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CIMETIDINE AND RELATED DRUGS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Histamine-2 (H2) receptor antagonists competitively inhibit the interaction of histamine with H2 receptors. They are highly selective and have little or minimal effect on H1 or other receptors. H2 antagonists mainly interfere with gastric secretion, although they exert inhibitory effects on the cardiovascular and other systems affected by H2 receptors.

Specific Substances

    A) CIMETIDINE
    1) 2-Cyano-1-methyl-3-(2-(5-methylimidazol-4-
    2) ylmethylthio) ethyl)guanidine
    3) SKF 92334
    4) CAS 51481-61-9
    FAMOTIDINE
    1) 3-(((2-((aminoiminomethyl)-amino)-4-thiazolyl)
    2) methyl)-thio)-N-(aminosulfonyl)-propanimidamide
    3) L-643341
    4) MK-208
    5) YM-11170
    6) CAS 76824-35-6
    NIZATIDINE
    1) 1,1-ethenediamine,N-(2-(((2-((dimethylamino)methyl)-4-
    2) thiazolyl)methyl)thio)ethyl)N-methyl-2-nitro.
    3) N-(2-(2-((dimethylamino)methyl))-4-thiazolyl methyl
    4) thio)-ethyl)-N-methyl-2-nitro-1,1-ethenediamine.
    5) LY 139037
    6) CAS 76963-41-2
    RANITIDINE
    1) AH 19065 (hydrochloride)
    2) N,N-Dimethyl-5-(2-(1-methylamino-2-nitrovinylamino)-
    3) ethylthiomethyl)furfurylamine
    4) CAS 66357-35-5
    ROXATIDINE ACETATE HYDROCHLORIDE
    1) 2-acetoxy-N-(3-(m-(1-piperidinylmethyl)phenoxy)
    2) propyl) acetamide hydrochloride
    3) HOE-062 (roxatidine)
    4) HOE-760 (roxatidine acetate hydrochloride)
    5) pifatidine
    6) TZU-0460 (roxatidine acetate hydrochloride)
    7) CAS 97900-88-4 (roxatidine)
    8) CAS 78628-28-1 (roxatidine acetate)
    9) CAS 93793-83-0 (roxatidine acetate hydrochloride)
    GNERAL TERMS
    1) H2 Antagonist
    2) H2 Antagonists

    1.2.1) MOLECULAR FORMULA
    1) CIMETIDINE HYDROCHLORIDE: C10H16N6S-HCl
    2) FAMOTIDINE: C8H15N7O2S3
    3) NIZATIDINE: C12H21N5O2S2
    4) RANITIDINE HYDROCHLORIDE: C13H22N4O3S-HCl

Available Forms Sources

    A) FORMS
    1) CIMETIDINE
    a) Tablets - 100 mg, 200 mg, 300 mg, 400 mg, and 800 mg
    b) Liquid - 300 mg/5 mL
    c) Injection - 300 mg/2 mL and 300 mg/50 mL normal saline
    2) FAMOTIDINE
    a) Tablets - 10 mg, 20 mg, and 40 mg
    b) Powder for oral suspension - 40 mg/5 mL
    c) Injection - 10 mg/mL (contains 0.9% benzyl alcohol)
    3) NIZATIDINE
    a) Capsules - 150 and 300 mg
    4) RANITIDINE
    a) Tablets - 150 mg and 300 mg
    b) Syrup - 15 mg/mL
    c) Injection - 25 mg/mL and 0.5 mg/mL in 100 mL

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: H2 histamine blockers (or H2 blockers) are available as prescription and non-prescription medications and are used to treat reflux esophagitis, heartburn, and peptic ulcers.
    B) PHARMACOLOGY: Antagonist of H2 histamine receptors. This effect decreases gastric acid secretion.
    C) TOXICOLOGY: Cimetidine inhibits the cytochrome P450 oxidase enzymes, 1A2, C219, and 2D6, and decreases the metabolism of many other medications.
    D) EPIDEMIOLOGY: Exposures to H2 blockers are common, but significant toxicity has not been described. Adverse effects during therapeutic use are rare.
    E) WITH THERAPEUTIC USE
    1) Dry mouth, delirium, and bone marrow suppression have been reported. Bradycardia and conduction effects are rare effects occurring mostly after rapid IV administration.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Mild drowsiness, dizziness or confusion.
    2) SEVERE TOXICITY: Severe toxicity is exceedingly rare. CNS depression and hypotension have been reported.
    0.2.3) VITAL SIGNS
    A) WITH THERAPEUTIC USE
    1) Hyperpyrexia and hypotension have been reported with therapeutic use.
    0.2.5) CARDIOVASCULAR
    A) WITH THERAPEUTIC USE
    1) Bradycardia, hypotension, AV block and sinus arrest (mainly following rapid IV administration) have been reported.
    2) Two severely ill patients developed QT prolongation and episodes of torsades de pointes following famotidine administration.
    0.2.6) RESPIRATORY
    A) WITH THERAPEUTIC USE
    1) Respiratory depression may rarely occur.
    0.2.7) NEUROLOGIC
    A) WITH THERAPEUTIC USE
    1) Confusion, disorientation, or delirium with dizziness, drowsiness, and slurred speech, have all been reported. Visual hallucinations, CNS depression, seizures, and coma have occurred. Dystonia and chorea have been reported.
    0.2.9) HEPATIC
    A) WITH THERAPEUTIC USE
    1) Liver enzyme elevations have been noted, probably due to an allergic reaction.
    2) Hepatitis and hepatic failure have occurred with therapeutic use of H2-receptor antagonists.
    0.2.10) GENITOURINARY
    A) WITH THERAPEUTIC USE
    1) Reversible renal failure has been reported with therapy
    0.2.13) HEMATOLOGIC
    A) WITH THERAPEUTIC USE
    1) Agranulocytosis, pancytopenia, aplastic anemia, and thrombocytopenia may occur following therapeutic doses of cimetidine and other H2-receptor antagonists.
    0.2.14) DERMATOLOGIC
    A) WITH THERAPEUTIC USE
    1) Dermatitis, vasculitis, urticaria, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), and psoriasis have been reported with the use of H2 blockers.
    0.2.15) MUSCULOSKELETAL
    A) WITH THERAPEUTIC USE
    1) Cimetidine and ranitidine may rarely cause a toxic myopathy.
    0.2.16) ENDOCRINE
    A) WITH THERAPEUTIC USE
    1) Gynecomastia and increased prolactin levels may be seen following therapeutic doses of cimetidine. With the other H2 receptor antagonists these effects are less common.
    B) WITH POISONING/EXPOSURE
    1) Gynecomastia and increased prolactin levels may be seen following overdose of cimetidine. With the other H2 receptor antagonists these effects are less common.
    0.2.18) PSYCHIATRIC
    A) H2 receptor antagonist-induced psychosis has been reported.
    0.2.20) REPRODUCTIVE
    A) CIMETIDINE, FAMOTIDINE, NIZATIDINE, and RANITIDINE are classified as FDA pregnancy category B. CIMETIDINE crosses the placental barrier. Spontaneous abortions have been seen in women taking ranitidine. However, cohort studies did not find any associations between H2-blocker during the first trimester exposure and congenital abnormalities.
    0.2.21) CARCINOGENICITY
    A) There is no evidence of carcinogenicity in humans with cimetidine.
    0.2.22) OTHER
    A) WITH THERAPEUTIC USE
    1) RANITIDINE reportedly has less CNS penetration, and fewer endocrine and cardiovascular effects than cimetidine.
    2) Isolated cases of bradycardia due to IV administration have been reported.
    3) Sexual impotence, gynecomastia, hallucinations, and delirium have been reported with oral ingestions.
    4) Interactions with cimetidine occurs with much greater frequency than with the other H2 receptor antagonists due to more extensive binding of cimetidine with microsomal cytochrome P450.

Laboratory Monitoring

    A) No specific laboratory testing is indicated in most patients.
    B) Obtain a basic metabolic screen and serum acetaminophen and salicylate concentrations after deliberate overdose.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Intravenous fluids for hypotension, supportive care for CNS depression.
    C) DECONTAMINATION
    1) PREHOSPITAL: No prehospital decontamination is recommended.
    2) HOSPITAL: No decontamination is warranted in most cases.
    D) AIRWAY MANAGEMENT
    1) Rare cases with significant CNS depression may require intubation for airway protection.
    E) ANTIDOTE
    1) None
    F) ENHANCED ELIMINATION
    1) Enhanced elimination is not indicated.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: Patients inadvertent ingestions can be managed at home. All patients with self-harm ingestions should be sent to a healthcare facility for mental health evaluation.
    2) OBSERVATION CRITERIA: Patients with deliberate overdose or more than mild symptoms should be referred to a healthcare facility and observed until symptoms resolve.
    3) ADMISSION CRITERIA: Patients with significant CNS depression or other symptoms that persist after 6 to 8 hours of observation should be admitted, but this is exceedingly rare.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance if symptoms are more than mild or if the diagnosis is unclear.
    H) PITFALLS
    1) Severe toxicity is exceedingly rare; the biggest risk is overtreatment. A careful medication history should be obtained to evaluate for potential drug interactions.
    I) PHARMACOKINETICS
    1) For all drugs in this class, peak plasma levels occur 0.5 to 3 hours after ingestion, approximately 20% to 30% of the drug is protein bound, and the volumes of distribution are 0.5 to 2 L/kg. All have some hepatic metabolism (approximately 50%) and 25% to 50% is excreted renally as unchanged drug. Cimetidine is an inhibitor of cytochrome P450 1A2, 2C19, and 2D6 enzymes.
    J) DIFFERENTIAL DIAGNOSIS
    1) H1 blockers, other medications that may cause sedation.

Range Of Toxicity

    A) TOXICITY: These medications have a large therapeutic window and no more than minimal toxicity is expected even with very large overdoses.
    B) THERAPEUTIC DOSE: CIMETIDINE: ADULT: 400 to 1600 mg/day orally; PEDIATRIC: 20 to 40 mg/kg/day orally. FAMOTIDINE: ADULT: 20 to 80 mg/day orally; PEDIATRIC: 0.5 to 2 mg/kg/day orally. RANITIDINE: ADULT: 150 to 300 mg/day orally; PEDIATRIC: 2 to 10 mg/kg/day orally, divided in 2 to 4 doses.

