Pantoprazole (Systemic)


VA CLASSIFICATION
Primary: GA304

Commonly used brand name(s): Pantoloc; Protonix; Protonix I.V.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Gastric acid pump inhibitor —

antiulcer agent—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Gastroesophageal reflux disease [GERD] (treatment)—Pantoprazole delayed-release tablets are indicated for the short-term (up to 8 weeks) treatment of heartburn and other symptoms associated with GERD. {01}{09}{12}{13} Pantoprazole for injection is indicated for the short-term (7 to 10 days) treatment of GERD in patients who are unable to continue taking pantoprazole delayed-release tablets.{14} Pantoprazole for injection is not indicated for initial treatment of GERD.{14}

[Gastroesophageal reflux disease [GERD] (prophylaxis) ]—Pantoprazole is indicated for the prevention of relapse in patients with reflux esophagitis.{12}

[Ulcer, duodenal (treatment) ]—Pantoprazole is indicated for short-term (up to 4 weeks) treatment for symptom relief and healing in patients with active duodenal ulcer.{01}{12}

[Ulcer, duodenal, Helicobacter pylori–associated (treatment)]— Pantoprazole, in combination with clarithromycin and either amoxicillin or metronidazole, is indicated for treatment of patients with an active duodenal ulcer who are H. pylori positive.
{12}
[Ulcer, gastric (treatment) ]—Pantoprazole is indicated for short-term (up to 8 weeks) treatment in patients with active benign gastric ulcer.{01}{12}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:

Chemical group—
    Substituted benzimidazole{01}{13}{14}
Molecular weight—
    Delayed-release tablets: 432.4{13}
    For injection: 405.4{14}


pH
    Reconstituted solution: 9 to 10.{14}

Mechanism of action/Effect:

Pantoprazole is a proton pump inhibitor. It accumulates in the acidic compartment of parietal cells and is converted to the active form, a sulfanilamide, which binds to hydrogen-potassium-ATP-ase at the secretory surface of gastric parietal cells. Inhibition of hydrogen-potassium-ATP-ase blocks the final step of gastric acid production, leading to inhibition of both basal and stimulated acid secretion. The duration of inhibition of acid secretion does not correlate with the much shorter elimination half-life of pantoprazole.{01}{06}{07}


Other actions/effects:

Pantoprazole reduced in vitro counts of Helicobacter pylori more than four times at pH 4 (no effect was obtained at pH 7). A minimum inhibitory concentration of 0.064 to 0.25 mg/mL (depending on H. pylori strain) was determined for pantoprazole, with significant decreases obtained as low as 0.016 mg/mL.{08}{10}

Absorption:

Rapidly absorbed.{01}{13} However, absorption may be delayed up to 2 hours or more if pantoprazole is taken with food.{13}

Bioavailability (oral)— 77%.{01}{03}

Distribution:

VolD—Following intravenous administration to extensive metabolizers: 0.17 L per kg (11 to 23.6 L).{03}{09}{13}{14}


Protein binding:

Very high (98%);{01}{13}{14} primarily to albumin.{13}{14}

Biotransformation:

Hepatic, extensive. The major enzyme involved in the metabolism of pantoprazole is the polymorphically expressed cytochrome P450 isoform S-mephenytoin hydroxylase, also known as CYP2C19. The primary metabolite is the conjugate desmethylpantoprazole. Some patients who are deficient in this enzyme system will be slow metabolizers of pantoprazole. Patients who are slow metabolizers (3% of Caucasians or African-Americans; 17% to 23% of Asians) can produce plasma concentrations 5 times or more higher than patients with the enzyme present.{04}{09}

Half-life:

Elimination—Following oral or intravenous administration: 1 hour.{13}{14}

The half-life of pantoprazole is prolonged (7 to 9 hours) in patients with cirrhosis of the liver and in genetically determined slow metabolizers (3.5 to 10 hours).{09}{13}{14}


Onset of action:

Fifty-one percent of gastric acid secretion was inhibited within 2.5 hours following an initial oral dose of 40 mg.{01}{13}

