Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/3585
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ZANTAC (Injection, Solution)
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Parenteral Administration: In some hospitalized patients with pathological hypersecretory
conditions or intractable duodenal ulcers, or in patients who are unable to
take oral medication, ZANTAC Injection may be administered parenterally according
to the following recommendations:<br/>Intramuscular Injection: 50 mg (2 mL) every 6 to 8 hours. (No dilution
necessary.)<br/>Intermittent Intravenous Injection:<br/>Continuous Intravenous Infusion: Add ZANTAC Injection to 5% dextrose injection or other compatible
IV solution (see Stability). Deliver at a rate of 6.25 mg/h (e.g., 150 mg
[6 mL] of ZANTAC Injection in 250 mL of 5% dextrose injection at
10.7 mL/h). For Zollinger-Ellison patients, dilute
ZANTAC Injection in 5% dextrose injection or other compatible IV solution
(see Stability) to a concentration no greater than 2.5 mg/mL. Start the
infusion at a rate of 1.0 mg/kg per hour. If after 4 hours either a measured
gastric acid output is>10 mEq/h or the patient becomes symptomatic,
the dose should be adjusted upward in 0.5-mg/kg per hour increments, and the
acid output should be remeasured. Dosages up to 2.5 mg/kg per hour and
infusion rates as high as 220 mg/h have been used.<br/>Pediatric Use: While limited data exist on the administration of IV ranitidine
to children, the recommended dose in pediatric patients is for a total daily
dose of 2 to 4 mg/kg, to be divided and administered every 6 to 8 hours,
up to a maximum of 50 mg given every 6 to 8 hours. This recommendation
is derived from adult clinical studies and pharmacokinetic data in pediatric
patients. Limited data in neonatal patients (less than one month of age) receiving
ECMO have shown that a dose of 2 mg/kg is usually sufficient to increase
gastric pH to>4 for at least 15 hours. Therefore, doses of 2 mg/kg
given every 12 to 24 hours or as a continuous infusion should be considered.<br/>Dosage Adjustment for Patients With Impaired Renal Function: The administration of ranitidine as a continuous infusion
has not been evaluated in patients with impaired renal function. On the basis
of experience with a group of subjects with severely impaired renal function
treated with ZANTAC, the recommended dosage in patients with a creatinine
clearance<50 mL/min is 50 mg every 18 to 24 hours. Should
the patient's condition require, the frequency of dosing may be increased
to every 12 hours or even further with caution. Hemodialysis reduces
the level of circulating ranitidine. Ideally, the dosing schedule should be
adjusted so that the timing of a scheduled dose coincides with the end of
hemodialysis. Elderly patients are more likely to have
decreased renal function, therefore caution should be exercised in dose selection,
and it may be useful to monitor renal function (see CLINICAL PHARMACOLOGY:
Pharmacokinetics: Geriatric Use and PRECAUTIONS: Geriatric Use).<br/>Stability: Undiluted, ZANTAC Injection tends to exhibit a yellow color
that may intensify over time without adversely affecting potency. ZANTAC Injection
is stable for 48 hours at room temperature when added to or diluted with
most commonly used IV solutions, e.g., 0.9% sodium chloride injection, 5%
dextrose injection, 10% dextrose injection, lactated ringer's injection, or
5% sodium bicarbonate injection. Note: Parenteral drug products should be inspected visually for particulate
matter and discoloration before administration whenever solution and container
permit.<br/>Directions for Dispensing:<br/>Pharmacy Bulk Package���Not for Direct Infusion: The pharmacy bulk package is for use in a pharmacy admixture
service only under a laminar flow hood. The closure should be penetrated only
once with a sterile transfer set or other sterile dispensing device, which
allows measured distribution of the contents, and the contents dispensed in
aliquots using aseptic technique. CONTENTS SHOULD BE USED AS SOON AS POSSIBLE
FOLLOWING INITIAL CLOSURE PUNCTURE. DISCARDANY UNUSED PORTION WITHIN 24 HOURS
OF FIRST ENTRY. Following closure puncture, container should be maintained
below 30��C (86��F) under a laminar flow hood until contents are dispensed.
