What the FDA changed in 2021

Approved uses

Added in this revision

• +Added: Risk Reduction of Nonsteroidal Anti-Inflammatory Drugs (NSAID)-Associated Gastric Ulcer NEXIUM delayed-release capsules and NEXIUM for delayed-release oral suspension are indicated for the reduction in the occurrence of gastric ulcers associated with continuous NSAID therapy in adult patients at risk for developing gastric ulcers.
• +Added: Patients are considered to be at risk due to their age (60 years and older) and/or documented history of gastric ulcers.

Removed in this revision

• -Removed: Risk Reduction of Nonsteroidal Anti-Inflammatory Drugs (NSAID)-Associated Gastric Ulcer NEXIUM is indicated for the long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison Syndrome.

Adverse reactions

This section was substantially rewritten in this revision: 10 entries added, 14 removed. A change this large is usually a reorganization of the document rather than a set of individual edits, so the wording is not quoted line by line.

14 entries reworded without a change of meaning.

Drug interactions

Removed in this revision

• -Removed: Table: Clinically Relevant Interactions Affecting Esomeprazole When Co-Administered with Other Drugs

Approved uses

Added in this revision

• +Added: Healing of Erosive Esophagitis (EE) Adults NEXIUM delayed-release capsules and NEXIUM for delayed-release oral suspension are indicated for the short-term treatment (4 to 8 weeks) in the healing and symptomatic resolution of diagnostically confirmed EE in adults.
• +Added: Pediatric Patients 12 Years to 17 Years of Age NEXIUM delayed-release capsules and NEXIUM for delayed-release oral suspension are indicated for the short-term treatment (4 to 8 weeks) for the healing of EE in pediatric patients 12 years to 17 years of age.
• +Added: Pediatric Patients 1 Year to 11 Years of Age NEXIUM for delayed-release oral suspension is indicated for the short-term treatment (8 weeks) for the healing of EE in pediatric patients 1 year to 11 years of age.
• +Added: Pediatric Patients 1 Month to Less Than 1 Year of Age NEXIUM for delayed-release oral suspension is indicated for short-term treatment (up to 6 weeks) of EE due to acid-mediated GERD in pediatric patients 1 month to less than 1 year of age.
• +Added: Maintenance of Healing of EE NEXIUM delayed-release capsules and NEXIUM for delayed-release oral suspension are indicated for the maintenance of healing of EE in adults.
• +Added: Treatment of Symptomatic GERD Adults NEXIUM delayed-release capsules and NEXIUM for delayed-release oral suspension are indicated for short-term treatment (4 to 8 weeks) of heartburn and other symptoms associated with GERD in adults.
• +Added: Pediatric Patients 12 Years to 17 Years of Age NEXIUM delayed-release capsules and NEXIUM for delayed-release oral suspension are indicated for short-term treatment (4 weeks) of heartburn and other symptoms associated with GERD in pediatric patients 12 years to 17 years of age.
• +Added: Pediatric Patients 1 Year to 11 Years of Age NEXIUM for delayed-release oral suspension is indicated for short-term treatment (up to 8 weeks) of heartburn and other symptoms associated with GERD in pediatric patients 1 year to 11 years of age.
• +Added: Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome NEXIUM delayed-release capsules and NEXIUM for delayed-release oral suspension are indicated for the long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison Syndrome, in adults.

Removed in this revision

• -Removed: Treatment of Gastroesophageal Reflux Disease (GERD) Healing of Erosive Esophagitis NEXIUM is indicated for the short-term treatment (4 to 8 weeks) in the healing and symptomatic resolution of diagnostically confirmed erosive esophagitis.
• -Removed: In infants 1 month to less than 1 year, NEXIUM is indicated for short-term treatment (up to 6 weeks) of erosive esophagitis due to acid-mediated GERD.
• -Removed: Maintenance of Healing of Erosive Esophagitis NEXIUM is indicated to maintain symptom resolution and healing of erosive esophagitis.
• -Removed: Symptomatic Gastroesophageal Reflux Disease NEXIUM is indicated for short-term treatment (4 to 8 weeks) of heartburn and other symptoms associated with GERD in adults and children 1 year or older.
• -Removed: Risk Reduction of NSAID-Associated Gastric Ulcer NEXIUM is indicated for the reduction in the occurrence of gastric ulcers associated with continuous NSAID therapy in patients at risk for developing gastric ulcers.
• -Removed: Patients are considered to be at risk due to their age (≥ 60) and/or documented history of gastric ulcers.

