: 331.45
    Ranitidine: 350.87

pKa—
    Cimetidine: 7.09
    Cimetidine hydrochloride: 7.11
    Ranitidine: 8.2 and 2.7

Mechanism of action/Effect:

H ₂-receptor antagonists inhibit basal and nocturnal gastric acid secretion by competitive inhibition of the action of histamine at the histamine H ₂-receptors of the parietal cells. They also inhibit gastric acid secretion stimulated by food, betazole, pentagastrin, caffeine, insulin, and physiological vagal reflex. ^{130}

Urticaria therapy adjunct—Cimetidine blocks H ₂-receptors, which in part are responsible for the inflammatory response, in the cutaneous blood vessels of humans. ^{68}


Other actions/effects:

Cimetidine—Inhibits hepatic cytochrome P450 and P448 mixed function oxidase (microsomal enzyme) systems; antagonizes dihydrotestosterone (antiandrogenic action); produces transient and clinically insignificant increases in prolactin concentrations (with intravenous bolus administration only). ^{26} May enhance gastromucosal defense and healing in acid-related disorders, particularly stress-induced ulceration and bleeding, by increasing production of gastric mucus, content of mucus glycoprotein, mucosal secretion of bicarbonate, gastric mucosal blood flow, endogenous mucosal prostaglandin synthesis, and rate of epithelial cell renewal ^{05}.

Famotidine—Weak inhibitor of hepatic cytochrome P450 mixed function oxidase system.

Nizatidine—Weak inhibitor of hepatic cytochrome P450 mixed function oxidase system.

Ranitidine—Weak inhibitor of hepatic cytochrome P450 mixed function oxidase system; produces small, transient, and clinically insignificant increases in serum prolactin concentrations (reported with intravenous bolus administration of 100 mg or more). ^{{09} {10}}

Distribution:

All H ₂-receptor antagonists are distributed in breast milk and cerebrospinal fluid ^{160}.

Onset of action:

Famotidine—Oral: 1 hour. ^{01}


Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to one of the histamine H ₂-receptor antagonists may be sensitive to the other histamine H ₂-receptor antagonists also. ^{235}

Carcinogenicity/Mutagenicity/Tumorigenicity

It is not known whether the histamine H ₂-receptor antagonists are carcinogenic or mutagenic in humans.

For cimetidine—Long-term toxicity studies in rats have shown a significantly higher incidence of benign Leydig cell tumors in cimetidine-treated groups than in controls at doses approximately 8 to 48 times the recommended human dose. ^{130}

For famotidine—Studies in rats and mice with oral doses approximately 2500 times the recommended human dose showed no evidence of carcinogenicity. Results of the Ames test were negative ^{235}. Studies in mice with a micronucleus test and a chromosomal aberration test showed no evidence of mutagenicity. ^{01}

For nizatidine—Studies in rats and mice with oral doses many times the recommended human dose showed no evidence of carcinogenicity. ^{165}

For ranitidine—Long-term studies in mice and rats with doses up to 2 grams per kg of body weight have not shown ranitidine to be carcinogenic. ^{102}


Pregnancy/Reproduction
Fertility—
For cimetidine: There has been no evidence of impaired mating performance or fertility in rats, rabbits, and mice at doses 40 times the human dose. ^{130}

For famotidine: Studies in rats and rabbits with oral doses of up to 2000 and 500 mg per kg of body weight (mg/kg) per day, respectively, have not shown that famotidine impairs fertility. ^{{01} {235}}

For nizatidine: Studies in rats and rabbits with oral doses up to 300 and 55 times the human dose, respectively, have not shown that nizatidine impairs fertility. ^{165}

For ranitidine: Studies in rats and rabbits at doses up to 160 times the human dose have not shown that ranitidine impairs fertility. ^{102}

Pregnancy—

For cimetidine

Adequate and well-controlled studies in humans have not been done.

Animal studies have shown that cimetidine crosses the placenta. Also, a study in rats exposed to cimetidine during intrauterine life and the immediate neonatal period showed a hypoandrogenization in adult life with decreased weights of androgen-dependent tissues and decreased concentrations of testosterone. ^{{07} {43}}

FDA Pregnancy Category B. ^{130}



For famotidine

Famotidine crosses the placenta. ^{01} Adequate and well-controlled studies in humans have not been done. ^{235}

Studies in rats and rabbits with oral doses of up to 2000 and 500 mg/kg per day, respectively, have not shown that famotidine has adverse effects on the fetus. ^{{01} {235}} Rabbits displaying a markedly decreased food intake at doses of 250 times the usual human dose experienced sporadic abortions ^{235}.

FDA Pregnancy Category B. ^{{01} {235}}



For nizatidine

Nizatidine crosses the placenta. ^{28} Adequate and well-controlled studies in humans have not been done.

Rabbits treated with a dose equivalent to 300 times the human dose had abortions, a decreased number of live fetuses, and depressed fetal weights. ^{165}

FDA Pregnancy Category B. ^{165}



For ranitidine

Ranitidine crosses the placenta. ^{102} Adequate and well-controlled studies in humans have not been done.

Studies in rats and rabbits at doses up to 160 times the human dose have not shown that ranitidine causes adverse effects on the fetus. ^{102}

FDA Pregnancy Category B. ^{102}


Breast-feeding

Problems in humans have not been documented; however, cimetidine ^{{34} {130}}, famotidine ^{{01} {47}}, nizatidine ^{{118} {165}}, and ranitidine ^{102} are distributed into breast milk and possibly could suppress gastric acidity, inhibit drug metabolism, and cause central nervous system (CNS) stimulation in the nursing infant. It has been found that very high acute and chronic milk/plasma ratios occur with the use of cimetidine; therefore, the Committee on Drugs of the American Academy of Pediatrics has recommended that cimetidine not be taken by mothers while they are breast-feeding ^{32}. Although, at present, data for ranitidine are insufficient, it appears that high milk/plasma ratios may also occur with ingestion of ranitidine.

Pediatrics

For cimetidine, famotidine, and ranitidine—Studies performed to date have not demonstrated pediatrics-specific problems that would limit the usefulness of cimetidine, famotidine, and ranitidine in children for short-term (6 to 8 weeks ^{181}) use. ^{{15} {44} {134} {135} {136} {137} {138} {139} {140} {141}} Cimetidine, famotidine, and ranitidine have been used for long-term treatment of chronic gastroesophageal reflux disease in children ^{{182} {183} {184} {185}}; however, cimetidine-induced cerebral toxicity ^{{186} {187}} and reported cimetidine effects on the hormonal system in adults ^{{203} {204} {205}} may be of concern with long-term use in children. ^{{188} {189}}

For nizatidine—Appropriate studies have not been performed in children up to 16 years of age.


