Drug Safety-related Labeling Changes (SrLC)

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NEXIUM (NDA-021957)

(ESOMEPRAZOLE MAGNESIUM)

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

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06/07/2018 (SUPPL-20)

Approved Drug Label (PDF)

5 Warnings and Precautions

Newly created subsection:

5.12 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

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

MEDICATION GUIDE

Additions and/or revisions underlined:

What are the possible side effects of NEXIUM?

NEXIUM can cause serious side effects, including:

  • 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.

12/20/2016 (SUPPL-18)

Approved Drug Label (PDF)

5 Warnings and Precautions

(Additions and/or revisions are underlined in subsection title)

5.9 Interaction with St. John’s Wort or Rifampin

5.11 Interaction with Methotrexate

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR )Conversion; Additions and/or revisions are underlined)

Risk Summary

Reproduction studies in rats and rabbits resulted in dose-dependent embryo-lethality at omeprazole doses that were approximately 3.4 to 34 times an oral human dose of 40 mg (based on a body surface area for a 60 kg person)…

…Changes in bone morphology were observed in offspring of rats dosed through most of pregnancy and lactation at doses equal to or greater than approximately 34 times an oral human dose of 40 mg. When maternal administration was confined to gestation only, there were no effects on bone physeal morphology in the offspring at any age.

The estimated background risks of major birth defects and miscarriage for the indicated population are unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Human Data

…A small prospective observational cohort study followed 113 women exposed to omeprazole during pregnancy (89% with first trimester exposures)…

 Animal Data

Omeprazole

Reproductive studies conducted with omeprazole in rats at oral doses up to 138 mg/kg/day (about 34 times an oral human dose of 40 mg on a body surface area basis) and in rabbits at doses up to 69.1 mg/kg/day (about 34 times an oral human dose of 40 mg on a body surface area basis) during organogenesis did not disclose any evidence for a teratogenic potential of omeprazole. In rabbits, omeprazole in a dose range of 6.9 to 69.1 mg/kg/day (about 3.4 to 34 times an oral human dose of 40 mg on a body surface area basis) administered during organogenesis produced dose-related increases in embryo- lethality, fetal resorptions, and pregnancy disruptions. In rats, dose-related embryo/fetal toxicity and postnatal developmental toxicity were observed in offspring resulting from parents treated with omeprazole at 13.8 to 138.0 mg/kg/day (about 3.4 to 34 times an oral human dose of 40 mg on a body surface area basis), administered prior to mating through the lactation period.

Esomeprazole

No effects on embryo-fetal development were observed in reproduction studies with esomeprazole magnesium in rats at oral doses up to 280 mg/kg/day (about 68 times an oral human dose of 40 mg on a body surface area basis) or in rabbits at oral doses up to 86 mg/kg/day (about 41 times an oral human dose of 40 mg on a body surface area basis) administered during organogenesis…

A follow up developmental toxicity study in rats with further time points to evaluate pup bone development from postnatal day 2 to adulthood was performed with esomeprazole magnesium at oral doses of 280 mg/kg/day (about 68 times an oral human dose of 40 mg on a body surface area basis) where esomeprazole administration was from either gestational day 7 or gestational day 16 until parturition. When maternal administration was confined to gestation only, there were no effects on bone physeal morphology in the offspring at any age.

8.2 Lactation

(Pregnancy and Lactation Labeling Rule Conversion; Additions and/or revisions are underlined)

Risk Summary

Esomeprazole is the S-isomer of omeprazole and limited data suggest that omeprazole may be present in human milk. There are no clinical data on the effects of esomeprazole 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 NEXIUM and any potential adverse effects on the breastfed infant from NEXIUM or from the underlying maternal condition.

10/24/2016 (SUPPL-19)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Presence of Gastric Malignancy

In adults, symptomatic response to therapy with NEXIUM 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)

5.2 Acute Interstitial Nephritis

Acute interstitial nephritis has been observed in patients taking PPIs including NEXIUM. Acute interstitial nephritis may occur at any point during PPI therapy and is generally attributed to an idiopathic hypersensitivity reaction. Discontinue NEXIUM if acute interstitial nephritis develops.

5.5 Cutaneous and Systemic Lupus Erythematosus

Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) have been reported in patients taking PPIs, including esomeprazole. These events have occurred as both new onset and an exacerbation of existing autoimmune disease. The majority of PPI-induced lupus erythematosus 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, histologicalfindings 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 NEXIUM, 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
6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of NEXIUM:

Immune System: anaphylactic reaction/shock; systemic lupus erythematosus

Skin and Subcutaneous Tissue: alopecia, erythema multiforme, hyperhidrosis, photosensitivity, Stevens- Johnson syndrome, toxic epidermal necrolysis (some fatal), cutaneous lupus erythematosus.

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

MEDICATION GUIDE

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

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

NEXIUM can cause serious side effects, including: (additions below)

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

  • 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

    Drug Interactions

    Advise patients to let you know if they are taking, or begin taking, other medications, because NEXIUM can interfere with antiretroviral drugs and drugs that are affected by gastric pH changes.

    Administration

    Let patients know that antacids …

Questions related to the drug data in these files should be directed to the Center for Drug Evaluation and Research, Division of Drug Information
druginfo@fda.hhs.gov.

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