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dailymed-instance:descripti... |
The active ingredient in ZANTAC Injection is ranitidine
hydrochloride (HCl), a histamine H-receptor antagonist. Chemically
it is N[2-[[[5-[(dimethylamino)methyl]-2-furanyl]methyl]thio]ethyl]-N���-methyl-2-nitro-1,1-ethenediamine,
hydrochloride. It has the following structure: The
empirical formula is CHNOS���HCl,
representing a molecular weight of 350.87. Ranitidine
HCl is a white to pale yellow, granular substance that is soluble in water. ZANTAC
Injection is a clear, colorless to yellow, nonpyrogenic liquid. The yellow
color of the liquid tends to intensify without adversely affecting potency.
The pH of the injection solution is 6.7 to 7.3. Each
1 mL of aqueous solution contains ranitidine 25 mg (as the hydrochloride);
phenol 5 mg as preservative; and 0.96 mg of monobasic potassium
phosphate and 2.4 mg of dibasic sodium phosphate as buffers. A
pharmacy bulk package is a container of a sterile preparation for parenteral
use that contains many single doses. The contents are intended for use in
a pharmacy admixture program and are restricted to the preparation of admixtures
for intravenous (IV) infusion.
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ZANTAC is a competitive, reversible inhibitor of the action
of histamine at the histamine H-receptors, including receptors
on the gastric cells. ZANTAC does not lower serum Ca++ in hypercalcemic states.
ZANTAC is not an anticholinergic agent.<br/>Pharmacokinetics:<br/>Absorption: ZANTAC is absorbed very rapidly after intramuscular (IM)
injection. Mean peak levels of 576 ng/mL occur within 15 minutes or less following
a 50-mg IM dose. Absorption from IM sites is virtually complete, with a bioavailability
of 90% to 100% compared with intravenous (IV) administration. Following oral
administration, the bioavailability of ZANTAC Tablets is 50%.<br/>Distribution: The volume of distribution is about 1.4 L/kg. Serum protein
binding averages 15%.<br/>Metabolism: In humans, the N-oxide is the principal metabolite in the
urine; however, this amounts to<4% of the dose. Other metabolites are
the S-oxide (1%) and the desmethyl ranitidine (1%). The remainder of the administered
dose is found in the stool. Studies in patients with hepatic dysfunction (compensated
cirrhosis) indicate that there are minor, but clinically insignificant, alterations
in ranitidine half-life, distribution, clearance, and bioavailability.<br/>Excretion: Following IV injection, approximately 70% of the dose is
recovered in the urine as unchanged drug. Renal clearance averages 530 mL/min,
with a total clearance of 760 mL/min. The elimination half-life is 2.0 to
2.5 hours. Four patients with clinically significant
renal function impairment (creatinine clearance 25 to 35 mL/min) administered
50 mg of ranitidine intravenously had an average plasma half-life of
4.8 hours, a ranitidine clearance of 29 mL/min, and a volume of
distribution of 1.76 L/kg. In general, these parameters appear to be
altered in proportion to creatinine clearance (see DOSAGE AND ADMINISTRATION).<br/>Geriatrics: The plasma half-life is prolonged and total clearance is
reduced in the elderly population due to a decrease in renal function. The
elimination half-life is 3.1 hours (see PRECAUTIONS: Geriatric Use and
DOSAGE AND ADMINISTRATION: Dosage Adjustment for Patients with Impaired Renal
Function).<br/>Pediatrics: There are no significant differences in the pharmacokinetic
parameter values for ranitidine in pediatric patients (from 1 month up to
16 years of age) and healthy adults when correction is made for body weight.