Geriatrics


For cimetidine, famotidine, and ranitidine—Although appropriate studies on the relationship of age to the effects of these medicines have not been performed in the geriatric population, no geriatrics-specific problems have been documented to date. However, confusion is more likely to occur in elderly patients with impaired hepatic or renal function. ^{{23} {36} {52} {155}}

For nizatidine—Studies performed to date have not demonstrated geriatrics-specific problems that would limit the usefulness of nizatidine in the elderly. ^{28}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Only specific interactions between histamine H ₂-receptor antagonists and other medications have been identified in this monograph. However, histamine H ₂-receptor antagonists, by increasing gastric pH, have the potential to affect the bioavailability of those medications and dosage forms (e.g., enteric-coated) ^{49} whose absorption is pH-dependent. Also, histamine H ₂-receptor antagonists may prevent the degradation of acid-labile drugs.
In addition, because of cimetidine's documented ability to inhibit hepatic microsomal drug metabolism, elimination of other medications that require hepatic metabolism via the cytochrome (P450) system or that are highly extracted by the liver, may be decreased during concurrent use with cimetidine. ^{{29} {30}} This same possibility should be kept in mind for ranitidine, although ranitidine's ability to inhibit hepatic microsomal drug metabolism is significantly less than that for cimetidine. To date, there is no evidence that famotidine or nizatidine binds to cytochrome P450 to a significant extent, and interactions with medications metabolized by this system have not been reported; however, clinical experience with famotidine and nizatidine is very limited. ^{{24} {26}}
Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.


For all histamine H ₂-receptor antagonists
Antacids    (concurrent use with histamine H ₂-receptor antagonists in the treatment of peptic ulcer may be indicated for the relief of pain; however, simultaneous administration of antacids of medium to high potency [80 mmol to 150 mmol HCl] is not recommended since absorption of histamine H ₂-receptor antagonists may be decreased; patients should be advised not to take any antacids within one-half to one hour of taking histamine H ₂-receptor antagonists ^{{01} {79} {80} {81} {82} {102} {165} {223}})


Bone marrow depressants (see Appendix II )    (concurrent use with H ₂-receptor antagonists may increase the risk of neutropenia or other blood dyscrasias ^{49})


» Itraconazole or
» Ketoconazole    (histamine H ₂-receptor antagonists may increase gastrointestinal pH; concurrent administration with histamine H ₂-receptor antagonists may result in a marked reduction in absorption of itraconazole or ketoconazole; patients should be advised to take histamine H ₂-receptor antagonists at least 2 hours after itraconazole or ketoconazole ^{{53} {83} {223} {224} {225} {226}})


Sucralfate    (although a decrease in absorption is only reported in the literature for cimetidine and ranitidine, concurrent use with sucralfate may decrease the absorption of any H ₂-receptor antagonist; patients should be advised to take an H ₂-receptor antagonist 2 hours before sucralfate ^{{177} {178} {179} {206}})


For cimetidine
Alcohol    (some studies in humans have found increased blood alcohol levels when oral cimetidine was given in conjunction with alcohol; the clinical significance of this effect has not been documented ^{{190} {191} {192} {193} {214}})


» Anticoagulants, coumarin- or indandione-derivative^{{83}{84}{85}{90}{91}{130}} or
» Antidepressants, tricyclic^{{83}{109}{110}{111}{130}} or
Benzodiazepines, especially chlordiazepoxide, diazepam, and midazolam^{{83}{92}{107}{112}{113}{130}} or
Glipizide^{70} or
Glyburide^{72}{73} or
» Metoprolol^{83}{125} or
Metronidazole^{{14}{130}{159}} or
» Phenytoin^{{83}{114}{130}} or
» Propranolol^{83}{130} or
» Xanthines^{{40}{54}{83}{93}{94}{96}{130}} , such as:
Aminophylline
Caffeine
Oxtriphylline
Theophylline    (inhibition of the cytochrome P450 enzyme system by cimetidine may cause a decrease in the hepatic metabolism of these medications, which may result in delayed elimination and increased blood concentrations, when these medications are used concurrently with cimetidine)

    (monitoring of blood concentrations, or prothrombin time for anticoagulants, as a guide to dosage is recommended since dosage adjustment of these medications may be necessary during and after cimetidine therapy to prevent bleeding due to anticoagulant potentiation ^{{25} {130}})

    (concurrent use of phenytoin with cimetidine may increase the risk of ataxia due to increased blood concentrations of phenytoin ^{{25} {130}})

    (concurrent use of metoprolol or propranolol with cimetidine may require monitoring of blood pressure)


Calcium channel blocking agents^{{83}{95}{115}{130}}    (concurrent use with cimetidine may result in accumulation of the calcium channel blocking agent as a result of inhibition of first-pass metabolism; caution and careful titration of the calcium channel blocking agent dose is recommended on initiation of therapy in patients receiving cimetidine ^{{83} {87} {95} {158}})


Cyclosporine    (although this effect is rare, cimetidine has been reported to increase plasma concentrations of cyclosporine and may increase the risk of nephrotoxicity ^{{57} {58} {131}})


Lidocaine    (concurrent administration of lidocaine with cimetidine may result in reduced hepatic clearance of lidocaine, possibly resulting in delayed elimination and increased blood concentrations; lower doses of lidocaine may be required ^{{126} {130}})


Paroxetine^{{238}{239}{240}{241}{242}{244}}    (in one study, steady-state plasma concentrations of paroxetine were increased by approximately 50% during concurrent administration of cimetidine; although the clinical significance of this interaction has not been definitively established, initial dosage reductions are not thought to be necessary, but subsequent dose titration should be based on clinical effects)


Procainamide    (renal elimination of procainamide may be decreased due to competition between cimetidine and procainamide for active tubular secretion, resulting in increased blood concentration of procainamide ^{{56} {83} {116} {117}})


Quinine    (concurrent use of quinine with cimetidine may reduce the clearance of quinine ^{180})


For ranitidine
Alcohol    (some studies in humans have found increased blood alcohol levels when oral ranitidine was given in conjunction with alcohol; the clinical significance of this effect has not been documented ^{{194} {195}})


Glipizide^{69} or
Glyburide^{71}{72}{73} or
Metoprolol^{128}{131} or
Midazolam^{86} or
Nifedipine^{87} or
Phenytoin^{88}{89} or
Theophylline^{{40}{41}{42}{129}} or
Warfarin^{{83}{84}{85}{103}}    (ranitidine is a weak inhibitor of hepatic drug metabolism; isolated cases of drug interactions have been reported between ranitidine and glipizide, glyburide, metoprolol, midazolam, nifedipine, phenytoin, theophylline, and warfarin)