3 entries reworded without a change of meaning.

Dosage and administration

This section was substantially rewritten in this revision: 36 entries added, 21 removed. A change this large is usually a reorganization of the document rather than a set of individual edits, so the wording is not quoted line by line.

6 entries reworded without a change of meaning.

Forms and strengths

Removed in this revision

• -Removed: NEXIUM Delayed-Release Capsules, 40 mg - opaque, hard gelatin, amethyst colored capsules with three radial bars in yellow on the cap and NEXIUM 40 mg in yellow on the body.

2 entries reworded without a change of meaning.

Contraindications

Added in this revision

• +Added: Hypersensitivity reactions may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, acute tubulointerstitial nephritis, and urticaria. • For information about contraindications of amoxicillin and clarithromycin, indicated in combination with NEXIUM for H. pylori eradication to reduce the risk of duodenal ulcer recurrence, refer to the Contraindications section of the respective prescribing information. • Proton pump inhibitors (PPIs), including NEXIUM, are contraindicated in...

Removed in this revision

• -Removed: Hypersensitivity reactions may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, acute tubulointerstitial nephritis, and urticaria.
• -Removed: For information about contraindications of antibacterial agents (clarithromycin and amoxicillin) indicated in combination with NEXIUM, refer to the CONTRAINDICATIONS section of their package inserts.

Adverse reactions

1 entry reworded without a change of meaning.

Drug interactions

Added in this revision

• +Added: Tables 3 and 4 include drugs with clinically important drug interactions and interaction with diagnostics when administered concomitantly with esomeprazole and instructions for preventing or managing them.
• +Added: Consult the labeling of concomitantly used drugs to obtain further information about interactions with PPIs.
• +Added: Table: Clinically Relevant Interactions Affecting Esomeprazole When Co-Administered with Other Drugs