The pharmacokinetics of ZANTAC in pediatric patients are summarized in Table
1. T= Terminal half-life;
CLp = Plasma clearance of ranitidine. ECMO
= extracorporeal membrane oxygenation. Plasma clearance
in neonatal patients (less than 1 month of age) receiving ECMO was considerably
lower (3 to 4 mL/min/kg) than observed in children or adults. The elimination
half-life in neonates averaged 6.6 hours as compared to approximately 2 hours
in adults and pediatric patients.<br/>Pharmacodynamics: Serum concentrations necessary to inhibit 50% of stimulated
gastric acid secretion are estimated to be 36 to 94 ng/mL. Following
single IV or IM 50-mg doses, serum concentrations of ZANTAC are in this range
for 6 to 8 hours.<br/>Antisecretory Activity:<br/>Other Pharmacologic Actions:<br/>Pediatrics: The ranitidine concentration necessary to suppress basal
acid secretion by at least 90% has been reported to be 40 to 60 ng/mL
in pediatric patients with duodenal or gastric ulcers. In
a study of 20 critically ill pediatric patients receiving ranitidine IV at
1 mg/kg every 6 hours, 10 patients with a baseline pH���4 maintained
this baseline throughout the study. Eight of the remaining 10 patients with
a baseline of pH���2 achieved pH���4 throughout varying periods
after dosing. It should be noted, however, that because these pharmacodynamic
parameters were assessed in critically ill pediatric patients, the data should
be interpreted with caution when dosing recommendations are made for a less
seriously ill pediatric population. In another small
study of neonatal patients (n = 5) receiving ECMO, gastric pH<4
pretreatment increased to>4 after a 2 mg/kg dose and remained above
4 for at least 15 hours.<br/>Clinical Trials:<br/>Active Duodenal Ulcer: In a multicenter, double-blind, controlled, US study of
endoscopically diagnosed duodenal ulcers, earlier healing was seen in the
patients treated with oral ZANTAC as shown in Table 3. *All patients were permitted p.r.n.
antacids for relief of pain. P<0.0001. In these
studies, patients treated with oral ZANTAC reported a reduction in both daytime
and nocturnal pain, and they also consumed less antacid than the placebo-treated
patients.<br/>Pathological Hypersecretory Conditions (such as Zollinger-Ellison syndrome): ZANTAC inhibits gastric acid secretion and reduces occurrence
of diarrhea, anorexia, and pain in patients with pathological hypersecretion
associated with Zollinger-Ellison syndrome, systemic mastocytosis, and other
pathological hypersecretory conditions (e.g., postoperative, "short-gut" syndrome,
idiopathic). Use of oral ZANTAC was followed by healing of ulcers in 8 of
19 (42%) patients who were intractable to previous therapy. In
a retrospective review of 52 Zollinger-Ellison patients given ZANTAC as a
continuous IV infusion for up to 15 days, no patients developed complications
of acid-peptic disease such as bleeding or perforation. Acid output was controlled
to���10 mEq/h.
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ZANTAC Injection is contraindicated for patients known to
have hypersensitivity to the drug.
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ZANTAC Injection, 25 mg/mL, containing phenol 0.5%
as preservative, in a 40-mL pharmacy bulk package (NDC 0173-0363-00). Store between 4��and 25��C (39��and 77��F);
excursions permitted to 30��C (86��F). Protect from light. Store vial
in carton until time of use. GlaxoSmithKline Research
Triangle Park, NC 27709 ZANTAC is a registered trademark
of Warner-Lambert Company, used under license. ��2006,
GlaxoSmithKline All rights reserved. July
2006 RL-2313
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General:<br/>Laboratory Tests: False-positive tests for urine protein with MULTISTIX'
may occur during therapy with ZANTAC, and therefore testing with sulfosalicylic
acid is recommended.<br/>Drug Interactions: Although ZANTAC has been reported to bind weakly to cytochrome
P-450 in vitro, recommended doses of the drug do not inhibit the action of
the cytochrome P-450���linked oxygenase enzymes in the liver. However,
there have been isolated reports of drug interactions that suggest that ZANTAC
may affect the bioavailability of certain drugs by some mechanism as yet unidentified
(e.g., a pH-dependent effect on absorption or a change in volume of distribution). Increased
or decreased prothrombin times have been reported during concurrent use of
ranitidine and warfarin. However, in human pharmacokinetic studies with dosages
of ranitidine up to 400 mg/day, no interaction occurred; ranitidine had
no effect on warfarin clearance or prothrombin time. The possibility of an
interaction with warfarin at dosages of ranitidine higher than 400 mg/day
has not been investigated. In a ranitidine-triazolam
drug-drug interaction study, triazolam plasma concentrations were higher during
b.i.d. dosing of ranitidine than triazolam given alone. The mean area under
the triazolam concentration-time curve (AUC) values in 18- to 60-year-old
subjects were 10% and 28% higher following administration of 75-mg and 150-mg
ranitidine tablets, respectively, than triazolam given alone. In subjects
older than 60 years of age, the mean AUC values were approximately 30% higher
following administration of 75-mg and 150-mg ranitidine tablets. It appears
that there were no changes in pharmacokinetics of triazolam and��-hydroxytriazolam,
a major metabolite, and in their elimination. Reduced gastric acidity due
to ranitidine may have resulted in an increase in the availability of triazolam.