Time to peak concentration:

Following an oral dose of 40 mg in extensive metabolizers with normal hepatic function—2.4 hours.{13} When pantoprazole is taken with food, the time to peak concentration is variable and may be significantly increased.{13}

Peak serum concentration:

Following an oral dose of 40 mg in extensive metabolizers with normal hepatic function—2.4 mcg per mL (mcg/mL).{13}

Following an intravenous dose of 40 mg administered over 15 minutes to extensive metabolizers with normal hepatic function—5.52 mcg/mL.{14}

Time to peak effect:

Oral—Acid secretion decreased by 85% on day 7 after administration of oral pantoprazole 40 mg.{09}

Intravenous—Acid secretion decreased by 100% after 2 hours of 80 mg intravenous administration.{14}

Duration of action:

Oral—Acid secretion returns to normal levels without rebound hypersecretion within 1 week.{09}{13}

Intravenous—Acid secretion returns to normal levels after 24 hours.{14}

Elimination:
    Renal—71% .{13}{14}
    Fecal—18% (biliary excretion).{09}{13}{14}
    Dialysis removes insignificant amounts of pantoprazole.{09}{13}{14}


Precautions to Consider

Carcinogenicity

A moderate increase in enterochromaffin-like (ECL) cell density was apparent after one year among 39 patients, the majority taking 40 to 80 mg pantoprazole for up to 5 years. ECL density appeared to plateau after 4 years.{09}

ECL hyperplasia and ECL carcinoid were produced in male Sprague-Dawley (SD) rats at pantoprazole doses of ³50 mg per kg daily and ³0.5 mg per kg daily in female SD rats after 17 months, most likely due to elevated gastrin levels during chronic therapy. ECL-cell neoplasms did not occur over 24 months observations in mice receiving 5, 25, or 150 mg per kg daily.{01}

Tumorigenicity

Pantoprazole doses ³50 mg per kg caused a slight increased frequency of hepatocellular tumor in rats, while in female mice dose of 150 mg per kg also resulted in an increased frequency. However, in both animals, the incidence of hepatocellular tumor was within historical control ranges for the strains tested. The tumors were characterized as late-appearing and primarily benign. Exposure to these unusually large doses for prolonged periods is associated with enzyme induction in rodents, leading to hepatomegaly and centrilobular hypertrophy. These findings not associated with the lower clinical doses and are apparently not applicable to human exposure.{01}

An increased incidence of thyroid tumor in rats, although within the historical ranges for the strain tested, was observed following exposure to pantoprazole 200 mg per kg daily. Pantoprazole-induced liver enzyme induction results in increased metabolism of thyroid hormone, leading in turn to increased production of TSH, with subsequent increased trophic changes within the thyroid gland. No similar effects have been observed in humans following exposure to usual clinical doses.{01}

Pregnancy/Reproduction

Pregnancy—
Adequate and well-controlled studies in humans have not been done.

Animal studies have demonstrated that pantoprazole crosses the placental barrier; however, no teratogenic effects were observed. Doses of 15 mg per kg resulted in delayed fetal skeletal development. {01}{09}{10}

FDA Pregnancy Category B.

Breast-feeding

It is not known whether pantoprazole is distributed into human breast milk. However, pantoprazole or its metabolites are distributed into the milk of rats (maximally 0.02% of an administered dose is excreted in the breast milk). Because pantoprazole has been shown to cause tumorigenic effects in animals, a decision should be made as to whether nursing should be discontinued or the medication withdrawn, taking into account the importance of pantoprazole to the mother. {01}{09}{10}

Pediatrics

Appropriate studies on the relationship of age to the effects of pantoprazole have not been performed in the pediatric population. Safety and efficacy have not been established.{01}{09}


Geriatrics


Appropriate studies performed to date have not demonstrated geriatrics-specific problems that would limit the usefulness of pantoprazole in the elderly. Efficacy and safety are similar to those reported for younger adults. {01}{09}


Pharmacogenetics

No differences in efficacy or safety between men and women are apparent.