Clinical Effects

Summary Of Exposure

    A) USES: H2 histamine blockers (or H2 blockers) are available as prescription and non-prescription medications and are used to treat reflux esophagitis, heartburn, and peptic ulcers.
    B) PHARMACOLOGY: Antagonist of H2 histamine receptors. This effect decreases gastric acid secretion.
    C) TOXICOLOGY: Cimetidine inhibits the cytochrome P450 oxidase enzymes, 1A2, C219, and 2D6, and decreases the metabolism of many other medications.
    D) EPIDEMIOLOGY: Exposures to H2 blockers are common, but significant toxicity has not been described. Adverse effects during therapeutic use are rare.
    E) WITH THERAPEUTIC USE
    1) Dry mouth, delirium, and bone marrow suppression have been reported. Bradycardia and conduction effects are rare effects occurring mostly after rapid IV administration.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Mild drowsiness, dizziness or confusion.
    2) SEVERE TOXICITY: Severe toxicity is exceedingly rare. CNS depression and hypotension have been reported.

Vital Signs

    3.3.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Hyperpyrexia and hypotension have been reported with therapeutic use.
    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) HYPERPYREXIA: Cimetidine, ranitidine, and famotidine have been associated with drug-induced fever, which typically resolves within 48 to 72 hours after discontinuation of the drug. The mechanism is thought to be CNS histamine receptor blockade (Norwood et al, 1990; Kavanagh et al, 1993; Chia et al, 1994).
    3.3.4) BLOOD PRESSURE
    A) WITH THERAPEUTIC USE
    1) HYPOTENSION has occurred following IV administration of cimetidine. This may be due to the rapid administration of cimetidine (Mahon & Kolton, 1978; Heining et al, 1983).
    3.3.5) PULSE
    A) WITH THERAPEUTIC USE
    1) TACHYCARDIA was reported following IV injection of cimetidine (Dickey & Symington, 1987).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) OPTIC NEUROPATHY was reported in two patients approximately 1 week after beginning cimetidine therapy, 1 gram daily. Both patients presented with progressive vision loss and optic pain bilaterally. Ophthalmic examinations revealed painful eye movements and swollen optic disks. Leakage of both optic disks were detected via fluorescein angiography. Following discontinuation of cimetidine, symptoms resolved and visual acuity improved in both patients. Rechallenge with cimetidine, 1 gram daily, in one patient resulted in a recurrence of eye symptoms and deterioration of visual acuity 1 week later. The patient again recovered following discontinuation of cimetidine therapy (Sa'adah et al, 1999).
    3.4.6) THROAT
    A) WITH THERAPEUTIC USE
    1) CASE REPORT/ PAROTITIS: A 60-year-old woman developed parotitis following cimetidine and ranitidine. When H2 receptor antagonists were discontinued the parotitis regressed completely (Caraman et al, 1986).

Cardiovascular

    3.5.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Bradycardia, hypotension, AV block and sinus arrest (mainly following rapid IV administration) have been reported.
    2) Two severely ill patients developed QT prolongation and episodes of torsades de pointes following famotidine administration.
    3.5.2) CLINICAL EFFECTS
    A) CARDIOVASCULAR FINDING
    1) WITH THERAPEUTIC USE
    a) Cimetidine and related drugs have been associated with sinus bradycardia, first-degree and complete atrioventricular block, hypotension, wide-complex tachycardia, and cardiac arrest after both oral and intravenous doses. Sinus bradycardia is the most frequently reported cardiovascular effect (Cohen et al, 1989).
    B) BRADYCARDIA
    1) WITH THERAPEUTIC USE
    a) CIMETIDINE
    1) Severe bradycardia has been reported following both oral and intravenous therapeutic doses of cimetidine (Jefferys & Vale, 1978; Reding et al, 1977; Al-Waili & Hasan, 1992).
    b) RANITIDINE
    1) Bradycardia has been reported with both oral and IV ranitidine (Camarri et al, 1982). Bradycardia occurred in a 4-year-old child chronically taking ranitidine 8 mg/kg orally for ten months (Balestrazzi et al, 1985).
    2) CASE REPORT: Nahum et al (1993) described the occurrence of bradycardia (60 beats/min with normal axis and QRS complex) in a 4-day-old neonate 2 hours following an IV dose of 1 mg/kg of ranitidine (Nahum et al, 1993).
    c) FAMOTIDINE
    1) CASE REPORT: Sinus bradycardia, associated with second-degree AV block and confirmed by rechallenge, was reported in a 40-year-old man 3 weeks after initiation of famotidine therapy 40 mg/day (Ahmad, 1991).
    2) CASE SERIES: Famotidine 40 mg for one week produced an increase in pre-ejection period and pre-ejection period/left-ventricular ejection in 12 healthy volunteers in a placebo controlled trial (Kirch et al, 1987).
    3) Berlin (1987) reported similar trials using intravenous famotidine that demonstrated no clinically significant negative inotropic effects (Berlin, 1987).
    C) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) CIMETIDINE: Hypotension has been noted following rapid IV infusion. IV administration of 200 mg cimetidine over 5 to 10 seconds resulted in a rapid fall in mean arterial pressure which peaked at 1.5 minutes after administration and then returned to normal at 5 minutes (Heining et al, 1983). This may be due to a histamine agonist effect of cimetidine, especially in critically ill patients. This may be blocked by diphenhydramine (Omote et al, 1991).
    1) CASE REPORT: Two patients receiving repeated doses of cimetidine (300 to 600 mg) IV over 4 to 5 minutes developed hypotension (Mahon & Kolton, 1978).
    D) CARDIAC ARREST
    1) WITH THERAPEUTIC USE
    a) CIMETIDINE
    1) Cardiac arrest has occurred following therapeutic IV administration of cimetidine (Shaw et al, 1980; Cohen et al, 1979; Hulisz et al, 1993).
    2) CASE REPORT: A previously healthy 48-year-old man and a 56-year-old man with no previous history of heart disease became profoundly hypotensive after receiving four 400 mg PO doses and one 400 mg IV dose of cimetidine, respectively.
    a) Both hypotensive episodes were followed shortly by sinus arrest (Cohen et al, 1979).
    b) FAMOTIDINE
    1) CASE REPORT: Cardiac arrest secondary to third-degree AV block was reported in a 59-year-old man after an intravenous therapeutic dose of famotidine. On rechallenge the next day, another episode of third-degree AV block occurred 45 minutes following the famotidine dose (Schoenwald et al, 1999).
    c) RANITIDINE
    1) CASE REPORT: Cardiac arrest was reported during infusion of the fifth dose of ranitidine 50 mg IV in a 47-year-old man with no history of cardiac abnormalities (Hart, 1989).
    2) WITH POISONING/EXPOSURE
    a) CIMETIDINE
    1) CASE REPORT: Severe bradycardia, hypotension, and death were reported in a 38-year-old woman following acute oral diazepam and cimetidine overdose (Hiss et al, 1982).
    a) At necropsy, the blood level of diazepam was 5.8 mcg/mL (therapeutic 0.5 to 2.5); digoxin was 0.2 ng/mL, and cimetidine was 110 mcg/mL (therapeutic 0.25 to 0.5).
    E) TACHYARRHYTHMIA
    1) WITH THERAPEUTIC USE
    a) CIMETIDINE
    1) Tachycardia has been reported following IV injection of cimetidine (Dickey & Symington, 1987).
    F) ATRIOVENTRICULAR BLOCK
    1) WITH THERAPEUTIC USE
    a) CIMETIDINE
    1) CASE REPORT: First-degree atrioventricular block (prolonged PQ interval) occurred one hour after administration of a single tablet of cimetidine 200 mg.
    a) The cimetidine concentration in plasma at the time of the tracing was 0.11 mcg/mL. This ECG finding resolved over 24 hours (Ishizaki et al, 1987).
    2) Complete atrioventricular block has been associated with long-term cimetidine therapy (Tordjman et al, 1984).
    b) FAMOTIDINE
    1) CASE REPORT: Third-degree AV block and cardiac arrest were reported in a 59-year-old man following a postoperative intravenous dose of famotidine. Third-degree AV block recurred the following day after a subsequent dose (Schoenwald et al, 1999).
    c) RANITIDINE
    1) CASE REPORT: A case of increase in AV block leading to syncope has been described in an 81-year-old man. The patient, with pre-existing AV block, presented to the ED with atrial flutter and prolonged R-R interval after 5 months of therapeutic ranitidine (Radhamanohar, 1993).
    G) VENTRICULAR ARRHYTHMIA
    1) WITH THERAPEUTIC USE
    a) CIMETIDINE
    1) CASE REPORT: Intravenous cimetidine has been associated with ventricular tachycardia and fibrillation in one case (MacMahon et al, 1981). Both in this case and another patient with sinus bradycardia, a prolonged QT interval was noted (Cohen et al, 1989).
    H) TORSADES DE POINTES
    1) WITH THERAPEUTIC USE
    a) FAMOTIDINE
    1) CASE REPORTS: Two patients developed QTc prolongation and episodes of torsades de pointes following famotidine administration. The first patient, a 92-year-old man with a history of diabetes, cardiovascular disease and sick sinus syndrome (with a ventricular paced rhythm at a rate of 60 bpm) was admitted with an acute myocardial infarction. After admission, famotidine 20 mg (via an NG tube) was started. Following two doses, the QTc became markedly prolonged at 618 ms (admission ECG was a paced rhythm at 60 bpm and a QTc of 439 ms). The QTc remained prolonged and transient episodes of self-terminating torsades de pointes occurred. On hospital day 5, famotidine was stopped and there were no further episodes of torsades; four days after discontinuation the QTc had returned to baseline (Lee et al, 2004)
    2) The second patient was a 50-year-old man with a history of congestive heart failure and valvular heart disease that underwent mitral and aortic valve replacement. Following surgery the patient was started on 20 mg of famotidine and within four hours developed a junctional escape rhythm and the QTc was markedly prolonged at 596 ms. He developed an episode of torsades that was terminated with cardioversion, and several more self-terminating episodes occurred. The QTc gradually returned to baseline after drug cessation (Lee et al, 2004).
    a) Although both patients were severely ill, the authors concluded that the onset of signs and symptoms, along with the resolution of marked QT prolongation and episodes of torsades after famotidine was discontinued, suggested a close temporal association. In both cases the patients had normal electrolyte levels. No other known drugs to produce ECG changes were administered with the exception of fentanyl (surgical patient only)(Lee et al, 2004).

