Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/1258
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Protonix (Injection, Powder, For Solution)
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PROTONIX I.V. for Injection
may be administered intravenously through a dedicated line or through
a Y-site. The intravenous line should be flushed before and after
administration of PROTONIX I.V. for Injection with either 5% Dextrose
Injection, USP, 0.9% Sodium Chloride Injection, USP, or Lactated Ringer's
Injection, USP. When administered through a Y-site, PROTONIX I.V.
for Injection is compatible with the following solutions: 5% Dextrose
Injection, USP, 0.9% Sodium Chloride Injection, USP, or Lactated Ringer's
Injection, USP. Midazolam
HCl has been shown to be incompatible with Y-site administration of
PROTONIX I.V. for Injection. PROTONIX I.V. for Injection
may not be compatible with products containing zinc. When PROTONIX I.V.
for Injection is administered through a Y-site, immediately stop use
if precipitation or discoloration occurs. Parenteral drug products should be inspected visually for particulate
matter and discoloration prior to and during administration whenever
solution and container permit. Treatment with PROTONIX I.V. for Injection should be discontinued
as soon as the patient is able to be treated with PROTONIX Delayed-Release
Tablets. Also, data on the safe and effective dosing for conditions
other than those described in INDICATIONS AND USAGE, such as life-threatening
upper gastrointestinal bleeds, are not available. PROTONIX I.V. 40 mg
once daily does not raise gastric pH to levels sufficient to contribute
to the treatment of such life-threatening conditions. Parenteral routes of administration
other than intravenous are not recommended. No dosage adjustment is necessary in patients with renal impairment,
hepatic impairment, or for elderly patients. Doses higher than 40 mg/day
have not been studied in hepatically-impaired patients. No dosage
adjustment is necessary in patients undergoing hemodialysis.<br/>Treatment of Gastroesophageal Reflux Disease Associated With
a History of Erosive Esophagitis: The recommended
adult dose is 40 mg pantoprazole given once daily by intravenous infusion
for 7 to 10 days. Safety and efficacy of PROTONIX I.V. for Injection
as a treatment of patients with GERD and a history of erosive esophagitis
for more than 10 days have not been demonstrated .<br/>Fifteen Minute Infusion: PROTONIX
I.V. for Injection should be reconstituted with 10 mL of 0.9%
Sodium Chloride Injection, USP, and further diluted (admixed) with
100 mL of 5% Dextrose Injection, USP, 0.9% Sodium Chloride
Injection, USP, or Lactated Ringer's Injection, USP, to a final
concentration of approximately 0.4 mg/mL. The reconstituted solution
may be stored for up to 6 hours at room temperature prior to
further dilution. The admixed solution may be stored at room temperature
and must be used within 24 hours from the time of initial reconstitution.
Both the reconstituted solution and the admixed solution do not need
to be protected from light. PROTONIX I.V. for Injection admixtures should be administered intravenously
over a period of approximately 15 minutes at a rate of approximately 7 mL/min.<br/>Two Minute Infusion: PROTONIX
I.V. for Injection should be reconstituted with 10 mL of 0.9%
Sodium Chloride Injection, USP, to a final concentration of approximately
4 mg/mL. The reconstituted solution may be stored for up to 24
hours at room temperature prior to intravenous infusion and does not
need to be protected from light. PROTONIX I.V. for Injection should
be administered intravenously over a period of at least 2 minutes.<br/>Pathological Hypersecretion Associated with Zollinger-Ellison
Syndrome: The dosage of PROTONIX
I.V. for Injection in patients with pathological hypersecretory conditions
associated with Zollinger-Ellison Syndrome or other neoplastic conditions
varies with individual patients. The recommended adult dosage is 80 mg q12h.
The frequency of dosing can be adjusted to individual patient needs
based on acid output measurements. In those patients who need a higher
dosage, 80 mg q8h is expected to maintain acid output below
10 mEq/h. Daily doses higher than 240 mg or administered
for more than 6 days have not been studied. (See Clinical Studies section.) Transition from oral to I.V. and from I.V. to
oral formulations of gastric acid inhibitors should be performed in
such a manner to ensure continuity of effect of suppression of acid
secretion. Patients with Zollinger-Ellison Syndrome may be vulnerable
to serious clinical complications of increased acid production even
after a short period of loss of effective inhibition.<br/>Fifteen Minute Infusion: Each vial
of PROTONIX I.V. for Injection should be reconstituted with 10 mL
of 0.9% Sodium Chloride Injection, USP. The contents of the two vials
should be combined and further diluted (admixed) with 80 mL of
5% Dextrose Injection, USP, 0.9% Sodium Chloride Injection, USP, or
Lactated Ringer's Injection, USP, to a total volume of 100 mL
with a final concentration of approximately 0.8 mg/mL. The reconstituted
solution may be stored for up to 6 hours at room temperature prior
to further dilution. The admixed solution may be stored at room temperature
and must be used within 24 hours from the time of initial reconstitution.
