Approved Drug Label (PDF)
5
Warnings and Precautions
5.10 Hypomagnesemia and Mineral Metabolism
Additions
and or revisions underlined
Hypomagnesemia,
symptomatic and asymptomatic, has been reported rarely in patients treated with
PPIs for at least three months, and in most cases after a year of therapy.
Serious adverse events include tetany, arrhythmias, and seizures. Hypomagnesemia
may lead to hypocalcemia and/or hypokalemia and may exacerbate underlying
hypocalcemia in at-risk patients. In most patients, treatment of
hypomagnesemia required magnesium replacement and discontinuation of the PPI.
![]()
…
Consider
monitoring magnesium and calcium levels prior to initiation of PROTONIX I.V.
and periodically while on treatment in patients with a preexisting risk of
hypocalcemia (e.g., hypoparathyroidism).
Supplement with magnesium and/or calcium as necessary. If hypocalcemia is
refractory to treatment, consider discontinuing the PPI.
5.7 Severe Cutaneous Adverse Reactions
New
subsection added
Severe
cutaneous adverse reactions, including erythema multiforme, Stevens-Johnson
syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with
eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous
pustulosis (AGEP) have been reported in association with the use of PPIs [see Adverse Reactions (6.2)]. Discontinue
PROTONIX I.V at the first signs or symptoms of severe cutaneous adverse
reactions or other signs of hypersensitivity and consider further evaluation.
6
Adverse Reactions
Additions underlined
…
Severe Cutaneous Adverse
Reactions [see Warnings
and Precautions (5.7)]
…
Hypomagnesemia and Mineral Metabolism [see Warnings and Precautions (5.10)]
…
6.2 Postmarketing
Experience
…
Skin and
Subcutaneous Tissue Disorders: severe dermatologic reactions (some
fatal), including erythema multiforme, SJS/TEN, DRESS, AGEP, angioedema
…
Metabolism and
Nutritional Disorders: hyponatremia, hypomagnesemia, hypocalcemia,
hypokalemia, hyponatremia
…
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
Additions
underlined
Adverse
Reactions
Advise
patients to report to their healthcare provider if they experience any signs or
symptoms consistent with:
…
Approved Drug Label (PDF)
4
Contraindications
Additions and/or revisions
underlined
PROTONIX
I.V. is contraindicated in patients with known hypersensitivity reactions
including anaphylaxis to the formulation or any substituted benzimidazole.
Hypersensitivity reactions may include anaphylaxis, anaphylactic shock,
angioedema, bronchospasm, acute tubulointerstitial nephritis, and
urticaria [see Warnings and Precautions
(5.2, 5.5), Adverse Reactions (6)].
…
5
Warnings and Precautions
5.5 Acute Tubulointerstitial Nephritis
Additions and/or
revisions underlined
Acute
tubulointerstitial nephritis (TIN) has been observed in patients
taking PPIs and may occur at any point during PPI therapy. Patients
may present with varying signs and symptoms from symptomatic hypersensitivity
reactions to non-specific symptoms of decreased renal function (e.g.,
malaise, nausea, anorexia). In reported case series, some patients were
diagnosed on biopsy and in the absence of extra-renal manifestations (e.g.,
fever, rash or arthralgia). Discontinue PROTONIX I.V. and evaluate
patients with suspected acute TIN [see Contraindications (4)].
6
Adverse Reactions
Additions and
revisions underlined
…
Acute
Tubulointerstitial Nephritis [see
Warnings and Precautions (5.5)]
…
6.2 Postmarketing
Experience
…
Renal and Urinary
Disorders: acute
tubulointerstitial nephritis
…
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
Additions and/or
revisions underlined
…
…
Approved Drug Label (PDF)
5
Warnings and Precautions
5.11 Interference with Investigations for Neuroendocrine Tumors
(Newly added subsection)
Serum chromogranin A (CgA) levels increase secondary to drug-induced decreases
in gastric acidity. The increased CgA level may cause false positive results in
diagnostic investigations for neuroendocrine tumors. Healthcare providers
should temporarily stop PROTONIX I.V. treatment at least 14 days before assessing
CgA levels and consider repeating the test if initial CgA levels are high. If
serial tests are performed (e.g. for monitoring), the same commercial
laboratory should be used for testing, as reference ranges between tests may vary.
