Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/2807
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Cimetidine (Injection, Solution)
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Parenteral Administration In hospitalized patients with pathological
hypersecretory conditions or intractable ulcers, or in patients who
are unable to take oral medication, cimetidine may be administered
parenterally. The doses and regimen for parenteral
administration in patients with GERD have not been established. Recommendations for Parenteral
Administration: Intramuscular Injection: 300 mg every 6 to 8 hours (no
dilution necessary). Transient pain at the site of injection has been
reported. Intravenous
Injection: 300 mg every 6 to 8 hours. In some patients it
may be necessary to increase dosage. When this is necessary, the increases
should be made by more frequent administration of a 300 mg dose, but
should not exceed 2400 mg per day. Dilute Cimetidine Injection, USP,
300 mg, in Sodium Chloride Injection (0.9%) or another compatible
I.V. solution (see Stability of Cimetidine Injection, USP) to a total
volume of 20 mL and inject over a period of not less than 5 minutes
(see PRECAUTIONS). Intermittent Intravenous Infusion: 300 mg every 6 to 8
hours, infused over 15 to 20 minutes. In some patients it may be necessary
to increase dosage. When this is necessary, the increases should be
made by more frequent administration of a 300 mg dose, but should
not exceed 2400 mg per day. Dilute Cimetidine
Injection, USP, 300 mg, in at least 50 mL of 5% Dextrose Injection,
or another compatible I.V. solution (see Stability of Cimetidine Injection,
USP). Continuous Intravenous
Infusion: 37.5 mg/hour (900 mg/day). For patients requiring
a more rapid elevation of gastric pH, continuous infusion may be preceded
by a 150 mg loading dose administered by I.V. infusion as described
above. Dilute 900 mg Cimetidine Injection, USP in a compatible I.V.
fluid (see Stability of Cimetidine Injection, USP) for constant rate
infusion over a 24-hour period. Note: Cimetidine Injection, USP may
be dilutedin 100 to 1000 mL; however, a volumetric pump is recommended
if the volume for 24-hour infusion is less than 250 mL. In one study
in patients with pathological hypersecretory states, the mean infused
dose of cimetidine was 160 mg/hour with a range of 40 to 600 mg/hour. These doses maintained the intragastric acid secretory
rate at 10 mEq/hour or less. The infusion rate should be adjusted
to individual patient requirements. Stability of Cimetidine Injection, USP When added to or diluted with most commonly used intravenous
solutions, e.g., Sodium Chloride Injection (0.9%), Dextrose Injection
(5% or 10%), Lactated Ringer's Injection, 5% Sodium Bicarbonate
Injection, Cimetidine Injection, USP should not be used after more
than 48 hours of storage at room temperature. NOTE: The products accompanying this insert
are for I.M./I.V. use only. Much of the following relates to the use
of oral cimetidine and is for informational purposes only. See Parenteral
Administration (above) for specific dosing recommendations. Duodenal Ulcer Active Duodenal
Ulcer Clinical studies have indicated
that suppression of nocturnal acid is the most important factor in
duodenal ulcer healing (see CLINICAL PHARMACOLOGY���Acid Secretion). This is supported by recent clinical
trials (see Clinical Trials���Active Duodenal Ulcer). Therefore, there
is no apparent rationale, except for familiarity with use, for treating
with anything other than a once-daily at bedtime oral dosage regimen
(h.s.). In a U.S. oral dose-ranging study of
400 mg h.s., 800 mg h.s. and 1600 mg h.s., a continuous dose response
relationship for ulcer healing was demonstrated. However, 800 mg h.s. is the dose of choice for most patients, as
it provides a high healing rate (the difference between 800 mg h.s.
and 1600 mg h.s. being small), maximal pain relief, a decreased potential
for drug interactions (see PRECAUTIONS���Drug Interactions) and maximal patient convenience. Patients
unhealed at four weeks, or those with persistent symptoms, have been
shown to benefit from two to four weeks of continued therapy. It has been shown that patients who both have an endoscopically
demonstrated ulcer larger than 1 cm and are also heavy smokers (i.e.,
smoke one pack of cigarettes or more per day) are more difficult to
heal. There is some evidence which suggests that more rapid healing
can be achieved in this subpopulation with cimetidine 1600 mg at bedtime.