Both the reconstituted solution and the admixed solution do not need
to be protected from light. PROTONIX I.V. for Injection should be administered intravenously
over a period of approximately 15 minutes at a rate of approximately 7 mL/min.<br/>Two minute Infusion: PROTONIX
I.V. for Injection should be reconstituted with 10 mL of 0.9%
Sodium Chloride Injection, USP, per vial to a final concentration
of approximately 4 mg/mL. The reconstituted solution may be stored
for up to 24 hours at room temperature prior to intravenous infusion
and does not need to be protected from light. The total volume from
both vials should be administered intravenously over a period of at
least 2 minutes.
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The active ingredient in
PROTONIX I.V. (pantoprazole sodium) for Injection
is a substituted benzimidazole, sodium 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl]
sulfinyl]-1H-benzimidazole, a compound that inhibits gastric acid
secretion. Its empirical formula is CHFNNaOS, with a molecular weight of
405.4. The structural formula is: Pantoprazole sodium is a white to off-white
crystalline powder and is racemic. Pantoprazole has weakly basic and
acidic properties. Pantoprazole sodium is freely soluble in water,
very slightly soluble in phosphate buffer at pH 7.4, and practically
insoluble in n-hexane. The stability of the compound in aqueous solution
is pH-dependent. The rate of degradation increases with decreasing
pH. The reconstituted solution of PROTONIX I.V. for Injection is in
the pH range 9.0 to 10.5. PROTONIX I.V. for Injection is supplied as a freeze-dried powder
in a clear glass vial fitted with a rubber stopper and crimp seal
containing pantoprazole sodium, equivalent to 40 mg of pantoprazole,
edetate disodium (1 mg), and sodium hydroxide to adjust pH.
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Pharmacokinetics: Pantoprazole peak
serum concentration (C) and area under the serum concentration-time
curve (AUC) increase in a manner proportional to intravenous doses
from 10 mg to 80 mg. Pantoprazole does not accumulate and
its pharmacokinetics are unaltered with multiple daily dosing. Following
the administration of PROTONIX I.V. for Injection, the serum concentration
of pantoprazole declines biexponentially with a terminal elimination
half-life of approximately one hour. In extensive metabolizers with normal liver function receiving a 40 mg dose
of PROTONIX I.V. for Injection by constant rate over 15 minutes, the
peak concentration (C) is 5.52��g/mL and
the total area under the plasma concentration versus time curve (AUC)
is 5.4��g��hr/mL. The total clearance is
7.6-14.0 L/h and the apparent volume of distribution is 11.0-23.6 L.<br/>Distribution: The apparent
volume of distribution of pantoprazole is approximately 11.0-23.6 L,
distributing mainly in extracellular fluid. The serum protein binding
of pantoprazole is about 98%, primarily to albumin.<br/>Metabolism: Pantoprazole
is extensively metabolized in the liver through the cytochrome P450
(CYP) system. Pantoprazole metabolism is independent of the route
of administration (intravenous or oral). The main metabolic pathway
is demethylation, by CYP2C19, with subsequent sulfation; other metabolic
pathways include oxidation by CYP3A4. There is no evidence that any
of the pantoprazole metabolites have significant pharmacologic activity.
CYP2C19 displays a known genetic polymorphism due to its deficiency
in some sub-populations (e.g., 3% of Caucasians and African-Americans
and 17-23% of Asians). Although these sub-populations of slow pantoprazole
metabolizers have elimination half-life values from 3.5 to 10.0 hours,
they still have minimal accumulation (���23%) with once daily
dosing.<br/>Elimination: After administration
of a single intravenous dose ofC-labeled pantoprazole
to healthy, normal metabolizer subjects, approximately 71% of the
dose was excreted in the urine with 18% excreted in the feces
through biliary excretion. There was no renal excretion of unchanged
pantoprazole.<br/>Special Populations:<br/>Drug-Drug Interactions: Pantoprazole is
metabolized mainly by CYP2C19 and to minor extents by CYPs 3A4, 2D6
and 2C9. In in vivo drug-drug
interaction studies with CYP2C19 substrates (diazepam [also a CYP3A4
substrate] and phenytoin [also a CYP3A4 inducer]), nifedipine, midazolam,
and clarithromycin (CYP3A4 substrates), metoprolol (a CYP2D6 substrate),
diclofenac, naproxen and piroxicam (CYP2C9 substrates) and theophylline
(a CYP1A2 substrate) in healthy subjects, the pharmacokinetics of
pantoprazole were not significantly altered. It is, therefore, expected
that other drugs metabolized by CYPs 2C19, 3A4, 2D6, 2C9 and 1A2 would
not significantly affect the pharmacokinetics of pantoprazole.In vivo studies also suggest that
pantoprazole does not significantly affect the kinetics of other drugs
(cisapride, theophylline, diazepam [and its active metabolite, desmethyldiazepam],
phenytoin, warfarin, metoprolol, nifedipine, carbamazepine, midazolam,
clarithromycin, naproxen, piroxicam and oral contraceptives [levonorgestrel/ethinyl
estradiol]) metabolized by CYPs 2C19, 3A4, 2D6, 2C9 and 1A2. Therefore,
it is expected that pantoprazole would not significantly affect the
pharmacokinetics of other drugs metabolized by these isozymes. Dosage
adjustment of such drugs is not necessary when they are co-administered
with pantoprazole. In other in vivo studies, digoxin, ethanol, glyburide, antipyrine, caffeine, metronidazole,
and amoxicillin had no clinically relevant interactions with pantoprazole.