The clinical significance of this triazolam and ranitidine pharmacokinetic
interaction is unknown.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: There was no indication of tumorigenic or carcinogenic effects
in life-span studies in mice and rats at oral dosages up to 2,000 mg/kg
per day. Ranitidine was not mutagenic in standard bacterial
tests (Salmonella, Escherichiacoli) for mutagenicity
at concentrations up to the maximum recommended for these assays. In
a dominant lethal assay, a single oral dose of 1,000 mg/kg to male rats
was without effect on the outcome of two matings per week for the next 9 weeks.<br/>Pregnancy:<br/>Teratogenic Effects: Pregnancy Category
B. Reproduction studies have been performed
in rats and rabbits at oral doses up to 160 times the human oral dose
and have revealed no evidence of impaired fertility or harm to the fetus due
to ZANTAC. There are, however, no adequate and well-controlled studies in
pregnant women. Because animal reproduction studies are not always predictive
of human response, this drug should be used during pregnancy only if clearly
needed.<br/>Nursing Mothers: ZANTAC is secreted in human milk. Caution should be exercised
when ZANTAC is administered to a nursing mother.<br/>Pediatric Use: The safety and effectiveness of ZANTAC Injection have been
established in the age-group of 1 month to 16 years for the treatment
of duodenal ulcer. Use of ZANTAC in this age-group is supported by adequate
and well-controlled studies in adults, as well as additional pharmacokinetic
data in pediatric patients, and an analysis of the published literature. Safety
and effectiveness in pediatric patients for the treatment of pathological
hypersecretory conditions have not been established. Limited
data in neonatal patients (less than one month of age) receiving ECMO suggest
that ZANTAC may be useful and safe for increasing gastric pH for patients
at risk of gastrointestinal hemorrhage.<br/>Geriatric Use: Clinical studies of ZANTAC Injection did not include sufficient
numbers of subjects aged 65 and over to determine whether they responded differently
from younger subjects. However, in clinical studies of oral formulations of
ZANTAC, of the total number of subjects enrolled in US and foreign controlled
clinical trials,for which there were subgroup analyses, 4,197 were 65 and
over, while 899 were 75 and over. No overall differences in safety or effectiveness
were observed between these subjects and younger subjects, and other reported
clinical experience has not identified differences in responses between the
elderly and younger patients, but greater sensitivity of some older individuals
cannot be ruled out. This drug is known to be substantially
excreted by the kidney and the risk of toxic reactions to this drug may be
greater in patients with impaired renal function. Because elderly patients
are more likely to have decreased renal function, caution should be exercised
in dose selection, and it may be useful to monitor renal function (see CLINICAL
PHARMACOLOGY: Pharmacokinetics: Geriatric Use and DOSAGE AND ADMINISTRATION:
Dosage Adjustment for Patients with Impaired Renal Function).
