Drug Safety-related Labeling Changes (SrLC)

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ZEGERID (NDA-021849)

(OMEPRAZOLE; SODIUM BICARBONATE)

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

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07/18/2023 (SUPPL-20)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

…

Urogenital: Tubulointerstitial nephritis, urinary tract infection, microscopic pyuria, urinary frequency, elevated serum creatinine, proteinuria, hematuria, glycosuria, testicular pain, gynecomastia, and erectile dysfunction

…

03/04/2022 (SUPPL-19)

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, 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 ZEGERID 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.

5.6 Severe Cutaneous Adverse Reactions

New subsection added

Severe cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS) and 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 ZEGERID at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation.

6 Adverse Reactions

Addition underlined

…

• Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.6)

• Hypomagnesemia and Mineral Metabolism [see Warnings and Precautions (5.10)]

…

6.2 Postmarketing Experience

…

Metabolism and Nutritional Disorders: Hypomagnesemia, hypocalcemia, hypokalemia [see Warnings and Precautions (5.10)], hyponatremia, hypoglycemia, and weight gain.

…

Skin: Severe generalized skin reactions including TEN (some fatal), SJS, DRESS, AGEP, cutaneous lupus erythematosus and erythema multiforme (some severe); purpura and/or petechiae (some with rechallenge); skin inflammation, urticaria, angioedema, pruritus, photosensitivity, alopecia, dry skin, and hyperhidrosis.

…

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

MEDICATION GUIDE

Additions underlined

…

What are the possible side effects of ZEGERID?

ZEGERID can cause serious side effects, including:

…

• Severe skin reactions. ZEGERID 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 ZEGERID 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 the patient to discontinue ZEGERID and immediately call their healthcare provider at first appearance of a severe cutaneous adverse reaction or other sign of hypersensitivity [see Warnings and Precautions (5.6)].

…

Hypomagnesemia and Mineral Metabolism

Advise the patient to report any clinical symptoms that may be associated with hypomagnesemia, hypocalcemia, and/or hypokalemia to their healthcare provider, if they have been receiving ZEGERID for at least 3 months [see Warnings and Precautions (5.10)].

…

11/27/2020 (SUPPL-16)

Approved Drug Label (PDF)

4 Contraindications

‘Tubulointerstitial’ replaces interstitial

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

6 Adverse Reactions

Additions and/or revisions underlined:

• Acute Tubulointerstitial Nephritis

6.2 Postmarketing Experience

Omeprazole

Urogenital:

‘Tubulointerstitial’ replaces interstitial

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

MEDICATION GUIDE

Additions and/or revisions underlined:

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

ZEGERID may help your acid-related symptoms, but you could still have serious stomach problems. Talk with your doctor.

ZEGERID can cause serious side effects, including:

A type of kidney problem (acute tubulointerstitial nephritis). Some people who take proton pump inhibitor (PPI) medicines, including ZEGERID, may develop a kidney problem called acute tubulointerstitial nephritis that can happen at any time during treatment with ZEGERID …

PATIENT COUNSELING INFORMATION

’Tubulointerstitial’ replaces interstitial in both the heading and in the sentence.

09/24/2019 (SUPPL-15)

Approved Drug Label (PDF)

4 Contraindications

(additions and/or revisions are underlined)

• ZEGERID is contraindicated in patients with known hypersensitivity to substituted benzimidazoles or to any component of the formulation. Hypersensitivity reactions may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, acute interstitial nephritis, and urticaria.

• Proton pump inhibitors (PPIs), including ZEGERID, are contraindicated in patients receiving rilpivirine containing products.

5 Warnings and Precautions

5.10 Interaction with St. John’s Wort or Rifampin

(renaming of subsection title)

5.11 Interactions with Investigations for Neuroendocrine Tumors

(additions and/or revisions are underlined)

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. Providers should temporarily stop ZEGERID treatment for 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.

5.12 Interaction with Methotrexate

(renaming of subsection title)

5.3 Sodium Bicarbonate Buffer Content

(renaming of subsection title)

(additions and/or revisions are underlined)

Each 20 mg and 40 mg ZEGERID capsule contains 1,100 mg (13 mEq) of sodium bicarbonate. The total content of sodium in each capsule is 304 mg.

Each 20 mg and 40 mg packet of ZEGERID for oral suspension contains 1,680 mg (20 mEq) of sodium bicarbonate. The total content of sodium in each packet is 460 mg.

Chronic administration of bicarbonate with calcium or milk can cause milk-alkali syndrome. Chronic use of sodium bicarbonate may lead to systemic alkalosis, and increased sodium intake can produce edema and weight gain.

The sodium content of ZEGERID products should be taken into consideration when administering to patients on a sodium-restricted diet or those at risk for developing congestive heart failure.

Avoid ZEGERID in patients with Bartter’s syndrome, hypokalemia, hypocalcemia, and problems with acid-base balance.