Although no significant drug-drug interactions have been observed
in clinical studies, the potential for significant drug-drug interactions
with more than once daily dosing with high doses of pantoprazole has
not been studied in poor metabolizers or individuals who are hepatically
impaired.<br/>Pharmacodynamics:<br/>Mechanism of Action: Pantoprazole
is a proton pump inhibitor (PPI) that suppresses the final step in
gastric acid production by covalently binding to the (H, K)-ATPase enzyme system at the secretory surface of
the gastric parietal cell. This effect leads to inhibition of both
basal and stimulated gastric acid secretion irrespective of the stimulus.
The binding to the (H, K)-ATPase results in
a duration of antisecretory effect that persists longer than 24 hours
for all doses tested.<br/>Antisecretory Activity: The magnitude
and time course for inhibition of pentagastrin-stimulated acid output
(PSAO) by single doses (20 to 120 mg) of PROTONIX I.V. for Injection
were assessed in a single-dose, open-label, placebo-controlled, dose-response
study. The results of this study are shown in the table below. Healthy
subjects received a continuous infusion for 25 hours of pentagastrin
(PG) at 1��g/kg/h, a dose known to produce submaximal gastric
acid secretion. The placebo group showed a sustained, continuous acid
output for 25 hours, validating the reliability of the testing model.
PROTONIX I.V. for Injection had an onset of antisecretory activity
within 15 to 30 minutes of administration. Doses of
20 to 80 mg of PROTONIX I.V. for Injection substantially reduced
the 24-hour cumulative PSAO in a dose-dependent manner, despite a
short plasma elimination half-life. Complete suppression of PSAO was
achieved with 80 mg within approximately 2 hours and no further
significant suppression was seen with 120 mg. The duration of
action of PROTONIX I.V. for Injection was 24 hours. In one
study of gastric pH in healthy subjects, pantoprazole was administered
orally (40 mg enteric coated tablets) or intravenously (40 mg)
once daily for 5 days and pH was measured for 24 hours following the
fifth dose. The outcome measure was median percent of time that pH
was���4 and the results were similar for intravenous and oral
medications; however, the clinical significance of this parameter
is unknown.<br/>Serum Gastrin Effects: Serum gastrin
concentrations were assessed in two placebo-controlled studies. In a 5-day study
of oral pantoprazole with 40 and 60 mg doses in healthy subjects,
following the last dose on day 5, median 24-hour serum gastrin concentrations
were elevated by 3-4 fold compared to placebo in both 40 and 60 mg
dose groups. However, by 24 hours following the last dose, median
serum gastrin concentrations for both groups returned to normal levels. In another placebo-controlled,
7-day study of 40 mg intravenous or oral pantoprazole in patients
with GERD and a history of erosive esophagitis, the mean serum gastrin
concentration increased approximately 50% from baseline and as compared
with placebo, but remained within the normal range. During 6 days of repeated
administration of PROTONIX I.V. for Injection in patients with Zollinger-Ellison
Syndrome, consistent changes of serum gastrin concentrations from
baseline were not observed.<br/>Enterochromaffin-Like (ECL) Cell Effects: There are
no data available on the effects of intravenous pantoprazole on ECL
cells. In a nonclinical study in Sprague-Dawley rats, lifetime exposure
(24 months) to pantoprazole at doses of 0.5 to 200 mg/kg/day
resulted in dose-related increases in gastric ECL-cell proliferation
and gastric neuroendocrine (NE)-cell tumors. Gastric NE-cell tumors
in rats may result from chronic elevation of serum gastrin concentrations.