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dailymed-instance:overdosag... |
There has been virtually no experience with overdosage with
ZANTAC Injection and limited experience with oral doses of ranitidine. Reported
acute ingestions of up to 18 g orally have been associated with transient
adverse effects similar to those encountered in normal clinical experience
(see ADVERSE REACTIONS). In addition, abnormalities of gait and hypotension
have been reported. When overdosage occurs, clinical
monitoring and supportive therapy should be employed. Studies
in dogs receiving dosages of ZANTAC in excess of 225 mg/kg per day have
shown muscular tremors, vomiting, and rapid respiration. Single oral doses
of 1,000 mg/kg in mice and rats were not lethal. Intravenous LDvalues
in mice and rats were 77 and 83 mg/kg, respectively.
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ranitidine hydrochloride
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ZANTAC (Injection, Solution)
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Transient pain at the site of IM injection has been reported.
Transient local burning or itching has been reported with IV administration
of ZANTAC. The following have been reported as events
in clinical trials or in the routine management of patients treated with oral
or parenteral ZANTAC. The relationship to therapy with ZANTAC has been unclear
in many cases. Headache, sometimes severe, seems to be related to administration
of ZANTAC.<br/>Central Nervous System: Rarely, malaise, dizziness, somnolence, insomnia, and vertigo.
Rare cases of reversible mental confusion, agitation, depression, and hallucinations
have been reported, predominantly in severely ill elderly patients. Rare cases
of reversible blurred vision suggestive of a change in accommodation have
been reported. Rare reports of reversible involuntary motor disturbances have
been received.<br/>Cardiovascular: As with other H-blockers, rare reports of arrhythmias
such as tachycardia, bradycardia, asystole, atrioventricular block, and premature
ventricular beats.<br/>Gastrointestinal: Constipation, diarrhea, nausea/vomiting, abdominal discomfort/pain,
and rare reports of pancreatitis.<br/>Hepatic: In normal volunteers, SGPT values were increased to at least
twice the pretreatment levels in 6 of 12 subjects receiving 100 mg
q.i.d. intravenously for 7 days, and in 4 of 24 subjects receiving
50 mg q.i.d. intravenously for 5 days. There have been occasional
reports of hepatocellular, cholestatic, or mixed hepatitis, with or without
jaundice. In such circumstances, ranitidine should be immediately discontinued.
These events are usually reversible, but in rare circumstances death has occurred.
Rare cases of hepatic failure have also been reported.<br/>Musculoskeletal: Rare reports of arthralgias and myalgias.<br/>Hematologic: Blood count changes (leukopenia, granulocytopenia, and thrombocytopenia)
have occurred in a few patients. These were usually reversible. Rare cases
of agranulocytosis, pancytopenia, sometimes with marrow hypoplasia, and aplastic
anemia and exceedingly rare cases of acquired immune hemolytic anemia have
been reported.<br/>Endocrine: Controlled studies in animals and humans have shown no stimulation
of any pituitary hormone by ZANTAC and no antiandrogenic activity, and cimetidine-induced
gynecomastia and impotence in hypersecretory patients have resolved when ZANTAC
has been substituted. However, occasional cases of gynecomastia, impotence,
and loss of libido have been reported in male patients receiving ZANTAC, but
the incidence did not differ from that in the general population.<br/>Integumentary: Rash, including rare cases of erythema multiforme. Rare
cases of alopecia and vasculitis.<br/>Respiratory: A large epidemiological study suggested an increased risk
of developing pneumonia in current users of histamine-2-receptor antagonists
(HRAs) compared to patients who had stopped HRA treatment,
with an observed adjusted relative risk of 1.63 (95% CI, 1.07-2.48). However,
a causal relationship between use of HRAs and pneumonia has not
been established.<br/>Other: Rare cases of hypersensitivity reactions (e.g., bronchospasm,
fever, rash, eosinophilia), anaphylaxis, angioneurotic edema, and small increases
in serum creatinine.
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ZANTAC Injection is indicated in some hospitalized patients
with pathological hypersecretory conditions or intractable duodenal ulcers,
or as an alternative to the oral dosage form for short-term use in patients
who are unable to take oral medication.
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ZANTAC
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