    (monitoring of blood concentrations or prothrombin time for anticoagulants as a guide to dosage is recommended since dosage adjustment of these medications may be necessary during and after ranitidine therapy to prevent bleeding due to anticoagulant potentiation ^{{25} {103}})

    (concurrent use of phenytoin with ranitidine may increase the risk of ataxia due to increased blood concentrations of phenytoin ^{{25} {103}})


Procainamide    (renal elimination of procainamide may be decreased due to competition between ranitidine and procainamide for active tubular secretion, resulting in increased blood concentration of procainamide ^{{56} {83} {108} {116} {117}})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
For all histamine H ₂-receptor antagonists
» Gastric acid secretion test    (histamine H ₂-receptor antagonists may antagonize the effect of pentagastrin and histamine in the evaluation of gastric acid secretory function; administration of histamine H ₂-receptor antagonists is not recommended during the 24 hours preceding the test)


Skin tests using allergen extracts    (histamine H ₂-receptor antagonists may inhibit the cutaneous histamine response, thus producing false-negative results; it is recommended that histamine H ₂-receptor antagonists be discontinued before the diagnostic use of immediate skin tests ^{17})

For nizatidine only (in addition to those listed above for all histamine H ₂-receptor antagonists)
Urine urobilinogen test    (a false-positive reaction may be produced during nizatidine therapy ^{165})

For ranitidine only (in addition to those listed above for all histamine H ₂-receptor antagonists)
Urine protein test    (a false-positive reaction may be produced during ranitidine therapy; testing with sulphosalicylic acid is recommended ^{102})

With physiology/laboratory test values
For cimetidine
Creatinine^{130}{236} and
Transaminase^{130}{236}    (serum values may be increased)


Parathyroid hormone    (concentrations may be decreased, especially when abnormally elevated as in primary hyperparathyroidism ^{01})


Prolactin    (serum concentrations may be increased after intravenous bolus administration ^{02})

For famotidine
Transaminase^{235}    (serum values may be increased ^{{26} {46} {47} {49}})

For nizatidine
Alanine aminotransferase (ALT [SGPT]) and
Alkaline phosphatase and
Aspartate aminotransferase (AST [SGOT])    (serum values may be increased ^{165})

For ranitidine
Creatinine^{230} and
Gamma-glutamyl transpeptidase and
Transaminase    (serum values may be increased)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
Cirrhosis, with history of portal systemic encephalopathy^{23}{162} or
Hepatic function impairment^{162} or
» Renal function impairment^{{23}{161}{163}{164}}    (decreased hepatic or renal clearance of histamine H ₂-receptor antagonists may result in increased plasma concentrations thus increasing the risk of side effects, especially CNS effects; dosage reduction of histamine H ₂-receptor antagonists or longer intervals between doses are recommended with renal function impairment and may be necessary with hepatic function impairment)


Immunocompromised patients^{221}    (decreased gastric acidity may increase the possibility of a hyperinfection of strongyloidiasis ^{221})


Phenylketonuria (PKU)    (the chewable tablet form and the oral disintegrating tablet form of Pepcid brand of famotidine ^{235}, and the effervescent granule form and the effervescent tablet form of Zantac brand of ranitidine ^{230} contain aspartame, which is metabolized to phenylalanine, and must be used with caution in patients with PKU)


Sensitivity to any of the histamine H ₂-receptor antagonists^{235}

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Cyanocobalamin (vitamin B ₁₂) concentration determinations    (monitoring may be needed in long-term treatment of patients likely to have impaired secretion of intrinsic factor, such as those with severe fundic gastritis, to prevent malabsorption of cyanocobalamin ^{18})




Side/Adverse Effects

Those indicating need for medical attention
Incidence rare
For all histamine H ₂-receptor antagonists
    
Cardiac arrhythmias ^{{230} {235}} including bradycardia ^{{102} {166} {167} {230} {236}} (slow heartbeat), tachycardia ^{{01} {102} {130} {165} {230} {236} {237}} (fast, pounding, or irregular heartbeat), and atrioventricular block ^{{230} {235} {236}} (dizziness; fainting; slow heartbeat; troubled breathing; unusual tiredness or weakness)
    
dermatologic reactions, including erythema multiforme ^{{230} {236}} (blisters on palms of hands and soles of feet ; fever; general feeling of discomfort or illness; joint pain; redness of skin), exfoliative dermatitis ^{{236} {237}} (chills; fever; redness and scaling of skin), pruritus ^{{235} {237}} (itching), Stevens-Johnson syndrome ^{236} (bleeding or crusting sores on lips; chills; fever; muscle cramps; pain; skin rash or itching; sore throat; sores, ulcers, or white spots on lips, in mouth, or on genitals; weakness), toxic epidermal necrolysis ^{{235} {236}} (blisters; chills; fever; general feeling of discomfort or illness ; muscle aches; peeling or sloughing of skin; red or irritated eyes; redness, tenderness, or burning of skin; sores or ulcers on lips or in mouth)
    
fever ^{{01} {102} {130} {165} {230} {235} {237}}
    
hematologic effects, including aplastic anemia ^{{230} {236}} (shortness of breath, troubled breathing, wheezing, or tightness in chest; sores, ulcers, or white spots on lips or in mouth; swollen or painful glands; unusual bleeding or bruising), leukopenia ^{{230} {235}} (chills; fever; sore throat), neutropenia ^{{122} {130} {168} {230}} (continuing sores or ulcers in mouth and throat ; fever; sore throat), pancytopenia ^{{230} {235} {236}} (fever; sore throat; sores or ulcers in mouth and throat ; unusual bleeding or bruising), thrombocytopenia ^{{01} {102} {130} {133} {165} {230} {235} {236} {237}} (unusual bleeding or bruising), and immune hemolytic anemia ^{{230} {236}} (back, leg, or stomach pain; fever; nausea, vomiting, or loss of appetite; unusual tiredness or weakness)—extremely rare ^{236}
    
hepatic effects ^{236} , including hepatitis ^{{230} {235} {237}} (dark-colored urine; flu-like symptoms; light-colored stools), and jaundice ^{{230} {235} {237}} (yellow eyes or skin)
    
hypersensitivity reactions ^{{01} {130} {165} {230} {236} {237}} , including anaphylaxis ^{{230} {235} {236} {237}} (chills; coughing; difficulty in swallowing; fast heartbeat; fever; skin rash, hives, or itching; shortness of breath, troubled breathing, wheezing, or tightness in chest; swelling of face, lips, or eyelids), angioedema ^{{230} {235}} (swelling of face, mouth, lips, tongue, hands or feet; sudden difficult breathing), eosinophilia ^{{230} {237}} (fever; loss of appetite; muscle ache; unusual tiredness or weakness; weight loss), laryngeal edema ^{237} ( shortness of breath, troubled breathing, or unusually slow or irregular breathing ), skin rash ^{{01} {46} {102} {130} {165} {230} {235} {237}}
urticaria ^{{235} {237}} (hives), vasculitis ^{{236} {237}} (inflammation of blood vessels)
    
mood or mental changes, including anxiety ^{{235} {237} {236}}
agitation ^{{230} {235} {236}}
confusion ^{{01} {52} {102} {130} {165} {230} {235} {236} {237}}
hallucinations ^{{230} {235} {236}} (seeing, hearing, or feeling things that are not there), mental depression ^{{230} {235} {236}}
nervousness ^{237}
psychosis ^{236} ( severe mental illness)
    
myalgia ^{{01} {102} {130} {230} {236} {237}} (muscle ache )