Respiratory

    3.6.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Respiratory depression may rarely occur.
    3.6.2) CLINICAL EFFECTS
    A) ACUTE RESPIRATORY INSUFFICIENCY
    1) WITH THERAPEUTIC USE
    a) CIMETIDINE
    1) CASE REPORT: Bostrom et al (1982) reported a 74-year-old man who received 50 mg IV cimetidine and became disoriented, somnolent, and developed Cheyne-Stokes respirations (Bostrom et al, 1982).
    2) CASE REPORT: A 46-year-old man chronically taking trifluoperazine and hydroxyzine developed CNS and respiratory depression after ingesting approximately 60 cimetidine tablets (Wilson, 1979).

Neurologic

    3.7.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Confusion, disorientation, or delirium with dizziness, drowsiness, and slurred speech, have all been reported. Visual hallucinations, CNS depression, seizures, and coma have occurred. Dystonia and chorea have been reported.
    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM DEFICIT
    1) WITH THERAPEUTIC USE
    a) CIMETIDINE
    1) CNS disturbances may occur with therapeutic or overdoses of all the H2 receptor antagonists, but is reported to a greater degree with cimetidine, which crosses the blood-brain barrier more readily than the other drugs in this class (Vial et al, 1991). The most common symptom reported has been confusion (Nelson, 1977; McMillan et al, 1978; Karlstadt & Palmer, 1991; Rodgers & Brengel, 1998) or delirium, dizziness, drowsiness, slurred speech, flushing, and sweating.
    2) EEG CHANGES: Cimetidine induced encephalopathy has been reported, with transient electroencephalographic changes consisting of symmetrical but irregular background activity with slow delta waves (2 to 4 m/s) and moderate cycling and an amplitude of 75 mV (Niv et al, 1986).
    3) CIMETIDINE PLASMA LEVELS: Mental confusion is more common with trough cimetidine levels in excess of 2 mcg/mL, although it has been documented in patients with lower levels (Kimelblatt et al, 1980; Schentag et al, 1979). The best correlations appear to be with CSF levels.
    b) FAMOTIDINE
    1) CASE REPORT: Two cases of confusion following intravenous famotidine therapy 20 milligrams every 12 hours were reported in elderly patients with mild renal insufficiency; onset was 2 to 3 days with resolution within one day.
    a) Both patients tolerated normal oral doses of cimetidine or ranitidine (Henann et al, 1988).
    2) CASE REPORT: Two days after being switched from ranitidine to famotidine 20 mg twice daily, a 77-year-old man developed mental status changes including confusion, restlessness, disturbing nightmares, and disorientation. After rechallenge, the patient developed confusion and visual hallucinations (Rodgers & Brengel, 1998).
    c) RANITIDINE
    1) Slugg et al (1992) have demonstrated significant CNS effects, especially lethargy, confusion, somnolence, and disorientation, occurring more frequently in patients with renal failure on ranitidine. Serum levels of ranitidine were consistently higher in a case series of patients with renal failure (Slugg et al, 1992).
    2) WITH POISONING/EXPOSURE
    a) CIMETIDINE
    1) CNS toxicity has not been reported after overdose in otherwise normal patients even with high plasma cimetidine concentrations. (Illingworth & Jarvie, 1979).
    B) HALLUCINATIONS
    1) WITH THERAPEUTIC USE
    a) Hallucinations and delirium have occurred with ranitidine (Hughes, 1983; Price et al, 1985; Goff et al, 1985), cimetidine (Lesser et al, 1987), and famotidine use (Rodgers & Brengel, 1998).
    b) CIMETIDINE
    1) Visual hallucinations, brain stem dysfunction, depression, and coma have been reported with the use of cimetidine (Jenike & Levy, 1983).
    C) SEIZURE
    1) WITH THERAPEUTIC USE
    a) CIMETIDINE
    1) Widespread muscle twitching in two patients and seizures in two other patients, have been reported (Edmonds et al, 1979).
    b) FAMOTIDINE
    1) Yoshimoto et al (1994) reported 2 cases of mental deterioration and seizures in patients with renal failure following neurosurgical procedures. IV doses of 10 and 40 mg/day of famotidine had been administered prior to the seizures. The CSF concentrations of famotidine were grossly elevated in these patients (160 and 249 ng/mL) as compared to patients with no CNS signs of toxicity (Yoshimoto et al, 1994).
    D) DYSTONIA
    1) WITH THERAPEUTIC USE
    a) CIMETIDINE
    1) CASE REPORT: A 20-year-old woman developed acute dystonia 3 hours after her fifth dose of cimetidine; she had been on 300 mg four times daily (Romisher et al, 1987).
    b) RANITIDINE
    1) CASE REPORT: A 26-year-old man developed sudden onset of dystonia with opisthotonic posturing and involuntary muscle spasms of the neck, trunk, and limb muscles after 2 doses of ranitidine (150 milligrams each) (Kapur et al, 1999).
    E) CHOREOATHETOSIS
    1) WITH THERAPEUTIC USE
    a) RANITIDINE
    1) CASE REPORT: Bilateral choreiform movements were described in a 76-year-old woman following therapy with ranitidine 150 mg twice daily for one month; the movements resolved after discontinuation and then recurred after subsequent treatment with cimetidine 400 mg twice daily for 5 days (Lehmann, 1988).
    F) HEADACHE
    1) WITH THERAPEUTIC USE
    a) FAMOTIDINE
    1) The most consistent adverse reaction reported with famotidine is a severe, throbbing headache, with an incidence of up to 4.7%. This has also been reported for ranitidine. Cimetidine was tolerated in one patient who experienced this effect with famotidine (Hirsch, 1989).
    G) DISTURBANCE IN SPEECH
    1) WITH THERAPEUTIC USE
    a) RANITIDINE
    1) CASE REPORT: Drowsiness and dysarthria were reported in a 4-year-old on chronic oral ranitidine therapy (Balestrazzi et al, 1985).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) SEIZURES
    a) RATS: Nakada et al (1995) studied the neurotoxicity of cimetidine in rats with acute renal failure. At the point of seizures, the CSF concentrations were measured. Concentrations were lower in rats with induced renal failure as compared to controls, suggesting that cimetidine in CSF equilibrates rapidly with the site of action for clonic seizures (Nakada et al, 1995).
    2) CNS EFFECTS
    a) MICE: Renal dysfunction has been shown in mice to be a significant risk factor for ranitidine neurotoxicity, as a result of increased drug concentrations in the plasma and brain due to impaired renal excretion (Shimokawa et al, 1994).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) BEZOAR
    1) WITH THERAPEUTIC USE
    a) CIMETIDINE
    1) CASE SERIES: Gastrointestinal phytobezoar formation was described in 4 adult patients taking 900 to 1200 mg of cimetidine daily (Nichols, 1981). All four patients had mastication problems.
    B) CARCINOMA OF STOMACH
    1) WITH THERAPEUTIC USE
    a) RANITIDINE
    1) CASE REPORT: Rao et al (1993) reported a patient with diabetes mellitus and chronic renal failure who developed multicentric gastric carcinoid tumors following 10 months of ranitidine therapy. The authors speculate a secondary hypergastrinemia exerting a trophic effect on the gastric enterochromaffin-like cells. Serum gastrin levels dropped to normal levels following segmental gastric resection and withdrawal of ranitidine (Rao et al, 1993).

Hepatic

    3.9.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Liver enzyme elevations have been noted, probably due to an allergic reaction.
    2) Hepatitis and hepatic failure have occurred with therapeutic use of H2-receptor antagonists.
    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Liver enzyme elevation is the most frequently reported hepatic effect of H2 receptor antagonists. The LFT's typically normalizes following discontinuation of the, and may be due to a hypersensitivity reaction.
    b) FAMOTIDINE
    1) CASE REPORT: A case of mixed hepatocellular jaundice with elevated liver function tests has been reported in a 55-year-old man following one week of famotidine therapy (Ament et al, 1994).
    B) TOXIC HEPATITIS
    1) WITH THERAPEUTIC USE
    a) CIMETIDINE
    1) CASE REPORT: Cimetidine-induced cholestatic hepatitis has been reported in an 83-year-old woman (Villeneuve & Warner, 1979).
    a) She developed hepatitis following each of three challenges with oral cimetidine. Clinical features of cimetidine-induced hepatitis include anorexia, fever, and jaundice (Ruiz Del Arbol et al, 1980; Villeneuve & Warner, 1979) Zucher, 1977).
    b) RANITIDINE
    1) There are case reports which suggest an association between ranitidine use and hepatotoxicity (Ramrakhiani et al, 1998) Bredfelt & von Huene, 1984; Souza Lima, 1984; (Black et al, 1984).
    2) CASE REPORT: 29-year-old man presented with pruritus, icteric sclerae, skin excoriations, and abnormal liver enzymes after receiving ranitidine 150 mg twice daily for gastroesophageal reflux. Lab testing revealed an elevated bilirubin of 10.8 mg/dL, with mild elevation of aminotransferases. After discontinuation of the ranitidine, the patient continued to have pruritus. A liver biopsy showed evidence of cholestatic hepatitis. The patient received tapered doses of oral corticosteroids and ursodeoxycholic acid and improved gradually after 4 weeks (Ramrakhiani et al, 1998).
    3) CASE REPORT: A 66-year-old woman presented with a 1-week history of jaundice that began 2 weeks after the patient initiated daily ranitidine therapy to treat dyspepsia. Laboratory data indicated elevated liver enzyme concentrations and a liver biopsy demonstrated severe acute hepatitis with confluent and bridging necrosis. Approximately 1 month after the onset of jaundice, the patient continued to deteriorate with the development of grade II/III hepatic encephalopathy. Liver transplantation was suggested, however the patient died 2 days later with grade IV encephalopathy, severe upper gastrointestinal bleeding, and hypovolemic shock (Ribeiro et al, 2000).
    c) FAMOTIDINE
    1) CASE REPORT/ADULT: A case of famotidine-induced hepatitis has been reported in a 51-year-old woman. Famotidine was discontinued and the hepatitis resolved. Following a month-long-course of omeprazole, without incident, the patient was switched back to cimetidine with a recurrence of hepatitis soon afterwards (Hashimoto et al, 1994).
    2) CASE REPORT/CHILD: A 13-year-old boy presented with progressive jaundice approximately 75 days after beginning famotidine therapy, 40 mg/day for 30 days, for treatment of epigastric pain. Nontender hepatomegaly was detected on physical examination, and laboratory data indicated elevated liver enzyme concentrations and hyperbilirubinemia. With supportive care, the patient gradually recovered with normalization of laboratory values 2 months post-presentation (Jimenez-Saenz et al, 2000).
    d) OXMETIDINE
    1) CASE SERIES: Oxmetidine was found to cause overt hepatic injury in 1% to 4% of recipients during clinical trials and has been withdrawn from further testing (Helfrich et al, 1985).
    C) HEPATIC FAILURE
    1) WITH THERAPEUTIC USE
    a) NIZATIDINE
    1) CASE REPORT: Chey et al (1995) reported a case of probable nizatidine-induced subfulminant hepatic failure. The patient had no predisposing conditions for liver failure, and no other drugs were consumed prior to the onset of jaundice. Lab values included an initial serum bilirubin level of 21.7 mg/dL, increased transaminases, and an increased prothrombin time. A mild encephalopathy was also present on admission. A liver biopsy revealed massive multilobular hepatic collapse (Chey et al, 1995).

