PANTOPRAZOLE SODIUM: Package Insert and Label Information

PANTOPRAZOLE SODIUM — pantoprazole sodium granule, delayed release
Sun Pharmaceutical Industries, Inc.

1 INDICATIONS AND USAGE

Pantoprazole sodium for delayed-release oral suspension is indicated for:

1.1 Short-Term Treatment of Erosive Esophagitis Associated With Gastroesophageal Reflux Disease (GERD)

Pantoprazole sodium for delayed-release oral suspension is indicated in adults and pediatric patients five years of age and older for the short-term treatment (up to 8 weeks) in the healing and symptomatic relief of erosive esophagitis (EE). For those adult patients who have not healed after 8 weeks of treatment, an additional 8-week course of pantoprazole sodium for delayed-release oral suspension may be considered. Safety of treatment beyond 8 weeks in pediatric patients has not been established.

1.2 Maintenance of Healing of Erosive Esophagitis

Pantoprazole sodium for delayed-release oral suspension is indicated for maintenance of healing of EE and reduction in relapse rates of daytime and nighttime heartburn symptoms in adult patients with GERD. Controlled studies did not extend beyond 12 months.

1.3 Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome

Pantoprazole sodium for delayed-release oral suspension is indicated for the long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison (ZE) Syndrome.

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosing Schedule

Pantoprazole sodium is supplied as delayed-release granules in packets for preparation of oral suspensions. The recommended dosages are outlined in Table 1.

Table 1: Recommended Dosing Schedule for Pantoprazole Sodium for Delayed-Release Oral Suspension

* For adult patients who have not healed after 8 weeks of treatment, an additional 8-week course of pantoprazole sodium for delayed-release oral suspension may be considered. † Controlled studies did not extend beyond 12 months ‡ Dosage regimens should be adjusted to individual patient needs and should continue for as long as clinically indicated. Doses up to 240 mg daily have been administered.
Indication	Dose	Frequency
Short-Term Treatment of Erosive Esophagitis Associated With GERD
Adults	40 mg	Once daily for up to 8 weeks *
Children (5 years and older) ≥ 40 kg	40 mg	Once daily for up to 8 weeks
Maintenance of Healing of Erosive Esophagitis
Adults	40 mg	Once daily †
Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome
Adults	40 mg	Twice daily ‡

2.2 Administration Instructions

Directions for method of administration are presented in Table 2.

Table 2: Administration Instructions

Formulation	Route	Instructions*
For Delayed-Release Oral Suspension	Oral	Administered in 1 teaspoonful of applesauce or apple juice approximately 30 minutes prior to a meal
For Delayed-Release Oral Suspension	Nasogastric tube	See instructions below

* Do not split, chew, or crush Pantoprazole Sodium for Delayed-Release Oral Suspension.

Take a missed dose as soon as possible. If it is almost time for the next dose, skip the missed dose and take the next dose at the regular scheduled time. Do not take 2 doses at the same time.

Administer pantoprazole sodium for delayed-release oral suspension approximately 30 minutes prior to a meal via oral administration in apple juice or applesauce or nasogastric tube in apple juice only. Because proper pH is necessary for stability, do not administer pantoprazole sodium for delayed-release oral suspension in liquids other than apple juice, or foods other than applesauce.

Do not divide the 40 mg pantoprazole sodium for delayed-release oral suspension packet to create a 20 mg dosage for pediatric patients who are unable to take the tablet formulation.

Pantoprazole Sodium for Delayed-Release Oral Suspension — Oral Administration in Applesauce

• Open packet.
• Sprinkle granules on one teaspoonful of applesauce. DO NOT USE OTHER FOODS OR CRUSH OR CHEW THE GRANULES.
• Take within 10 minutes of preparation.
• Take sips of water to make sure granules are washed down into the stomach. Repeat water sips as necessary.

Pantoprazole Sodium for Delayed-Release Oral Suspension — Oral Administration in Apple Juice

• Open packet.
• Empty granules into a small cup or teaspoon containing one teaspoon of apple juice.
• Stir for 5 seconds (granules will not dissolve) and swallow immediately.
• To make sure that the entire dose is taken, rinse the container once or twice with apple juice to remove any remaining granules. Swallow immediately.

Pantoprazole Sodium for Delayed-Release Oral Suspension — Nasogastric (NG) Tube or Gastrostomy Tube Administration

For patients who have a nasogastric tube or gastrostomy tube in place, pantoprazole sodium for delayed-release oral suspension can be given as follows:

• Remove the plunger from the barrel of a 2 ounce (60 mL) catheter-tip syringe. Discard the plunger.
• Connect the catheter tip of the syringe to a 16 French (or larger) tube.
• Hold the syringe attached to the tubing as high as possible while giving pantoprazole sodium for delayed-release oral suspension to prevent any bending of the tubing.
• Empty the contents of the packet into the barrel of the syringe.