Approximately 3% of Caucasians and African-Americans and between 17% and 23% of Asians have deficiency of the CYP2C19 hepatic enzyme system, resulting in slow metabolism. Although certain pharmacokinetic values such as half-life and serum concentrations of pantoprazole will be enhanced in these patients, no specific dose adjustments are recommended, and no differences in safety or efficacy are apparent.{09}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Pantoprazole, by increasing gastric pH, has the potential to affect the bioavailability of any medication for which absorption is pH-dependent. Also, pantoprazole may prevent the degradation of acid-labile drugs.{01}
Pantoprazole, although metabolized by hepatic cytochrome P 450 systems, does not appear to either inhibit or induce cytochrome P 450 enzyme activity. To date, no clinically significant interactions have been noted for such commonly used drugs as diazepam, phenytoin, nifedipine, theophylline, digoxin, warfarin, or oral contraceptives.{01}{13}{14}

Ampicillin{14} or
Iron salts{14} or
Ketoconazole{14}    (pantoprazole causes prolonged inhibition of gastric acid secretion, and thereby may interfere with the absorption of these medications and others for which bioavailability is determined by gastric pH{14})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Alanine aminotransferase (ALT [SGPT]){13}{14}    (mild and sporadic increases may occur during treatment{13}{14})


Cholesterol, serum{13}{14} and
Creatinine, serum{13}{14} and
Glucose, blood{13}{14} and
Lipoprotein{13}{14}
Uric acid, serum and/or urine{13}{14}    (concentrations may be increased{13}{14})


Gastrin, serum {01}{13}{14}    (a moderate increase in fasting serum gastrin concentration may occur during treatment {01}{13}{14})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
Hepatic function impairment{13}{14}    (modest accumulation of drug [£ 21%] may occur following once-daily administration to patients with severe hepatic function impairment;{13}{14}this risk should be weighed against the potential for reduced acid control that may occur following every-other-day administration;{13}no dosage adjustment is needed in patients with mild or moderate hepatic function impairment{13}{14})


» Hypersensitivity to pantoprazole{01}


Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence less frequent or rare
    
Anaphylaxis {13}{14}(changes in facial skin color; fast or irregular breathing; puffiness or swelling of the eyelids or around the eyes; shortness of breath, troubled breathing, tightness in chest, and/or wheezing; skin rash, hives, and itching)
    
angioedema {13}{14}(large, hive-like swellings on eyelids, face, lips, mouth, and/or tongue)
    
chest pain {13}{14}— occurs more frequently following intravenous administration{14}
    
dyspnea {13}{14}(shortness of breath)
    
erythema multiforme {13}{14}(pain in joints or muscles; itching or redness of skin; bull's eye–like lesion on skin)
    
gastroenteritis {13}{14}(abdominal pain; anorexia; diarrhea; nausea; weakness)
    
hyperglycemia {13}{14}(increased frequency and volume of urination; unusual thirst)
    
infection {13}{14}
    
injection site reaction {14}(bleeding; blistering ; burning; coldness; discoloration of skin; feeling of pressure; hives; infection; inflammation ; itching; lumps; numbness ; pain; rash; redness; scarring; soreness; stinging; swelling; tenderness; tingling ; ulceration; warmth)
    
jaundice {13}{14}(yellow eyes or skin)
    
optic neuropathy, anterior ischemic {13}{14}(loss of vision, sudden)
    
pancreatitis {13}{14}(abdominal pain; nausea; vomiting)
    
speech disorder {13}{14}
    
Stevens-Johnson syndrome {13}{14}(aching joints and muscles; blistering, loosening, peeling, or redness of skin; unusual tiredness or weakness)
    
toxic epidermal necrolysis {13}{14}(itching or redness of skin; loosening and/or stripping off of top layer of skin; skin tenderness with burning)
    
urinary tract infection {13}{14}(difficulty in urinating; frequent urge to urinate ; painful urination)



