Rabeprazole Sodium

Rabeprazole sodium delayed-release tablets is a proton pump inhibitor (PPI) indicated in adults for:

• Healing of Erosive or Ulcerative Gastroesophageal Reflux Disease (GERD) (
  
  
  
  1.1 Healing of Erosive or Ulcerative GERD in Adults

  Rabeprazole sodium delayed-release tablets are indicated for short-term (4 to 8 weeks) treatment in the healing and symptomatic relief of erosive or ulcerative gastroesophageal reflux disease (GERD). For those patients who have not healed after 8 weeks of treatment, an additional 8-week course of rabeprazole sodium delayed-release tablets may be considered.
  ).
  
  
• Maintenance of Healing of Erosive or Ulcerative GERD (
  
  
  
  1.2 Maintenance of Healing of Erosive or Ulcerative GERD in Adults

  Rabeprazole sodium delayed-release tablets are indicated for maintaining healing and reduction in relapse rates of heartburn symptoms in patients with erosive or ulcerative gastroesophageal reflux disease (GERD Maintenance). Controlled studies do not extend beyond 12 months.
  ).
  
  
• Treatment of Symptomatic GERD (
  
  
  
  1.3 Treatment of Symptomatic GERD in Adults

  Rabeprazole sodium delayed-release tablets are indicated for the treatment of daytime and nighttime heartburn and other symptoms associated with GERD in adults for up to 4 weeks.
  ).
  
  
• Healing of Duodenal Ulcers (
  
  
  
  1.4 Healing of Duodenal Ulcers in Adults

  Rabeprazole sodium delayed-release tablets are indicated for short-term (up to four weeks) treatment in the healing and symptomatic relief of duodenal ulcers. Most patients heal within four weeks.
  ).
  
  
• Helicobacter pylori
  Eradication to Reduce Risk of Duodenal Ulcer Recurrence (
  
  
  
  1.5

  Helicobacter pylori

  Eradication to Reduce the Risk of Duodenal Ulcer Recurrence in Adults

  Rabeprazole sodium delayed-release tablets, in combination with amoxicillin and clarithromycin as a three drug regimen, are indicated for the treatment of patients with

  H. pylori

  infection and duodenal ulcer disease (active or history within the past 5 years) to eradicate

  H. pylori

  . Eradication of

  H. pylori

  has been shown to reduce the risk of duodenal ulcer recurrence.

  In patients who fail therapy, susceptibility testing should be done. If resistance to clarithromycin is demonstrated or susceptibility testing is not possible, alternative antimicrobial therapy should be instituted [

  see Clinical Pharmacology

  and the full prescribing information for clarithromycin

  ]

  .
  ).
  
  
• Treatment of Pathological Hypersecretory Conditions, Including Zollinger-Ellison Syndrome (
  
  
  
  1.6 Treatment of Pathological Hypersecretory Conditions, Including Zollinger-Ellison Syndrome in Adults

  Rabeprazole sodium delayed-release tablets are indicated for the long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison syndrome.
  ).
  
  

In adolescent patients 12 years of age and older for:

•   Short-term Treatment of Symptomatic GERD (
  
  
  
  1.7 Treatment of Symptomatic GERD in Adolescent Patients 12 Years of Age and Older

  Rabeprazole sodium delayed-release tablets are indicated for the treatment of symptomatic GERD in adolescents 12 years of age and above for up to 8 weeks.
  ).
  
  

• Swallow rabeprazole sodium delayed-release tablets whole. Do not chew, crush or split the tablets.
• For the treatment of duodenal ulcers take rabeprazole sodium delayed-release tablets after a meal.
• For
  Helicobacter pylori
  eradication take rabeprazole sodium delayed-release tablets with food.
• For all other indications rabeprazole sodium delayed-release tablets can be taken with or without food.

Delayed-Release Tablets: 20 mg (

• Gastric Malignancy
  : In adults, symptomatic response to therapy with rabeprazole does not preclude the presence of gastric malignancy. Consider additional follow-up and diagnostic testing (
  5.1 Presence of Gastric Malignancy

  In adults, symptomatic response to therapy with rabeprazole sodium delayed-release tablets 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.
  ).
• Use with Warfarin
  : Monitor for increases in INR and prothrombin time (
  5.2 Interaction with Warfarin

  Steady state interactions of rabeprazole and warfarin have not been adequately evaluated in patients. There have been reports of increased INR and prothrombin time in patients receiving a proton pump inhibitor and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with rabeprazole sodium delayed-release tablets and warfarin concomitantly may need to be monitored for increases in INR and prothrombin time

  [see Drug Interactions ]

  .
  ,
  7 DRUG INTERACTIONS

  See full prescribing information for a list of clinically important drug interactions .