5.8 Cyanocobalamin (Vitamin B-12) Deficiency

(additions and/or revisions are underlined)

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 in patients treated with ZEGERID.

6 Adverse Reactions

6.1 Clinical Trials Experience

(additions and/or revisions are underlined)

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of ZEGERID has been established, in part, based on oral studies of an oral delayed-release omeprazole product.

Clinical Trials with Omeprazole

In the U.S. clinical trial population of 465 adult patients, the adverse reactions summarized in Table 3 were reported to occur in 1% or more of patients on therapy with omeprazole.

Table 3: Adverse Reactions Occurring in 1% or More of Adult Patients in US Clinical Trials of Omeprazole Therapy

 …

Table 4 summarizes the adverse reactions that occurred in 1% or more of omeprazole-treated patients from international double-blind and open-label clinical trials in which 2,631 patients and subjects received omeprazole.

Table 4: Adverse Reactions Occurring in 1% or More of Adult Patients in International Clinical Trials of Omeprazole Therapy

 …

Clinical Trial of 40 mg ZEGERID for Oral Suspension

Adverse reactions reported in at least 3% of critically ill adult patients in a clinical trial of 40 mg ZEGERID for oral suspension compared to intravenous cimetidine for up to 14 days are presented in Table 5.

Table 5: Common Adverse Reactions by Body System and Preferred Term in a Randomized Controlled Trial of Critically Ill Adult Patients Treated up to 14 Days

 …

6.2 Postmarketing Experience

(additions and/or revisions are underlined)

The following adverse reactions have been identified during post-approval use of omeprazole. and sodium bicarbonate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Omeprazole

Body as a Whole: Hypersensitivity reactions, including anaphylaxis, anaphylactic shock, angioedema, bronchospasm, interstitial nephritis, urticaria (see also Skin below), fever, pain, fatigue, malaise, and systemic lupus erythematosus.

Cardiovascular: Chest pain or angina, tachycardia, bradycardia, palpitation, elevated blood pressure, and peripheral edema.

Gastrointestinal: Pancreatitis (some fatal), anorexia, irritable colon, flatulence, fecal discoloration, esophageal candidiasis, mucosal atrophy of the tongue, dry mouth, stomatitis, abdominal swelling and fundic gland polyps. Gastroduodenal carcinoids have been reported in patients with Zollinger-Ellison syndrome on long-term treatment with omeprazole. This finding is believed to be a manifestation of the underlying condition, which is known to be associated with such tumors.

Hepatic: Mild and, rarely, marked elevations of liver function tests [ALT (SGPT), AST (SGOT), ?-glutamyl transpeptidase, alkaline phosphatase, and bilirubin (jaundice)]. In rare instances, overt liver disease has occurred, including hepatocellular, cholestatic, or mixed hepatitis, liver necrosis (some fatal), hepatic failure (some fatal), and hepatic encephalopathy.

Infections and Infestations: Clostridium difficile-associated diarrhea.

Metabolism and Nutritional Disorders: Hyponatremia, hypoglycemia, hypomagnesemia, and weight gain.

Musculoskeletal: Muscle cramps, myalgia, muscle weakness, joint pain, bone fracture, and leg pain.

Nervous System/Psychiatric: Psychic disturbances including depression, agitation, aggression, hallucinations, confusion, insomnia, nervousness, tremors, apathy, somnolence, anxiety, dream abnormalities; vertigo; paresthesia; and hemifacial dysesthesia.

Respiratory: Epistaxis, pharyngeal pain.

Skin: Severe generalized skin reactions including toxic epidermal necrolysis (TEN; some fatal), Stevens-Johnson syndrome, cutaneous lupus erythematosus and erythema multiforme (some severe); purpura and/or petechiae (some with rechallenge); skin inflammation, urticaria, angioedema, pruritus, photosensitivity, alopecia, dry skin, and hyperhidrosis.

Special Senses: Tinnitus, taste perversion.

Ocular: Blurred vision, ocular irritation, dry eye syndrome, optic atrophy, anterior ischemic optic neuropathy, optic neuritis, and double vision.

Urogenital: Interstitial nephritis (some with positive rechallenge), urinary tract infection, microscopic pyuria, urinary frequency, elevated serum creatinine, proteinuria, hematuria, glycosuria, testicular pain, and gynecomastia.

Hematologic: Rare instances of pancytopenia, agranulocytosis (some fatal), thrombocytopenia, neutropenia, leukopenia, anemia, leukocytosis, and hemolytic anemia have been reported.

Sodium Bicarbonate

metabolic alkalosis, seizures, and tetany.

7 Drug Interactions

(extensive revisions; please refer to labeling for complete information)

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) conversion; please refer to labeling for complete information)

8.2 Lactation

(Pregnancy and Lactation Labeling Rule (PLLR) conversion)

Risk Summary

Available data from the published literature suggest both components of ZEGERID, omeprazole and sodium bicarbonate, are present in human milk. There are no clinical data on the effects of omeprazole or sodium bicarbonate on the breastfed infant or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ZEGERID and any potential adverse effects on the breastfed infant from ZEGERID or from the underlying maternal condition.