Genitourinary

    3.10.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Reversible renal failure has been reported with therapy
    3.10.2) CLINICAL EFFECTS
    A) RENAL FAILURE SYNDROME
    1) WITH THERAPEUTIC USE
    a) CIMETIDINE
    1) Reversible renal failure has been noted with cimetidine (Seidelin, 1980).
    a) Decreased creatinine clearance and increased serum creatinine levels have been reported in normal subjects and patients with pre-existing renal insufficiency during cimetidine therapy (Burgess et al, 1982; Dubb et al, 1978; Larsson et al, 1980; Larsson et al, 1979).
    B) INTERSTITIAL NEPHRITIS
    1) WITH THERAPEUTIC USE
    a) RANITIDINE
    1) CASE REPORT: Acute interstitial nephritis with severe low back pain has been reported in a patient on therapeutic doses of ranitidine. The patient presented to the ED 2 days after beginning ranitidine therapy. She had not been on any other medications and was previously healthy except for presumed gastritis (Karras, 1994).
    2) CASE REPORT: Neelakantappa et al (1993) presented a case of therapeutic ranitidine-induced interstitial nephritis and Fanconi Syndrome in a 39-year-old woman. Significant elevation of serum creatinine without an increase in BUN occurred, reflecting a marked reduction in GFR (Neelakantappa et al, 1993).
    3) CASE REPORT: Another case of interstitial nephritis induced by therapeutic ranitidine has been described by Gaughan et al (1993) (Gaughan et al, 1993).
    C) IMPOTENCE
    1) WITH THERAPEUTIC USE
    a) RANITIDINE
    1) CASE REPORT: Impotence was described in a 41-year-old man who used ranitidine 150 mg twice daily for 5 days (Viana, 1983). The drug was discontinued for 5 days and the symptoms resolved. His condition recurred after ranitidine rechallenge.

Hematologic

    3.13.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Agranulocytosis, pancytopenia, aplastic anemia, and thrombocytopenia may occur following therapeutic doses of cimetidine and other H2-receptor antagonists.
    3.13.2) CLINICAL EFFECTS
    A) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) CIMETIDINE
    1) Reversible leukopenia has been reported with therapeutic doses of cimetidine (Lopez-Lugue,1978).
    2) INCIDENCE: Between January 1977 and December 1987 there were 38 published cases of cimetidine-induced leukopenia.
    3) The time of onset varied widely (from 4 to 450 days after initiation of therapy), and four patients died.
    4) The mechanism is probably related to an inhibitory effect on myeloid progenitor cells. Patients with renal failure may be at increased risk (Aymard et al, 1988).
    b) RANITIDINE
    1) Bone marrow hypoplasia was associated with administration of ranitidine in patients with renal failure (Amos et al, 1987).
    2) CASE REPORT: A case of reversible granulocytopenia has been reported in a 61-year-old man following 3 weeks of ranitidine therapy 300 mg daily and phenytoin 300 mg daily. Both drugs were discontinued, and after normalization of the patient's leukocyte count, the patient was discharged on cimetidine 1200 mg daily. One month later the patient was readmitted with a return of granulocytopenia (List et al, 1988).
    c) FAMOTIDINE
    1) CASE REPORT: A case of reversible neutropenia and thrombocytopenia has been reported in a 62-year-old man following a one week course of famotidine 40 mg/day (Oymak et al, 1994).
    B) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) CIMETIDINE
    1) Between January 1977 and December 1987 there were 15 reported cases of cimetidine-induced thrombocytopenia, with an onset of 1 to 60 days after initiation of therapy (Aymard et al, 1988).
    2) CASE REPORT: Arbiser et al (1993) reported a case of thrombocytopenia in an 81-year-old woman taking cimetidine, phenytoin and dexamethasone. The authors suggested a drug interaction resulting in downregulation of epoxide hydrolase by glucocorticoids.
    3) The manufacturer states that incidence is 3 per million patients (Prod Info cimetidine oral tablets, 2010). Caution should be observed when anticoagulants, such as heparin, are used in conjunction with H2-receptor-antagonists, as these agents may more commonly cause thrombocytopenia (Burnakis, 1994).
    4) CASE REPORT: A 76-year-old man developed thrombocytopenia 24 hours after initiation of cimetidine 300 mg IV every 8 hours; his platelet count rose gradually after discontinuation of cimetidine and returned to normal after 9 days (Bourghol & Rindone, 1990).
    b) FAMOTIDINE
    1) CASE REPORT: Thrombocytopenia was reported in a 39-year-old man 37 hours after initiation of famotidine 20 mg IV every 12 hours, with a nadir of 13,000/mm(3). Prior chronic therapy with cimetidine had not resulted in toxicity.
    a) The platelet count gradually returned to normal after discontinuation of all medications; no rechallenge was attempted (Comer et al, 1989). Other cases of reversible thrombocytopenia following famotidine therapy have been reported (Oymak et al, 1994; Humphries, 1992; Zimmermann et al, 1991).
    c) NIZATIDINE
    1) Leukocytosis, eosinophilia, and mild thrombocytopenia have been observed following therapeutic use of nizatidine (Callaghan et al, 1985).
    d) RANITIDINE
    1) The Australian Adverse Drug Reaction Committee had 5 reports over a 7-year period of thrombocytopenia where ranitidine was the sole suspected drug, and 5 cases where other drugs were suspected in addition to ranitidine.
    2) CASE REPORT: A 57-year-old man with polycystic kidney disease and mild renal failure developed purpuric leg lesions and a platelet count of 70,000/mm(3) two weeks after initiation of ranitidine 300 mg/day; eosinophilia was also present.
    a) The platelet and eosinophil counts normalized 48 hours after discontinuation of ranitidine.
    b) Subsequent immunologic testing demonstrated both cell-mediated and IgE-mediated hypersensitivity to ranitidine and cimetidine (Gafter et al, 1989).
    C) PLATELET AGGREGATION
    1) WITH THERAPEUTIC USE
    a) CIMETIDINE
    1) Cimetidine appears to inhibit ADP-induced platelet aggregation and may have a significant effect in patients at risk for GI bleeding (Bertaglia & Miglietta, 1993).
    D) LEUKOCYTOSIS
    1) WITH THERAPEUTIC USE
    a) CIMETIDINE
    1) CASE REPORT: An isolated case of cimetidine-induced fever and leukocytosis with severe abdominal pain is reported in a 74-year-old man. All blood cultures were negative. The leukocytosis, fever and abdominal pain resolved within 24 hours of discontinuing cimetidine (Chia et al, 1994).
    b) NIZATIDINE
    1) Leukocytosis, eosinophilia, and mild thrombocytopenia have been observed following therapeutic use of nizatidine (Callaghan et al, 1985).
    E) PANCYTOPENIA
    1) WITH THERAPEUTIC USE
    a) CIMETIDINE
    1) Pancytopenia (Nagler et al, 1987; Nielsen, 1994) and aplastic anemia (Chang & Morrison, 1979) have occurred with therapeutic doses of cimetidine.
    b) RANITIDINE
    1) CASE SERIES: Twelve cases of pancytopenia related to ranitidine have been reported. Of these 12 cases, 6 were in patients with coexisting renal dysfunction (ADRAC, 1990).

