The following serious adverse reactions are described below and elsewhere in labeling:
Acute Interstitial Nephritis [see Warnings and Precautions (5.3)]
Clostridium difficile-Associated Diarrhea [see Warnings and Precautions (5.4)]
Bone Fracture [see Warnings and Precautions (5.5)]
Cutaneous and Systemic Lupus Erythematosus [see Warnings and Precautions (5.6)]
Cyanocobalamin (Vitamin B-12) Deficiency [see Warnings and Precautions (5.7)]
Hypomagnesemia [see Warnings and Precautions (5.8)] Fundic Gland Polyps [see WARNINGS AND PRECAUTIONS (5.10)]
6.1 Clinical Studies Experience
Because clinical trials are conducted under varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The data described below reflect exposure to rabeprazole sodium delayed-release tablets in 1064 adult patients exposed for up to 8 weeks. The studies were primarily placebo-and active-controlled trials in adult patients with Erosive or Ulcerative Gastroesophageal Reflux Disease (GERD), Duodenal Ulcers and Gastric Ulcers. The population had a mean age of 53 years (range 18 to 89 years) and had a ratio of approximately 60% male: 40% female. The racial distribution was 86% Caucasian, 8% African American, 2% Asian, and 5% other. Most patients received either 10 mg, 20 mg or 40 mg per day of rabeprazole sodium delayed-release tablets.
An analysis of adverse reactions appearing in ≥2% of patients treated with rabeprazole sodium delayed-release tablets (n=1064) and with a greater frequency than placebo (n=89) in controlled North American and European acute treatment trials, revealed the following adverse reactions: pain (3% vs. 1%), pharyngitis (3% vs. 2%), flatulence (3% vs. 1%), infection (2% vs. 1%), and constipation (2% vs. 1%).
Three long-term maintenance studies consisted of a total of 740 adult patients; at least 54% of adult patients were exposed to rabeprazole sodium delayed-release tablets for 6 months and at least 33% were exposed for 12 months. Of the 740 adult patients, 247 (33%) and 241 (33%) patients received 10 mg and 20 mg of rabeprazole sodium delayed-release tablets, respectively, while 169 (23%) patients received placebo and 83 (11%) received omeprazole.
The safety profile of rabeprazole in the maintenance studies in adults was consistent with what was observed in the acute studies.
Less common adverse reactions seen in controlled clinical trials (<2% of patients treated with rabeprazole sodium delayed-release tablets and greater than placebo) and for which there is a possibility of a causal relationship to rabeprazole, include the following: headache, abdominal pain, diarrhea, dry mouth, dizziness, peripheral edema, hepatic enzyme increase, hepatitis, hepatic encephalopathy, myalgia, and arthralgia.
Combination Treatment with Amoxicillin and Clarithromycin: In clinical trials using combination therapy with rabeprazole plus amoxicillin and clarithromycin (RAC), no adverse reactions unique to this drug combination were observed. In the U.S. multicenter study, the most frequently reported drug related adverse reactions for patients who received RAC therapy for 7 or 10 days were diarrhea (8% and 7%) and taste perversion (6% and 10%), respectively.
No clinically significant laboratory abnormalities particular to the drug combinations were observed.
For more information on adverse reactions or laboratory changes with amoxicillin or clarithromycin, refer to their respective prescribing information, Adverse Reactions section.
In a multicenter, open-label study of adolescent patients 12 to 16 years of age with a clinical diagnosis of symptomatic GERD or endoscopically proven GERD, the adverse event profile was similar to that of adults. The adverse reactions reported without regard to relationship to rabeprazole sodium delayed-release tablets that occurred in ≥2% of 111 patients were headache (9.9%), diarrhea (4.5%), nausea (4.5%), vomiting (3.6%), and abdominal pain (3.6%). The related reported adverse reactions that occurred in ≥2% of patients were headache (5.4%) and nausea (1.8%). There were no adverse reactions reported in this study that were not previously observed in adults.
6.2 Postmarketing Experience
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
Gastrointestinal Disorders: fundic gland polyps
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
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
|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 (4)]. 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.|
|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 (5.2)].|
|Intervention:||Monitor INR and prothrombin time. Dose adjustment of warfarin may be needed to maintain target INR range. See prescribing information for warfarin.|
|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 (5.9)].|
|Intervention:||A temporary withdrawal of rabeprazole sodium delayed-release tablets may be considered in some patients receiving high dose methotrexate administration.|
|Clinical Impact:||Potential for increased exposure of digoxin [see Clinical Pharmacology (12.3)].|
|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.|
|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.|
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