While early pain relief with either 800 mg h.s. or 1600 mg h.s. is
equivalent in all patients, 1600 mg h.s. provides an appropriate alternative
when it is important to ensure healing within four weeks for this
subpopulation. Alternatively, approximately 94% of all patients will
also heal in eight weeks with cimetidine 800 mg h.s. Other cimetidine oral regimens in the U.S. which have been shown
to be effective are: 300 mg four times daily, with meals and at bedtime,
the original regimen with which U.S. physicians have the most experience,
and 400 mg twice daily, in the morning and at bedtime (see Clinical Trials���Active Duodenal Ulcer). Concomitant antacids should be given as needed for relief of pain.
However, simultaneous administration of oral cimetidine and antacids is not recommended, since
antacids have been reported to interfere with the absorption of oral
cimetidine. While healing with cimetidine often
occurs during the first week or two, treatment should be continued
for 4 to 6 weeks unless healing has been demonstrated by endoscopic
examination. Maintenance
Therapy for Duodenal Ulcer In those
patients requiring maintenance therapy, the recommended adult oral
dose is 400 mg at bedtime. Active Benign Gastric Ulcer The recommended adult oral dosage for short-term treatment
of active benign gastric ulcer is 800 mg h.s., or 300 mg four
times a day with meals and at bedtime. Controlled clinical studies
were limited to six weeks of treatment (see Clinical Trials). 800 mg h.s. is the preferred regimen
for most patients based upon convenience and reduced potential for
drug interactions. Symptomatic response to cimetidine does not preclude
the presence of a gastric malignancy. It is important to follow gastric
ulcer patients to assure rapid progress to complete healing. Prevention of Upper Gastrointestinal
Bleeding The recommended adult dosing
regimen is continuous I.V. infusion of 50 mg/hour. Patients with creatinine
clearance less than 30 cc/min. should receive half the recommended
dose. Treatment beyond 7 days has not been studied. Pathological Hypersecretory Conditions (such as Zollinger-Ellison Syndrome) Recommended
adult dosage: 300 mg four times a day with meals and at bedtime. In
some patients it may be necessary to administer higher doses more
frequently. Doses should be adjusted to individual patient needs,
but should not usually exceed 2400 mg per day and should continue
as long as clinically indicated. Dosage Adjustment for Patients with Impaired Renal
Function Patients with severely impaired
renal function have been treated with cimetidine. However, such usage
has been very limited. On the basis of this experience the recommended
dosage is 300 mg every 12 hours orally or by intravenous injection.
Should the patient's condition require, the frequency of dosing
may be increased to every 8 hours or even further with caution. In
severe renal failure, accumulation may occur and the lowest frequency
of dosing compatible with an adequate patient response should be used.
When liver impairment is also present, further reductions in dosage
may be necessary. Hemodialysis reduces the level of circulating cimetidine.
Ideally, the dosage schedule should be adjusted so that the timing
of a scheduled dose coincides with the end of hemodialysis. Patients with creatinine clearance less than 30 cc/min.
who are being treated for prevention of upper gastrointestinal bleeding
should receive half the recommended dose. Do
not administer product unless solution is clear and container is undamaged.
Discard unused portion. All parenteral drug products should be inspected
visually for particulate matter and discoloration prior to administration,
whenever solution and container permit.
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Cimetidine is a histamine H-receptor
antagonist. Chemically it is N��-cyano-N-methyl-N���-[2-[[(5-methyl-1H-imidazol-4-yl)methyl]thio]-ethyl]-guanidine. The molecular formula for cimetidine hydrochloride is
CHNS���HCl and the molecular
weight is 288.80. The structural formula of cimetidine hydrochloride
is: Cimetidine Hydrochloride Cimetidine contains
an imidazole ring, and is chemically related to histamine. Cimetidine hydrochloride has a bitter taste and characteristic
odor. Cimetidine hydrochloride is freely soluble
in water, soluble in alcohol, very slightly soluble in chloroform
and practically insoluble in ether. Single-dose Vials for Intramuscular or Intravenous
Administration: Cimetidine Injection,
USP is a sterile aqueous solution. Each mL contains cimetidine hydrochloride
equivalent to 150 mg cimetidine. May contain sodium hydroxide and/or
hydrochloric acid for pH adjustment. pH is 5.4 (3.8 to 6.0). Multiple-dose Vials for Intramuscular
or Intravenous Administration: Cimetidine
Injection, USP is a sterile aqueous solution. Each mL contains cimetidine
hydrochloride equivalent to 150 mg cimetidine; benzyl alcohol added
as a bacteriostatic preservative, 9 mg. May contain sodium hydroxide
and/or hydrochloric acid for pH adjustment. pH is 5.4 (3.8 to 6.0).