  Table 2 includes drugs with clinically important drug interactions and interaction with diagnostics when administered concomitantly with rabeprazole sodium 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 Rabeprazole Sodium Delayed-Release Tablets and Interactions with Diagnostics

  Antiretrovirals
  Clinical Impact:	The effect of PPI 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 rabeprazole may reduce antiviral effect and promote the development of drug resistance. • Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with rabeprazole may increase toxicity . • There are other antiretroviral drugs which do not result in clinically relevant interactions with rabeprazole.
  Intervention:	Rilpivirine-containing products : Concomitant use with rabeprazole sodium delayed-release tablets is contraindicated [see Contraindications ] . See prescribing information. Atazanavir : See prescribing information for atazanavir for dosing information. Nelfinavir : Avoid concomitant use with rabeprazole sodium delayed-release tablets. See prescribing information for nelfinavir. Saquinavir : See the prescribing information for saquinavir and monitor for potential saquinavir toxicities. Other antiretrovirals : See prescribing information.
  Warfarin
  Clinical Impact:	Increased INR and prothrombin time in patients receiving PPIs, including rabeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death [see Warnings and Precautions ].
  Intervention:	Monitor INR and prothrombin time. Dose adjustment of warfarin may be needed to maintain target INR range. See prescribing information for warfarin.
  Methotrexate
  Clinical Impact:	Concomitant use of rabeprazole with methotrexate (primarily at high dose) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of methotrexate with PPIs have been conducted [see Warnings and Precautions ].
  Intervention:	A temporary withdrawal of rabeprazole sodium delayed-release tablets may be considered in some patients receiving high dose methotrexate administration.
  Digoxin
  Clinical Impact:	Potential for increased exposure of digoxin [see Clinical Pharmacology ].
  Intervention:	Monitor digoxin concentrations. Dose adjustment of digoxin may be needed to maintain therapeutic drug concentrations. See prescribing information for digoxin.
  Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole, itraconazole)
  Clinical Impact:	Rabeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
  Intervention:	Mycophenolate mofetil (MMF): Co-administration of PPIs 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 rabeprazole sodium delayed-release tablets and MMF. Use rabeprazole sodium delayed-release tablets with caution in transplant patients receiving MMF. See the prescribing information for other drugs dependent on gastric pH for absorption.
  Combination Therapy with Clarithromycin and Amoxicillin
  Clinical Impact:	Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions.
  Intervention:	See Contraindications and Warnings and Precautions in prescribing information for clarithromycin. See Drug Interactions in prescribing information for amoxicillin.
  Tacrolimus
  Clinical Impact:	Potentially increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.
  Intervention:	Monitor tacrolimus whole blood trough concentrations. Dose adjustment of tacrolimus 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.
  Intervention:	Temporarily stop rabeprazole sodium delayed-release tablets 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 treatment with rabeprazole sodium delayed-release tablets at least 14 days before assessing to allow gastrin levels to return to baseline.
  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.
  ).
• Acute Tubulointerstitial Nephritis
  : Discontinue treatment and evaluate patients (
  5.3 Acute Tubulointerstitial Nephritis

  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 rabeprazole sodium and evaluate patients with suspected acute TIN

  [see Contraindication ].
  ).
• Clostridium difficile-
  Associated Diarrhea
  : PPI therapy may be associated with increased risk of (
  5.4

  Clostridium difficile

  -Associated Diarrhea

  Published observational studies suggest that PPI therapy like rabeprazole sodium may be associated with an increased risk of

  Clostridium difficile

  -associated diarrhea, especially in hospitalized patients. This diagnosis should be considered for diarrhea that does not improve

  [

  see Adverse Reactions

  ]

  .

  Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.

  Clostridium difficile

  -associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents. For more information specific to antibacterial agents (clarithromycin and amoxicillin) indicated for use in combination with rabeprazole sodium, refer to

  Warnings

  and

  Precautions

  sections of the corresponding prescribing information.
  ).
• Bone Fracture
  : Long-term and multiple daily dose PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine (
  5.5 Bone Fracture

  Several published observational studies in adults suggest that PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long-term PPI therapy (a year or longer). Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Patients at risk for osteoporosis-related fractures should be managed according to established treatment guidelines

  [see Dosage and Administration ,

  Adverse Reactions

  ]