The high density of ECL cells in the rat stomach makes this species
highly susceptible to the proliferative effects of elevated gastrin
concentrations produced by proton pump inhibitors. However, there
were no observed elevations in serum gastrin following theadministration
of pantoprazole at a dose of 0.5 mg/kg/day. In a separate study,
a gastric NE-cell tumor without concomitant ECL-cell proliferative
changes was observed in 1 female rat following 12 months of dosing
with pantoprazole at 5 mg/kg/day and a 9 month off-dose recovery
(see PRECAUTIONS,
Carcinogenesis, Mutagenesis, Impairment of Fertility).<br/>Other Effects: No clinically
relevant effects of pantoprazole on cardiovascular, respiratory, ophthalmic,
or central nervous system function have been detected. In a clinical
pharmacology study, pantoprazole 40 mg given orally once daily
for 2 weeks had no effect on the levels of the following hormones:
cortisol, testosterone, triiodothyronine (T3), thyroxine (T4), thyroid-stimulating
hormone, thyronine-binding protein, parathyroid hormone, insulin,
glucagon, renin, aldosterone, follicle-stimulating hormone, luteinizing
hormone, prolactin and growth hormone.<br/>Clinical Studies:<br/>Gastroesophageal Reflux Disease (GERD) Associated With a History
of Erosive Esophagitis: A multicenter,
double-blind, two-period placebo-controlled study was conducted to
assess the ability of PROTONIX I.V. (pantoprazole
sodium) for Injection to maintain gastric acid suppression in patients
switched from the oral dosage form of pantoprazole to the intravenous
dosage form. Gastroesophageal reflux disease (GERD) patients (n=65,
26 to 64 years; 35 female; 9 black, 11 Hispanic, 44 white, 1 other)
with a history of erosive esophagitis were randomized to receive either
20 or 40 mg of oral pantoprazole once per day for 10 days (period
1) and, then were switched in period 2 to either daily intravenous
pantoprazole or placebo for 7 days, matching their respective dose
level from period 1. Patients were administered all test medication
with a light meal. Maximum acid output (MAO) and basal acid output
(BAO) were determined 24 hours following the last day of oral medication
(day 10), the first day (day 1) of intravenous administration and
the last day of intravenous administration (day 7). MAO was estimated
from a 1 hour continuous collection of gastric contents following
subcutaneous injection of 6.0��g/kg of pentagastrin. This study demonstrated
that, after 10 days of repeated oral administration followed by 7
days of intravenous administration, the oral and intravenous dosage
forms of PROTONIX 40 mg are similar in their ability to suppress
MAO and BAO in patients with GERD and a history of erosive esophagitis
(see table below). Also, patients
on oral PROTONIX who were switched to intravenous placebo experienced
a significant increase in acid output within 48 hoursof their last
oral dose. However, at 48 hours after their last oral dose, patients
treated with PROTONIX I.V. for Injection had a significantly lower
mean basal acid output than those treated with placebo. To evaluate
the effectiveness of PROTONIX I.V. (pantoprazole sodium) for Injection
as an initial treatment to suppress gastric acid secretion, two studies
were conducted. Study 1 was a multicenter, double-blind, placebo controlled, study
of the pharmacodynamic effects of PROTONIX I.V. for Injection and
oral PROTONIX. Patients with GERD and a history of erosive esophagitis
(n=78, 20-67 years; 39 females; 7 black, 19 Hispanic, 52 white) were
randomized to receive either 40 mg intravenous pantoprazole, 40 mg
oral pantoprazole, or placebo once daily for 7 days. Following an
overnight fast, test medication was administered and patients were
given a light meal within 15 minutes. MAO and BAO were determined
24 hours following the last day of study medication. MAO was estimated
from a 1 hour continuous collection of gastric contents following
subcutaneous injection of 6.0��g/kg of pentagastrin to stimulate
acid secretion. This study demonstrated that, after treatment for
7 days, patients treated with PROTONIX I.V. for Injection had a significantly
lower MAO and BAO than those treated with placebo (p<0.001), and
results were comparable to those of patients treated with oral PROTONIX
(see table below). Study
2 was a single-center, double-blind, parallel-group study to compare
the clinical effects of PROTONIX I.V. for Injection and oral PROTONIX.
Patients (n=45, median age 56 years, 21 males and 24 females)
with acute endoscopically proven reflux esophagitis (Savary/Miller
Stage II or III) with at least 1 of 3 symptoms typical for reflux
esophagitis (acid eructation, heartburn, or pain on swallowing) were
randomized to receive either 40 mg intravenous pantoprazole or 40
mg oral pantoprazole daily for 5 days. After the initial 5 days, all
patients were treated with 40 mg oral pantoprazole daily tocomplete
a total of 8 weeks of treatment. Symptom relief was assessed by calculating
the daily mean of the sums of the average scores for these 3 symptoms
and the daily mean of the average score for each of the symptoms separately.
There was no significant difference in symptom relief between PROTONIX
I.V. and oral PROTONIX therapy within the first 5 days. A repeat endoscopy
after 8 weeks of treatment revealed that 20 out of 23 (87%) of the
PROTONIX I.V. plus oral PROTONIX patients and 19 out of 22 (86%)
of the oral PROTONIX patients had endoscopically proven healing of
their esophageal lesions. Data comparing PROTONIX I.V. for Injection to other proton pump inhibitors
(oral or I.V.) or H2 receptor antagonists (oral or I.V.) are limited,
and therefore, are inadequate to support any conclusions regarding
comparative efficacy.<br/>Pathological Hypersecretion Associated with Zollinger-Ellison
Syndrome: Two studies
measured the pharmacodynamic effects of 6 day treatment with PROTONIX
I.V. for Injection in patients with Zollinger-Ellison Syndrome (with
and without multiple endocrine neoplasia type I). In one of these
studies, an initial treatment with PROTONIX I.V. for Injection in
21 patients (29 to 75 years; 8 female; 4 black, 1 Hispanic, 16 white)
reduced acid output to the target level (���10 mEq/h)
and significantly reduced Hconcentration and the volume
of gastric secretions; target levels were achieved within 45 minutes
of drug administration. In the other study of 14 patients (38 to 67 years; 5 female; 2 black,
12 white) with Zollinger-Ellison Syndrome, treatment was switched
from an oral proton pump inhibitor to PROTONIX I.V. for Injection.
