ZEGERID: Package Insert and Label Information (Page 2 of 8)

5.10 Hypomagnesemia and Mineral Metabolism

​ 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.

​ 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 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.

5.11 Interaction with St. John’s wort or Rifampin

Drugs which induce CYP2C19 or CYP3A4 (such as St. John’s wort or rifampin) can substantially decrease omeprazole concentrations [see Drug Interactions (7)]. Avoid concomitant use of ZEGERID with St. John’s wort or rifampin.

5.12 Interactions 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. 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 [see Drug Interactions (7)] .

5.13 Interaction with Methotrexate

Literature suggests that concomitant use of PPIs with methotrexate (primarily at high dose) 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)].

5.14 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 PPIs 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

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 (5.4)]

•

Bone Fracture [see Warnings and Precautions (5.5)]

•

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

•

Cutaneous and Systemic Lupus Erythematosus [see Warnings and Precautions (5.7)]

•

Cyanocobalamin (Vitamin B-12) Deficiency [see Warnings and Precautions (5.9)]

•

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

•

Fundic Gland Polyps [see Warnings and Precautions (5.14)]

6.1 Clinical Trials Experience

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

	Omeprazole % (n = 465)	Placebo % (n = 64)	Ranitidine % (n = 195)
Headache	7	6	8
Diarrhea	3	3	2
Abdominal Pain	2	3	3
Nausea	2	3	4
Upper Respiratory Infection (URI)	2	2	3
Dizziness	2	0	3
Vomiting	2	5	2
Rash	2	0	0
Constipation	1	0	0
Cough	1	0	2
Asthenia	1	2	2
Back Pain	1	0	1

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

	Omeprazole % (N = 2631)	Placebo % (N = 120)
Abdominal Pain	5.2	3.3
Nausea	4.0	6.7
Diarrhea	3.7	2.5
Vomiting	3.2	10.0
Headache	2.9	2.5
Flatulence	2.7	5.8
Acid Regurgitation	1.9	3.3
Constipation	1.5	0.8
Asthenia	1.3	0.8

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

* reported in at least 3% of patients in either treatment group. † In this trial, clinically significant upper gastrointestinal bleeding was considered a serious adverse reaction, but it is not included in this table.
Body System Preferred Term	ZEGERID 40 mg for oral suspension once daily % (N=178)	Intravenous Cimetidine 1,200 mg per day % (N=181)
Blood and Lymphatic System Disorders
Anemia NOS	7.9	7.7
Anemia NOS Aggravated	2.2	3.9
Thrombocytopenia	10.1	6.1
Cardiac Disorders
Atrial Fibrillation	6.2	3.9
Bradycardia NOS	3.9	2.8
Supraventricular Tachycardia	3.4	1.1
Tachycardia NOS	3.4	3.3
Ventricular Tachycardia	4.5	3.3
Gastrointestinal Disorders †
Constipation	4.5	4.4
Diarrhea NOS	3.9	8.3
Gastric Hypomotility	1.7	3.3
General Disorders and Administration Site Conditions
Hyperpyrexia	4.5	1.7
Edema NOS	2.8	6.1
Pyrexia	20.2	16.0
Infections and Infestations
Candidal Infection NOS	1.7	3.9
Oral Candidiasis	3.9	0.6
Sepsis NOS	5.1	5.0
Urinary Tract Infection	2.2	3.3
Investigations
Liver Function Tests NOS Abnormal	1.7	3.3
Metabolism and Nutrition Disorders
Fluid Overload	5.1	7.7
Hyperglycemia NOS	10.7	11.6
Hyperkalemia	2.2	3.3
Hypernatremia	1.7	5.0
Hypocalcemia	6.2	5.5
Hypoglycemia NOS	3.4	4.4
Hypokalemia	12.4	13.3
Hypomagnesemia	10.1	9.9
Hyponatremia	3.9	2.8
Hypophosphatemia	6.2	3.9
Psychiatric Disorders
Agitation	3.4	8.8
Respiratory, Thoracic and Mediastinal Disorders
Acute Respiratory Distress Syndrome	3.4	3.9
Nosocomial Pneumonia	11.2	9.4
Pneumothorax NOS	0.6	4.4
Respiratory Failure	1.7	3.3
Skin and Subcutaneous Tissue Disorders
Decubitus Ulcer	3.4	2.8
Rash NOS	5.6	6.1
Vascular Disorders
Hypertension NOS	7.9	3.3
Hypotension NOS	9.6	6.6
NOS = not otherwise specified