Removed in this revision

• -Removed: Interference with Antiretroviral Therapy Concomitant use of atazanavir and nelfinavir with proton pump inhibitors is not recommended.
• -Removed: Co-administration of atazanavir with proton pump inhibitors is expected to substantially decrease atazanavir plasma concentrations and may result in a loss of therapeutic effect and the development of drug resistance.
• -Removed: Co-administration of saquinavir with proton pump inhibitors is expected to increase saquinavir concentrations, which may increase toxicity and require dose reduction.
• -Removed: Omeprazole, of which esomeprazole is an enantiomer, has been reported to interact with some antiretroviral drugs.
• -Removed: The clinical importance and the mechanisms behind these interactions are not always known.
• -Removed: Increased gastric pH during omeprazole treatment may change the absorption of the antiretroviral drug.
• -Removed: Other possible interaction mechanisms are via CYP2C19.
• -Removed: Reduced concentrations of atazanavir and nelfinavir For some antiretroviral drugs, such as atazanavir and nelfinavir, decreased serum levels have been reported when given together with omeprazole.
• -Removed: Following multiple doses of nelfinavir (1250 mg, twice daily) and omeprazole (40 mg daily), AUC was decreased by 36% and 92%, C max by 37% and 89% and C min by 39% and 75% respectively for nelfinavir and M8.
• -Removed: Following multiple doses of atazanavir (400 mg, daily) and omeprazole (40 mg, daily, 2 hours before atazanavir), AUC was decreased by 94%, C max by 96%, and C min by 95%.
• -Removed: Concomitant administration with omeprazole and drugs such as atazanavir and nelfinavir is therefore not recommended.
• -Removed: Increased concentrations of saquinavir For other antiretroviral drugs, such as saquinavir, elevated serum levels have been reported, with an increase in AUC by 82%, in C max by 75%, and in C min by 106%, following multiple dosing of saquinavir/ritonavir (1000/100 mg) twice daily for 15 days with omeprazole 40 mg daily co-administered days 11 to 15.
• -Removed: Therefore, clinical and laboratory monitoring for saquinavir toxicity is recommended during concurrent use with NEXIUM.
• -Removed: Dose reduction of saquinavir should be considered from the safety perspective for individual patients.
• -Removed: There are also some antiretroviral drugs of which unchanged serum levels have been reported when given with omeprazole.
• -Removed: Drugs for Which Gastric pH Can Affect Bioavailability Due to its effects on gastric acid secretion, esomeprazole can reduce the absorption of drugs where gastric pH is an important determinant of their bioavailability.
• -Removed: Like with other drugs that decrease the intragastric acidity, the absorption of drugs such as ketoconazole, atazanavir, iron salts, erlotinib, and mycophenolate mofetil (MMF) can decrease, while the absorption of drugs such as digoxin can increase during treatment with esomeprazole.
• -Removed: Esomeprazole is an enantiomer of omeprazole.
• -Removed: Concomitant treatment with omeprazole (20 mg daily) and digoxin in healthy subjects increased the bioavailability of digoxin by 10% (30% in two subjects).
• -Removed: Co-administration of digoxin with NEXIUM is expected to increase the systemic exposure of digoxin.
• -Removed: Therefore, patients may need to be monitored when digoxin is taken concomitantly with NEXIUM.
• -Removed: 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.
• -Removed: The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving NEXIUM and MMF.
• -Removed: Use NEXIUM with caution in transplant patients receiving MMF.
• -Removed: Effects on Hepatic Metabolism/Cytochrome P-450 Pathways Esomeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4.
• -Removed: In vitro and in vivo studies have shown that esomeprazole is not likely to inhibit CYPs 1A2, 2A6, 2C9, 2D6, 2E1, and 3A4.
• -Removed: No clinically relevant interactions with drugs metabolized by these CYP enzymes would be expected.
• -Removed: Drug interaction studies have shown that esomeprazole does not have any clinically significant interactions with phenytoin, warfarin, quinidine, clarithromycin, or amoxicillin.
• -Removed: However, postmarketing reports of changes in prothrombin measures have been received among patients on concomitant warfarin and esomeprazole therapy.
• -Removed: Increases in INR and prothrombin time may lead to abnormal bleeding and even death.
• -Removed: Patients treated with proton pump inhibitors and warfarin concomitantly may need to be monitored for increases in INR and prothrombin time.
• -Removed: Esomeprazole may potentially interfere with CYP2C19, the major esomeprazole metabolizing enzyme.
• -Removed: Co-administration of esomeprazole 30 mg and diazepam, a CYP2C19 substrate, resulted in a 45% decrease in clearance of diazepam.
• -Removed: Clopidogrel Clopidogrel is metabolized to its active metabolite in part by CYP2C19.
• -Removed: Concomitant use of esomeprazole 40 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition.
• -Removed: Avoid concomitant administration of NEXIUM with clopidogrel.
• -Removed: When using NEXIUM, consider use of alternative anti-platelet therapy.
• -Removed: Omeprazole acts as an inhibitor of CYP2C19.
• -Removed: Omeprazole, given in doses of 40 mg daily for one week to 20 healthy subjects in cross-over study, increased C max and AUC of cilostazol by 18% and 26% respectively.
• -Removed: C max and AUC of one of its active metabolites, 3,4-dihydrocilostazol, which has 4-7 times the activity of cilostazol, were increased by 29% and 69%, respectively.
• -Removed: Co-administration of cilostazol with esomeprazole is expected to increase concentrations of cilostazol and its above mentioned active metabolite.
• -Removed: Therefore, a dose reduction of cilostazol from 100 mg twice daily to 50 mg twice daily should be considered.
• -Removed: Concomitant administration of esomeprazole and a combined inhibitor of CYP2C19 and CYP3A4, such as voriconazole, may result in more than doubling of the esomeprazole exposure.
• -Removed: Dose adjustment of esomeprazole is not normally required.
• -Removed: However, in patients with Zollinger-Ellison's Syndrome, who may require higher doses up to 240 mg/day, dose adjustment may be considered.
• -Removed: Drugs known to induce CYP2C19 or CYP3A4 or both (such as rifampin) may lead to decreased esomeprazole serum levels.
• -Removed: Omeprazole, of which esomeprazole is an enantiomer, has been reported to interact with St.
• -Removed: John's Wort, an inducer of CYP3A4.
• -Removed: In a cross-over study in 12 healthy male subjects, St.
• -Removed: John's Wort (300 mg three times daily for 14 days) significantly decreased the systemic exposure of omeprazole in CYP2C19 poor metabolisers (C max and AUC decreased by 37.5% and 37.9%, respectively) and extensive metabolisers (C max and AUC decreased by 49.6% and 43.9%, respectively).
• -Removed: Avoid concomitant use of St.
• -Removed: John's Wort or rifampin with NEXIUM.
• -Removed: Interactions with Investigations of Neuroendocrine Tumors Drug-induced decrease in gastric acidity results in enterochromaffin-like cell hyperplasia and increased Chromogranin A levels which may interfere with investigations for neuroendocrine tumors.
• -Removed: Tacrolimus Concomitant administration of esomeprazole and tacrolimus may increase the serum levels of tacrolimus.
• -Removed: Combination Therapy with Clarithromycin Co-administration of esomeprazole, clarithromycin, and amoxicillin has resulted in increases in the plasma levels of esomeprazole and 14-hydroxyclarithromycin.
• -Removed: Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions due to drug interactions.
• -Removed: Because of these drug interactions, clarithromycin is contraindicated for co-administration with certain drugs.
• -Removed: Methotrexate Case reports, published population pharmacokinetic studies, and retrospective analyses suggest that concomitant administration of PPIs and methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate.
• -Removed: However, no formal drug interaction studies of methotrexate with PPIs have been conducted.