PROTONIX I.V. for Injection maintained or improved control of gastric
acid secretion. In both studies, PROTONIX I.V. for Injection 160 or 240 mg per
day in divided doses maintained basal acid secretion below target
levels in all patients. Target levels were 10 mEq/h in patients
without prior gastric surgery, and 5 mEq/h in all patients with
prior gastric acid-reducing surgery. Once gastric acid secretion
was controlled, there was no evidence of tolerance during this 7 day
study. Basal acid secretion was maintained below target levels for
at least 24 hours in all patients and through the end of treatment
in these studies (3 to 7 days) in all but 1 patient who required a
dose adjustment guided by acid output measurements until acid control
was achieved. In both studies, doses were adjusted to the individual
patient need, but gastric acid secretion was controlled in greater
than 80% of patients by a starting regimen of 80 mg q12h.
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PROTONIX I.V. for Injection
is contraindicated in patients with known hypersensitivity to the
formulation.
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PROTONIX I.V. (pantoprazole sodium) for Injection is supplied as a freeze-dried
powder containing 40 mg of pantoprazole per vial. PROTONIX I.V. for Injection is
available as follows: NDC 0008-0923-51 One carton containing 1 vial of PROTONIX I.V.
for Injection (each vial containing 40-mg pantoprazole).<br/>Storage: Store PROTONIX I.V.
for Injection vials at 20��- 25��C (68��- 77��F);
excursions permitted to 15��- 30��C (59��- 86��F).
[See USP Controlled Room Temperature.] Protect from light. Caution: the reconstituted
product should not be frozen. U.S. Patent No. 4,758,579 Marketed by Wyeth Pharmaceuticals Inc.Philadelphia, PA 19101under license fromALTANA PharmaD78467 Konstanz, Germany W10447C015ET01Rev 04/07
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General: Immediate hypersensitivity
reactions: Anaphylaxis has been reported with use of intravenous pantoprazole.
This may require emergency medical treatment. Injection site reactions: Thrombophlebitis was associated with the
administration of intravenous pantoprazole. Hepatic effects: Mild, transient transaminase elevations have been
observed in clinical studies. The clinical significance of this finding
in a large population of subjects administered intravenous pantoprazole
is unknown. (See ADVERSE
REACTIONS section). Symptomatic response to therapy with pantoprazole does not preclude
the presence of gastric malignancy. As with any other intravenous product containing edetate disodium
(the salt form of EDTA) which is a potent chelator of metal ions including
zinc, zinc supplementation should be considered in patients treated
with PROTONIX I.V. for Injection who are prone to zinc deficiency.
Caution should be used when other EDTA containing products are also
co-administered intravenously. Treatment with PROTONIX I.V. (pantoprazole sodium)
for Injection should be discontinued as soon as the patient is able
to resume treatment with PROTONIX Delayed-Release Tablets.<br/>Drug Interactions: Pantoprazole is
metabolized through the cytochrome P450 system, primarily the CYP2C19
and CYP3A4 isozymes, and subsequently undergoes Phase II conjugation.
(See CLINICAL PHARMACOLOGY,
Drug-Drug Interactions.) Based on studies evaluating possible interactions of pantoprazole
with other drugs, no dosage adjustment is needed with concomitant
use of the following: theophylline, cisapride, antipyrine, caffeine,
carbamazepine, diazepam (and its active metabolite, desmethyldiazepam),
diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral
contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine,
phenytoin, warfarin (see below), midazolam, clarithromycin, metronidazole,
or amoxicillin. Clinically relevant interactions of pantoprazole with
other drugs with the same metabolic pathways are not expected. Therefore,
when co-administered with pantoprazole, adjustment of the dosage of
pantoprazole or of such drugs may not be necessary. There was also
no interaction with concomitantly administered antacids. There have
been postmarketing reports of increased INR and prothrombin time in
patients receiving proton pump inhibitors, including pantoprazole,
and warfarin concomitantly. Increases in INR and prothrombin time
may lead to abnormal bleeding and even death. Patients treated with
proton pump inhibitors and warfarin concomitantly should be monitored
for increases in INR and prothrombin time. Based on information about other proton pump inhibitors, concomitant
administration of pantoprazole may reduce the plasma levels of atazanavir.