7
Drug Interactions
Table 2: Clinically Relevant Interactions Affecting Drugs Co-Administered
with PROTONIX I.V. and Interaction with Diagnostics (Table has been revised; please
refer to label)
Approved Drug Label (PDF)
4
Contraindications
(additions
underlined)
PROTONIX
I.V. is contraindicated in patients with known hypersensitivity
reactions including anaphylaxis to the formulation [see Warnings and Precautions (5.2)] or any substituted
benzimidazole. Hypersensitivity reactions may include anaphylaxis, anaphylactic
shock, angioedema, bronchospasm, acute interstitial nephritis, and urticarial.
7
Drug Interactions
(section
revised, additions underline. Please refer to label to view Table 2)
Table 2 includes drugs
with clinically important drug interactions and interaction with diagnostics
when administered concomitantly with PROTONIX I.V. and instructions
for preventing or managing them.
Consult the labeling of concomitantly used
drugs to obtain further information about interactions with PPIs.
8
Use in Specific Populations
8.1 Pregnancy Teratogenic Effects
(additions
underlined)
Pregnancy
Category C
Reproduction studies have been performed in rats at
intravenous pantoprazole doses up to
20 mg/kg/day (4 times the recommended human dose based on
body surface area) and rabbits at intravenous doses up to 15 mg/kg/day (6 times
the recommended human dose based on body surface area) with administration
of pantoprazole sodium during organogenesis in pregnant animals and have
revealed no evidence of impaired fertility or harm to the fetus due to
pantoprazole.
A pre- and postnatal development toxicity
study in rats with additional endpoints to evaluate the effect on bone
development was performed with pantoprazole sodium. Oral pantoprazole doses of
5, 15, and 30 mg/kg/day (approximately 1, 3, and 6 times the human dose of 40
mg/day on a body surface area basis) were administered to pregnant females from
gestation day (GD) 6 through lactation day (LD) 21. On postnatal day (PND 4)
through PND 21, the pups were administered oral doses at 5, 15, and 30
mg/kg/day (approximately 1, 2.3, and 3.2 times the exposure (AUC) in humans at
a dose of 40 mg). There were no drug-related findings in
maternal animals. During the preweaning dosing phase (PND 4 to 21) of the pups,
there were increased mortality and/or moribundity and decreased body weight and
body weight gain at 5 mg/kg/day (approximately equal exposures (AUC) in humans
receiving the 40 mg dose) and higher doses. On PND 21, decreased mean femur
length and weight and changes in femur bone mass and geometry were observed in
the offspring at 5 mg/kg/day (approximately equal exposures (AUC) in humans at
the 40 mg dose) and higher doses. The femur findings included lower total area,
bone mineral content and density, periosteal and endosteal circumference, and
cross-sectional moment of inertia. There were no microscopic changes in the
distal femur, proximal tibia, or stifle joints. Changes in bone parameters were
partially reversible following a recovery period, with findings on PND 70
limited to lower femur metaphysis cortical/subcortical bone mineral density in
female pups at 5 mg/kg/day (approximately equal exposures (AUC) in humans at
the 40 mg dose) and higher doses.
There are no adequate and well-controlled studies in
pregnant women. Advise pregnant women of the potential risk of fetal harm.
Because animal reproduction studies are not always predictive of human
response, this drug should be used during pregnancy only if the potential
benefit justifies the potential risk to the fetus.
8.4 Pediatric Use
(additions
underlined)
The safety and effectiveness of
PROTONIX I.V. have not been established in pediatric patients. Animal
Toxicity Data
In a pre- and post-natal development toxicity
study in rats, the pups were administered oral doses of pantoprazole at 5, 15,
and 30 mg/kg/day on postnatal day (PND 4) through PND 21, in addition to
lactational exposure through milk. On PND 21, decreased mean femur length and
weight and changes in femur bone mass and geometry were observed in the
offspring at 5 mg/kg/day and higher doses. Changes in bone parameters were
partially reversible following a recovery period.
In neonatal/juvenile animals (rats and dogs)
toxicities were similar to those observed in adult animals, including gastric
alterations, decreases in red cell mass, increases in lipids, enzyme induction
and hepatocellular hypertrophy. An increased incidence of eosinophilic chief
cells in adult and neonatal/juvenile rats, and atrophy of chief cells in adult
rats and in neonatal/juvenile dogs, was observed in the fundic mucosa of
stomachs in repeated-dose studies. Full to partial recovery of these effects
were noted in animals of both age groups following a recovery period.