Dermatologic

    3.14.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Dermatitis, vasculitis, urticaria, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), and psoriasis have been reported with the use of H2 blockers.
    3.14.2) CLINICAL EFFECTS
    A) VASCULITIS
    1) WITH THERAPEUTIC USE
    a) CIMETIDINE
    1) CASE REPORT: Cimetidine has been reported to cause leukoplastic vasculitis following exposure in a 72-year-old man (Dernbach & Taylor, 1981) and urticarial vasculitis in a 63-year-old man (Mitchell et al, 1983).
    a) Biopsy findings in the second case demonstrated an immune complex mechanism, suggestive of a type III hypersensitivity reaction.
    b) RANITIDINE
    1) CASE REPORT: Dermal microvasculitis was reported in a 65-year-old man approximately one month after beginning ranitidine therapy, 300 mg/day (Coutellier et al, 1993).
    B) DERMATITIS
    1) WITH POISONING/EXPOSURE
    a) OCCUPATIONAL EXPOSURES
    1) RANITIDINE
    a) CASE SERIES: Dermatitis consisting of hand, forearm, or foot eczema, erythematous edematous papules on the face and neck, and palpebral edema has been reported in workers involved in the manufacturing of ranitidine.
    1) Patch testing revealed positive reactions to ranitidine in all of 11 patients tested (Romaguera et al, 1988).
    b) CASE REPORT: Contact dermatitis with positive patch test occurred in a 41-year-old man pharmacy technician handling ranitidine HCl (Alomar et al, 1987).
    c) RANITIDINE INTERMEDIATES: Several intermediate products in the synthesis of ranitidine have been implicated by positive patch testing in causing occupational contact dermatitis.
    1) These include cystofur, MTM, a diamino compound, and cistoran (Rycroft, 1983; Goh & Ng, 1984; Valsecchi et al, 1989; Romaguera et al, 1990).
    2) FAMOTIDINE
    a) CASE REPORT: Occupational hand dermatitis was attributed to famotidine handling by a 35-year-old nurse. No cross-reactivity to cimetidine or ranitidine was found (Monteseirin & Conde, 1990). Three cases of occupational airborne contact dermatitis during famotidine synthesis has been reported (Guimaraens et al, 1994).
    C) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    a) RANITIDINE
    1) CASE REPORT: A case of delayed hypersensitivity from therapeutic oral ranitidine, resulting in a severe dermatitis has been reported. No cross reaction with a cimetidine challenge was observed (Juste et al, 1992).
    2) CASE REPORT: Urticaria and laryngospasm were seen in an adult who ingested one 150 mg ranitidine tablet (Picardo & Santucci, 1983).
    D) GENERALIZED PUSTULAR PSORIASIS
    1) WITH THERAPEUTIC USE
    a) CIMETIDINE
    1) CASE REPORT: One case of psoriasis has been reported in a patient receiving cimetidine 1 gram daily for one month, which improved following a reduction in dosage (Rai & Webster, 1979).
    E) LYELL'S TOXIC EPIDERMAL NECROLYSIS, SUBEPIDERMAL TYPE
    1) WITH THERAPEUTIC USE
    a) FAMOTIDINE
    1) CASE REPORT: A case of famotidine-induced toxic epidermal necrolysis (TEN) has been reported in a 22-year-old male 5 days after starting famotidine 40 mg/day. The patient was taking no other medication at the time of the reaction. A lymphocyte transformation test confirmed famotidine as the causative agent (Brunner et al, 1995).
    b) RANITIDINE
    1) CASE REPORT: Toxic epidermal necrolysis related to ranitidine has been reported in a patient with idiopathic thrombocytopenic purpura. The condition slowly improved upon discontinuation of ranitidine (Miralles et al, 1995).
    F) URTICARIA
    1) WITH THERAPEUTIC USE
    a) FAMOTIDINE
    1) CASE REPORT: SYMPTOMATIC DERMATOGRAPHISM has been described in 2 patients taking therapeutic doses of famotidine (Warner et al, 1994).
    G) STEVENS-JOHNSON SYNDROME
    1) WITH THERAPEUTIC USE
    a) CIMETIDINE
    1) Stevens-Johnson syndrome has been described following therapeutic use of cimetidine (Guan & Yeo, 1983).

Musculoskeletal

    3.15.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Cimetidine and ranitidine may rarely cause a toxic myopathy.
    3.15.2) CLINICAL EFFECTS
    A) MUSCLE PAIN
    1) WITH THERAPEUTIC USE
    a) CIMETIDINE
    1) CASE REPORT: A 71-year-old woman receiving cimetidine for 7 months, presented with pancytopenia, encephalopathy, and myalgias. Following discontinuation of cimetidine these symptoms resolved (Nagler et al, 1987).
    2) INCIDENCE: Twelve cases of myalgias suspected to be related to cimetidine have been reported to the Australian Adverse Drug Reaction Committee.
    a) Ten of these patients promptly recovered after discontinuation of cimetidine; 3 cases were confirmed by positive rechallenge (ADRAC, 1989).
    B) MYOSITIS
    1) WITH THERAPEUTIC USE
    a) RANITIDINE
    1) CASE REPORT: A case of polymyositis has been reported in a 65-year-old following ranitidine therapy (300 mg/day). Electromyogram demonstrated signs of myopathy and a muscle biopsy confirmed the presence of polymyositis. The patient recovered following discontinuation of ranitidine (Coutellier et al, 1993).

Endocrine

    3.16.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Gynecomastia and increased prolactin levels may be seen following therapeutic doses of cimetidine. With the other H2 receptor antagonists these effects are less common.
    B) WITH POISONING/EXPOSURE
    1) Gynecomastia and increased prolactin levels may be seen following overdose of cimetidine. With the other H2 receptor antagonists these effects are less common.
    3.16.2) CLINICAL EFFECTS
    A) GYNECOMASTIA
    1) WITH THERAPEUTIC USE
    a) CIMETIDINE
    1) Idiopathic gynecomastia in males, galactorrhea, breast pain and breast enlargement in females, have been reported in patients receiving chronic cimetidine therapy (Rodriguez & Jick, 1994; Meltzer et al, 1993).
    a) These symptoms were associated with elevated serum prolactin levels in some cases. The incidence is dose-related, occurring in up to 1% of patients receiving usual therapeutic doses and up to 41% in patients receiving 1200 to 10,800 mg/day.
    b) Substitution with ranitidine may be successful (Ehrinpreis et al, 1989).
    b) FAMOTIDINE
    1) Famotidine does not appear to be associated with antiandrogenic effects in men taking high doses (Vinayek et al, 1986; Berardi et al, 1988).
    c) RANITIDINE
    1) CASE REPORT: A 69-year-old man developed painful gynecomastia after 8 days of ranitidine therapy. The gynecomastia resolved when ranitidine was discontinued and reappeared upon rechallenge with the drug (Tosi & Cagnoli, 1982).
    2) WITH POISONING/EXPOSURE
    a) FAMOTIDINE
    1) CASE REPORT: Hyperprolactinemia and breast engorgement have been reported in a 67-year-old woman who accidentally received twice the ordered dose of famotidine (80 mg per day) for 5 months. Prolactin levels were increased to 130 ng/mL (normal: 5 to 15) and these returned to normal within 3 months of discontinuing famotidine (Delpre et al, 1993).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ACUTE ALLERGIC REACTION
    1) WITH THERAPEUTIC USE
    a) Liver enzyme elevations may occur.
    b) Other effects which have been reported include:
    1) Maculopapular rash (Lavarenne & Moreau, 1980; Pasquier et al, 1981; Peters, 1986)
    2) Urticaria and angioneurotic edema (Pasquier et al, 1981; Mitchell et al, 1983)
    3) Stevens-Johnson syndrome (Guan & Yeo, 1983; Mitchell et al, 1983)
    4) Toxic epidermal necrolysis (TEN)(Dabadie et al, 1983; Brunner et al, 1995)
    5) Pustular psoriasis (Mitchell et al, 1983)
    6) Erythema annulare centrifugum (Mitchell et al, 1983)
    7) A seborrheic dermatitis-like eruption (Mitchell et al, 1983)
    8) Xerosis and asteatotic dermatitis (Mitchell et al, 1983)
    9) Exfoliative dermatitis (Mitchell et al, 1983)
    10) Cutaneous vasculitis (Lavarenne & Moreau, 1980; Mitchell et al, 1983)
    B) ANAPHYLACTOID REACTION
    1) WITH THERAPEUTIC USE
    a) Anaphylaxis has been reported with both cimetidine and ranitidine (Whalen, 1985) Picardo & Santucci, 1983; (Brayko, 1984). One case was reported when ranitidine was used during labor (Greer & Fellows, 1990).
    b) CASE REPORT: A case of a ranitidine-induced type I hypersensitivity was reported in a patient who did not react to other H2-receptor antagonists (Lazaro et al, 1993).
    c) Anaphylactoid reactions to prophylactic ranitidine have been reported in obstetric patients (Barry et al, 1993; Powell & Maycock, 1993).
    d) CASE REPORT: Anaphylaxis has been reported in a 59-year-old man after he received 300 mg IV of cimetidine by slow infusion (Knapp et al, 1982). Sensitivity was confirmed with dermal testing.

Reproductive

    3.20.1) SUMMARY
    A) CIMETIDINE, FAMOTIDINE, NIZATIDINE, and RANITIDINE are classified as FDA pregnancy category B. CIMETIDINE crosses the placental barrier. Spontaneous abortions have been seen in women taking ranitidine. However, cohort studies did not find any associations between H2-blocker during the first trimester exposure and congenital abnormalities.
    3.20.2) TERATOGENICITY
    A) LACK OF EFFECT
    1) CIMETIDINE: Fetal and perinatal cimetidine exposure appears to have no significant effect on sexual characteristics in male rats (Hoie et al, 1994).
    2) NIZATIDINE: Teratology studies in rats and rabbits using doses up to 1500 mg/kg/day during the critical period of organogenesis produced no adverse effects (Morton, 1987).
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF EFFECT
    1) A retrospective cohort study involving a total of 84,823 deliveries demonstrated that the use of H2-blockers (ie, cimetidine, ranitidine, and famotidine) during the first trimester (n=1148) is not associated with an increase in congenital malformations. The adjusted odds ratio (OR) for major congenital malformations associated with the use of H2-blockers was 1.03 (95% confidence interval (CI) 0.80 to 1.32). In addition, there was no association between H2-blocker exposure during any trimester and preterm delivery, low birth weight, low Apgar scores, and perinatal mortality (Matok et al, 2010).
    B) PLACENTAL BARRIER
    1) CIMETIDINE crosses the placental barrier (Ellenhorn & Barceloux, 1988). Of 23 reported first trimester exposures to H2 receptor antagonists, 18 resulted in normal births. RANITIDINE: Two spontaneous abortions occurred in women taking ranitidine and two therapeutic abortions were preformed due to concern over teratogenic risk. Only one adverse outcome was reported, an upper eyelid hemangioma that required surgical removal (Koren & Zemlickis, 1991).
    C) PREGNANCY CATEGORY
    1) CIMETIDINE, FAMOTIDINE, NIZATIDINE, and RANITIDINE are classified as FDA pregnancy category B (Prod Info cimetidine hydrochloride oral solution, 2003; Prod Info PEPCID(R) oral tablets, 2010; Prod Info nizatidine oral solution, 2009; Prod Info ZANTAC(R) IV, IM injection, IV premixed injection, 2009).
    2) There are no adequate and well-controlled studies of famotidine/ibuprofen use during pregnancy in humans. Because data are limited, famotidine/ibuprofen should only be used during pregnancy if the maternal benefit outweighs the fetal risk. The use of NSAIDs such as famotidine/ibuprofen during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus (Prod Info DUEXIS(R) oral tablets, 2016a).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) CIMETIDINE is concentrated in human breast milk (Ellenhorn & Barceloux, 1988; Oo et al, 1995).
    2) FAMOTIDINE/IBUPROFEN: No studies of the use of famotidine/ibuprofen in lactating women have been performed, but limited studies have independently reported that low levels of famotidine and ibuprofen are present in human milk (Prod Info DUEXIS(R) oral tablets, 2016).
    3) RANITIDINE is concentrated into breast milk (Kearns et al, 1985).
    4) ROXATIDINE ACETATE: 0.22% of a single dose was excreted the breast milk of lactating women. The peak roxatidine concentration was about 400 ng/mL in plasma and 995 ng/mL in breast milk in one subject (pp 1-9).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) There is no evidence of carcinogenicity in humans with cimetidine.
    3.21.3) HUMAN STUDIES
    A) LACK OF EFFECT
    1) CIMETIDINE: There is no evidence that cimetidine is carcinogenic (Ellenhorn & Barceloux, 1988).
    3.21.4) ANIMAL STUDIES
    A) LACK OF EFFECT
    1) FAMOTIDINE: No evidence of carcinogenicity was noted in rodents (Berlin et al, 1986).