Appropriate clinical monitoring is recommended. Because of profound and long lasting inhibition of gastric acid secretion,
pantoprazole may interfere with absorption of drugs where gastric
pH is an important determinant of their bioavailability (e.g., ketoconazole,
ampicillin esters, and iron salts).<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: In a 24-month carcinogenicity
study, Sprague-Dawley rats were treated orally with doses of 0.5 to
200 mg/kg/day, about 0.1 to 40 times the exposure on a body surface
area basis, of a 50-kg person dosed at 40 mg/day. In the gastric
fundus, treatment at 0.5 to 200 mg/kg/day produced enterochromaffin-like
(ECL) cell hyperplasia and benign and malignant neuroendocrine cell
tumors in a dose-related manner. In the forestomach, treatment at
50 and 200 mg/kg/day (about 10 and 40 times the recommended human
dose on a body surface area basis) produced benign squamous cell papillomas
and malignant squamous cell carcinomas. Rare gastrointestinal tumors
associated with pantoprazole treatment included an adenocarcinoma
of the duodenum at 50 mg/kg/day, and benign polyps and adenocarcinomas
of the gastric fundus at 200 mg/kg/day. In the liver, treatment
at 0.5 to 200 mg/kg/day produced dose-related increases in the
incidences of hepatocellular adenomas and carcinomas. In the thyroid
gland, treatment at 200 mg/kg/day produced increased incidences
of follicular cell adenomas and carcinomas for both male and female
rats. Sporadic
occurrences of hepatocellular adenomas and a hepatocellular carcinoma
were observed in Sprague-Dawley rats exposed to pantoprazole in 6-month
and 12-month oral toxicity studies. In a 24-month carcinogenicity study, Fischer 344 rats were treated
orally with doses of 5 to 50 mg/kg/day, approximately
1 to 10 times the recommended human dose based on body surface area.
In the gastric fundus, treatment at 5 to 50 mg/kg/day produced
enterochromaffin-like (ECL) cell hyperplasia and benign and malignant
neuroendocrine cell tumors. Dose selection for this study may not
have been adequate to comprehensively evaluate the carcinogenic potential
of pantoprazole. In a 24-month carcinogenicity study, B6C3F1 mice were treated orally
with doses of 5 to 150 mg/kg/day, 0.5 to 15 times the
recommended human dose based on body surface area. In the liver, treatment
at 150 mg/kg/day produced increased incidences of hepatocellular
adenomas and carcinomas in female mice. Treatment at 5 to 150 mg/kg/day
also produced gastric fundic ECL cell hyperplasia. Pantoprazole was positive in the in
vitro human lymphocyte chromosomal aberration assays, in
one of two mouse micronucleus tests for clastogenic effects, and in
the in vitro Chinese hamster
ovarian cell/HGPRT forward mutation assay for mutagenic effects. Equivocal
results were observed in the in vivo rat liver DNA covalent binding assay. Pantoprazole was negative
in the in vitro Ames mutation assay, the invitro unscheduled DNA synthesis (UDS)
assay with rat hepatocytes, the in vitro AS52/GPT mammalian cell-forward gene mutation assay, the in vitro thymidine kinase mutation test
with mouse lymphoma L5178Y cells, and the in vivo rat bone marrow cell chromosomal aberration assay.
A 26-week p53 +/- transgenic mouse carcinogenicity study was
not positive. Pantoprazole at oral doses up to 500 mg/kg/day in male rats
(98 times the recommended human dose based on body surface area) and
450 mg/kg/day in female rats (88 times the recommended human
dose based on body surface area) was found to have no effect on fertility
and reproductive performance.<br/>Pregnancy:<br/>Teratogenic Effects:<br/>Nursing Mothers: Pantoprazole and
its metabolites are excreted in the milk of rats. Pantoprazole excretion
in human milk has been detected in a study of a single nursing mother
after a single 40 mg oral dose. The clinical relevance of this finding
is not known. Many drugs which are excreted in human milk have a potential
for serious adverse reactions in nursing infants. Based on the potential
for tumorigenicity shown for pantoprazole in rodent carcinogenicity
studies, a decision should be made whether to discontinue nursing
or to discontinue the drug, taking into account the benefit of the
drug to the mother.<br/>Pediatric Use: Safety and effectiveness
in pediatric patients have not been established.<br/>Use in Women: No gender-related
differences in the safety profile of intravenous pantoprazole were
seen in international trials involving 166 men and 120 women with
erosive esophagitis associated with GERD. Erosive esophagitis healing
rates in the 221 women treated with oral pantoprazole in U.S. clinical
trials were similar to those found in men. The incidence rates of
adverse events were also similar between men and women.<br/>Use in Elderly: No age-related differences
in the safety profile of intravenous pantoprazole were seen in international
trials involving 86 elderly (���65 years old) and 200 younger
(<65 years old) patients with erosive esophagitis associated with
GERD. Erosive esophagitis healing rates in the 107 elderly patients
(���65 years old) treated with oral pantoprazole in U.S. clinical
trials were similar to those found in patients under the age of 65.
The incidence rates of adverse events and laboratory abnormalities
in patients aged 65 years and older were similar to those associated
with patients younger than 65 years of age.<br/>Laboratory Tests: There have been
reports of false-positive urine screening tests for tetrahydrocannabinol
(THC) in patients receiving most proton pump inhibitors, including
pantoprazole. An alternative confirmatory method should be considered
to verify positive results.