Note: Blood dyscrasias are more likely to occur in patients with serious concomitant illnesses or in those who also received antimetabolites, alkylating agents, or other medications and/or treatment known to produce neutropenia; appear to be reversible and tend to occur within the first 30 days of administration. ^{38}
Cardiac effects reported for nizatidine are less than those of the other agents, and include short episodes of asymptomatic ventricular tachycardia in two patients ^{237}.
Hepatic effects are usually reversible ^{230}; rarely deaths have occurred ^{{230} {236}}; rare cases of hepatic failure ^{230} have been reported, as have rare cases of cholestatic or mixed hepatocellular and cholestatic liver toxicity ^{237}
Mental changes are especially likely to occur in severely ill elderly patients. ^{230}


For cimetidine
    
Agranulocytosis ^{{130} {236}} (fever; sore throat; unusual tiredness or weakness)
    
arthralgia ^{236} (joint pain)
    
pancreatitis ^{236} (abdominal pain; fever; muscle ache; vomiting)

For famotidine
    
Agranulocytosis ^{{01} {235}} (fever; sore throat; unusual tiredness or weakness)
    
arthralgia ^{235} (joint pain)
    
asthenia ^{235} (unusual tiredness or weakness)
    
bronchospasm ^{01} (wheezing or troubled breathing, severe)
    
fatigue ^{235} (unusual tiredness or weakness)
    
palpitations ^{235} (fast, pounding, or irregular heartbeat)

For nizatidine
    
Amblyopia ^{237} (changes in vision)
    
anemia ^{237} (unusual tiredness or weakness)
    
asthenia ^{237} (unusual tiredness or weakness)
    
bronchospasm ^{{165} {237}} (wheezing or troubled breathing, severe)
    
hyperuricemia ^{237} (joint pain)—not associated with gout or nephrolithiasis ^{237}
    
increased cough ^{237}
    
infection ^{237} , including pharnygitis ^{237} and sinusitis ^{237}
    
pain ^{237} , including chest pain ^{237} and back pain ^{237}
    
serum sickness ^{237} (fever; itching or hives; joint pain; skin rash)

For ranitidine
    
Agranulocytosis ^{{102} {230}} (fever; sore throat; unusual tiredness or weakness)
    
arthralgia ^{230} (joint pain)
    
blurred vision ^{{102} {230}}
    
bronchospasm ^{{102} {230}} (wheezing or troubled breathing, severe)
    
pancreatitis ^{230} (abdominal pain; fever; muscle ache ; vomiting)
    
premature ventricular beats ^{230} (fast or irregular heartbeat; sudden faintness or weakness)




Those indicating need for medical attention only if they continue or are bothersome
Incidence less frequent or rare
For all histamine H ₂-receptor antagonists
    
Decreased libido ^{{01} {46} {102} {165} {230} {235} {237}} (decrease in sexual desire)
    
diarrhea ^{{46} {102} {130} {230} {235} {236} {237}}
    
dizziness ^{{102} {122} {130} {230} {235} {236} {237}}
    
gynecomastia ^{{46} {230} {235} {236} {237}} (swelling of the breasts or breast soreness in both females and males)
    
headache ^{{31} {46} {122} {168} {230} {235} {236} {237}}
    
impotence ^{{102} {130} {165} {230} {235} {236} {237}} (decrease in sexual ability)
    
somnolence ^{{130} {230} {235} {236} {237}} (drowsiness)

Note: Gynecomastia occurs most commonly in patients with hypersecretory conditions who are treated with cimetidine for over a month ^{236}. With the other agents, the incidence of gynecomastia is the same as that in the general population ^{{230} {235}}.
Decreased libido and impotence occur most commonly in patients with hypersecretory conditions who are treated with cimetidine, especially at high doses for longer than 12 months ^{236}; at regular doses of cimetidine ^{236}, as with the other histamine H2-receptor antagonists, incidence is the same as that in the general population. ^{{230} {235} {237}}


For cimetidine
    
Alopecia ^{{130} {236}} (hair loss)
    
interstitial nephritis ^{236} (fever; increase or decrease in urination; skin rash or hives)
    
polymyositis ^{236} (fever; joint pain; muscle tenderness, weakness, or pain ; skin rash; unusual tiredness or weakness ; weight loss)
    
urinary retention ^{236} (difficulty in urinating)

For famotidine
    
Abdominal pain ^{235}
    
alopecia ^{235} (hair loss)
    
anorexia ^{235} (loss of appetite)
    
constipation ^{{01} {46} {235}}
    
dryness of mouth ^{{01} {235}}
    
dryness of skin ^{01}
    
insomnia ^{235} (trouble in sleeping)
    
nausea ^{{01} {46} {235}}
    
tinnitus ^{01} (ringing or buzzing in ears)
    
vomiting ^{{01} {46} {235}}

For nizatidine
    
Abdominal pain ^{237}
    
constipation ^{{122} {237}}
    
dryness of mouth ^{237}
    
increased sweating ^{{165} {237}}
    
insomnia ^{237} (trouble in sleeping )
    
nausea ^{{122} {237}}
    
rhinitis ^{237} (runny nose)
    
vomiting ^{{122} {237}}

For ranitidine
    
Abdominal pain ^{230}
    
alopecia ^{{102} {235} {236}} (hair loss)
    
constipation ^{{46} {102} {122} {237}}
    
insomnia ^{230} (trouble in sleeping )
    
nausea ^{{102} {230}}
    
vomiting ^{{102} {230}}






Overdose
For specific information on the agents used in the management of overdose with histamine H ₂-receptor antagonists, see:
   • Atropine in Anticholinergics/Antispasmodics (Systemic) monograph;
   • Diazepam in Benzodiazepines (Systemic) monograph; and/or
   • Lidocaine Hydrochloride (Systemic)monograph.
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Treatment of overdose
There is no specific antidote for overdose with histamine H ₂-receptor antagonists ^{169}; treatment is symptomatic and supportive ^{{230} {235} {236} {237}} with possible utilization of the following:


To decrease absorption:
Induction of emesis and/or use of gastric lavage. ^{{169} {230} {235} {236} {237}}



Specific treatment:
For seizures—Treatment with intravenous diazepam. ^{169}

For bradycardia—Treatment with atropine. ^{169}

For ventricular arrhythmias—Treatment with lidocaine. ^{169}



Monitoring:
Clinical monitoring should be instituted. ^{{230} {235} {236} {237}}



Supportive care:
Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Histamine H ₂-receptor Antagonists (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to any of the H ₂-receptor antagonists

Pregnancy—All cross placenta





Breast-feeding—Cimetidine, famotidine, nizatidine, and ranitidine are distributed into breast milk; nursing is not recommended during cimetidine therapy, because of high concentration in breast milk





Use in the elderly—Confusion more likely with cimetidine, famotidine, and ranitidine in elderly patients with impaired hepatic or renal function
Other medications, especially itraconazole, ketoconazole (with all histamine H ₂-receptor antagonists); anticoagulants, metoprolol, phenytoin, xanthines (with cimetidine and possibly ranitidine only); propranolol or tricyclic antidepressants (with cimetidine only)
Other medical problems, especially renal function impairment

Proper use of this medication
For patients taking nonprescription strengths: not taking maximum daily dose continuously for more than 2 weeks unless directed by physician; seeing physician promptly if having trouble swallowing or persistent abdominal pain

Dosing schedule for patients taking prescription strengths:

• 1 dose a day—Taking at bedtime


• 2 doses a day—Taking in the morning and at bedtime


• Several doses a day—Taking with meals and at bedtime


For patients taking famotidine chewable tablets, chewing the tablet well before swallowing

For patients taking famotidine oral disintegrating tablets: leave tablets in unopened package until the time of use, then open pack with dry hands and place tablet on the tongue to dissolve and be swallowed with saliva. ^{235}

For patients taking ranitidine effervescent granules or tablets, removing foil wrapping and dissolving dose in 6 to 8 ounces of water before drinking

Taking antacids for relief of ulcer pain; not taking within one-half to one hour of histamine H ₂-receptor antagonists

» Compliance with full course of therapy

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses

» Proper storage

Precautions while using this medication
Possible interference with gastric acid secretion tests or skin tests using allergens; need to inform physician of use of medication

Avoiding use of foods, drinks, or other medication that may cause gastrointestinal irritation

Discontinuing smoking or at least avoiding smoking after last dose of day ^{16}

Avoiding alcoholic beverages

Checking with physician if condition does not improve or worsens ^{16}


Side/adverse effects
Signs of possible side effects, especially cardiac arrhythmias, dermatologic reactions, fever, hematologic effects, hepatic effects, hypersensitivity reactions, mood or mental changes, myalgia, arthralgia, pancreatitis, asthenia, fatigue, palpitations, amblyopia, anemia, hyperuricemia, increased cough, infection, pain, serum sickness, blurred vision, premature ventricular beats


General Dosing Information
Use of histamine H ₂-receptor antagonists in the treatment of duodenal ulcer rarely continues beyond 8 weeks, since no long-term, carefully monitored studies have been done with these medications. Also, most patients taking histamine H ₂-receptor antagonists heal within 6 to 8 weeks.

Although the symptoms of duodenal ulcers may subside within 1 or 2 weeks after initiation of therapy, treatment should be continued for at least 4 to 6 weeks, unless healing has been documented by endoscopic examination or x-rays ^{11}.

Histamine H ₂-receptor antagonists may be used, in reduced doses, to prevent ulcer recurrence. However, until consequences of very long term use are fully determined, such use should be limited to patients likely to need surgical treatment, patients with concomitant illnesses in whom surgery would constitute a greater-than-usual risk ^{197}, and patients with recurrent ulcers ^{196}.

Initial titration of doses and subsequent dosage adjustment of histamine H ₂-receptor antagonists is recommended in the long-term treatment of pathological hypersecretory conditions (e.g., Zollinger-Ellison syndrome, systemic mastocytosis, multiple endocrine adenomas). Doses of cimetidine should generally not exceed 2.4 grams per day; however, doses up to 12 grams per day have been used. Up to 160 mg of famotidine every 6 hours and up to 6 grams of ranitidine per day have been administered to some patients with severe Zollinger-Ellison syndrome.

The efficacy of histamine H ₂-receptor antagonists in inhibiting nocturnal gastric acid secretion may be decreased by cigarette smoking. Patients with peptic ulcer disease should discontinue smoking, ^{{105} {172}} or at least avoid smoking after their last dose of the day.

Dosage of histamine H ₂-receptor antagonists may need to be increased in burn patients to achieve adequate control of gastric pH, because of enhanced clearance of histamine H ₂-receptor antagonists in these patients. Individualization of dosage should be based on monitoring of gastric pH and/or plasma concentrations of histamine H ₂-receptor antagonists since their clearance varies in proportion to burn size. ^{{03} {135}}

No dosage adjustment of histamine H ₂-receptor antagonists is necessary for hemodialysis and peritoneal dialysis patients, since only small amounts of the medications are removed. ^{{08} {74}}

For oral dosage forms only
In the treatment of peptic ulcer and other hypersecretory conditions, optimal therapeutic effect is obtained when histamine H ₂-receptor antagonists are taken with meals and at bedtime. ^{170} By administering histamine H ₂-receptor antagonists with meals, maximum serum concentrations and antisecretory effects are achieved when the stomach is no longer protected by the buffering capacity of the food. ^{20} However, more recent information indicates that ulcer healing rates may be greatest with a bedtime-only dosage regimen. ^{74}

If required, antacids of standard neutralizing capacity (e.g., 13 mEq per 15 mL) may be administered concurrently with histamine H ₂-receptor antagonists for the relief of pain. However, spacing of doses one-half to one hour apart is recommended, especially with antacids of greater neutralizing capacity, since absorption of histamine H ₂-receptor antagonists may be decreased. ^{{01} {52} {79} {80} {81} {82}}

For parenteral dosage forms only
Parenteral administration may be indicated in hospitalized patients with pathological hypersecretory disorders or intractable ulcers, or in patients who are unable to take oral medication.

Rapid intravenous bolus administration of cimetidine, famotidine, or ranitidine is not recommended because it may increase the risk of cardiac arrhythmias and hypotension. ^{{19} {23}}

Diet/Nutrition
Patients with phenylketonuria (PKU) should be informed that the chewable tablet form of Pepcid AC brand of famotidine contains 1.4 mg of phenylalanine per 10-mg dose, the oral disintegrating tablet form of Pepcid RPD brand of famotidine contains 1.05 mg of phenylalanine per 20-mg dose ^{244}, and the EFFERdose granule and the EFFERdose tablet forms of the Zantac brand of ranitidine contain 16.84 mg of phenylalanine per 150-mg dose. ^{230}

CIMETIDINE
Summary of Differences


Indications:
Also used in treatment of pancreatic insufficiency and as a treatment adjunct in acute urticaria.



