Drug Safety-related Labeling Changes (SrLC)

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PROTONIX (NDA-022020)

(PANTOPRAZOLE SODIUM)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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07/18/2023 (SUPPL-23)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

Renal and Genitourinary Disorders: acute tubulointerstitial nephritis, erectile dysfunction

03/04/2022 (SUPPL-21)

Approved Drug Label (PDF)

5 Warnings and Precautions

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

5.8 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 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.

6 Adverse Reactions

Additions underlined

…

• Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.5)]

…

• Hypomagnesemia and Mineral Metabolism [see Warnings and Precautions (5.8)]

  …

  6.2 Postmarketing Experience

  …

  Metabolism and Nutritional Disorders: hypomagnesemia, hypocalcemia, hypokalemia, hyponatremia

  …

  Skin and Subcutaneous Tissue Disorders: severe dermatologic reactions (some fatal), including erythema multiforme, SJS/TEN, DRESS, AGEP, angioedema (Quincke’s edema) and cutaneous lupus erythematosus

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions underlined

…

PROTONIX can cause serious side effects, including:

…

• Low magnesium and other mineral levels in your body can happen in people who have taken PROTONIX for at least 3 months. Tell your doctor if you have symptoms of low magnesium levels, including seizures, dizziness, irregular heartbeat, jitteriness, muscle aches or weakness, and spasms of hands, feet or voice.

  …

  Before taking PROTONIX, tell your doctor about all of your medical conditions, including if you:

• have low magnesium levels, low calcium levels and low potassium levels in your blood.

  …

  What are the possible side effects of PROTONIX?

  PROTONIX can cause serious side effects, including:

  …

• Severe skin reactions. PROTONIX can cause rare but severe skin reactions that may affect any part of your body. These serious skin reactions may need to be treated in a hospital and may be life threatening:

  • Skin rash which may have blistering, peeling or bleeding on any part of your skin (including your lips, eyes, mouth, nose, genitals, hands or feet).

  • You may also have fever, chills, body aches, shortness of breath, or enlarged lymph nodes. Stop taking PROTONIX and call your doctor right away. These symptoms may be the first sign of a severe skin reaction.

    …

PATIENT COUNSELING INFORMATION

Additions underlined

…

Severe Cutaneous Adverse Reactions

Advise patients to discontinue PROTONIX and immediately call their healthcare provider for further evaluation [see Warnings and Precautions (5.5)].

…

Hypomagnesemia and Mineral Metabolism

Advise patients to report any clinical symptoms that may be associated with hypomagnesemia, hypocalcemia, and/or hypokalemia, to their healthcare provider, if they have been receiving PROTONIX for at least 3 months [see Warnings and Precautions (5.8)].

…

11/27/2020 (SUPPL-18)

Approved Drug Label (PDF)

4 Contraindications

Additions and/or revisions underlined

• PROTONIX 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)].

      …

5 Warnings and Precautions

5.2 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 and evaluate patients with suspected acute TIN [see Contraindications (4)].

6 Adverse Reactions

6.2 Postmarketing Experience

…

Renal and Urinary Disorders: acute tubulointerstitial nephritis

…

Addition and/or revision underlined

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

• Acute Tubulointerstitial Nephritis [see Warnings and Precautions (5.2)]

…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined

…

PROTONIX can cause serious side effects, including:

• A type of kidney problem (acute tubulointerstitial nephritis). Some people who take proton pump inhibitor (PPI) medicines, including PROTONIX, may develop a kidney problem called acute tubulointerstitial nephritis that can happen at any time during treatment with PROTONIX. Call your doctor right away if you have a decrease in the amount that you urinate or if you have blood in your urine.

  …

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined

…

Acute Tubulointerstitial Nephritis

Advise patients to call their healthcare provider immediately if they experience signs and/or symptoms associated with acute tubulointerstitial nephritis [see Contraindications (4), Warnings and Precautions (5.2)].

…

04/25/2019 (SUPPL-17)

Approved Drug Label (PDF)

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

8.1 Pregnancy

8.2 Lactation

PLLR conversion; please refer to label for complete information.

06/07/2018 (SUPPL-16)

Approved Drug Label (PDF)

5 Warnings and Precautions

Newly created subsection:

5.9 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.