8.5 Geriatric Use
(subsection
revised, additions underlined)
Of 286 patients in clinical studies of
intravenous pantoprazole sodium in patients with GERD and a history of EE, 86 (43%)
were 65 years of age and over. No overall differences in safety or
effectiveness were observed between these subjects and younger subjects, and
other reported clinical experience with oral pantoprazole sodium has not
identified differences in responses between the elderly and younger patients,
but greater sensitivity of some older individuals cannot be ruled out.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
(additions
underlined)
…
Drug Interactions
Instruct patients to inform their healthcare provider of
any other medications they are currently taking, including rilpivirine-containing
products, high dose methotrexate and over-the-counter medications.
Pregnancy
Inform female patients of reproductive
potential that PROTONIX I.V. may cause fetal harm and to inform their
prescriber of a known or suspected pregnancy
Approved Drug Label (PDF)
5
Warnings and Precautions
5.1 Presence of Gastric Malignancy
In adults, symptomatic
response to therapy with PROTONIX I.V.
does not preclude the presence of gastric malignancy. Consider additional
follow-up and diagnostic testing in adult patients who have a suboptimal
response or an early symptomatic relapse after completing treatment with a PPI.
In older patients, also consider an endoscopy. (Additions and/or revisions underlined)
5.8 Cutaneous and Systemic Lupus Erythematosus (Added subsection)
Cutaneous lupus erythematosus (CLE) and systemic lupus
erythematosus (SLE) have been reported in patients taking PPIs, including
pantoprazole. These events have occurred as both new onset and an exacerbation
of existing autoimmune disease. The majority of PPI-induced lupus erythematous
cases were CLE.
The most common form of CLE reported in patients
treated with PPIs was subacute CLE (SCLE) and occurred within weeks to years
after continuous drug therapy in patients ranging from infants to the elderly.
Generally, histological findings were observed without organ involvement.
Systemic lupus erythematosus (SLE) is less commonly
reported than CLE in patients receiving PPIs. PPI associated SLE is usually
milder than non-drug induced SLE. Onset of SLE typically occurred within days
to years after initiating treatment primarily in patients ranging from young
adults to the elderly. The majority of patients presented with rash; however,
arthralgia and cytopenia were also reported.
Avoid administration of PPIs for longer than
medically indicated. If signs or symptoms consistent with CLE or SLE are noted
in patients receiving PROTONIX I.V., discontinue the drug and refer the patient
to the appropriate specialist for evaluation. Most patients improve with
discontinuation of the PPI alone in 4 to 12 weeks. Serological testing
(e.g. ANA) may be positive and elevated serological test results may take
longer to resolve than clinical manifestations.
6
Adverse Reactions
The following serious adverse reactions are described below and elsewhere
in labeling:
- Hypersensitivity and Severe Skin Reactions
- Injection Site Reactions
- Potential for Exacerbation of Zinc Deficiency
- Acute Interstitial Nephritis
- Clostridium difficile-Associated
Diarrhea
- Bone Fracture
- Cutaneous and Systemic Lupus Erythematosus
- Hepatic Effects
- Hypomagnesemia
6.1 Clinical Trials Experience
…clinical trials of
another drug and
may
not reflect the
rates observed
in clinical practice…
Worldwide,
approximately 80,500 patients have been
treated
with pantoprazole in clinical trials involving various dosages and
duration of treatment.
6.2 Postmarketing Experience
These
adverse reactions are listed below by body system:
Immune
System Disorders: anaphylaxis (including anaphylactic
shock), systemic lupus erythematosus.
Skin
and Subcutaneous Tissue Disorders: severe
dermatologic reactions (some fatal), including erythema multiforme,
Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), angioedema
(Quincke’s edema) and cutaneous lupus erythematosus.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
Adverse Reactions
Advise patients
to report to their healthcare provider if they experience any
signs or symptoms consistent with:
Hypersensitivity
and Severe Skin Reactions
Injection
Site Reactions
Potential
for Exacerbation of Zinc Deficiency
Acute
Interstitial Nephritis
Clostridium difficile-Associated Diarrhea
Bone
Fracture
Cutaneous
and Systemic Lupus Erythematosus
Hepatic
Effects
Hypomagnesemia
Drug
Interactions
Instruct patients to
inform their healthcare provider of any other medications they are currently
taking, including over-the-counter medications.
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