  .
  ).
• Severe Cutaneous Adverse Reactions
  : Discontinue at the first signs or symptoms of severe cutatneous adverse reactions or other signs of hypersensitivity and consider further evaluation (
  5.6 Severe Cutaneous Adverse Reactions

  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 ]

  . Discontinue rabeprazole sodium delayed-release tablets at first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation.
  ).
• Cutaneous and Systemic Lupus Erythematosus
  : Mostly cutaneous, new onset or exacerbation of existing disease; discontinue rabeprazole sodium delayed-release tablets and refer to specialist for evaluation .
• Cyanocobalamin (Vitamin B-12) Deficiency
  : Daily long-term use (e.g., longer than 3 years) may lead to malabsorption or a deficiency of cyanocobalamin .
• Hypomagnesemia and Mineral Metabolism
  : Reported rarely with prolonged treatment with PPIs (
  5.9 Hypomagnesemia and Mineral Metabolism

  Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias, and seizures. 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.

  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), health care professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically

  [see Adverse Reactions ]

  .

  Consider monitoring magnesium and calcium levels prior to initiation of rabeprazole sodium delayed-release tablets 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.
  ).
• Interaction with Methotrexate
  : Concomitant use with PPIs may elevate and/or prolong serum concentrations of methotrexate and/or its metabolite, possibly leading to toxicity. With high dose methotrexate administration, consider a temporary withdrawal of rabeprazole sodium delayed-release tablets (
  5.11 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.
  ,
  7 DRUG INTERACTIONS

  See full prescribing information for a list of clinically important drug interactions .

  Table 2 includes drugs with clinically important drug interactions and interaction with diagnostics when administered concomitantly with rabeprazole sodium 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 Rabeprazole Sodium Delayed-Release Tablets and Interactions with Diagnostics

  Antiretrovirals
  Clinical Impact:	The effect of PPI 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 rabeprazole may reduce antiviral effect and promote the development of drug resistance. • Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with rabeprazole may increase toxicity . • There are other antiretroviral drugs which do not result in clinically relevant interactions with rabeprazole.
  Intervention:	Rilpivirine-containing products : Concomitant use with rabeprazole sodium delayed-release tablets is contraindicated [see Contraindications ] . See prescribing information. Atazanavir : See prescribing information for atazanavir for dosing information. Nelfinavir : Avoid concomitant use with rabeprazole sodium delayed-release tablets. See prescribing information for nelfinavir. Saquinavir : See the prescribing information for saquinavir and monitor for potential saquinavir toxicities. Other antiretrovirals : See prescribing information.
  Warfarin
  Clinical Impact:	Increased INR and prothrombin time in patients receiving PPIs, including rabeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death [see Warnings and Precautions ].
  Intervention:	Monitor INR and prothrombin time. Dose adjustment of warfarin may be needed to maintain target INR range. See prescribing information for warfarin.
  Methotrexate
  Clinical Impact:	Concomitant use of rabeprazole with methotrexate (primarily at high dose) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of methotrexate with PPIs have been conducted [see Warnings and Precautions ].
  Intervention:	A temporary withdrawal of rabeprazole sodium delayed-release tablets may be considered in some patients receiving high dose methotrexate administration.
  Digoxin
  Clinical Impact:	Potential for increased exposure of digoxin [see Clinical Pharmacology ].
  Intervention:	Monitor digoxin concentrations. Dose adjustment of digoxin may be needed to maintain therapeutic drug concentrations. See prescribing information for digoxin.
  Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole, itraconazole)
  Clinical Impact:	Rabeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.
  Intervention:	Mycophenolate mofetil (MMF): Co-administration of PPIs 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 rabeprazole sodium delayed-release tablets and MMF. Use rabeprazole sodium delayed-release tablets with caution in transplant patients receiving MMF. See the prescribing information for other drugs dependent on gastric pH for absorption.
  Combination Therapy with Clarithromycin and Amoxicillin
  Clinical Impact:	Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions.
  Intervention:	See Contraindications and Warnings and Precautions in prescribing information for clarithromycin. See Drug Interactions in prescribing information for amoxicillin.
  Tacrolimus
  Clinical Impact:	Potentially increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.
  Intervention:	Monitor tacrolimus whole blood trough concentrations. Dose adjustment of tacrolimus 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.
  Intervention:	Temporarily stop rabeprazole sodium delayed-release tablets 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 treatment with rabeprazole sodium delayed-release tablets at least 14 days before assessing to allow gastrin levels to return to baseline.
  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.
  ).
• Fundic Gland Polyps
  : Risk increases with long-term use, especially beyond one year. Use the shortest duration of therapy (
  5.11 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.
  ).