6 Adverse Reactions

Addition of the following:

• Fundic Gland Polyps

6.2 Postmarketing Experience

Gastrointestinal:

Addition of: fundic gland polyps

12/20/2017 (SUPPL-13)

Approved Drug Label (PDF)

4 Contraindications

(Additions and/or revisions are underlined)

…

• Proton pump inhibitors (PPIs), including PROTONIX, are contraindicated with rilpivirine-containing products

5 Warnings and Precautions

5.7 Hypomagnesemia

(Additions and/or revisions are 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…

5.9 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 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 4: Clinically Relevant Interactions Affecting Drugs Co-Administered with PROTONIX and Interactions with Diagnostics (Table has been revised; please refer to label)

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

Gastric Malignancy

Advise patients to return to their healthcare provider if they have a suboptimal response or an early symptomatic relapse.

Acute Interstitial Nephritis

Advise patients to call their healthcare provider immediately if they experience signs and/or symptoms associated with acute interstitial nephritis.

Clostridium difficile-Associated Diarrhea

Advise patients to immediately call their healthcare provider if they experience diarrhea that does not improve.

Bone Fracture

Advise patients to report any fractures, especially of the hip, wrist or spine, to their healthcare provider.

Cutaneous and Systemic Lupus Erythematosus

Advise patients to immediately call their healthcare provider for any new or worsening of symptoms associated with cutaneous or systemic lupus erythematosus.

Cyanocobalamin (Vitamin B-12) Deficiency

Advise patients to report any clinical symptoms that may be associated with cyancobalamin deficiency to their healthcare provider if they have been receiving PROTONIX for longer than 3 years.

Hypomagnesemia

Advise patients to report any clinical symptoms that may be associated with hypomagnesemia to their healthcare provider, if they have been receiving PROTONIX for at least 3 months.

Drug Interactions

Instruct patients to inform their healthcare provider of any other medications they are currently taking, including rilpivirine-containing products, digoxin and high dose methotrexate.

Administration

• Administer PROTONIX For Delayed-Release Oral Suspension in apple juice or applesauce, as described in the Instructions for Use. Do not administer in water, other liquids, or foods.

• For patients with a nasogastric (NG) or gastrostomy tube, PROTONIX For Delayed- Release Oral Suspension can be administered with apple juice, as described in the Instructions for Use.

• 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.

MEDICATION GUIDE

(Additions and/or revisions are underlined)

What is the most important information I should know about PROTONIX?

You should take PROTONIX exactly as prescribed, at the lowest dose possible and for the shortest time needed.                     

…

PROTONIX can cause serious side effects, including:

…

• Diarrhea caused by an infection (Clostridium difficile) in your intestines. Call your doctor right away if you have watery stools or stomach pain that does not go away. You may or may not have a fever.

• Bone fractures (hip, wrist, or spine). Bone fractures in the hip, wrist, or spine may happen in people who take multiple daily doses of PPI medicines and for a long period of time (a year or longer). Tell your doctor if you have a bone fracture, especially in the hip, wrist, or spine.

  …

  Talk to your doctor about your risk of these serious side effects…

  What is PROTONIX?

  In adults, PROTONIX is used for:

• up to 8 weeks for the healing and symptom relief of acid-related damage to the lining of the esophagus (called erosive esophagitis or EE). Your doctor may prescribe another 8 weeks of PROTONIX in patients whose EE does not heal.

  ...

  In children 5 years of age and older, PROTONIX is used for: …

  It is not known if PROTONIX is safe and effective in children for treatment other than EE.

  Before taking PROTONIX, tell your doctor about all of your medical conditions, including if you:

• are pregnant or plan to become pregnant. PROTONIX may harm your unborn baby. Tell your doctor if you become pregnant or think you may be pregnant during treatment with PROTONIX.

  Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements. Especially tell your doctor if you take methotrexate (Otrexup, Rasuvo, Trexall, XATMEP), digoxin (LANOXIN), or a water pill (diuretic).

  How should I take PROTONIX?

• Take PROTONIX exactly as prescribed by your doctor.

  PROTONIX delayed-release tablets (PROTONIX tablets):

  • Do not split, chew, or crush PROTONIX tablets.

  • Swallow PROTONIX tablets whole, with or without food.

  • Tell your doctor if you are not able to swallow your PROTONIX tablet.

  • You may use antacids while taking PROTONIX tablets.

    PROTONIX for delayed-release oral suspension (PROTONIX for oral suspension):

  • Do not split, chew, or crush PROTONIX for oral suspension.

  • Take PROTONIX for oral suspension about 30 minutes before a meal.

  • PROTONIX for oral suspension should only be given by mouth mixed in apple juice or applesauce or through a nasogastric (NG) tube or gastrostomy tube mixed in apple juice. Do not mix PROTONIX for oral suspension in liquids other than apple juice or foods other than applesauce.

  • Do not divide a packet of PROTONIX for oral suspension to make a smaller dose.

