CIMETIDINE
DESCRIPTION:
Tagamed (cimetidine) is a histamine H2-receptor antagonist. Chemically it is
N''-cyano-N-methyl- N'-(2-(((5-methyl-1 H-imidazol-4-yl)methyl)thio)- ethyl)-
guanidine.
The empirical formula for cimetidine is C10H16N6S and for cimetidine
hydrochloride, C10H16N6SHCl; these represent molecular weights of 252.34 and
288.80, respectively.
Cimetidine contains an imidazole ring, and is chemically related to histamine.
(The liquid and injection dosage forms contain cimetidine as the hydrochloride.)
Cimetidine has a bitter taste and characteristic odor.
SOLUBILITY CHARACTERISTICS: Cimetidine is soluble in alcohol, slightly soluble
in water, very slightly soluble in chloroform and insoluble in ether. Cimetidine
hydrochloride is freely soluble in water, soluble in alcohol, very slightly
soluble in chloroform and practically insoluble in ether.
ACTIONS/CLINICAL PHARMACOLOGY:
Tagamed (cimetidine) competitively inhibits the action of histamine at the
histamine H2 receptors of the parietal cells and thus is a histamine H2-receptor
antagonist.
Tagamed is not an anticholinergic agent. Studies have shown that Tagamed
inhibits both daytime and nocturnal basal gastric acid secretion. Tagamed also
inhibits gastric acid secretion stimulated by food, histamine, pentagastrin,
caffeine and insulin.
ANTISECRETORY ACTIVITY
1) ACID SECRETION: Nocturnal: Tagamed 800 mg orally at bedtime reduces mean
hourly H+ activity by greater than 85% over an 8-hour period in duodenal ulcer
patients, with no effect on daytime acid secretion. Tagamed 1600 mg orally h.s.
produces 100% inhibition of mean hourly H+ activity over an 8-hour period in
duodenal ulcer patients, but also reduces H+ activity by 35% for an additional 5
hours into the following morning. Tagamed 400 mg b.i.d. and 300 mg q.i.d.
decrease nocturnal acid secretion in a dose-related manner, i.e., 47% to 83%
over a 6- to 8-hour period and 54% over a 9-hour period, respectively.
Food Stimulated: During the first hour after a standard experimental meal, oral
Tagamed 300 mg inhibited gastric acid secretion in duodenal ulcer patients by at
least 50%. During the subsequent 2 hours Tagamed inhibited gastric acid
secretion by at least 75%.
The effect of a 300 mg breakfast dose of Tagamed continued for at least 4 hours
and there was partial suppression of the rise in gastric acid secretion
following the luncheon meal in duodenal ulcer patients. This suppression of
gastric acid output was enhanced and could be maintained by another 300 mg dose
of Tagamed given with lunch.
In another study, Tagamed 300 mg given with the meal increased gastric pH as
compared with placebo.
MEAN GASTRIC PH
TAGAMED PLACEBO
1 hour 3.5 2.6
2 hours 3.1 1.6
3 hours 3.8 1.9
4 hours 6.1 2.2
24-Hour Mean H+ Activity: Tagamed 800 mg h.s., 400 mg b.i.d. and 300 mg q.i.d.
all provide a similar, moderate (less than 60%) level of 24-hour acid
suppression. However, the 800 mg h.s. regimen exerts its entire effect on
nocturnal acid, and does not affect daytime gastric physiology.
Chemically Stimulated: Oral Tagamed (cimetidine) significantly inhibited gastric
acid secretion stimulated by betazole (an isomer of histamine), pentagastrin,
caffeine and insulin as follows:
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STIMULANT
STIMULANT DOSE TAGAMED % INHIBITION
Betazole 1.5mg/kg 300mg 85% at 2 1/2
(sc) (po) hours
Penta- 6mcg/kg/ 100mg/hr 60% at 1
gastrin hr (iv) (iv) hour
Caffeine 5mg/kg/ 300mg 100% at 1
hr (iv) (po) hour
Insulin 0.03 units/ 100mg/hr 82% at 1
kg/hr (iv) (iv) hour
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When food and betazole were used to stimulate secretion, inhibition of hydrogen
ion concentration usually ranged from 45% to 75% and the inhibition of volume
ranged from 30% to 65%.
Parenteral administration also significantly inhibits gastric acid secretion. In
a crossover study involving patients with active or healed duodenal or gastric
ulcers, either continuous I.V. infusion of Tagamed 37.5 mg/hour (900 mg/day) or
intermittent injection of Tagamed 300 mg q6h (1200 mg/day) maintained gastric pH
above 4.0 for more than 50% of the time under steady-state conditions.