8.4 Pediatric Use

(additions and/or revisions are underlined)

Safety and effectiveness of ZEGERID have not been established in pediatric patients.

Juvenile Animal Data

Esomeprazole, an enantiomer of omeprazole, was shown to decrease body weight, body weight gain, femur weight, femur length, and overall growth at oral doses about 34 to 68 times a daily human dose of 40 mg esomeprazole or 40 mg omeprazole based on body surface area in a juvenile rat toxicity study. The animal to human dose multiples are based on the assumption of equal systemic exposure to esomeprazole in humans following oral administration of either 40 mg esomeprazole or 40 mg omeprazole.

A 28-day toxicity study with a 14-day recovery phase was conducted in juvenile rats with esomeprazole magnesium at doses of 70 to 280 mg/kg/day (about 17 to 68 times a daily oral human dose of 40 mg esomeprazole or 40 mg omeprazole on a body surface area basis). An increase in the number of deaths at the high dose of 280 mg/kg/day was observed when juvenile rats were administered esomeprazole magnesium from postnatal day 7 through postnatal day 35. In addition, doses equal to or greater than 140 mg/kg/day (about 34 times a daily oral human dose of 40 mg esomeprazole or 40 mg omeprazole on a body surface area basis), produced treatment-related decreases in body weight (approximately 14%) and body weight gain, decreases in femur weight and femur length, and affected overall growth. Comparable findings described above have also been observed in this study with another esomeprazole salt, esomeprazole strontium, at equimolar doses of esomeprazole.

8.6 Hepatic Impairment

(additions and/or revisions are underlined)

In patients with hepatic impairment (Child-Pugh Class A, B, or C) exposure to omeprazole substantially increased compared to healthy subjects. Avoid use of ZEGERID in patients with hepatic impairment for maintenance of healing of erosive esophagitis.

8.7 Asian Population

(additions and/or revisions are underlined)

In studies of healthy subjects, Asians had approximately a four-fold higher exposure than Caucasians. Avoid use of ZEGERID in Asian patients for maintenance of healing of erosive esophagitis.

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

MEDICATION GUIDE

(extensive revisions; please refer to labeling for complete information)

PATIENT COUNSELING INFORMATION

(extensive revisions; please refer to labeling for complete information)

06/07/2018 (SUPPL-14)

Approved Drug Label (PDF)

5 Warnings and Precautions

Newly created subsection:

5.13 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

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

MEDICATION GUIDE

What are the possible side effects of ZEGERID?

ZEGERID may cause serious side effects, including:

Additions and/or revisions underlined:

• Stomach growths (fundic gland polyps). People who take PPI medicines for a long time have an increased risk of developing a certain type of stomach growths called fundic gland polyps, especially after taking PPI medicines for more than 1 year. The most common side effects …

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 ZEGERID 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)

5.6 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:

• 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

Tables 3 and 4 have been revised; please refer to label.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of omeprazole…

Body as a Whole: Hypersensitivity reactions, including anaphylaxis, anaphylactic shock, angioedema, bronchospasm, interstitial nephritis, urticaria (see also Skin below), fever, pain, fatigue, malaise, systemic lupus erythematosus.

Skin: Severe generalized skin reactions including toxic epidermal necrolysis (TEN; some fatal), Stevens- Johnson syndrome, cutaneous lupus erythematosus and erythema multiforme (some severe); purpura and/or petechiae (some with rechallenge); skin inflammation, urticaria, angioedema, pruritus, photosensitivity, alopecia, dry skin, and hyperhidrosis.

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

MEDICATION GUIDE

ZEGERID can cause serious side effects, including:

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

General information about ZEGERID

For more information, go to www.Salix.com or 1-800-321-4576.

PATIENT COUNSELING INFORMATION

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

Adverse Reactions

Advise patients to report to their healthcare provider if they experience any signs or symptoms consistent with:

·         Hypersensitivity Reactions

·         Acute Interstitial Nephritis

·         Clostridium difficile-Associated Diarrhea

·         Bone Fracture

·         Cutaneous and Systemic Lupus Erythematosus

·         Cyanocobalamin (Vitamin B-12) Deficiency

·         Hypomagnesemia

Sodium content

Patients on a sodium-restricted diet or patients at risk of developing congestive heart failure (CHF) should be informed of the sodium content of ZEGERID Capsules (304 mg per capsule) and ZEGERID Powder (460 mg per packet). Patients should be informed that chronic use of sodium bicarbonate may cause problems and increased sodium intake can cause swelling and weight gain. If this occurs, they should contact their healthcare provider.

Drug Interactions

Advise patients to report to their healthcare provider if they start treatment with clopidogrel, St. John’s

Wort or rifampin, or, if they take high-dose methotrexate.

Administration

Instruct patients that ZEGERID should be taken on an empty stomach at least one hour prior to a meal...