Genotoxicity

    A) FAMOTIDINE: In mutagenicity studies of famotidine, no effect was observed in the Ames test or in V-79 Chinese hamster lung cells (Prod Info DUEXIS(R) oral tablets, 2016; Berlin et al, 1986).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) No specific laboratory testing is indicated in most patients.
    B) Obtain a basic metabolic screen and serum acetaminophen and salicylate concentrations after deliberate overdose.

Methods

    A) CHROMATOGRAPHY
    1) The relationship between serum levels and clinical toxicity has not been studied.
    2) HPLC with UV detection methods have been used to determine plasma fractions of the H2 receptor antagonists (Probst et al, 1989; Callaghan et al, 1987; Knadler et al, 1986; Slugg et al, 1992).
    B) SPECTROSCOPY/SPECTROMETRY
    1) A liquid scintillation spectrometry method for blood, urine, feces, saliva, and breath samples has been described (Knadler et al, 1986).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with significant CNS depression or other symptoms that persist after 6 to 8 hours of observation should be admitted, but this is exceedingly rare.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Patients inadvertent ingestions can be managed at home. All patients with self-harm ingestions should be sent to a healthcare facility for mental health evaluation.
    B) In a series of 881 patients who ingested cimetidine alone (including 500 patients 5-years-old or younger), none of the children developed more than mild effects (Krenzelok et al, 1987). The dose ingested was not reported. While it appears safe to manage most accidental pediatric ingestions at home, the maximum tolerated pediatric dose has not been defined.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance if symptoms are more than mild or if the diagnosis is unclear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with deliberate overdose or more than mild symptoms should be referred to a healthcare facility and observed until symptoms resolve.

Monitoring

    A) No specific laboratory testing is indicated in most patients.
    B) Obtain a basic metabolic screen and serum acetaminophen and salicylate concentrations after deliberate overdose.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) No prehospital decontamination is recommended.
    6.5.2) PREVENTION OF ABSORPTION
    A) No decontamination is warranted in most cases.
    6.5.3) TREATMENT
    A) SUPPORT
    1) For the management of mild to moderate toxicity, treatment is symptomatic and supportive. Administer IV fluids for treatment of hypotension, and supportive care for CNS depression.
    B) MONITORING OF PATIENT
    1) No specific laboratory testing is indicated in most patients.
    2) Obtain a basic metabolic screen and serum acetaminophen and salicylate concentrations after deliberate overdose.
    C) PSYCHOMOTOR AGITATION
    1) CNS disturbances are among the most common effects and usually subside within 24 hours.
    2) INDICATION
    a) If patient is severely agitated, sedate with IV benzodiazepines.
    3) DIAZEPAM DOSE
    a) ADULT: 5 to 10 mg IV initially, repeat every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) CHILD: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    4) LORAZEPAM DOSE
    a) ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed (Manno, 2003).
    b) CHILD: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    5) Extremely large doses of benzodiazepines may be required in patients with severe intoxication in order to obtain adequate sedation. Titrate dose to clinical response and monitor for hypotension, CNS and respiratory depression, and the need for endotracheal intubation.
    6) PHYSOSTIGMINE: Cimetidine-induced agitation and delirium has been reversed by physostigmine in several reported cases. However, the use of physostigmine for this purpose is still very questionable. Doses used in adults were 1 milligram intravenously, repeated once if needed.
    7) PHYSOSTIGMINE/CASE REPORT: A 48-year-old chronic alcoholic woman became severely agitated, anxious, combative, and disoriented on her ninth hospital day.
    a) During this time her medications included spironolactone, penicillin, tobramycin, Riopan(R), and cimetidine (300 milligrams every six hours). She was treated with diazepam and droperidol without improvement.
    b) After 2 mg of physostigmine was administered intravenously, she was able to answer questions accurately and cooperate in her treatment (Jenike & Levy, 1983).
    8) PHYSOSTIGMINE/CASE REPORT: Probable ranitidine-induced confusion partially resolved after treatment with physostigmine in a 25-year-old woman (Goff et al, 1985).
    9) PHYSOSTIGMINE/CASE REPORT: Respiratory depression in a 74-year-old man who received a small intravenous dose of cimetidine was reversed with physostigmine (Bostrom et al, 1982).
    10) PHYSOSTIGMINE/CASE REPORT: A 58-year-old man who was receiving 300 milligrams cimetidine intravenously every 6 hours, became increasingly obtunded over the course of 3 days. He'd responded to 1 milligram of intravenous physostigmine. After 4 hours his mental state again deteriorated and he was given to another 1 milligram dose of physostigmine intravenously, to which he responded again (Mogelnicki et al, 1979).
    11) PHYSOSTIGMINE/CASE REPORT: A 60-year-old man with renal failure became obtunded after several doses of cimetidine (300 milligrams every 6 hours). The patient responded to 1 mg physostigmine intravenously (Mogelnicki et al, 1979).
    D) BRADYCARDIA
    1) ATROPINE/DOSE
    a) ADULT BRADYCARDIA: BOLUS: Give 0.5 milligram IV, repeat every 3 to 5 minutes, if bradycardia persists. Maximum: 3 milligrams (0.04 milligram/kilogram) intravenously is a fully vagolytic dose in most adults. Doses less than 0.5 milligram may cause paradoxical bradycardia in adults (Neumar et al, 2010).
    b) PEDIATRIC DOSE: As premedication for emergency intubation in specific situations (eg, giving succinylchoine to facilitate intubation), give 0.02 milligram/kilogram intravenously or intraosseously (0.04 to 0.06 mg/kg via endotracheal tube followed by several positive pressure breaths) repeat once, if needed (de Caen et al, 2015; Kleinman et al, 2010). MAXIMUM SINGLE DOSE: Children: 0.5 milligram; adolescent: 1 mg.
    1) There is no minimum dose (de Caen et al, 2015).
    2) MAXIMUM TOTAL DOSE: Children: 1 milligram; adolescents: 2 milligrams (Kleinman et al, 2010).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Enhanced elimination is generally not indicated.
    2) CIMETIDINE/RANITIDINE: Less than 20 percent of a single dose is recoverable in the dialysate of patients undergoing hemodialysis (Larsson et al, 1982; Vaziri et al, 1978; Comstock et al, 1985). Peritoneal dialysis may remove 20 to 30 milligrams per day of cimetidine (Abate et al, 1982).
    3) FAMOTIDINE has negligible protein-binding and is primarily excreted unchanged in the urine.
    a) A study in 5 anuric patients given a single 20 milligram dose of famotidine demonstrated a reduction of 58 percent of the AUC during 5 hours of hemodialysis, with a 4.6-fold increase in the elimination rate constant.
    b) Peak serum famotidine levels were not significantly different, with a mean of 195 nanograms/milliliter without dialysis and 141.5 nanograms/milliliter during dialysis (Inotsume et al, 1990).
    B) HEMOFILTRATION
    1) NIZATIDINE: Saima et al (1993) have found that nizatidine and its metabolites are not removed from the systemic circulation to a clinically significant degree by intermittent hemofiltration in their study of patients with renal failure.

Abstracts

Case Reports

    A) ADULT
    1) Accidental ingestion of twice the recommended dose of cimetidine for 2 days in a 50-year-old man resulted in lightheadedness, dizziness, neck pain, profuse sweating, flushing, and mental confusion. Symptoms dissipated in 24 hours after reverting to a normal dose (Grimson, 1977).
    2) BROAD-COMPLEX TACHYCARDIA: The heart rate of an 85-year-old woman was reported to increase from 72 beats per minute to 150 beats per minute following 200 mg cimetidine injected intravenously over 2 minutes. Onset of the tachycardia was about 5 minutes after the injection of cimetidine.
    a) EKG demonstrated a wide-complex tachycardia without evidence of atrioventricular dissociation. She returned to a sinus rhythm at 100 beats per minute 10 minutes later.
    b) On rechallenge 12 hours later, an identical tachycardia occurred which did not revert spontaneously, and 5 mg of verapamil was given by slow IV injection. The verapamil caused an immediate conversion to atrial fibrillation (72 beats per minute) which then converted to a sinus rhythm in about 3 hours (Dickey & Symington, 1987).
    3) A 35-year-old man became comatose following an ingestion of 24 grams of cimetidine. Treatment included gastric lavage and forced diuresis. He awoke 6 hours later, and his blood cimetidine concentration was 18.7 mg/L at 8 hours after ingestion (van Rijthoven, 1979).
    B) PEDIATRIC
    1) Two intravenous injections of cimetidine (2 mg/kg within 4 hours) in an 11-year-old girl produced unconsciousness (Bacigalupo et al, 1978).

