6.2 Postmarketing Experience

Additions and/or revisions underlined:

Renal and Genitourinary Disorders: interstitial nephritis, erectile dysfunction

New subsection added

Severe cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported in association with the use of PPIs [see Adverse Reactions (6.2)]. Discontinue ACIPHEX at first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation.

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… 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.

…

Consider monitoring magnesium and calcium levels prior to initiation of ACIPHEX 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.

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

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• Hypomagnesemia and Mineral Metabolism [see Warnings and Precautions (5.9)]

6.2 Postmarketing Experience

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

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Metabolism and Nutrition Disorders: hyperammonemia, hypomagnesemia, hypocalcemia, hypokalemia [Warnings and Precautions 5.8], hyponatremia

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Before you take ACIPHEX, tell your doctor about all of your medical conditions, including if you:

• have low magnesium levels, low calcium levels and low potassium levels in your blood.

  …

  What are the possible side effects of ACIPHEX?

  ACIPHEX can cause serious side effects, including:

  …

   

• Severe skin reactions. ACIPHEX can cause rare but serious skin reactions that may affect any part of your body. These serious skin reactions may need to be treated in a hospital and may be life threatening:

  • Skin rash which may have blistering, peeling or bleeding on any part of your skin (including your lips, eyes, mouth, nose, genitals, hands or feet).

  • You may also have fever, chills, body aches, shortness of breath, or enlarged lymph nodes. Stop taking ACIPHEX and call your doctor right away. These symptoms may be the first sign of a severe skin reaction.

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Severe Cutaneous Adverse Reactions

Advise the patient or caregiver to discontinue ACIPHEX and report any signs and symptoms of a severe cutaneous adverse reaction or other sign of hypersensitivity to the healthcare provider [see Warnings and Precautions (5.6)].

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Hypomagnesemia and Mineral Metabolism

Advise the patient or caregiver to report any clinical symptoms that may be associated with hypomagnesemia, hypocalcemia, hypokalemia and hyponatremia to the patient’s healthcare provider, if they have been receiving ACIPHEX for at least 3 months [see Warnings and Precautions (5.8)].

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• ACIPHEX 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)].

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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 and evaluate patients with suspected acute TIN [see Contraindication (4)].

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

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

        …

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ACIPHEX 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, may develop a kidney problem called acute tubulointerstitial nephritis that can happen at any time during treatment with ACIPHEX. Call your doctor right away if you have a decrease in the amount that you urinate or if you have blood in your urine.

 …

Additions and/or revisions underlined

Advise the patient 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 Warnings and Precautions (5.3)].

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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.

Addition of the following:

• Fundic Gland Polyps

6.2 Postmarketing Experience

Gastrointestinal:

Addition of: fundic gland polyps

(additions underlined)

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

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Table 2 includes drugs with clinically important drug interactions and interaction with diagnostics when administered concomitantly with ACIPHEX delayed-release tablets 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 Delayed-Release Tablets and Interactions with Diagnostics

(please refer to label to view Table 2)

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Risk Summary

There are no available human data on ACIPHEX use in pregnant women to inform the drug associated risk. The background risk of major birth defects and miscarriage for the indicated populations are unknown. However, the background risk in the U.S. general population of major birth defects is 2 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies. No evidence of adverse developmental effects were seen in animal reproduction studies with rabeprazole administered during organogenesis at 13 and 8 times the human area under the plasma concentration-time curve (AUC) at the recommended dose for GERD, in rats and rabbits, respectively [see Data].

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

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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.

(extensive additions and revisions, please refer to label).

(additions underlined)

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

Acute Interstitial Nephritis

Advise the patient or caregiver to call the patient’s healthcare provider immediately if they experience signs and/or symptoms associated with acute interstitial nephritis.

Clostridium difficile-Associated Diarrhea

Advise the patient or caregiver to immediately call the patient’s healthcare provider if they experience diarrhea that does not improve.

Bone Fracture

Advise the patient or caregiver to report any fractures, especially of the hip, wrist or spine, to the patient’s healthcare provider.

Cutaneous and Systemic Lupus Erythematosus

Advise the patient or caregiver to immediately call the patient’s healthcare provider for any new or worsening of symptoms associated with cutaneous or systemic lupus erythematosus.

Cyanocobalamin (Vitamin B-12) Deficiency

Advise the patient or caregiver to report any clinical symptoms that may be associated with cyanocobalamin deficiency to the patient’s healthcare provider if they have been receiving ACIPHEX for longer than 3 years.

Hypomagnesemia

Advise the patient or caregiver to report any clinical symptoms that may be associated with hypomagnesemia to the patient’s healthcare provider, if they have been receiving ACIPHEX for at least 3 months.

Drug Interactions

Advise patients to report to their healthcare provider if they are taking rilpivirine-containing products warfarin, digoxin or high-dose methotrexate.

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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. (additions and/or revisions underlined)

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, 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.

…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), healthcare professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically. (additions underlined)

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

What is the most important information I should know about ACIPHEX

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

ACIPHEX can cause serious side effects, including:

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

What are the possible side effects of ACIPHEX?

ACIPHEX may cause serious side effects, including:

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

Adverse Reactions (additions underlined)

Advise patients to report to their healthcare provider if they experience any signs or symptoms consistent with:

• Cutaneous and Systemic Lupus Erythematosus

• Cyanocobalamin (Vitamin B-12 Deficiency)