Pharmacology/pharmacokinetics:
Other actions/effects—Inhibits hepatic cytochrome P450 and P448 mixed function oxidase (microsomal enzyme) systems; possesses antiandrogenic activity; increases prolactin concentration (with IV bolus injection); enhances gastromucosal defense and healing in stress-induced ulceration and bleeding.



Precautions:
Drug interactions and/or related problems—May interact with alcohol, anticoagulants, tricyclic antidepressants, benzodiazepines, glipizide, glyburide, metoprolol, metronidazole, phenytoin, propranolol, xanthines, calcium channel blocking agents, cyclosporine, lidocaine, procainamide, sucralfate, quinine.

Laboratory value alterations—May increase serum prolactin concentrations; may decrease parathyroid hormone concentrations.



Side/adverse effects:
Constipation has not been reported. Bronchospasms have not been reported as a side/adverse effect with cimetidine.



Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

CIMETIDINE TABLETS USP

Usual adult and adolescent dose
Duodenal ulcer
Treatment: Oral, 300 mg four times a day, with meals and at bedtime; 400 or 600 mg two times a day, in the morning and at bedtime; or 800 mg at bedtime. ^{{54} {130}}

Note: A 1600-mg dose of cimetidine at bedtime has been found to produce a more rapid healing in some ulcer patients who have an endoscopically demonstrated ulcer larger than 1 cm and are also heavy smokers. ^{130}


Prophylaxis of recurrent duodenal ulcer: Oral, 300 mg two times a day, in the morning and at bedtime; or 400 mg at bedtime. Patients have been maintained on continued treatment with 400 mg at bedtime for periods of up to five years. ^{{54} {130}}

Gastric ulcer, benign, active
Oral, 300 mg four times a day, with meals and at bedtime; or 600 mg two times a day, in the morning and at bedtime; or 800 mg at bedtime. ^{{54} {130}}

Heartburn, acid indigestion, and sour stomach
Treatment: Oral, 200 mg with water as symptoms occur; dose may be repeated once in twenty-four hours ^{222}

Prophylaxis: Oral, 100 to 200 mg with water up to one hour before consuming food or beverages expected to cause symptoms ^{{222} {231}}

Gastric hypersecretory conditions (e.g., Zollinger-Ellison syndrome, systemic mastocytosis, multiple endocrine adenomas)
Oral, 300 mg four times a day, with meals and at bedtime, the dosage being adjusted as needed, and therapy continued for as long as clinically indicated. ^{130}

Gastroesophageal reflux
Oral, 800 to 1600 mg per day in divided doses for 12 weeks. ^{{77} {78} {130}}

Upper gastrointestinal bleeding
Oral, 300 mg every six hours; or 600 mg two times a day, in the morning and at bedtime.


Note: For patients with impaired renal function—Oral, 300 mg every twelve hours, the dosage being increased to 300 mg every eight hours or more frequently, if necessary. Further reduction in dosage may be required if hepatic function impairment is also present. ^{130}


Usual adult prescribing limits
Up to 2.4 grams daily ^{130}; however, doses up to 12 grams per day have been used in the treatment of pathological hypersecretory conditions.

Usual pediatric dose
Duodenal ulcer; or
Gastric ulcer
Oral, 20 to 40 mg per kg of body weight a day in divided doses four times a day, with meals and at bedtime. ^{{171} {198}}

Gastroesophageal reflux
Oral, 40 to 80 mg per kg of body weight a day in divided doses four times a day. ^{208}


Note: In certain circumstances, doses may be titrated based on gastric pH. ^{212}
Clinical experience with the use of cimetidine in children up to 16 years of age is limited; risk-benefit must be considered.
In children with impaired renal function, dosage should be reduced to 10 to 15 mg per kg of body weight a day, and the dosing interval increased to eight hours. ^{{21} {22}}


Usual geriatric dose
See Usual adult and adolescent dose .

Strength(s) usually available
U.S.—


100 mg (OTC) [Tagamet HB][Generic]


200 mg (OTC) [Tagamet HB 200][Generic]


200 mg (Rx) [Tagamet (film-coated)][Generic]


300 mg (Rx) [Tagamet (film-coated)][Generic]


400 mg (Rx) [Tagamet (film-coated)][Generic]


800 mg (Rx) [Tagamet (film-coated)][Generic]

Canada—


100 mg (OTC) [Apo-Cimetidine (film-coated)]


200 mg (Rx) [Apo-Cimetidine (film-coated)] [Gen-Cimetidine (film-coated)] [Novo-Cimetine (scored; film-coated)] [Nu-Cimet ( film-coated)] [PMS-Cimetidine (film-coated)][Generic]


300 mg (Rx) [Apo-Cimetidine (film-coated)] [Gen-Cimetidine (film-coated )] [Novo-Cimetine (scored; film-coated)] [Nu-Cimet (film-coated)] [Peptol ( film-coated)] [PMS-Cimetidine (film-coated)] [Tagamet (film-coated)][Generic]


400 mg (Rx) [Apo-Cimetidine (film-coated)] [Gen-Cimetidine (film-coated )] [Novo-Cimetine (scored; film-coated)] [Nu-Cimet (film-coated)] [Peptol ( film-coated)] [PMS-Cimetidine (film-coated)] [Tagamet (film-coated)][Generic]


600 mg (Rx) [Apo-Cimetidine (film-coated)] [Gen-Cimetidine (film-coated )] [Novo-Cimetine (scored; film-coated)] [Nu-Cimet (film-coated)] [Peptol] [PMS-Cimetidine (film-coated)] [Tagamet (film-coated)][Generic]


800 mg (Rx) [Apo-Cimetidine (film-coated)] [Gen-Cimetidine (film-coated )] [Novo-Cimetine (scored; film-coated)] [Peptol] [PMS-Cimetidine (film-coated)][Generic]

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), in a tight, light-resistant container.

Auxiliary labeling:
   • Continue medicine for full time of treatment.

Note: Tablets have a characteristic odor, which does not represent any risk to the patient.



CIMETIDINE HYDROCHLORIDE ORAL SOLUTION

Note: The dosing and strengths of the dosage forms available are expressed in terms of cimetidine base (not the hydrochloride salt).


Usual adult and adolescent dose
See Cimetidine Tablets USP.

Usual adult prescribing limits
See Cimetidine Tablets USP .

Usual pediatric dose
See Cimetidine Tablets USP .

Usual geriatric dose
See Usual adult and adolescent dose .