Add 10 mL (2 teaspoonfuls) of apple juice and gently tap and/or shake the barrel of the syringe to help rinse the syringe and tube. Repeat at least twice more using the same amount of apple juice (10 mL or 2 teaspoonfuls) each time. No granules should remain in the syringe.

3 DOSAGE FORMS AND STRENGTHS

For Delayed-Release Oral Suspension:

• 40 mg pantoprazole, pale yellowish to dark brownish, enteric-coated granules in a unit-dose packet

4 CONTRAINDICATIONS

• Pantoprazole sodium for delayed-release oral suspension is contraindicated in patients with known hypersensitivity to any component of 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), Adverse Reactions (6)].
• Proton pump inhibitors (PPIs), including pantoprazole sodium for delayed-release oral suspension, are contraindicated in patients receiving rilpivirine-containing products [see Drug Interactions (7)].

5 WARNINGS AND PRECAUTIONS

5.1 Presence of Gastric Malignancy

In adults, symptomatic response to therapy with pantoprazole sodium for delayed-release oral suspension 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.

5.2 Acute Tubulointerstitial Nephritis

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 pantoprazole sodium for delayed-release oral suspension and evaluate patients with suspected acute TIN [see Contraindications (4)].

5.3 Clostridium difficile -Associated Diarrhea

Published observational studies suggest that PPI therapy like pantoprazole may be associated with an increased risk of Clostridium difficile associated diarrhea, especially in hospitalized patients. This diagnosis should be considered for diarrhea that does not improve [see Adverse Reactions (6.2)].

Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.

5.4 Bone Fracture

Several published observational studies suggest that PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long-term PPI therapy (a year or longer). Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Patients at risk for osteoporosis-related fractures should be managed according to established treatment guidelines [see Dosage and Administration (2), Adverse Reactions (6.2)].

5.5 Severe Cutaneous Adverse Reactions

​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 pantoprazole at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation.

5.6 Cutaneous and Systemic Lupus Erythematosus

Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) have been reported in patients taking PPIs, including pantoprazole sodium. 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 pantoprazole, 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.

5.7 Cyanocobalamin (Vitamin B-12) Deficiency

Generally, daily treatment with any acid-suppressing medications over a long period of time (e.g., longer than 3 years) may lead to malabsorption of cyanocobalamin (Vitamin B-12) caused by hypo- or achlorhydria. Rare reports of cyanocobalamin deficiency occurring with acid-suppressing therapy have been reported in the literature. This diagnosis should be considered if clinical symptoms consistent with cyanocobalamin deficiency are observed.

5.8 Hypomagnesemia and Mineral Metabolism

​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. Hypomagnesemia may lead to hypocalcemia and/or hypokalemia and may exacerbate underlying hypocalcemia in at-risk patients. Serious adverse events include tetany, arrhythmias, and seizures. In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuation of the PPI.

​For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), health care professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically [see Adverse Reactions (6.2)]. Consider monitoring magnesium and calcium levels prior to initiation of pantoprazole 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.

5.9 Tumorigenicity

Due to the chronic nature of GERD, there may be a potential for prolonged administration of pantoprazole. In long-term rodent studies, pantoprazole was carcinogenic and caused rare types of gastrointestinal tumors. The relevance of these findings to tumor development in humans is unknown [see Nonclinical Toxicology (13.1)].

5.10 Fundic Gland Polyps

PPI use is associated with an increased risk of fundic gland polyps that increases with long-term use, especially beyond one year. Most PPI users who developed fundic gland polyps were asymptomatic and fundic gland polyps were identified incidentally on endoscopy. Use the shortest duration of PPI therapy appropriate to the condition being treated.

5.11 Interference with Investigations for Neuroendocrine Tumors

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 pantoprazole sodium for delayed-release oral suspension 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 [see Clinical Pharmacology (12.2)].

5.12 Interference with Urine Screen for THC

There have been reports of false-positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs, including pantoprazole [see Drug Interactions (7)].

5.13 Concomitant Use of Pantoprazole with Methotrexate

Literature suggests that concomitant use of PPIs with methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities. In high-dose methotrexate administration, a temporary withdrawal of the PPI may be considered in some patients [see Drug Interactions (7) ].

6 ADVERSE REACTIONS

The following serious adverse reactions are described below and elsewhere in labeling:

• Acute Tubulointerstitial Nephritis [see Warnings and Precautions (5.2)]
• Clostridium difficile-Associated Diarrhea [see Warnings and Precautions (5.3)]
• Bone Fracture [see Warnings and Precautions (5.4)]
• Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.5)]
• Cutaneous and Systemic Lupus Erythematosus [see Warnings and Precautions (5.6)]
• Cyanocobalamin (Vitamin B-12) Deficiency [see Warnings and Precautions (5.7)]
• Hypomagnesemia and Mineral Metabolism [see Warnings and Precautions (5.8)]
• Fundic Gland Polyps [see Warnings and Precautions (5.10)]