2) PEPSIN: Oral Tagamed 300 mg reduced total pepsin output as a result of the
decrease in volume of gastric juice.
3) INTRINSIC FACTOR: Intrinsic factor secretion was studied with betazole as a
stimulant. Oral Tagamed 300 mg inhibited the rise in intrinsic factor
concentration produced by betazole, but some intrinsic factor was secreted at
all times.
OTHER
LOWER ESOPHAGEAL SPHINCTER PRESSURE AND GASTRIC EMPTYING
Tagamed has no effect on lower esophageal sphincter (LES) pressure or the rate
of gastric emptying.
PHARMACOKINETICS
Tagamed is rapidly absorbed after oral administration and peak levels occur in
45 to 90 minutes. The half-life of Tagamed 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
Tagamed 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 Tagamed 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.
CLINICAL STUDIES:
CLINICAL TRIALS
DUODENAL ULCER
Tagamed (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.
ACTIVE DUODENAL ULCER: Tagamed accelerates the rate of duodenal ulcer healing.
Healing rates reported in U.S. and foreign controlled trials with Tagamed are
summarized below, beginning with the regimen providing the lowest nocturnal
dose.
DUODENAL ULCER HEALING RATES
WITH VARIOUS TAGAMED DOSAGE REGIMENS*
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300 MG 400 MG 800 MG 1600 MG
REGIMEN Q.I.D. B.I.D. H.S. H.S.
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week 4 68% 73% 80% 86%
week 6 80% 80% 89% --
week 8 -- 92% 94% --
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* Averages from controlled clinical trials.
A U.S., double-blind, placebo-controlled, dose- ranging study demonstrated that
all once-daily at bedtime (h.s.) Tagamed regimens were superior to placebo in
ulcer healing and that Tagamed 800 mg h.s. healed 75% of patients at 4 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 Tagamed 800 mg
h.s. experienced nocturnal pain relief after 1 day. Relief from daytime pain was
reported in approximately 70% of patients after 2 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 Tagamed 800mg h.s., 79% to 85% of patients
were healed at four weeks.
While short-term treatment with Tagamed (cimetidine) can result in complete
healing of the duodenal ulcer, acute therapy will not prevent ulcer recurrence
after Tagamed 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 Tagamed than for patients healed on other forms of therapy;
however, the Tagamed- treated patients generally had more severe disease.
MAINTENANCE THERAPY IN DUODENAL ULCER: Treatment with a reduced dose of Tagamed
has been proven effective as maintenance therapy following healing of active
duodenal ulcers.
In numerous placebo-controlled studies conducted worldwide, the percent of
patients with observed ulcers at the end of 1 year's therapy with Tagamed 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 1 year with Tagamed 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 Tagamed.
ACTIVE BENIGN GASTRIC ULCER
Tagamed 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 Tagamed 300 mg four times a day
or with placebo for 6 weeks. Patients were limited to those with ulcers ranging
from 0.5 to 2.5 cm in size. Endoscopically confirmed healing at 6 weeks was seen
in significantly* more Tagamed-treated patients than in patients receiving
placebo, as shown below:
TAGAMED PLACEBO
week 2 14/63 (22%) 7/63 (11%)
total at week 6 43/65 (66%)* 30/67 (45%)
*p<0.05
In a similar multicenter U.S. study of the 800 mg h.s. oral regimen, the
endoscopically confirmed healing rates were:
TAGAMED PLACEBO
total at week 6 63/83 (76%)* 44/80 (55%)
*p = 0.005
Similarly, in worldwide double-blind clinical studies, endoscopically evaluated
benign gastric ulcer healing rates were consistently higher with Tagamed than
with placebo.
GASTROESOPHAGEAL REFLUX DISEASE
In two multicenter, double-blind, placebo- controlled studies in patients with
gastroesophageal reflux disease (GERD) and endoscopically proven erosions and/or
ulcers, Tagamed was significantly more effective than placebo in healing
lesions. The endoscopically confirmed healing rates were:
P-VALUE
TAGAMED TAGAMED (800 mg
(800 mg (400 mg b.i.d. vs.
TRIAL b.i.d.) q.i.d.) PLACEBO placebo)
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1 Week 6 45% 52% 26% 0.02
Week 12 60% 66% 42% 0.02
2 Week 6 50% 20% <0.01
Week 12 67% 36% <0.01
In these trials Tagamed was superior to placebo by most measures in improving
symptoms of day- and night-time heartburn, with many of the differences
statistically significant. The q.i.d. regimen was generally somewhat better than
the b.i.d. regimen where these were compared.
PREVENTION OF UPPER GASTROINTESTINAL BLEEDING IN CRITICALLY ILL PATIENTS
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 percentage 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.
