ZEGERID: Package Insert and Label Information (Page 3 of 8)

6.2 Postmarketing Experience

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, 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), ᵞ-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: Hypomagnesemia, hypocalcemia, hypokalemia [see Warnings and Precautions (5.10)] , hyponatremia, hypoglycemia, 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 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.

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: Tubulointerstitial nephritis, 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

Tables 6 and 7 include drugs with clinically important drug interactions and interaction with diagnostics when administered concomitantly with omeprazole and instructions for preventing or managing them.

Consult the labeling of concomitantly used drugs to obtain further information about interactions with PPIs.

Table 6: Clinically Relevant Interactions Affecting Drugs Co-Administered with Omeprazole and Interaction with Diagnostics
Antiretrovirals

Clinical Impact:

The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known.

Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir and nelfinavir) when used concomitantly with omeprazole may reduce antiviral effect and promote the development of drug resistance [see Clinical Pharmacology (12.3)].
Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with omeprazole may increase toxicity [see Clinical Pharmacology (12.3)].
There are other antiretroviral drugs which do not result in clinically relevant interactions with omeprazole.

Intervention:

Rilpivirine-containing products: Concomitant use with ZEGERID is contraindicated [see Contraindications (4) ].

Atazanavir: Avoid concomitant use with ZEGERID. See prescribing information for atazanavir for dosing information.

Nelfinavir: Avoid concomitant use with ZEGERID. See prescribing information for nelfinavir.

Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities.

Other antiretrovirals: See prescribing information for specific antiretroviral drugs.

Warfarin

Clinical Impact:

Increased INR and prothrombin time in patients receiving PPIs, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death.

Intervention:

Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain target INR range.

Methotrexate

Clinical Impact:

Concomitant use of omeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions (5.12)].

Intervention:

A temporary withdrawal of ZEGERID may be considered in some patients receiving high-dose methotrexate.

CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam)
Clopidogrel

Clinical Impact:

Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology (12.3)].

There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel.

Intervention:

Avoid concomitant use with ZEGERID. Consider use of alternative anti-platelet therapy [see Warnings and Precautions (5.7)].

Citalopram

Clinical Impact:

Increased exposure of citalopram leading to an increased risk of QT prolongation [see Clinical Pharmacology (12.3)].

Intervention:

Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram.

Cilostazol

Clinical Impact:

Increased exposure of one of the active metabolites of cilostazol (3,4-dihydro-cilostazol) [see Clinical Pharmacology (12.3)].

Intervention:

Reduce the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol.

Phenytoin

Clinical Impact:

Potential for increased exposure of phenytoin.

Intervention:

Monitor phenytoin serum concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for phenytoin.

Diazepam

Clinical Impact:

Increased exposure of diazepam [see Clinical Pharmacology (12.3)].

Intervention:

Monitor patients for increased sedation and reduce the dose of diazepam as needed.

Digoxin

Clinical Impact:

Potential for increased exposure of digoxin [see Clinical Pharmacology(12.3)].

Intervention:

Monitor digoxin concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See digoxin prescribing information.

Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)

Clinical Impact:

Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.

Intervention:

Mycophenolate mofetil (MMF): Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving ZEGERID and MMF. Use ZEGERID with caution in transplant patients receiving MMF [see Clinical Pharmacology (12.3)].

See the prescribing information for other drugs dependent on gastric pH for absorption.

Tacrolimus

Clinical Impact:

Potential for increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.

Intervention:

Monitor tacrolimus whole blood concentrations. Dose adjustment may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus.

Interactions with Investigations of Neuroendocrine Tumors

Clinical Impact:

Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions (5.11) and Clinical Pharmacology (12.2)].

Intervention:

Temporarily stop PRILOSEC 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.

Interaction with Secretin Stimulation Test

Clinical Impact:

Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.

Intervention:

Temporarily stop ZEGERID treatment at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology (12.2)].

False Positive Urine Tests for THC

Clinical Impact:

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

Intervention:

An alternative confirmatory method should be considered to verify positive results.

Other

Clinical Impact:

There have been clinical reports of interactions with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram).

Intervention:

Monitor patients to determine if it is necessary to adjust the dosage of these other drugs when taken concomitantly with ZEGERID.

Table 7: Clinically Relevant Interactions Affecting Omeprazole When Co-Administered with Other Drugs
CYP2C19 or CYP3A4 Inducers

Clinical Impact:

Decreased exposure of omeprazole when used concomitantly with strong inducers [see Clinical Pharmacology (12.3)].

Intervention:

St. John’s wort, rifampin: Avoid concomitant use with ZEGERID [see Warnings and Precautions (5.10)].

Ritonavir-containing products: See prescribing information for specific drugs.

CYP2C19 or CYP3A4 Inhibitors

Clinical Impact:

Increased exposure of omeprazole [see Clinical Pharmacology (12.3)].

Intervention:

Voriconazole: Dosage adjustment of ZEGERID is not required.

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