Strength(s) usually available
U.S.—


300 mg (base) per 5 mL (Rx) [Tagamet (light orange, mint-peach flavored) (alcohol 2.8%)][Generic]

Canada—


300 mg (base) per 5 mL (Rx) [Tagamet (light orange, bittersweet melon-pineapple flavored) (alcohol 2.8%)]

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), in a tight, light-resistant container, unless otherwise specified by manufacturer. Protect from freezing.

Auxiliary labeling:
   • Continue medicine for full time of treatment.



Parenteral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

CIMETIDINE HYDROCHLORIDE INJECTION

Note: The dosing and strengths of the dosage forms available are expressed in terms of cimetidine base (not the hydrochloride salt).


Usual adult and adolescent dose
Duodenal ulcer or
Gastric ulcer or
Gastric hypersecretory conditions (e.g., Zollinger-Ellison syndrome, systemic mastocytosis, multiple endocrine adenomas) or
Upper gastrointestinal bleeding
Intramuscular, 300 mg (base) every six to eight hours. ^{130}

Intravenous, 300 mg (base) every six to eight hours, diluted with a compatible intravenous solution and administered over a period of not less than five minutes. ^{130}

Intravenous infusion, 300 mg (base) every six to eight hours, diluted in a compatible intravenous solution and administered over a fifteen- to twenty-minute period. ^{130}

Note: If necessary, increases in dosage should be made by more frequent administration of a 300-mg dose.


Continuous intravenous infusion, 37.5 (base) mg per hour (900 mg per day), diluted in a compatible intravenous solution. The infusion rate should be adjusted to individual patient requirements. ^{130}

Note: For patients requiring a rapid elevation of gastric pH, a loading dose of 150 mg may be administered by intravenous infusion before continuous infusion is begun. ^{130}


Prophylaxis of stress-related mucosal bleeding
Continuous intravenous infusion, 50 mg (base) per hour, diluted in a compatible intravenous solution for up to 7 days. ^{130}

Note: Patients with a creatinine clearance less than 30 mL per minute should receive 25 mg per hour. ^{130}


[Prophylaxis of aspiration pneumonitis]
Intramuscular, 300 mg (base) one hour before induction of anesthesia, and 300 mg (base) given intramuscularly or intravenously every four hours until patient responds to verbal commands. ^{22}

[Urticaria therapy adjunct ]
Intravenous, 300 mg over 15 to 20 minutes. ^{66}


Note: For patients with impaired renal function—Intravenous, 300 mg (base) every twelve hours, the dosage being increased to 300 mg every eight hours or more frequently, if necessary. Further reduction in dosage may be required if hepatic function impairment is also present. ^{130}


Usual adult prescribing limits
2.4 grams (base) daily. ^{130}

Usual pediatric dose
Duodenal ulcer or
Gastric ulcer
Intramuscular, 5 to 10 mg (base) per kg of body weight every six to eight hours.

Intravenous, 5 to 10 mg (base) per kg of body weight every six to eight hours, diluted to a suitable volume with a compatible intravenous solution and administered over a period of not less than two minutes. ^{199}

Intravenous infusion, 5 to 10 mg (base) per kg of body weight every six to eight hours, diluted to a suitable volume with a compatible intravenous solution and administered over a fifteen- to twenty-minute period. ^{199}


Note: In certain circumstances, doses may be titrated based on gastric pH. ^{212}
Clinical experience with the use of cimetidine in children up to 16 years of age is limited; risk-benefit must be considered.
In children with impaired renal function, doses should be reduced and dosing interval increased.


Usual geriatric dose
See Usual adult and adolescent dose .

Strength(s) usually available
U.S.—


300 mg (base) per 2 mL (Rx) [Tagamet][Generic]


300 mg (base) per 50 mL (premixed) (Rx) [Tagamet]

Canada—


300 mg (base) per 2 mL (Rx) [Novo-Cimetine] [Tagamet]


300 mg (base) per 50 mL (premixed) (Rx) [Tagamet]

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from light. Protect from freezing.

Preparation of dosage form:
Not for premixed dosage form

   • For intravenous use, cimetidine hydrochloride injection must be diluted prior to use with a compatible intravenous solution, such as sodium chloride injection (0.9%). ^{130}
   • For intermittent intravenous infusion, cimetidine hydrochloride injection must be diluted prior to use in 50 mL of a compatible intravenous solution, such as dextrose injection (5%). ^{130}

Stability:
Diluted solutions of cimetidine hydrochloride injection are stable for 48 hours at room temperature. ^{130}

Exposure to cold may lead to development of cloudiness. However, this is of no clinical significance, and solution clears on returning to room temperature. ^{130}

Injection should not be used if discolored or if a precipitate is present. ^{130}


FAMOTIDINE
Summary of Differences
Side/adverse effects: Loss of appetite, dryness of mouth or skin, ringing or buzzing in ears have been reported.

Bioequivalence: Famotidine tablets, oral suspension, and oral disintegrating tablets are bioequivalent ^{235}.


Oral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

FAMOTIDINE FOR ORAL SUSPENSION

Usual adult and adolescent dose
Duodenal ulcer
Treatment: Oral, 40 mg once a day at bedtime or 20 mg two times a day. ^{01}

Prophylaxis of recurrent duodenal ulcer: Oral, 20 mg at bedtime. ^{01}

Gastric ulcer, benign, active
Treatment: Oral, 40 mg once a day at bedtime. ^{01}

Gastric hypersecretory conditions (e.g., Zollinger-Ellison syndrome, systemic mastocytosis, multiple endocrine adenomas)
Oral, 20 mg every six hours, the dosage being adjusted as needed and therapy continued for as long as clinically indicated. Doses up to 160 mg every six hours have been administered to some patients with severe Zollinger-Ellison syndrome. ^{01}

Gastroesophageal reflux
Oral, 20 mg two times a day for up to six weeks. ^{235}

Note: The recommended oral dose for esophagitis due to gastroesophageal reflux disease is 20 to 40 mg two times a day for up to twelve weeks. ^{01}


[Prophylaxis of aspiration pneumonitis]
Oral, 40 mg given either the night before or the morning of surgery. ^{{131} {132}}


Note: For patients with severely impaired renal function (creatinine clearance less than 10 mL per minute)—Oral, 20 mg at bedtime. Depending on patient`s response, the dosing interval may have to be increased to thirty-six to forty-eight hours. ^{01}


Usual pediatric dose
Duodenal ulcer or
Gastric ulcer
Oral, initially 0.5 mg per kg of body weight a day, at bedtime or in two divided doses. ^{235}

Gastroesophageal reflux disease
For children weighing more than 10 kg: Oral, 1 to 2 mg per kg of body weight a day, in two divided doses. ^{{185} {200}}

For children weighing less than 10 kg: Oral, 1 to 2 mg per kg per day, in three divided doses. ^{{185} {200}}


Note: In certain circumstances, doses may be titrated based on gastric pH. ^{212}


Usual pediatric prescribing limits
40 mg a day. ^{235}

Usual geriatric dose
See Usual adult and adolescent dose.