  • See the “Instructions for Use” at the end of this Medication Guide for instructions on how to mix and take PROTONIX for oral suspension by mouth in applesauce or apple juice or how to mix and give the suspension through an NG tube or gastrostomy tube mixed in apple juice.

    …

• If you take too much PROTONIX, call your doctor or your poison control center at 1-800-222-1222 right away or go to the nearest emergency room.

  What are the possible side effects of PROTONIX?

  PROTONIX can cause serious side effects, including:

• Low vitamin B-12 levels in your body can happen in people who have taken PROTONIX for a long time (more than 3 years). Tell your doctor if you have symptoms of low vitamin B-12 levels, including shortness of breath, lightheadedness, irregular heartbeat, muscle weakness, pale skin, feeling tired, mood changes, and tingling or numbness in the arms and legs.

• Low magnesium levels in your body can happen in people who have taken PROTONIX for at least 3 months. Tell your doctor if you have symptoms of low magnesium levels, including seizures, dizziness, irregular heartbeat, jitteriness, muscle aches or weakness, and spasms of hands, feet or voice.

  What are the ingredients in PROTONIX?

  Active ingredient: pantoprazole sodium sesquihydrate

07/06/2017 (SUPPL-15)

Approved Drug Label (PDF)

4 Contraindications

(additions underlined)

• PROTONIX 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 interstitial nephritis, and urticaria .
• Proton pump inhibitors (PPIs), including PROTONIX, are contraindicated in patients receiving rilpivirine-containing products.

5 Warnings and Precautions

5.9 Interference with Urine Screen for THC

(additions underlined)

There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs, including PROTONIX.

7 Drug Interactions

(section revised, additions underline. Please refer to label to view Table 4)

Table 4 includes drugs with clinically important drug interactions and interaction with diagnostics when administered concomitantly with PROTONIX 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 oral pantoprazole doses up to

450 mg/kg/day (about 88 times the recommended human dose based on body surface area) and in rabbits at oral doses up to 40 mg/kg/day (about 16 times the recommended human dose based on body surface area) with administration of pantoprazole sodium during organogenesis in pregnant animals. The studies 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)

…

Animal Toxicity Data

In a pre- and post-natal development study in rats, the pups were administered oral doses of pantoprazole at 5, 15, and 30 mg/kg/day (approximately 1, 2.3, and 3.2 times the exposure (AUC) in children aged 6 to 11 years at a dose of 40 mg) 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 (approximately equal exposures (AUC) in children aged 6 to 11 years at the 40 mg dose) 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.

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 may cause fetal harm and to inform their prescriber of a known or suspected pregnancy.

…

10/24/2016 (SUPPL-12)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Presence of Gastric Malignancy

In adults, symptomatic response to therapy with PROTONIX 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)

 

5.5 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, 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:

• Acute Interstitial Nephritis

• Clostridium difficile-Associated Diarrhea

• Bone Fracture

• Cutaneous and Systemic Lupus Erythematosus

• Cyanocobalamin (Vitamin B-12) Deficiency

• Hypomagnesemia

6.1 Clinical Trials Experience

The adverse reaction profiles for PROTONIX (pantoprazole sodium) …

6.2 Postmarketing Experience

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, some fatal), angioedema (Quincke’s edema) and cutaneous lupus erythematosus.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

PROTONIX can cause serious side effects, including:

• A type of kidney problem (acute interstitial nephritis). Some people who take proton pump inhibitor (PPI) medicines, including PROTONIX, may develop a kidney problem called acute interstitial nephritis that can happen at any time during treatment with PROTONIX. Call your doctor if you have a decrease in the amount that you urinate or if you have blood in your urine.

• Bone fractures. People who take multiple daily doses of PPI medicines for a long period of time …

• Certain types of lupus erythematosus. Lupus erythematosus is an autoimmune disorder (the body’s immune cells attack other cells or organs in the body). Some people who take PPI medicines, including PROTONIX, may develop certain types of lupus erythematosus or have worsening of the lupus they already have. Call your doctor right away if you have new or worsening joint pain or a rash on your cheeks or arms that gets worse in the sun.

PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Adverse Reactions

• Hypersensitivity Reactions
• Acute Interstitial Nephritis
• Clostridium difficile-Associated Diarrhea
• Bone Fracture
• Cutaneous and Systemic Lupus Erythematosus
• Cyanocobalamin (Vitamin B-12) Deficiency
• Hypomagnesemia

Drug Interactions

Instruct patients to inform their healthcare provider of any other medications they are currently taking, including over-the-counter medications.

Administration

• Caution patients that PROTONIX …