Range Of Toxicity

Summary

    A) TOXICITY: These medications have a large therapeutic window and no more than minimal toxicity is expected even with very large overdoses.
    B) THERAPEUTIC DOSE: CIMETIDINE: ADULT: 400 to 1600 mg/day orally; PEDIATRIC: 20 to 40 mg/kg/day orally. FAMOTIDINE: ADULT: 20 to 80 mg/day orally; PEDIATRIC: 0.5 to 2 mg/kg/day orally. RANITIDINE: ADULT: 150 to 300 mg/day orally; PEDIATRIC: 2 to 10 mg/kg/day orally, divided in 2 to 4 doses.

Therapeutic Dose

    7.2.1) ADULT
    A) SPECIFIC SUBSTANCE
    1) CIMETIDINE
    a) ORAL: The recommended dose ranges are 400 to 1600 mg once daily at bedtime or 800 to 1600 mg in 2 to 4 divided doses daily, depending on the indication. MAXIMUM DOSE: 2400 mg/day. The dose may be continued as long as clinically indicated; however, the use of cimetidine beyond 12 weeks has not been established(Prod Info cimetidine oral tablets, 2010; Prod Info cimetidine HCl oral solution, 2009).
    b) INJECTION: The recommended dose is 300 mg every 6 to 8 hours IV or IM injection. IV injection should be given over a period of not less than 5 minutes. Intermittent IV infusion should be given over 15 to 20 minutes. MAXIMUM DOSE: 2400 mg/day (Prod Info cimetidine HCl IM, IV injection, 2006)..
    c) CONTINUOUS IV INFUSION: The recommended dose is 37.5 mg/hr (900 mg/day). A loading dose of 150 mg may be administered for more rapid elevation of gastric pH (Prod Info cimetidine HCl IM, IV injection, 2006).
    2) FAMOTIDINE
    a) ORAL (ACUTE THERAPY): The recommended dose is to 40 mg once daily at bedtime, or in 2 divided doses for up to 12 weeks (Prod Info PEPCID(R) oral tablets, 2011; Prod Info PEPCID(R) powder for oral suspension, 2010).
    b) ORAL (MAINTENANCE THERAPY): The recommended dose is 20 mg once daily at bedtime (Prod Info PEPCID(R) oral tablets, 2011; Prod Info PEPCID(R) powder for oral suspension, 2010).
    c) IV: The recommended dose is 20 mg every 12 hours (Prod Info famotidine solution for IV injection, 2011).
    3) NIZATIDINE
    a) ORAL: The recommended dose is 150 to 300 mg daily at bedtime or 300 mg divided into 2 doses daily (Prod Info nizatidine oral solution , 2009; Prod Info nizatidine oral capsules, 2006).
    4) RANITIDINE
    a) ORAL: The recommended dose is 150 mg or 10 mL of syrup (equivalent to 150 mg ranitidine) twice daily. As an alternative, a single daily dose of 300 mg or 20 mL (equivalent to 300 mg ranitidine) after the evening meal or at bedtime may be used (Prod Info ZANTAC(R) oral effervescent tablets, oral syrup, oral tablets, 2009).
    b) IM INJECTION: The recommended dose is 50 mg every 6 to 8 hours. MAXIMUM DOSE: 400 mg/day (Prod Info ZANTAC(R) IV, IM injection, IV premixed injection, 2009).
    c) IV BOLUS: The recommended dose is 50 mg every 6 to 8 hours in 0.9% sodium chloride solution to a concentration no greater than 2.5 mg/mL at an injection rate no greater than 4 mL/minute (5 minutes total infusion time). MAXIMUM DOSE: 400 mg/day (Prod Info ZANTAC(R) IV, IM injection, IV premixed injection, 2009).
    d) IV INTERMITTENT INFUSION: The recommended dose is 50 mg every 6 to 8 hours in 5% dextrose to a concentration no greater than 0.5 mg/mL at an infusion rate no greater than 5 to 7 mL/min (15 to 20 minutes total infusion time). MAXIMUM DOSE: 400 mg/day (Prod Info ZANTAC(R) IV, IM injection, IV premixed injection, 2009).
    e) IV CONTINUOUS INFUSION: The recommended dose is 6.25 mg/hr in 5% dextrose (Prod Info ZANTAC(R) IV, IM injection, IV premixed injection, 2009).
    7.2.2) PEDIATRIC
    A) SPECIFIC SUBSTANCE
    1) CIMETIDINE
    a) CHILDREN UNDER 16 YEARS OF AGE
    1) GASTROINTESTINAL CONDITIONS
    a) ORAL or INJECTION: Clinical experience with cimetidine in children is limited and use is not recommended for those under 16 years of age. Doses of 20 to 40 mg/kg/day have been used in select cases when the benefits outweigh the potential risks (Prod Info cimetidine oral tablets, 2010; Prod Info cimetidine HCl oral solution, 2009). MAXIMUM DOSE: 800 mg/day (Kato et al, 1994; Kato et al, 1991).
    b) CHILDREN 1 YEAR OF AGE AND OLDER
    1) RECALCITRANT WARTS
    a) ORAL: The recommended dose is 30 to 40 mg/kg/day orally in 3 or 4 divided doses for approximately 2 to 3 months (Dasher et al, 2009; Mullen et al, 2005; Gooptu et al, 2000; Dohil & Prendiville, 1996). MAXIMUM DOSE: 800 mg/dose. Cimetidine has been used concurrently with levamisole (Parsad et al, 2001).
    c) CHILDREN 16 YEARS OF AGE AND OLDER
    1) GASTROINTESTINAL CONDITIONS
    a) ORAL: The recommended dose ranges are 400 to 1600 mg once daily at bedtime or 800 to 1600 mg in 2 to 4 divided doses daily, depending on the indication. MAXIMUM DOSE: 2400 mg/day. The dose may be continued as long as clinically indicated; however, the use of cimetidine beyond 12 weeks has not been established(Prod Info cimetidine oral tablets, 2010; Prod Info cimetidine HCl oral solution, 2009).
    b) INJECTION: The recommended dose is 300 mg every 6 to 8 hours IV or IM injection. IV injection should be given over a period of not less than 5 minutes. Intermittent IV infusion should be given over 15 to 20 minutes. MAXIMUM DOSE: 2400 mg/day (Prod Info cimetidine HCl IM, IV injection, 2006)..
    2) FAMOTIDINE
    a) ORAL
    1) INFANTS LESS THAN 1 YEAR OF AGE
    a) LESS THAN 3 MONTHS OF AGE: The recommended dose is 0.5 mg/kg/dose of oral suspension once daily for up to 8 weeks (Prod Info PEPCID(R) oral tablets, 2011; Prod Info PEPCID(R) powder for oral suspension, 2010; Wenning et al, 2005; Orenstein et al, 2003).
    b) 3 MONTHS TO 1 YEAR OF AGE: The recommended dose is 0.5 mg/kg/dose of oral suspension twice daily for up to 8 weeks (Prod Info PEPCID(R) oral tablets, 2011; Prod Info PEPCID(R) powder for oral suspension, 2010; Wenning et al, 2005; Orenstein et al, 2003).
    2) CHILDREN 1 TO 16 YEARS OF AGE: The recommended dose is 0.5 to 1 mg/kg/day orally at bedtime or divided into twice daily doses. MAXIMUM DOSE: 40 mg/day (Prod Info PEPCID(R) oral tablets, 2011; Prod Info PEPCID(R) oral tablets, suspension, 2006).
    b) INJECTION OR INFUSION
    1) INFANTS LESS THAN 1 YEAR OF AGE: The safety and efficacy of IV famotidine in infants less than 1 year of age have not been established (Prod Info famotidine solution for IV injection, 2011). However, IV famotidine has been used in select cases within this age group:
    a) LESS THAN 3 MONTHS OF AGE: 0.25 mg/kg IV once daily (Wenning et al, 2005).
    b) 3 MONTHS TO 1 YEAR OF AGE: 0.25 mg/kg IV every 12 hours (Wenning et al, 2005).
    2) CHILDREN 1 TO 16 YEARS OF AGE: Suggested dose is 0.25 mg/kg IV injected over at least 2 minutes or infused over 15 minutes every 12 hours. MAXIMUM DOSE: 40 mg/day (Prod Info famotidine solution for IV injection, 2011).
    3) NIZATIDINE
    a) ORAL SOLUTION
    1) CHILDREN LESS THAN 12 YEARS OF AGE: Nizatidine is not currently recommended for the treatment of pediatric patients less than 12 years of age (Prod Info nizatidine oral solution , 2009). However, in patients 29 days to less than 12 years of age, doses of 5 to 10 mg/kg/day oral solution divided twice daily for 8 weeks have been used (Orenstein et al, 2005; Abdel-Rahman et al, 2004; Abdel-Rahman et al, 2002; Rudolph et al, 2001).(Simeone et al, 1997). MAXIMUM DOSE: 300 mg/day.
    2) CHILDREN 12 YEARS OF AGE AND OLDER: The recommended dose is 150 mg twice daily for up to 8 weeks. MAXIMUM DOSE: 300 mg/day (Prod Info nizatidine oral solution , 2009; Orenstein et al, 2005).
    b) ORAL CAPSULE
    1) Nizatidine oral capsules are not currently indicated for use in children (Prod Info nizatidine oral capsules, 2006).
    4) RANITIDINE
    a) ORAL
    1) INFANTS AND CHILDREN 1 MONTH TO 16 YEARS OF AGE: For treatment and maintenance of duodenal and gastric ulcers, the recommended dose range is 2 to 4 mg/kg 1 to 2 times daily. MAXIMUM DOSE: 300 mg/day. For treatment of GERD and erosive esophagitis, the recommended dose range is 5 to 10 mg/kg/day in 2 divided doses (Prod Info ZANTAC(R) oral effervescent tablets, oral syrup, oral tablets, 2009).
    b) IV INFUSION
    1) INFANTS AND CHILDREN 1 MONTH TO 16 YEARS OF AGE: The recommended dose is a total of 2 to 4 mg/kg daily divided and administered every 6 to 8 hours. MAXIMUM DOSE: 50 mg every 6 to 8 hours (Prod Info ZANTAC(R) IV, IM injection, IV premixed injection, 2009).