PATHOLOGICAL HYPERSECRETORY CONDITIONS
(such as Zollinger-Ellison Syndrome)
Tagamed 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 Tagamed was also followed by healing of intractable
ulcers.
INDICATIONS AND USAGE:
Tagamed (cimetidine) is indicated in:
(1) SHORT-TERM TREATMENT OF ACTIVE DUODENAL ULCER. Most patients heal within 4
weeks and there is rarely reason to use Tagamed 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 Tagamed and antacids is not recommended, since antacids have
been reported to interfere with the absorption of Tagamed.
(2) MAINTENANCE THERAPY FOR DUODENAL ULCER PATIENTS AT REDUCED DOSAGE AFTER
HEALING OF ACTIVE ULCER. Patients have been maintained on continued treatment
with Tagamed 400 mg h.s. for periods of up to 5 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) EROSIVE GASTROESOPHAGEAL REFLUX DISEASE (GERD). Erosive esophagitis
diagnosed by endoscopy. Treatment is indicated for 12 weeks for healing of
lesions and control of symptoms. The use of Tagamed beyond 12 weeks has not been
established (see Dosage and Administration- -GERD).
(5) PREVENTION OF UPPER GASTROINTESTINAL BLEEDING IN CRITICALLY ILL PATIENTS.
(6) THE TREATMENT OF PATHOLOGICAL HYPERSECRETORY CONDITIONS (i.e., Zollinger-
Ellison Syndrome, systemic mastocytosis, multiple endocrine adenomas).
CONTRAINDICATIONS:
Tagamed is contraindicated for patients known to have hypersensitivity to the
product.
PRECAUTIONS:
GENERAL: Rare instances of cardiac arrhythmias and hypotension have been
reported following the rapid administration of Tagamed (cimetidine
hydrochloride) Injection by intravenous bolus.
Symptomatic response to Tagamed 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 Tagamed therapy. In
cases where discontinuation was judged necessary, the condition usually cleared
within 3 to 4 days of drug withdrawal.
DRUG INTERACTIONS: Tagamed, 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 Tagamed 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 Tagamed 300 mg
q.i.d. or 800 mg h.s. concomitantly with a 300 mg b.i.d. dosage of theophylline
(Theo-Dur(R), Key Pharmaceuticals, Inc.) demonstrated less alteration in steady-
state theophylline peak serum levels with the 800mg h.s. regimen, particularly
in subjects aged 54 years and older. Data beyond 10 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 Tagamed 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 Tagamed.
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.
Tagamed (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 Tagamed, as compared with controls. The cases of gynecomastia seen in
patients treated for 1 month or longer may be related to this effect.
In human studies, Tagamed has been shown to have no effect on spermatogenesis,
sperm count, motility, morphology or In Vitro fertilizing capacity.
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 Tagamed. 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.
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.
PEDIATRIC USE: Clinical experience in children is limited. Therefore, Tagamed
therapy cannot be recommended for children 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.
DRUG INTERACTIONS:
Tagamed, 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 Tagamed 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 Tagamed 300 mg
q.i.d. or 800 mg h.s. concomitantly with a 300 mg b.i.d. dosage of theophylline
(Theo-Dur(R), Key Pharmaceuticals, Inc.) demonstrated less alteration in steady-
state theophylline peak serum levels with the 800mg h.s. regimen, particularly
in subjects aged 54 years and older. Data beyond 10 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 Tagamed 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 Tagamed.
(See Also PRECAUTIONS)
ADVERSE REACTIONS:
Adverse effects reported in patients taking Tagamed 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 1600mg/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 Tagamed therapy and have cleared
within 3 to 4 days of discontinuation of the drug.
ENDOCRINE: Gynecomastia has been reported in patients treated for 1 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
Tagamed (cimetidine) treatment.
Reversible impotence has been reported in patients with pathological
hypersecretory disorders, e.g., Zollinger-Ellison Syndrome, receiving Tagamed,
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 Tagamed-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 H2-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 H2-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 Tagamed.
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 H2-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 Tagamed (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 H2-receptor antagonists. Reversible alopecia has been
reported very rarely.
IMMUNE FUNCTION: There have been extremely rare reports of strongyloidiasis
hyperinfection in immunocompromised patients.
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 Tagamed 4800 mg intravenously over a 24-hour period
experienced mental deterioration with reversal on Tagamed discontinuation.
There have been two deaths in adults who were reported to have ingested over 40
grams orally on a single occasion.
DOSAGE AND ADMINISTRATION:
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 dosage regimen (h.s.).
In a U.S. 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 4 weeks, or those with persistent symptoms, have been shown to
benefit from 2 to 4 weeks of continued therapy.
