Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/1139
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Cimetidine in Sodium Chloride (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. 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. 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. Note: 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. NOTE: The products accompanying this insert are for I.V.
infusion 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 DuodenalUlcer). 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 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 followgastric 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
oral dosage: 300 mg four times a day with meals and at bedtime. In some patients
it may be necessary to administer higher doses more frequently. Doses should
be adjusted to individual patient needs, but should not usually exceed 2400
mg per day and should continue as long as clinically indicated. 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 add other drugs to premixed Cimetidine in 0.9% Sodium
Chloride Injection, USP in plastic containers. All
parenteral drug products should be inspected visually for particulate matter
and discoloration prior to administration.
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Cimetidine in 0.9% Sodium Chloride Injection, USP is a sterile,
nonpyrogenic solution of cimetidine hydrochloride in 0.9% sodium chloride
injection. It is administered by the intravenous route. Each mL contains cimetidine
HCl equivalent to 6 mg cimetidine and sodium chloride 9 mg in water for injection.
The osmolar concentration is 356 mOsmol/L (calc.); pH is 6.0 (5.0 to 7.0).
May contain hydrochloric acid and/or sodium hydroxide for pH adjustment. The
solution contains no bacteriostat, antimicrobial agent or added buffer and
is intended only for use as a single-dose administration. When smaller doses
are required, the unused portion should be discarded. Cimetidine
hydrochloride 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. Sodium
Chloride, USP is chemically designated NaCI, a white crystalline compound
freely soluble in water. Water for Injection, USP is
chemically designated HO. The flexible plastic
container is fabricated from a specially formulated polyvinylchloride. Water
can permeate from inside the container into the overwrap but not in amounts
sufficient to affect the solution significantly. Solutions in contact with
the plastic container may leach out certain chemical components from the
plastic in very small amounts; however, biological testing was supportive
of the safety of the plastic container materials. Exposure to temperatures
above 25��C/77��F during transport and storage will lead to minor
losses in moisture content. Higher temperatures lead to greater losses. It
is unlikely that these minor losses will lead to clinically significant changes
within the expiration period.
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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 Cimetidine
is rapidly absorbed after oral administration and peak levels occur in 45
to 90 minutes. 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 basalgastric 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 drugis recovered from
the urine after 24 hours as the parent compound. Sodium
chloride in water dissociates to provide sodium (Na) and chloride
(Cl��) ions. Sodium (Na) is the principal cation of the extracellular
fluid and plays a large part in the therapy of fluid and electrolyte disturbances.
Chloride (Cl��) has an integral role in buffering action when oxygen and
carbon dioxide exchange occurs in the red blood cells. The distribution and
excretion of sodium (Na) are largely under the control of the
kidney which maintains a balance between intake and output. Water
is an essential constituent of all body tissues and accounts for approximately
70% of total body weight. Average normal adult daily
requirements range from two to three liters (1.0 to 1.5 liters each for insensible
water loss by perspiration and urine production). Waterbalance is maintained by various regulatory mechanisms. Water distribution
depends primarily on the concentration of electrolytes in the body compartments
and sodium (Na) plays a major role in maintaining physiologic
equilibrium.
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Cimetidine is contraindicated for patients known to have
hypersensitivity to the product.
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Cimetidine in 0.9% Sodium Chloride Injection, USP is supplied
in a single-dose flexible container as follows: Exposure of pharmaceutical products to heat should be minimized.
Avoid excessive heat. Protect from freezing. It is recommended that the product
be stored at room temperature (25��C/77��F). HOSPIRA, INC., LAKE FOREST,
IL 60045 USA
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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 preexisting 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. Studies
with solutions from flexible plastic containers have not been performed to
evaluate carcinogenic potential, mutagenic potential or effects on fertility.<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. Caution
should be exercised when solutions from flexible plastic containers are administered
to a nursing mother.<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. Safety and effectiveness of
solutions from flexible plastic containers in pediatric patients have not
been well established. 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 that 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 have been reported to have ingested over
40 grams orally on a single occasion.
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Cimetidine and Sodium Chloride
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Cimetidine in Sodium Chloride (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. The
collection of this information has been derived largely from trials associated
with oral cimetidine. 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 Hreceptor
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 preexisting 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 hydrochloride injection is indicated in: (1) Short-term treatment of active duodenal ulcer. Most
patients heal within 4 weeks and there is rarely reason to use cimetidine
at full dosage for longer than 6 to 8 weeks (see DOSAGE
AND ADMINISTRATION���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. (2) Maintenance therapy for duodenal ulcer patients at reduced
dosage after healing of active ulcer. Patients have been maintained
on continued treatment with cimetidine 400 mg h.s. for periods of up to five
years. (3) Short-term treatment
of active benign gastric ulcer. There is no information concerning
usefulness of treatment periods of longer than 8 weeks. (4) Prevention of upper gastrointestinal bleeding in critically
ill patients. (5)
The treatment of pathological hypersecretory conditions (i.e., Zollinger-Ellison
Syndrome, systemic mastocytosis, multiple endocrine adenomas).
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Cimetidine in Sodium Chloride
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