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dailymed-instance:overdosag... |
Experience in patients taking
very high doses of pantoprazole is limited. There have been spontaneous
reports of overdosage with pantoprazole, including a suicide in which
pantoprazole 560 mg and undetermined amounts of chloroquine and
zopiclone were also ingested. There have also been spontaneous reports
of patients taking similar amounts of pantoprazole (400 and 600 mg)
with no adverse effects. Pantoprazole is not removed by hemodialysis. In case of overdose,
treatment should be symptomatic and supportive. Single intravenous doses of pantoprazole at 378, 230, and 266 mg/kg
(38, 46, and 177 times the recommended human dose based on body surface
area) were lethal to mice, rats and dogs, respectively. The symptoms
of acute toxicity were hypoactivity, ataxia, hunched sitting, limb-splay,
lateral position, segregation, absence of ear reflex, and tremor.
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dailymed-instance:genericMe... |
pantoprazole sodium
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dailymed-instance:fullName |
Protonix (Injection, Powder, For Solution)
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dailymed-instance:adverseRe... |
Safety Experience with Intravenous Pantoprazole: Intravenous pantoprazole
has been studied in clinical trials in several populations including
patients with GERD and a history of erosive esophagitis, patients
with Zollinger-Ellison Syndrome, patients involved in clinical trials
for other disorders which may respond to proton pump inhibitor therapy,
and healthy subjects. Adverse experiences occurring in>1% of patients
treated with intravenous pantoprazole (n=836) in domestic or international
clinical trials are shown below by body system. In most instances,
the relationship to pantoprazole was unclear. BODY AS A WHOLE: abdominal pain, headache, injection site reaction
(including thrombophlebitis and abscess). DIGESTIVE SYSTEM: constipation, dyspepsia, nausea, diarrhea. NERVOUS SYSTEM: insomnia,
dizziness. RESPIRATORY
SYSTEM: rhinitis. Head-to-head comparative studies between PROTONIX I.V. for Injection
and oral PROTONIX, other proton pump inhibitors (oral or I.V.), or
H2 receptor antagonists (oral or I.V.) have been limited. The available
information does not provide sufficient evidence to distinguish the
safety profile of these regimens.<br/>Safety Experience with Oral Pantoprazole: In short-term clinical
trials in patients with erosive esophagitis associated with GERD treated
with oral pantoprazole, the following adverse events, regardless of
causality, occurred at a rate of���1%. BODY AS A WHOLE: headache, asthenia, back pain, chest pain, neck
pain, flu syndrome, infection, pain. CARDIOVASCULAR SYSTEM: migraine. DIGESTIVE SYSTEM: diarrhea, flatulence, abdominal pain, eructation,
constipation, dyspepsia, gastroenteritis, gastrointestinal disorder,
nausea, rectal disorder, vomiting. HEPATO-BILIARY SYSTEM: liver function tests abnormal, SGPT increased. METABOLIC AND NUTRITIONAL:
hyperglycemia, hyperlipemia. MUSCULOSKELETAL SYSTEM: arthralgia. NERVOUS SYSTEM: insomnia, anxiety, dizziness, hypertonia. RESPIRATORY SYSTEM: bronchitis,
cough increased, dyspnea, pharyngitis, rhinitis, sinusitis, upper
respiratory tract infection. SKIN AND APPENDAGES: rash. UROGENITAL SYSTEM: urinary frequency, and urinary tract infection. Additional adverse experiences
occurring in<1% of patients with erosive esophagitis associated
with GERD receiving oral pantoprazole based on pooled results from
either short-term domestic or international trials are shown below
within each body system. In most instances, the relationship to pantoprazole
was unclear. BODY AS A WHOLE: abscess, allergic reaction, chills, cyst, face edema,
fever, generalized edema, heat stroke, hernia, laboratory test abnormal,
malaise, moniliasis, neoplasm, non-specified drug reaction. CARDIOVASCULAR SYSTEM:
abnormal electrocardiogram, angina pectoris, arrhythmia, cardiovascular
disorder, chest pain substernal, congestive heart failure, hemorrhage,
hypertension, hypotension, myocardial ischemia, palpitation, retinal
vascular disorder, syncope, tachycardia, thrombophlebitis, thrombosis,
vasodilatation. DIGESTIVE SYSTEM: anorexia, aphthous stomatitis, cardiospasm, colitis,
dry mouth, duodenitis, dysphagia, enteritis, esophageal hemorrhage,
esophagitis, gastrointestinal carcinoma, gastrointestinal hemorrhage,
gastrointestinal moniliasis, gingivitis, glossitis, halitosis, hematemesis,
increased appetite, melena, mouth ulceration, oral moniliasis, periodontal
abscess, periodontitis, rectal hemorrhage, stomach ulcer, stomatitis,
stools abnormal, tongue discoloration, ulcerative colitis. ENDOCRINE SYSTEM: diabetes
mellitus, glycosuria, goiter. HEPATO-BILIARY SYSTEM: biliary pain, hyperbilirubinemia, cholecystitis,