It has been shown that patients who both have an endoscopically demonstrated
ulcer larger than 1.0 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 Tagamed 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 4 weeks
for this subpopulation. Alternatively, approximately 94% of all patients will
also heal in 8 weeks with Tagamed 800 mg h.s.
Other Tagamed 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 Tagamed and antacids is not recommended, since
antacids have been reported to interfere with the absorption of Tagamed
(cimetidine).
While healing with Tagamed 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 6 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 Tagamed does not preclude the presence of a gastric malignancy. It
is important to follow gastric ulcer patients to assure rapid progress to
complete healing.
EROSIVE GASTROESOPHAGEAL REFLUX DISEASE (GERD)
The recommended adult oral dosage for the treatment of erosive esophagitis that
has been diagnosed by endoscopy is 1600 mg daily in divided doses (800 mg b.i.d.
or 400 mg q.i.d.) for 12 weeks. The use of Tagamed beyond 12 weeks has not been
established.
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.
PARENTERAL ADMINISTRATION
In hospitalized patients with pathological hypersecretory conditions or
intractable ulcers, or in patients who are unable to take oral medication,
Tagamed may be administered parenterally.
The doses and regimen for parenteral administration in patients with GERD have
not been established.
All parenteral drug products should be inspected visually for particulate matter
and discoloration prior to administration.
RECOMMENDATIONS FOR PARENTERAL ADMINISTRATION:
INTRAMUSCULAR INJECTION: 300 mg q 6 to 8 hours (no dilution necessary).
Transient pain at the site of injection has been reported.
INTRAVENOUS INJECTION: 300 mg q 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 Tagamed (cimetidine hydrochloride) Injection, 300 mg, in
Sodium Chloride Injection (0.9%) or another compatible I.V. solution (see
Stability of Tagamed Injection) 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 q 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. VIALS: Dilute Tagamed Injection,
300 mg, in at least 50 mL of 5% Dextrose Injection, or another compatible I.V.
solution (see Stability of Tagamed Injection). PLASTIC CONTAINERS: Use premixed
Tagamed Injection, 300 mg, in 0.9% Sodium Chloride in 50 mL plastic containers.
ADD- VANTAGE(R) VIALS: Dilute contents of one vial in an ADD-Vantage(R) Diluent
Container, available in 50 mL and 100 mL sizes of 0.9% Sodium Chloride
Injection, and 5% Dextrose Injection.
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 Tagamed Injection in a compatible I.V. fluid (see Stability
of Tagamed Injection) for constant rate infusion over a 24-hour period. Note:
Tagamed may be diluted in 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.
DIRECTIONS FOR USE OF TAGAMED (CIMETIDINE HYDROCHLORIDE) INJECTION IN PLASTIC
CONTAINERS
To open: Tear overwrap down side at slit and remove solution containers.
Some opacity of the plastic due to moisture absorption during the sterilization
process may be observed. This is normal and does not affect solution quality or
safety. The opacity will diminish gradually.
DO NOT ADD OTHER DRUGS TO PREMIXED TAGAMED INJECTION IN PLASTIC CONTAINERS.
CAUTION: Check for minute leaks by squeezing inner bag firmly. If leaks are
found, discard solution as sterility may be impaired. Additives should not be
introduced into this solution. Do not use if the solution is cloudy or
precipitated or if the seal is not intact.
Do not use plastic containers in series connections. Such use could result in
air embolism due to residual air being drawn from the primary container before
administration of the fluid from the secondary container is complete.
Use sterile equipment.
PREPARATION FOR ADMINISTRATION:
1. Suspend container from eyelet support.
2. Remove plastic protector from outlet port at bottom of container.
3. Attach administration set. Refer to complete directions accompanying set.
DIRECTIONS FOR USE OF TAGAMED(R) INJECTION IN ADD-VANTAGE(R) VIALS are enclosed
in ADD- Vantage(R) Vial packaging.
STABILITY OF TAGAMED INJECTION
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 Solution, 5% Sodium Bicarbonate Injection, Tagamed (cimetidine
hydrochloride) Injection should not be used after more than 48 hours of storage
at room temperature.
Tagamed Injection premixed in plastic containers is stable through the labeled
expiration date when stored under the recommended conditions.
DOSAGE ADJUSTMENT FOR PATIENTS WITH IMPAIRED RENAL FUNCTION
Patients with severely impaired renal function have been treated with Tagamed.
However, such usage has been very limited. On the basis of this experience the
recommended dosage is 300 mg q 12 hours orally or by intravenous injection.
Should the patient's condition require, the frequency of dosing may be increased
to q 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 Tagamed. 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.
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