Maximum Tolerated Exposure

    A) SPECIFIC SUBSTANCE
    1) CIMETIDINE
    a) Patients ingesting as much as 20 grams of cimetidine have remained asymptomatic (Meredith & Volans, 1979; Illingworth & Jarvie, 1979; Krenzelok et al, 1987).
    B) ANIMAL DATA
    1) RANITIDINE
    a) The maximum dose of ranitidine that did not produce hepatotoxicity was 100 milligrams/kilogram/day (Lewis, 1987).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) SPECIFIC SUBSTANCE
    a) CIMETIDINE
    1) Serum levels as high as 57 micrograms/milliliter have been reported without the development of serious toxic sequelae (Illingworth & Jarvie, 1979).
    2) Symptoms of cimetidine toxicity have been associated with trough cimetidine concentrations exceeding 1.25 milligrams/liter (Schentag, 1980).
    3) Mean plasma concentration necessary to produce 50% inhibition of stimulated acid secretion (Berardi et al, 1988)
    a) Cimetidine - 750 nanograms/milliliter
    b) Famotidine - 13 nanograms/milliliter
    c) Ranitidine - 100 nanograms/milliliter

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (INTRAPERITONEAL)MOUSE:
    1) 470 mg/kg
    B) LD50- (ORAL)MOUSE:
    1) 2600 mg/kg
    C) LD50- (INTRAPERITONEAL)RAT:
    1) 650 mg/kg
    D) LD50- (ORAL)RAT:
    1) 5000 mg/kg

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Cimetidine is a histamine H(2)-receptor antagonist that acts by inhibiting histamine action at the histamine H(2) receptors of the parietal cells, thus lowering basal gastric acid secretion (Prod Info TAGAMET(R) oral tablet, 2005).
    1) H2 receptor antagonists are highly selective and do not affect the H1 receptors. They do not exhibit anticholinergic properties.
    2) It is postulated that by blocking H2 receptors on the parietal cell, the ability of histamine, gastrin, and acetylcholine to stimulate acid secretion is blocked.
    3) Cimetidine, ranitidine, and famotidine have no effect on gastric emptying; cimetidine and famotidine have no effect on lower esophageal sphincter tone. Ranitidine, famotidine, and nizatidine have little or no effect on fasting or postprandial gastrin secretion.
    4) Ranitidine is 5 to 12 times better than cimetidine, and famotidine is 30 to 60 times better cimetidine on a molar basis in controlling gastric acid hypersecretion. There is no substantiation that this greater potency offers any clinical advantage.
    B) Because human T lymphocytes have H2 receptors, it has been speculated that cimetidine may alter cell-mediated immune responses.

Toxicologic Mechanism

    A) CYTOCHROME P-450
    1) The evidence that cimetidine may exhibit a cytoprotective effect in addition to its antisecretory effect was reviewed (Cheli et al, 1986; Kimmey & Silverstein, 1985), concluding that cimetidine may have a cytoprotective effect at doses less than those which inhibit acid secretion. The mechanism of this action is not known, but it does not appear to result from an increase in prostaglandins. Cytoprotective activity of cimetidine, and other antisecretory compounds has been theorized to be due to changes in mucous/alkaline secretion and gastric mucosal barrier, increased gastric mucosal cell renewal, increased mucosal blood flow, or activation of humoral factors (prostaglandins, epidermal growth factors, somatostatin) (Konturek, 1985).
    2) Research suggests that cimetidine inhibits 5-aminolaevulinic acid (ALA) synthase. Initially, cimetidine inhibits the hepatic cytochrome P450 system which leads to the inhibition of heme oxidase activity. Inhibition of heme oxidase activity results in the reduction of heme metabolism thereby inhibiting ALA synthase by negative feedback (Tefferi et al, 1994; Lip et al, 1993).
    3) Famotidine, nizatidine, and roxatidine have minimal or no effect on the cytochrome P-450 oxidase system and thus have less potential for drug interactions than cimetidine (Reynolds, 1996).
    B) HEPATIC INJURY
    1) Hepatic injury associated with cimetidine and ranitidine is rare and is thought to be an idiosyncratic or hypersensitivity reaction. Zimmerman (1978) speculated that a toxic metabolite is responsible given the absence of clinical hallmarks of hypersensitivity (eosinophilia, fever, and rash). The absence of a direct hepatotoxic effect is supported by the lack of injury in high-dose animal studies (Vial et al, 1991).
    C) CNS DISTURBANCES
    1) CNS disturbances may occur with therapeutic doses or overdoses of all the H2 receptor antagonists, but are reported to a greater degree with cimetidine, which crosses the blood-brain barrier well. The mechanism is unclear, but it is thought to be due to both histaminic and cholinergic/ adrenergic mediation. CNS H2-receptor blockade has been hypothesized (Vial et al, 1991).
    2) Amabeoku & Chikuni (1993) suggested the involvement of the GABA system in cimetidine-induced seizures. Their studies in mice have shown that muscimol, a selective GABA agonist, protects mice against cimetidine seizures. The anticonvulsant effect of muscimol against cimetidine-induced seizures may be due to GABA receptor activation.
    D) LEUKOPENIA/AGRANULOCYTOSIS
    1) H2-receptor antagonists may have a reversible, dose-dependent cytotoxic, effect on myeloid stem cells, most likely mediated by inhibition of medullary H2-receptors. Cimetidine has the most pronounced effect. This is supported by reports of agranulocytosis in ranitidine treated patients which recurred with cimetidine. Increased risk may occur in overdose or renal failure (Aymard et al, 1988; List et al, 1988).
    E) CARDIOVASCULAR
    1) The exact mechanism of cardiovascular effects, including bradycardia, is unknown. Studies have shown the existence of H2-receptors in the myocardium and peripheral blood vessels. Stimulation of these can cause positive ionotropic and chronotropic responses, dilatation of coronary vessels, and decreased peripheral vascular resistance. It is theoretically possible that an antagonistic effect on these receptors, or an anticholinesterase activity, may result in changes in cardiac rate or rhythm (Baller & Huchzermeyer, 1989).
    a) Cohen et al (1989) suggested that blockade of cardiac H2 receptors caused:
    1) Reversal of histamine-induced positive chronotropic and inotropic effects
    2) Predominance of H1 receptor activity and prolongation of AV conduction time
    3) Blockade of H2-mediated coronary artery dilation
    4) Dysrhythmias due to prolactin release.
    2) Bradycardia may also be an idiosyncratic response or may involve nonspecific effects not related to H2-receptor blockade (Poulakos & Gertner, 1989).
    3) Animal and in vitro human studies have shown that toxic concentrations of ranitidine potentiate the action of acetylcholine via an inhibition of cholinesterases, thus resulting in cardiovascular effects (Gwee & Cheah, 1986) Hansen & Bertl, 1983).
    a) Gwee & Cheah (1991) provide evidence that cimetidine and ranitidine can cause blockade of muscarinic receptors in humans, thus resulting in tachycardia, urinary retention and blurred vision which is also occasionally seen with these agents.
    F) ENDOCRINE FUNCTION
    1) Cimetidine has been reported to alter gonadal function, an effect related to its antiandrogenic properties. Studies do not support other H2-receptor antagonists as sharing the antiandrogenic properties of cimetidine in clinical use (pp 87-95).
    2) Cimetidine produces transient increases in plasma prolactin levels in man which has been attributed, in part, to indirect central serotonergic mechanisms involving 5-HT2 receptors in the hypothalamus, although the evidence is inconclusive (Meltzer et al, 1993).

Physicochemical

Physical Characteristics

    A) CIMETIDINE is a crystalline powder (JEF Reynolds , 1988) that is soluble in alcohol, slightly soluble in water, very slightly soluble in chloroform, and insoluble in ether (Prod Info TAGAMET(R) oral tablets, 2005).
    B) CIMETIDINE HYDROCHLORIDE is freely soluble in water, soluble in alcohol, very slightly soluble in chloroform, and practically insoluble in ether (Prod Info cimetidine hydrochloride oral solution, 2003).
    C) FAMOTIDINE is a white to pale yellow crystalline compound that is freely soluble in glacial acetic acid, slightly soluble in methanol, very slightly soluble in water, and practically insoluble in ethanol (Prod Info DUEXIS(R) oral tablets, 2011).
    D) NIZATIDINE is an off-white to buff crystalline solid that is soluble in water and has a bitter taste and mild sulfur-like odor (Prod Info nizatidine oral solution, 2009).
    E) RANITIDINE: pale yellow to white granular substance (p 1996)
    F) RANITIDINE HYDROCHLORIDE is a white to pale yellow, granular substance that is soluble in water and has a slightly bitter taste and sulfur-like odor (Prod Info ZANTAC(R) oral effervescent tablets, oral syrup, oral tablets, 2009).

Molecular Weight

    A) CIMETIDINE: 252.34 (Prod Info TAGAMET(R) oral tablets, 2005)
    B) CIMETIDINE HYDROCHLORIDE: 288.8 (Prod Info cimetidine hydrochloride oral solution, 2003)
    C) FAMOTIDINE: 337.45 (Prod Info DUEXIS(R) oral tablets, 2011)
    D) NIZATIDINE: 331.47 (Prod Info nizatidine oral solution, 2009)
    E) RANITIDINE: 314.4
    F) RANITIDINE HYDROCHLORIDE: 350.87 (Prod Info ZANTAC(R) oral effervescent tablets, oral syrup, oral tablets, 2009)
    G) ROXATIDINE: 384.9

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    175) Product Information: nizatidine oral capsules, nizatidine oral capsules. Dr Reddy's Laboratories Limited, Bachepalli, India, 2006.
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    177) Product Information: nizatidine oral solution, nizatidine oral solution. Amneal Pharmaceuticals, Glasgow, KY, 2009.
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