Approved uses

1 entry reworded without a change of meaning.

Contraindications

Added in this revision

• +Added: Serious hypersensitivity reactions including anaphylaxis and angioedema have been reported with RYBELSUS.

1 entry reworded without a change of meaning.

Warnings and precautions

Added in this revision

• +Added: Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin Patients receiving RYBELSUS in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia.
• +Added: The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea (or other concomitantly administered insulin secretagogue) or insulin.
• +Added: Inform patients using these concomitant medications of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia.
• +Added: Hypersensitivity Serious hypersensitivity reactions (e.g., anaphylaxis, angioedema) have been reported in patients treated with RYBELSUS.

Removed in this revision

• -Removed: Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin The risk of hypoglycemia is increased when RYBELSUS is used in combination with insulin secretagogues (e.g., sulfonylureas) or insulin.
• -Removed: Patients may require a lower dose of the secretagogue or insulin to reduce the risk of hypoglycemia in this setting.
• -Removed: Hypersensitivity Serious hypersensitivity reactions (e.g., anaphylaxis, angioedema) have been reported with GLP-1 receptor agonists, including semaglutide.

Adverse reactions

Added in this revision

• +Added: Postmarketing Experience The following adverse reactions have been reported during post-approval use of semaglutide, the active ingredient of RYBELSUS.
• +Added: 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.
• +Added: Hypersensitivity: anaphylaxis, angioedema, rash, urticaria

1 entry reworded without a change of meaning.

Drug interactions

Added in this revision

• +Added: Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin When initiating RYBELSUS, consider reducing the dose of concomitantly administered insulin secretagogue (such as sulfonylureas) or insulin to reduce the risk of hypoglycemia.

Removed in this revision

• -Removed: Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin The risk of hypoglycemia is increased when RYBELSUS is used in combination with insulin secretagogues (e.g., sulfonylureas) or insulin.
• -Removed: The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea (or other concomitantly administered insulin secretagogues) or insulin.

Warnings and precautions

Added in this revision

• +Added: Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin Patients receiving TRULICITY in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia.
• +Added: The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea (or other concomitantly administered insulin secretagogue) or insulin.
• +Added: Inform patients using these concomitant medications of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia.

Removed in this revision

• -Removed: Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin The risk of hypoglycemia is increased when TRULICITY is used in combination with insulin secretagogues (e.g., sulfonylureas) or insulin.
• -Removed: Patients may require a lower dose of sulfonylurea or insulin to reduce the risk of hypoglycemia in this setting.