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Diarrhea {13}{14}—occurs less frequently following intravenous administration{14}
    
headache {13}{14}—occurs less frequently following intravenous administration{14}

Incidence less frequent or rare
    
Abdominal pain {13}{14}—occurs more frequently following intravenous administration{14}
    
anxiety {13}{14}
    
arthralgia {13}{14}(pain in joints)
    
asthenia {13}{14}(loss of energy or strength; weakness)
    
back pain {13}{14}
    
belching {13}{14}
    
blurred vision {14}
    
bronchitis {13}{14}(chills; cough; headache; hoarseness)
    
confusion {13}{14}
    
constipation {13}{14}
    
cough, increased {13}{14}
    
dizziness {13}{14}
    
dyspepsia {13}{14}(indigestion)
    
flatulence {13}{14}
    
flu-like syndrome {13}{14}(abdominal pain; chills; cough; headache; pain in joints or muscles; runny nose; sneezing; sore throat)
    
hypertonia {13}{14}(muscle rigidity or stiffness)
    
hypokinesia {13}{14}(difficulty in moving)
    
insomnia {13}{14}(trouble in sleeping)
    
migraine headache {13}{14}
    
nausea {13}{14}
    
neck pain {13}{14}
    
pain {13}{14}
    
pharyngitis {13}{14}(sore throat)
    
rectal disorders {13}{14}
    
rhinitis {13}{14}(runny or stuffy nose)
    
salivation, increased {13}{14}
    
sinusitis {13}{14}(aching, fullness, or tension in area of affected sinus; headache; runny nose)
    
skin rash or itching {13}{14}
    
tinnitus {13}{14}(ringing or buzzing in the ears)
    
upper respiratory tract infection {13}{14}(cough ; runny or stuffy nose; sore throat)
    
vertigo {13}{14}(dizziness; feeling of constant movement of self or surroundings; sensation of spinning)
    
vomiting {13}{14}





Overdose
For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing).

Clinical effects of overdose
No adverse effects were reported in single-agent overdose with pantoprazole in doses of 400 and 600 mg. Death following multi-agent ingestion was attributed to chloroquine and zopiclone rather than pantoprazole.{09}

The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Limited human overdose data available with any proton pump inhibitors. Signs or symptoms of overdose may include:{11}

mild tachycardia

vasodilation

somnolence

confusion

headache

blurred vision

abdominal pain

nausea & vomiting

Treatment of overdose
Decontamination— activated charcoal, gastric lavage. {11}

Symptomatic and supportive— therapy as indicated. {01}{11}

Monitoring parameters— Cardiac monitoring and blood pressure evaluation with significant overdose. Monitor fluid status and electrolytes with prolonged vomiting.{11}

Due to extensive protein binding, pantoprazole is not readily dialyzable. {01}

Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Pantoprazole (Systemic).

In providing consultation, consider advising the patient on the following (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to pantoprazole

Pregnancy—Causes delayed fetal skeletal development in animal studies





Breast-feeding—Distributed into milk in animal studies; may cause potentially serious adverse effects in nursing infants

Proper use of this medication
Taking the tablet in the morning, with or without food

» Swallowing tablet form of this medication whole without breaking, chewing, or crushing

Taking antacids for pain relief for several days until pantoprazole begins to relieve pain; unless otherwise instructed by physician

» Compliance with full course of therapy

» Proper dosing
Taking as soon as possible; not taking if almost time for next dose; not doubling doses

» Proper storage

Precautions while using this medication
» Regular visits to physician to check progress


Side/adverse effects
Signs of potential side effects, especially anaphylaxis, angioedema, chest pain, dyspnea, erythema multiforme, gastroenteritis, infection, injection site reaction (for intravenous dose), jaundice, optic neuropathy, pancreatitis, speech disorder, Stevens-Johnson syndrome, toxic epidermal necrolysis, and urinary tract infection