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Cimetidine competitively inhibits the action of histamine
at the histamine Hreceptors of the parietal cells and
thus is a histamine H-receptor antagonist. Cimetidine is not an anticholinergic agent. Studies have
shown that cimetidine inhibits both daytime and nocturnal basal gastric
acid secretion. Cimetidine also inhibits gastric acid secretion stimulated
by food, histamine, pentagastrin, caffeine and insulin. Antisecretory Activity Other Lower Esophageal Sphincter Pressure
and Gastric Emptying Cimetidine has
no effect on lower esophageal sphincter (LES) pressure or the rate
of gastric emptying. Pharmacokinetics The half-life
of cimetidine is approximately 2 hours. Both oral and parenteral (I.V.
or I.M.) administration provide comparable periods of therapeutically
effective blood levels; blood concentrations remain above that required
to provide 80% inhibition of basal gastric acid secretion for 4 to
5 hours following a dose of 300 mg. Steady-state
blood concentrations of cimetidine with continuous infusion of cimetidine
hydrochloride are determined by the infusion rate and clearance of
the drug in the individual patient. In a study of peptic ulcer patients
with normal renal function, an infusion rate of 37.5 mg/hour
produced average steady-state plasma cimetidine concentrations of
about 0.9 mcg/mL. Blood levels with other infusion rates will
vary in direct proportion to the infusion rate. The principal route of excretion of cimetidine is the urine. Following
parenteral administration, most of the drug is excreted as the parent
compound; following oral administration, the drug is more extensively
metabolized, the sulfoxide being the major metabolite. Following a
single oral dose, 48% of the drug is recovered from the urine after
24 hours as the parent compound. Following I.V. or I.M. administration,
approximately 75% of the drug is recovered from the urine after 24
hours as the parent compound.
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Cimetidine is contraindicated for patients known
to have hypersensitivity to the product.
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Cimetidine Injection, USP 300 mg/2 mL cimetidine
is supplied as follows: *For use with the LifeShield blunt
cannula. Store at 20 to 25��C (68 to 77��F).
[See USP Controlled Room Temperature.] Do not refrigerate. August, 2006
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General:: Rare instances of cardiac arrhythmias and hypotension
have been reported following the rapid administration of cimetidine
hydrochloride injection by intravenous bolus. Symptomatic response to cimetidine therapy does not preclude the
presence of a gastric malignancy. There have been rare reports of
transient healing of gastric ulcers despite subsequently documented
malignancy. Reversible confusional states (see
ADVERSE REACTIONS) have been observed on occasion, predominantly,
but not exclusively, in severely ill patients. Advancing age (50 or
more years) and pre-existing liver and/or renal disease appear to
be contributing factors. In some patients these confusional states
have been mild and have not required discontinuation of cimetidine
therapy. In cases where discontinuation was judged necessary, the
condition usually cleared within 3 to 4 days of drug withdrawal.<br/>Drug Interactions:: Cimetidine, apparently through an effect on certain
microsomal enzyme systems, has been reported to reduce the hepatic
metabolism of warfarin-type anticoagulants, phenytoin, propranolol,
nifedipine, chlordiazepoxide, diazepam, certain tricyclic antidepressants,
lidocaine, theophylline and metronidazole, thereby delaying elimination
and increasing blood levels of these drugs. Clinically significant effects have been reported with the warfarin
anticoagulants; therefore, close monitoring of prothrombin time is
recommended, and adjustment of the anticoagulant dose may be necessary
when cimetidine is administered concomitantly. Interaction with phenytoin,
lidocaine and theophylline has also been reported to produce adverse
clinical effects. However, a crossover study
in healthy subjects receiving either cimetidine 300 mg q.i.d. or 800 mg
h.s. concomitantly with a 300 mg b.i.d. dosage of theophylline extended-release
tablets demonstrated less alteration in steady-state theophylline
peak serum levels with the 800 mg h.s. regimen, particularly in subjects
aged 54 years and older. Data beyond ten days are not available. (Note:
All patients receiving theophylline should be monitored appropriately,
regardless of concomitant drug therapy.) Dosage
of the drugs mentioned above and other similarly metabolized drugs,
particularly those of low therapeutic ratio or in patients with renal
and/or hepatic impairment, may require adjustment when starting or
stopping concomitantly administered cimetidine to maintain optimum
therapeutic blood levels. Alteration of pH may
affect absorption of certain drugs (e.g., ketoconazole). If these
products are needed, they should be given at least 2 hours before
cimetidine administration. Additional clinical
experience may reveal other drugs affected by the concomitant administration
of cimetidine.<br/>Carcinogenesis, Mutagenesis,
Impairment of Fertility:: In a 24-month toxicity study conducted in rats, at
dose levels of 150, 378 and 950 mg/kg/day (approximately 8 to 48 times
the recommended human dose), there was a small increase in the incidence
of benign Leydig cell tumors in each dose group; when the combined
drug-treated groups and control groups were compared, this increase
reached statistical significance. In a subsequent 24 month study,
there were no differences between the rats receiving 150 mg/kg/day
and the untreated controls. However, a statistically significant increase
in benign Leydig cell tumor incidence was seen in the rats that received
378 and 950 mg/kg/day. These tumors were common in control groups
as well as treated groups and the difference became apparent only
in aged rats. Cimetidine has demonstrated a
weak antiandrogenic effect. In animal studies this was manifested
as reduced prostate and seminal vesicle weights. However, there was
no impairment of mating performance or fertility, nor any harm to
the fetus in these animals at doses 8 to 48 times the full therapeutic
dose of cimetidine, as compared with controls. The cases of gynecomastia
seen in patients treated for one month or longer may be related to
this effect. In human studies, cimetidine has
been shown to have no effect on spermatogenesis, sperm count, motility,
morphology or in vitro fertilizing
capacity.<br/>Pregnancy:: Teratogenic Effects.Pregnancy Category B: Reproduction
studies have been performed in rats, rabbits and mice at doses up
to 40 times the normal human dose and have revealed no evidence of
impaired fertility or harm to the fetus due to cimetidine. There are,
however, no adequate and well-controlled studies in pregnant women.
Because animal reproductive studies are not always predictive of human
response, this drug should be used during pregnancy only if clearly
needed.<br/>Nursing Mothers:: Cimetidine is secreted in human milk and, as a general
rule, nursing should not be undertaken while a patient is on a drug.<br/>Pediatric Use:: Clinical experience in pediatric patients is limited.
Therefore, cimetidine therapy cannot be recommended for pediatric
patients under 16, unless, in the judgment of the physician, anticipated
benefits outweigh the potential risks. In very limited experience,
doses of 20 to 40 mg/kg per day have been used. Immunocompromised Patients: In immunocompromised patients, decreased gastric acidity,
including that produced by acid-suppressing agents such as cimetidine,
may increase the possibility of a hyperinfection of strongyloidiasis.
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Studies in animals indicate that toxic doses are
associated with respiratory failure and tachycardia which may be controlled
by assisted respiration and the administration of a beta blocker. Reported acute ingestions orally of up to 20 grams have
been associated with transient adverse effects similar to those encountered
in normal clinical experience. The usual measures to remove unabsorbed
material from the gastrointestinal tract, clinical monitoring and
supportive therapy, should be employed. There
have been reports of severe CNS symptoms, including unresponsiveness,
following ingestion of between 20 and 40 grams of cimetidine, and
extremely rare reports following concomitant use of multiple CNS-
active medications and ingestion of cimetidine at doses less than
20 grams. An elderly, terminally ill dehydrated patient with organic
brain syndrome receiving concomitant antipsychotic agents and cimetidine
4800 mg intravenously over a 24 hour period experienced mental deterioration
with reversal on cimetidine discontinuation. There have been two deaths in adults who were reported to have ingested
over 40 grams orally on a single occasion.