Strength(s) usually available
U.S.—


40 mg per 5 mL (Rx) [Pepcid (cherry-banana-mint flavor) (sucrose) (sodium benzoate 0.1%) ( sodium methylparaben 0.1%) (sodium propylparaben 0.02%)]

Canada—
Not commercially available.

Packaging and storage:
Prior to constitution, store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer.

After constitution, store below 30 °C (86 °F), unless otherwise specified by manufacturer. Protect from freezing. ^{01}

Preparation of dosage form:
At time of dispensing, slowly add 46 mL of purified water. Shake vigorously for 5 to 10 seconds immediately after adding the water and immediately before use. ^{01}

Stability:
Unused oral suspension of famotidine should be discarded after 30 days. ^{{01} {235}}

Auxiliary labeling:
   • Shake well.
   • Continue medicine for full time of treatment.


FAMOTIDINE TABLETS USP

Usual adult and adolescent dose
Duodenal ulcer
Treatment: Oral, 40 mg once a day at bedtime or 20 mg two times a day. ^{01}

Prophylaxis of recurrent duodenal ulcer: Oral, 20 mg at bedtime. ^{01}

Gastric ulcer, benign, active
Treatment: Oral, 40 mg once a day at bedtime. ^{01}

Heartburn, acid indigestion, and sour stomach
Treatment: Oral, 10 mg at onset of symptoms; dose may be repeated once in twenty-four hours ^{217}

Prophylaxis: Oral, 10 mg up to one hour before consuming food or beverages expected to cause symptoms ^{217}

Gastric hypersecretory conditions (e.g., Zollinger-Ellison syndrome, systemic mastocytosis, multiple endocrine adenomas)
Oral, 20 mg every six hours, the dosage being adjusted as needed and therapy continued for as long as clinically indicated. Doses up to 160 mg every six hours have been administered to some patients with severe Zollinger-Ellison syndrome. ^{01}

Gastroesophageal reflux
Oral, 20 mg two times a day for up to six weeks. ^{235}

Note: The recommended oral dose for esophagitis due to gastroesophageal reflux disease is 20 to 40 mg two times a day for up to twelve weeks. ^{01}


[Prophylaxis of aspiration pneumonitis]
Oral, 40 mg given either the night before or the morning of surgery. ^{{131} {132}}


Note: For patients with severely impaired renal function (creatinine clearance less than 10 mL per minute)—Oral, 20 mg at bedtime. Depending on patient's response, the dosing interval may have to be increased to thirty-six to forty-eight hours ^{01}


Usual pediatric dose
See Famotidine for Oral Suspension .

Usual geriatric dose
See Usual adult and adolescent dose.

Strength(s) usually available
U.S.—


10 mg (OTC) [Mylanta AR Acid Reducer] [Pepcid AC Acid Controller]


20 mg (Rx) [Pepcid]


40 mg (Rx) [Pepcid]

Canada—


10 mg (OTC) [Acid Control (film-coated)] [Act (film-coated)] [Apo-Famotidine] [Dyspep HB (film-coated)] [Gen-Famotidine] [Maalox H2 Acid Controller (film-coated )] [Pepcid AC (film-coated)] [Ulcidine-HB]


20 mg (Rx) [Apo-Famotidine (film-coated)] [Gen-Famotidine (film-coated)] [Novo-Famotidine (film-coated)] [Nu-Famotidine (film-coated)] [Pepcid (film-coated )] [Ulcidine (film-coated)][Generic]


40 mg (Rx) [Apo-Famotidine (film-coated)] [Gen-Famotidine (film-coated)] [Novo-Famotidine (film-coated)] [Nu-Famotidine (film-coated)] [Pepcid (film-coated )] [Ulcidine (film-coated)][Generic]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a well-closed container, unless otherwise specified by manufacturer. Protect from light.

Auxiliary labeling:
   • Continue medicine for full time of treatment.


FAMOTIDINE TABLETS (CHEWABLE)

Usual adult and adolescent dose
See Famotidine Tablets USP .

Usual pediatric dose
See Famotidine for Oral Suspension .

Usual geriatric dose
See Famotidine Tablets USP .

Strength(s) usually available
U.S.—


10 mg (OTC) [Pepcid AC (phenylalanine 1.4 mg)]

Canada—


10 mg (OTC) [Pepcid AC (aspartame)]

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), in a well-closed container, unless otherwise specified by manufacturer. ^{233}

Auxiliary labeling:
   • Chew tablets well before swallowing.


Caution:
Pepcid AC brand of chewable tablets contain aspartame, which is metabolized to phenylalanine and must be used with caution in patients with phenylketonuria. ^{245}


FAMOTIDINE ORAL DISINTEGRATING TABLETS

Note: Pepcid RPD brand of oral disintegrating tablets rapidly disintegrate on the tongue and do not require water to aid dissolution or swallowing. ^{235}


Usual adult and adolescent dose
See Famotidine Oral Tablets .

Usual pediatric dose
See Famotidine Oral Suspension .

Usual geriatric dose
See Famotidine Oral Tablets .

Strength(s) usually available
U.S.—


20 mg (Rx) [Pepcid RPD (phenylalanine 1.05 mg) (mint flavor)]


40 mg (Rx) [Pepcid RPD (phenylalanine 2.1 mg) ( mint flavor)]

Canada—
Not commercially available.

Packaging and storage:
Store between 2 and 30 °C (36 and 86 °F), unless otherwise specified by manufacturer. Protect from light.

Auxiliary labeling:
   • Continue medicine for full time of treatment.


Caution:
Pepcid RPD brand of oral disintegrating tablets contain aspartame, which is metabolized to phenylalanine and must be used with caution in patients with phenylketonuria. ^{235}

Additional information:
Proper handling/administration—With dry hands, peel back the foil backing of one blister. Gently remove the tablet and place it immediately on top of the tongue. It will dissolve in seconds, and should then be swallowed with saliva.



Parenteral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

FAMOTIDINE INJECTION

Usual adult and adolescent dose
Duodenal ulcer or
Gastric ulcer, benign, active or
Gastric hypersecretory conditions (e.g., Zollinger-Ellison syndrome, systemic mastocytosis, multiple endocrine adenomas)
Intravenous, 20 mg every twelve hours, diluted with a compatible intravenous solution and administered over a period of not less than two minutes. ^{01}

Intravenous infusion, 20 mg every twelve hours, diluted with a compatible intravenous solution and administered ov