General Dosing Information
In the treatment of gastroesophageal reflux disease and gastric ulcer, relief of symptoms usually occurs within 2 weeks and healing within 4 weeks. Therapy should not exceed 8 weeks.{01}{09}{12} Controlled studies of pantoprazole used as maintenance therapy to prevent reflux esophagitis recurrence have not been conducted beyond 12 months, although in a limited number of patients have received continuous maintenance treatment for up to 8 years.{12} In the treatment of duodenal ulcer, relief of symptoms usually occurs within 1 week and healing within 2 weeks. Therapy should not exceed 4 weeks.{01}{09}

Since pantoprazole is acid-labile, it is administered as an enteric-coated tablet to prevent gastric decomposition and to increase bioavailability. Tablets should be swallowed whole, and not split, chewed, or crushed.{01}{09}{12}

Diet/Nutrition
Tablets may be taken before, during, or following the morning meal.{12} Neither food nor antacids altered the bioavailability of pantoprazole.{01}


Oral Dosage Forms

Note: Bracketed information in the Dosage Forms section refers to categories of use and/or indications that are not included in U.S. product labeling.

PANTOPRAZOLE SODIUM SESQUIHYDRATE DELAYED-RELEASE TABLETS

Usual adult dose
Gastroesophageal reflux disease (treatment)
Oral, 40 mg per day for up to eight weeks.{13} An additional eight-week course may be considered in patients who have not healed after four to eight weeks of treatment.{01}{09}{12}{13}

[Gastroesophageal reflux disease (prophylaxis)]
Oral, 20 mg once a day in the morning. Dose can be increased to 40 mg once a day in the morning in the case of recurrence.{12}

[Ulcer, duodenal, H. pylori–associated (treatment)]
Oral, triple therapy regimens of pantoprazole 40 mg, plus clarithromycin 500 mg, plus either amoxicillin 1000 mg or metronidazole 500 mg, in which all three medications are taken two times a day for seven days.{12}

[Ulcer, duodenal (treatment) ]
Oral, 40 mg per day for up to two weeks. An additional two–week course may be considered in patients who have not healed after two weeks of treatment.{01}{12}

[Ulcer, gastric (treatment) ]
Oral, 40 mg per day for up to four weeks. An additional four–week course may be considered in patients who have not healed after four weeks of treatment.{01}{12}


Usual pediatric dose
Safety and efficacy have not been established.{01}

Usual geriatric dose
See Usual adult dose.

Strength(s) usually available
U.S.—


40 mg pantoprazole [equivalent to 45.1 mg of pantoprazole sodium sesquihydrate] (Rx) [Protonix{13}]

Canada—


20 mg pantoprazole [equivalent to 22.6 mg of pantoprazole sodium sesquihydrate] (Rx) [Pantoloc]


40 mg pantoprazole [equivalent to 45.1 mg of pantoprazole sodium sesquihydrate] (Rx) [Pantoloc]

Packaging and storage:
Store at 15 to 30° C (59 and 86° F).{01}{09}

Auxiliary labeling:
   • Swallow tablets whole. Do not break, chew, or crush.



Parenteral Dosage Forms

PANTOPRAZOLE SODIUM  FOR INJECTION

Usual adult dose
Gastroesophageal reflux disease (treatment)
Intravenous infusion, 40 mg at a rate of 3 mg (7 mL) per minute over approximately fifteen minutes each day for seven to ten days.{14}


Note: Treatment with pantoprazole should be discontinued as soon as the patient is able to resume taking pantoprazole delayed-release tablets.{14}


Usual adult prescribing limits
Safety and efficacy of use for more than ten days have not been established.{14}

Usual pediatric dose
Safety and efficacy have not been established.{14}

Usual geriatric dose
See Usual adult dose.