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Cimetidine hydrochloride
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Cimetidine (Injection, Solution)
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Adverse effects reported in patients taking cimetidine
are described below by body system. Incidence figures of 1 in 100
and greater are generally derived from controlled clinical studies. Gastrointestinal: Diarrhea
(usually mild) has been reported in approximately 1 in 100 patients. CNS: Headaches, ranging
from mild to severe, have been reported in 3.5% of 924 patients taking
1600 mg/day, 2.1% of 2,225 patients taking 800 mg/day and 2.3% of
1,897 patients taking placebo. Dizziness and somnolence (usually mild)
have been reported in approximately 1 in 100 patients on either 1600
mg/day or 800 mg/day. Reversible confusional
states, e.g., mental confusion, agitation, psychosis, depression,
anxiety, hallucinations, disorientation, have been reported predominantly,
but not exclusively, in severely ill patients. They have usually developed
within 2 to 3 days of initiation of cimetidine therapy and have cleared
within 3 to 4 days of discontinuation of the drug. Endocrine: Gynecomastia has been
reported in patients treated for one month or longer. In patients
being treated for pathological hypersecretory states, this occurred
in about 4% of cases while in all others the incidence was 0.3% to
1% in various studies. No evidence of induced endocrine dysfunction
was found, and the condition remained unchanged or returned toward
normal with continuing cimetidine treatment. Reversible impotence has been reported in patients with pathological
hypersecretory disorders, e.g., Zollinger-Ellison Syndrome, receiving
cimetidine, particularly in high doses, for at least 12 months
(range 12 to 79 months, mean 38 months). However, in large-scale surveillance
studies at regular dosage, the incidence has not exceeded that commonly
reported in the general population. Hematologic: Decreased white blood cell
counts in cimetidine-treated patients (approximately 1 per 100,000
patients), including agranulocytosis (approximately 3 per million
patients), have been reported, including a few reports of recurrence
on rechallenge. Most of these reports were in patients who had serious
concomitant illnesses and received drugs and/or treatment known to
produce neutropenia. Thrombocytopenia (approximately 3 per million
patients) and, very rarely, cases of pancytopenia or aplastic anemia
have also been reported. As with some other H-receptor
antagonists, there have been extremely rare reports of immune hemolytic
anemia. Hepatobiliary: Dose-related increases in serum transaminase have been reported.
In most cases they did not progress with continued therapy and returned
to normal at the end of therapy. There have been rare reports of cholestatic
or mixed cholestatic hepatocellular effects. These were usually reversible.
Because of the predominance of cholestatic features, severe parenchymal
injury is considered highly unlikely. However, as in the occasional
liver injury with other H-receptor antagonists, in exceedingly
rare circumstances fatal outcomes have been reported. There has been reported a single case of biopsy-proven periportal
hepatic fibrosis in a patient receiving cimetidine. Rare cases of pancreatitis, which cleared on withdrawal of the drug,
have been reported. Hypersensitivity: Rare cases of fever and allergic reactions
including anaphylaxis and hypersensitivity vasculitis, which cleared
on withdrawal of the drug, have been reported. Renal: Small, possibly dose-related
increases in plasma creatinine, presumably due to competition for
renal tubular secretion, are not uncommon and do not signify deteriorating
renal function. Rare cases of interstitial nephritis and urinary retention,
which cleared on withdrawal of the drug, have been reported. Cardiovascular: Rare
cases of bradycardia, tachycardia and A-V heart block have been reported
with H-receptor antagonists. Musculoskeletal: There have been rare reports
of reversible arthralgia and myalgia; exacerbation of joint symptoms
in patients with pre-existing arthritis has also been reported. Such
symptoms have usually been alleviated by a reduction in cimetidine
dosage. Rare cases of polymyositis have been reported, but no causal
relationship has been established. Integumental: Mild rash and, very rarely,
cases of severe generalized skin reactions including Stevens-Johnson
syndrome, epidermal necrolysis, erythema multiforme, exfoliative dermatitis
and generalized exfoliative erythroderma have been reported with H-receptor antagonists. Reversible alopecia has been reported
very rarely. Immune
Function: There have been extremely rare reports of strongyloidiasis
hyperinfection in immunocompromised patients.
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Cimetidine Injection, USP is indicated in:
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dailymed-instance:name |
Cimetidine
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