Drug Safety-related Labeling Changes (SrLC)

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ACIPHEX SPRINKLE (NDA-204736)

(RABEPRAZOLE SODIUM)

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

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11/27/2020 (SUPPL-12)

Approved Drug Label (PDF)

4 Contraindications

Additions and/or revisions underlined

  • ACIPHEX Sprinkle is contraindicated in patients with known hypersensitivity to rabeprazole, substituted benzimidazoles, or to any component of the formulation. Hypersensitivity reactions may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, acute tubulointerstitial nephritis, and urticaria [see Warnings and Precautions (5.3), Adverse Reactions (6)].

5 Warnings and Precautions

5.3 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, 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 ACIPHEX Sprinkle and evaluate patients with suspected acute TIN [see Contraindications (4)].

6 Adverse Reactions

Additions and/or revisions underlined

The following serious adverse reactions are described below and elsewhere in labeling:

  • Acute Tubulointerstitial Nephritis [see Warnings and Precautions (5.3)]

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

MEDICATION GUIDE

Additions and/or revisions underlined

ACIPHEX Sprinkle can cause serious side effects, including:

  • A type of kidney problem (acute tubulointerstitial nephritis). Some people who take proton pump inhibitor (PPI) medicines, including ACIPHEX Sprinkle, may develop a kidney problem called acute tubulointerstitial nephritis that can happen at any time during treatment with ACIPHEX Sprinkle. Call your child’s doctor right away if your child has a decrease in the amount that they urinate or if they have blood in their urine.

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined

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

Acute Tubulointerstitial Nephritis

Advise the patient or caregiver to call the patient’s healthcare provider immediately if they experience signs and/or symptoms associated with acute tubulointerstitial nephritis [see Contraindications (4), Warnings and Precautions (5.3)].

06/07/2018 (SUPPL-10)

Approved Drug Label (PDF)

5 Warnings and Precautions

Newly created subsection:

5.10 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

07/27/2017 (SUPPL-8)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Presence of Gastric Malignancy

(subsection revised; additions underlined)

In adults, symptomatic response to therapy with ACIPHEX 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.

5.6 Cutaneous and Systemic Lupus Erythematosus

(new subsection added)

Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) have been reported in patients taking PPIs, including rabeprazole. 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, 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 ACIPHEX Sprinkle, 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

(additions underlined)


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

(additions underlined)

The following adverse reactions have been identified during post approval use of rabeprazole sodium. 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.

Blood and Lymphatic System Disorders: agranulocytosis, hemolytic anemia, leukopenia, pancytopenia, and thrombocytopenia

Ear and Labyrinth Disorders: vertigo

Eye Disorders: blurred vision

General Disorders and Administration Site Conditions: sudden death

Hepatobiliary Disorders: jaundice

Immune System Disorders: anaphylaxis, angioedema, systemic lupus erythematosus, Stevens- Johnson syndrome, toxic epidermal necrolysis (some fatal)

Infections and Infestations: Clostridium difficile-associated diarrhea

Investigations: Increases in prothrombin time/INR (in patients treated with concomitant warfarin), TSH elevations

Metabolism and Nutrition Disorders: hyperammonemia, hypomagnesemia

Musculoskeletal System Disorders: bone fracture, rhabdomyolysis

 Nervous System Disorders: coma

Psychiatric Disorders: delirium, disorientation

Renal and Urinary Disorders: interstitial nephritis

Respiratory, Thoracic and Mediastinal Disorders: interstitial pneumonia

Skin and Subcutaneous Tissue Disorders: severe dermatologic reactions, including bullous and other drug eruptions of the skin; cutaneous lupus erythematosus, erythema multiforme

7 Drug Interactions

(additions underlined)

Table 2 includes clinically important drug interactions and interaction with diagnostics when administered concomitantly with ACIPHEX Sprinkle and instructions for preventing or managing them.

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

Table 2: Clinically Relevant Interactions Affecting Drugs Co-Administered with ACIPHEX Sprinkle and Interactions with Diagnostics

(please refer to label to view Table 2)

8 Use in Specific Populations

8.1 Pregnancy

(additions underlined)

Risk Summary

Changes in bone morphology were observed in offspring of rats treated with oral doses of a different PPI through most of pregnancy and lactation. When maternal administration was confined to gestation only, there were no effects on bone physeal morphology in the offspring at any age [see Data].

Data

Animal Data

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 a different PPI at oral doses of 280 mg/kg/day (about 68 times an oral human dose on a body surface area basis) where drug 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.

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

MEDICATION GUIDE

(additions and revisions; please refer to label)

PATIENT COUNSELING INFORMATION

(additions and revisions; please refer to label)

10/24/2016 (SUPPL-7)

5 Warnings and Precautions

5.1 Presence of Gastric Malignancy

In adults, symptomatic response to therapy with ACIPHEX SPRINKLE 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)


5.5 Cutaneous and Systemic Lupus Erythematosus (additional section)

Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) have been reported in patients taking PPIs. 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, 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 ACIPHEX SPRINKLE, 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:

(Addition of the following)

  • Cutaneous and Systemic Lupus Erythematosus
  • Cyanocobalamin (Vitamin B-12) Deficiency
6.2 Postmarketing Experience

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

delirium; anaphylaxis; angioedema; systemic lupus erythematosus, bullous and other drug eruptions of the skin; severe dermatologic reactions, including toxic epidermal necrolysis (some fatal), Stevens-Johnson syndrome, cutaneous lupus erythematosus and erythema multiforme…

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

MEDICATION GUIDE

What is the most important information I should know about ACIPHEX SPRINKLE?

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

ACIPHEX SPRIINKLE can cause serious side effects, including: (additions underlined)

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

Talk to your doctor about your risk of these serious side effects if you take ACIPHEX SPRINKLE.

What are the possible side effects of ACIPHEX SPRINKLE?

ACIPHEX SPRINKLE may cause serious side effects, including:

  • See “What is the most important information I should know about ACIPHEX SPRINKLE?”
  • Interaction with warfarin. Taking warfarin with a PPI medicine may lead to an increased risk of bleeding… (addition underlined)
PATIENT COUNSELING INFORMATION

Adverse Reactions (additions and/or revisions underlined)

Advise the patient or caregiver to report to the patient’s healthcare provider if they experience any signs or symptoms consistent with:

•           Cutaneous and Systemic Lupus Erythematosus

•           Cyanocobalamin (Vitamin B-12) deficiency

Drug Interactions

Advise the patient or caregiver to report to the patient’s healthcare provider if they are taking warfarin or high-dose methotrexate.

04/04/2016 (SUPPL-3)

Approved Drug Label (PDF)

4 Contraindications

PPIs, including ACIPHEX, are contraindicated with rilpivirine-containing products.

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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