Sodium Chloride Information
Sodium chloride (Heparin sodium)
Sodium chloride (Heparin sodium) Description
Cimetidine in 0.9% Sodium chloride (Heparin sodium) Injection, USP is a sterile,
nonpyrogenic solution of cimetidine hydrochloride in 0.9% Sodium chloride (Heparin sodium)
injection. It is administered by the intravenous route. Each mL contains cimetidine
HCl equivalent to 6 mg cimetidine and Sodium chloride (Heparin sodium) 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 -cyano--methyl--[2-[[(5-methyl-1-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.
Sodium chloride (Heparin sodium) Clinical Pharmacology
Cimetidine competitively inhibits the action of histamine
at the histamine H receptors 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.
Cimetidine has no effect on lower esophageal
sphincter (LES) pressure or the rate of gastric emptying.
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 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.
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.
Sodium chloride (Heparin sodium) Clinical Trials
Cimetidine
has been shown to be effective in the treatment of active duodenal ulcer and,
at reduced dosage, in maintenance therapy following healing of active ulcers.
*Averages from controlled clinical trials.
A
U.S., double-blind, placebo-controlled, dose-ranging study demonstrated that
all once-daily at bedtime (h.s.) cimetidine regimens were superior to placebo
in ulcer healing and that cimetidine 800 mg h.s. healed 75% of patients at
four weeks. The healing rate with 800 mg h.s. was significantly superior to
400 mg h.s. (66%) and not significantly different from 1600 mg h.s. (81%).
In
the U.S. dose-ranging trial, over 80% of patients receiving cimetidine 800
mg h.s. experienced nocturnal pain relief after one day. Relief from daytime
pain was reported in approximately 70% of patients after two days. As with
ulcer healing, the 800 mg h.s. dose was superior to 400 mg h.s. and not different
from 1600 mg h.s.
In foreign, double-blind studies with
cimetidine 800 mg h.s., 79% to 85% of patients were healed at four weeks.
While
short-term treatment with cimetidine can result in complete healing of the
duodenal ulcer, acute therapy will not prevent ulcer recurrence after cimetidine
has been discontinued. Some follow-up studies have reported that the rate
of recurrence once therapy was discontinued was slightly higher for patients
healed on cimetidine than for patients healed on other forms of therapy; however,
the cimetidine-treated patients generally had more severe disease.
In
numerous placebo-controlled studies conducted worldwide, the percent of patients
with observed ulcers at the end of one year's therapy with cimetidine 400
mg h.s. was significantly lower (10 to 45%) than in patients receiving placebo
(44% to 70%). Thus, from 55% to 90% of patients were maintained free of observed
ulcers at the end of one year with cimetidine 400 mg h.s.
Factors
such as smoking, duration and severity of disease, gender, and genetic traits
may contribute to variations in actual percentages.
Trials
of other anti-ulcer therapy, whether placebo-controlled, positive-controlled
or open, have demonstrated a range of results similar to that seen with cimetidine.
Cimetidine
has been shown to be effective in the short-term treatment of active benign
gastric ulcer.
In a multicenter, double-blind U.S. study,
patients with endoscopically confirmed benign gastric ulcer were treated with
cimetidine 300 mg four times a day or with placebo for six weeks. Patients
were limited to those with ulcers ranging from 0.5 to 2.5 cm in size. Endoscopically
confirmed healing at six weeks was seen in significantly* more cimetidine-treated
patients than in patients receiving placebo, as shown below:
In a similar multicenter U.S. study of the 800 mg h.s.
oral regimen, the endoscopically confirmed healing rates were:
Similarly, in worldwide double-blind clinical studies,
endoscopically evaluated benign gastric ulcer healing rates were consistently
higher with cimetidine than with placebo.
A
double-blind, placebo-controlled randomized study of continuous infusion cimetidine
was performed in 131 critically ill patients (mean APACHE II score = 15.99)
to compare the incidence of upper gastrointestinal bleeding, manifested as
hematemesis or bright red blood which did not clear after adjustment of the
nasogastric tube and a 5 to 10 minute lavage, persistent Gastroccult (R) positive
coffee grounds for 8 consecutive hours which did not clear with 100 cc lavage
and/or which were accompanied by a drop in hematocrit of 5 percent points,
or melena, with an endoscopically documented upper gastrointestinal source
of bleed. 14% (9/65) of patients treated with cimetidine continuous infusion
developed bleeding compared to 33% (22/66) of the placebo group. Coffee grounds
was the manifestation of bleeding that accounted for the difference between
groups. Another randomized, double-blind placebo-controlled study confirmed
these results for an end point of upper gastrointestinal bleeding with a confirmed
upper gastrointestinal source noted on endoscopy, and by post hoc analyses
of bleeding episodes between groups.
Cimetidine
significantly inhibited gastric acid secretion and reduced occurrence of diarrhea,
anorexia and pain in patients with pathological hypersecretion associated
with Zollinger-Ellison Syndrome, systemic mastocytosis and multiple endocrine
adenomas. Use of cimetidine was also followed by healing of intractable ulcers.
Sodium chloride (Heparin sodium) Indications And Usage
Cimetidine hydrochloride injection is indicated in:
Sodium chloride (Heparin sodium) Contraindications
Cimetidine is contraindicated for patients known to have
hypersensitivity to the product.
Sodium chloride (Heparin sodium) Precautions
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 ) 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.
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.
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 fertilizing capacity.
Studies
with solutions from flexible plastic containers have not been performed to
evaluate carcinogenic potential, mutagenic potential or effects on fertility.
Teratogenic Effects:
Pregnancy Category B:
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.
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:
Sodium chloride (Heparin sodium) Adverse Reactions
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.
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.
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.
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.
Sodium chloride (Heparin sodium) Overdosage
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.
Sodium chloride (Heparin sodium) Dosage And 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.
These doses maintained
the intragastric acid secretory rate at 10 mEq/hour or less. The infusion
rate should be adjusted to individual patient requirements.
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 ) 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 −).
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 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.
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 ). 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.
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.
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.
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.
All
parenteral drug products should be inspected visually for particulate matter
and discoloration prior to administration.
Sodium chloride (Heparin sodium) Instructions For Use
Tear
outer wrap at notch and remove solution container. Some opacity of the plastic
due to moisture absorption during the sterilization process may be observed.
This is normal and does not affect the solution quality or safety. The opacity
will diminish gradually.
Sodium chloride (Heparin sodium) How Supplied
Cimetidine in 0.9% Sodium chloride (Heparin sodium) 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).