Size(s) usually available:
U.S.—


40 mg (base) (Rx) [Protonix I.V.{14}]

Packaging and storage:
Store the freeze-dried powder below 40° C (104° F), preferably between 2 and 8° C (36 and 46° F).{14} Protect from freezing and from light.{14}

Preparation of dosage form:
Pantoprazole should be reconstituted with 10 mL of 0.9% sodium chloride injection.{14} This solution should then be further diluted (admixed) with 100 mL of 5% dextrose injection, 0.9% sodium chloride injection, or lactated Ringer's injection to produce a final concentration of approximately 0.4 mg per mL.{14}

Stability:
The reconstituted solution may be stored for up to 2 hours at room temperature prior to further dilution.{14} The admixed solution may be stored for up to 12 hours at room temperature prior to administration.{14}

Incompatibilities:
It is recommended that pantoprazole, after reconstitution and admixture, be administered through a separate line, by itself, and without mixing with other intravenous fluids or medications.{14} The in-line filter provided with the medication must be used to remove the precipitates that may form when the reconstituted solution is mixed with intravenous solutions.{14}

Additional information:
The intravenous line should be flushed with 5% dextrose injection, 0.9% sodium chloride injection, or lactated Ringer's injection before and after administration of pantoprazole.{14}

For Y-site administration, the in-line filter should be positioned below the Y-site that is closest to the patient.{14}



Developed: 04/03/2000
Revised: 05/25/2001



References
  1. Product Information: Pantoloc™, pantoprazole. Solvay Pharma/Byk- Canada. In: Krogh CME (ed): Compendium of Pharmaceuticals and Specialties, 34th ed. Canadian Pharmaceutical Association, Ottawa, Ontario, Canada, 1999. p 1343–1344.
  1. Canada JR (ed): USP Dictionary of USAN and International Drug Names. The United States Pharmacopeial Convention, Inc., Rockville, MD, 1998. p 548.
  1. Pue MA, Laroche J, Meineke I et al: Pharmacokinetics of pantoprazole following single intravenous and oral administration to healthy male subjects. Eur J Clin Pharmacol 1993; 44:575-578.
  1. Andersson T: Pharmacokinetics, metabolism and interactions of acid pump inhibitors: focus on omeprazole, lansoprazole, and pantoprazole. Clin Pharmcokinet 1996; 31:9-28.
  1. Bliesath H, Huber R, Hartmann M et al: Dose linearity of the pharmacokinetics of the new H+/K+-ATPase inhibitor pantoprazole after single intravenous administration. Int J Clin Pharmacol Ther 1994; 32:44-50.
  1. Simon B, Mueller P, Hartmann M et al: Pentagrastin-stimulated gastric acid secretion and pharmacokinetics following single and repeated intravenous administration of the gastic H+, K+ -ATPase-inhibitor pantoprazole (BY1023/SK&F96022) in healthy volunteers. Z Gastroenterol 1990; 28:443-447.
  1. Mears JM & Kaplan B: Proton pump inhibitors: new drugs and indications. Am Fam Physician 1996; 53:285-292.
  1. Suerbaum S, Leying H, Klemm K et al: Antibacterial activity of pantoprazole and omeprazole against Heliobacter pylori. Eur J Clin Microbiol Infect Dis 1991; 10:92-93.
  1. Product Information: Protonix®, pantoprazole sodium. Wyeth-Ayerst, Philadelphia, PA (PI revised 2/2000) reviewed 2/2000.
  1. Fachinformation: Pantozol®, pantoprazole. Byk-Gulden, Konstanz, 1995.
  1. Editorial Staff: Omeprazole and Related Agents (Management/Treatment Protocol). In: Toll LL & Hurlbut KM (Eds): POISINDEX(R) System. MICROMEDEX, Inc., Englewood, Colorado (Edition 105 Expires 5/2000).
  1. Product Information: Pantoloc, pantoprazole. Solvay Pharma, Ontario, Canada. (PI Revised 7/2000) PI Reviewed 1/2001.
  1. Product Information: Protonix®, pantoprazole sodium. Wyeth-Ayerst, Philadelphia, PA (PI Revised 3/2001) PI Reviewed 5/2001.
  1. Product Information: Protonix® I.V., pantoprazole sodium (for injection). Wyeth-Ayerst, Philadelphia, PA (PI Issued 3/2001) PI Reviewed 5/2001.
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