cholelithiasis, cholestatic jaundice, hepatitis, alkaline phosphatase
increased, gamma glutamyl transpeptidase increased, SGOT increased. HEMIC AND LYMPHATIC SYSTEM:
anemia, ecchymosis, eosinophilia, hypochromic anemia, iron deficiency
anemia, leukocytosis, leukopenia, thrombocytopenia. METABOLIC AND NUTRITIONAL: dehydration, edema, gout,
peripheral edema, thirst, weight gain, weight loss. MUSCULOSKELETAL SYSTEM: arthritis, arthrosis, bone disorder, bone
pain, bursitis, joint disorder, leg cramps, neck rigidity, myalgia,
tenosynovitis. NERVOUS SYSTEM: abnormal dreams, confusion, convulsion, depression,
dry mouth, dysarthria, emotional lability, hallucinations, hyperkinesia,
hypesthesia, libido decreased, nervousness, neuralgia, neuritis, paresthesia,
reflexes decreased, sleep disorder, somnolence, thinking abnormal,
tremor, vertigo. RESPIRATORY SYSTEM: asthma, epistaxis, hiccup, laryngitis, lung disorder,
pneumonia, voice alteration. SKIN AND APPENDAGES: acne, alopecia, contact dermatitis, dry skin,
eczema, fungal dermatitis, hemorrhage, herpes simplex, herpes zoster,
lichenoid dermatitis, maculopapular rash, pain, pruritus, skin disorder,
skin ulcer, sweating, urticaria. SPECIAL SENSES: abnormal vision, amblyopia, cataract specified, deafness,
diplopia, ear pain, extraocular palsy, glaucoma, otitis externa, taste
perversion, tinnitus. UROGENITAL SYSTEM: albuminuria, balanitis, breast pain, cystitis,
dysmenorrhea, dysuria, epididymitis, hematuria, impotence, kidney
calculus, kidney pain, nocturia, prostatic disorder, pyelonephritis,
scrotal edema, urethral pain, urethritis, urinary tract disorder,
urination impaired, vaginitis. In addition, the following adverse experiences occurred at a rate
of<1% in long-term clinical trials in patients treated with oral
pantoprazole: atrial fibrillation/flutter, myocardial infarction,
neuropathy, photosensitivity reaction. In most instances, the relationship
to pantoprazole was unclear.<br/>Postmarketing Reports: The postmarketing
safety profile of intravenous pantoprazole is not substantially different
from that of oral pantoprazole (described below). There have been spontaneous reports of adverse events with postmarketing
use of intravenous or oral pantoprazole. These reports include the
following: BODY AS A WHOLE: anaphylaxis (including anaphylactic shock), angioedema
(Quincke's edema). DIGESTIVE SYSTEM: increased salivation, nausea, pancreatitis. HEMIC AND LYMPHATIC SYSTEM:
pancytopenia. HEPATO-BILIARY SYSTEM: hepatocellular damage leading to jaundice
and hepatic failure. MUSCULOSKELETAL SYSTEM: elevated CPK (creatine phosphokinase), rhabdomyolysis. NERVOUS SYSTEM: confusion,
hypokinesia, speech disorder, vertigo. SKIN AND APPENDAGES: severe dermatologic reactions,
including erythema multiforme, Stevens-Johnson syndrome, and
toxic epidermal necrolysis (TEN, some fatal). SPECIAL SENSES: anterior ischemic optic neuropathy, blurred vision,
tinnitus. UROGENITAL
SYSTEM: interstitial nephritis.<br/>Laboratory Values: In U.S. clinical
trials of patients with GERD and a history of erosive esophagitis
and international clinical trials of patients with erosive esophagitis
associated with GERD, the overall percentages of transaminase elevations
did not increase during treatment with intravenous pantoprazole. For
other laboratory parameters, there were no clinically important changes
identified. In
two U.S. controlled trials of oral pantoprazole in patients with erosive
esophagitis associated with GERD, 0.4% of the patients on 40 mg
oral pantoprazole experienced SGPT elevations of greater than three
times the upper limit of normal at the final treatment visit. Except
in those patients where there was a clear alternative explanation
for a laboratory value change, such as intercurrent illness, the elevations
tended to be mild and sporadic. The following changes in laboratory
parameters were reported as adverse events: creatinine increased,
hypercholesterolemia, and hyperuricemia.
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dailymed-instance:indicatio... |
Treatment of Gastroesophageal Reflux Disease Associated With
a History of Erosive Esophagitis: PROTONIX I.V. for
Injection is indicated for short-term treatment (7 to 10 days) of
patients with gastroesophageal reflux disease (GERD) and a history
of erosive esophagitis.<br/>Pathological Hypersecretion Associated with Zollinger-Ellison
Syndrome: PROTONIX I.V. for
Injection is indicated for the treatment of pathological hypersecretory
conditions associated with Zollinger-Ellison Syndrome or other neoplastic
conditions.
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dailymed-instance:represent... | |
dailymed-instance:routeOfAd... | |
dailymed-instance:name |
Protonix
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