preloder

Rabeprazole Sodium


Dosing
Adult dosing:
Important Note:
Beers Criteria:

Use

caution or avoid

use as

potentially inappropriate in older adults

Duodenal ulcer disease:
20 mg ORALLY once daily after the morning meal for up to 4 weeks

Duodenal ulcer disease; Triple therapy – Helicobacter pylori gastrointestinal tract infection:
20 mg orally twice daily in combination with amoxicillin 1000 mg twice daily and clarithromycin 500 mg twice daily for 7 days (FDA dosage)

Clarithromycin triple regimen; 20 to 40 mg orally twice daily in combination with clarithromycin 500 mg orally twice daily and either amoxicillin 1 g orally twice daily or metronidazole 500 mg orally 3 times per day; continue regimen for 14 days (guideline dosage)

Sequential regimen; 20 mg orally twice daily plus amoxicillin 1 g orally twice daily for 5 to 7 days; then follow with clarithromycin 500 mg twice daily; metronidazole or tinidazole 500 mg twice daily; and

rabeprazole 20 mg

twice daily for 5 to 7 days (guideline dosage)

Levofloxacin triple regimen; 20 mg orally twice daily in combination with amoxicillin 1 g orally twice daily and levofloxacin 500 mg orally once daily; continue regimen for 10 to 14 days (guideline dosage).

Gastric hypersecretion:
Initial; 60 mg ORALLY once daily; individualize

dose

to patient needs; doses up to 100 mg/day or 60 mg twice daily have been

used

.

Gastroesophageal reflux disease:
20 mg ORALLY once daily up to 4 weeks

Gastroesophageal reflux disease; Erosive or ulcerative:
20 mg ORALLY once daily for 4 to 8 weeks

Gastroesophageal reflux disease; Erosive or ulcerative; maintenance:
20 mg ORALLY once daily

Helicobacter pylori gastrointestinal tract infection – Peptic ulcer disease; Quadruple therapy:
Bismuth quadruple regimen:
20 mg orally twice daily in combination with tetracycline 500 mg orally 4 times per day; metronidazole 250 mg orally 4 times per day or 500 mg orally 3 or 4 times per day; and either bismuth subcitrate 120 to 300 mg orally 4 times per day or bismuth subsalicylate 300 mg orally 4 times per day; continue regimen for 10 to 14 days (guideline dosage)

Concomitant regimen:
20 mg orally twice daily in combination with amoxicillin 1 g orally twice daily; clarithromycin 500 mg orally twice daily; and metronidazole or tinidazole 500 mg orally twice daily; continue regimen for 10 to 14 days (guideline dosage)

Hybrid regimen:
20 mg orally twice daily plus amoxicillin 1 g orally twice daily for 7 days; then follow with amoxicillin 1 g twice daily; clarithromycin 500 mg twice daily; metronidazole or tinidazole 500 mg twice daily; and

rabeprazole 20 mg twice daily

for 7 days (guideline dosage)

Levofloxacin sequential regimen:
20 to 40 mg orally twice daily plus amoxicillin 1 g orally twice daily for 5 to 7 days; then follow with amoxicillin 1 g orally twice daily; metronidazole or tinidazole 500 mg orally twice daily;

rabeprazole 20 mg orally

twice daily; and levofloxacin 500 mg orally once daily for 5 to 7 days (guideline dosage)

LOAD regimen:
40 mg orally once daily in combination with levofloxacin 250 mg orally once daily; doxycycline 100 mg orally once daily; and nitazoxanide 500 mg twice daily; continue regimen for 7 to 10 days (guideline dosage).

Pediatric dosing:
Important Note:
Beers Criteria: Use caution or avoid use as potentially inappropriate in older adults.

General Dosage Information:
Safety and efficacy for treatment of GERD not established in pediatric patients younger than 1 year

Gastroesophageal reflux disease:
12 years or older;
20 mg ORALLY once daily up to 8 weeks

1 to 11 years:
15 kg or greater; 10 mg (

manufacturer dose

) to 20 mg (

study dose

) ORALLY once daily for up to 12 weeks

1 to 11 years:
less than 15 kg; 5 mg ORALLY once daily for up to 12 weeks; may increase to 10 mg ORALLY once daily if inadequate response.

Indications
FDA-LABELED INDICATIONS:
Allergic conjunctivitis
Allergic rhinitis; Perennial and seasonal
Anaphylaxis; Adjunct
Dermatographic urticaria
Hypersensitivity reaction; To blood or plasma; or mild allergic skin manifestations
Urticaria due to cold
Vasomotor rhinitis

NON-FDA LABELED INDICATIONS:
Loss of appetite
Pruritus
Schizophrenia
Spasticity – Spinal cord injury

Mechanism of Action

Rabeprazole sodium

is a gastric proton pump inhibitor that does not possess anticholinergic or histamine H(2)-receptor antagonist properties. It suppresses gastric acid secretion by inhibiting the gastric H+; K+-ATPase at the secretory surface of parietal cells
Adverse Effect
Common:
Gastrointestinal:
Abdominal pain (3.6% to 5%)
Diarrhea (up to 5%)
Nausea (4.5%)
Vomiting (3.6%)

Neurologic:
Headache (up to 9.9%)
Serious:
Dermatologic:
Cutaneous lupus erythematosus
Erythema multiforme
Stevens-Johnson syndrome
Toxic epidermal necrolysis

Gastrointestinal:
Clostridium difficile diarrhea

Immunologic:
Anaphylaxis
Systemic lupus erythematosus

Musculoskeletal:
Fracture of bone
Rhabdomyolysis

Renal:
Interstitial nephritis
Contraindication
Concomitant

use of

rilpivirine-containing products
Hypersensitivity reactions; including anaphylaxis; anaphylactic shock; angioedema; bronchospasm; acute interstitial nephritis; and urticaria; to

rabeprazole

; substituted benzimidazoles; or any component of the product

Interaction
Drugs Metabolized by CYP450:
Rabeprazole is metabolized by the cytochrome P450 (CYP450) drug metabolizing enzyme system. Studies in healthy subjects have shown that rabeprazole does not have clinically significant interactions with other drugs metabolized by the CYP450 system; such as warfarin and theophylline given as single oral doses; diazepam as a single

intravenous dose

and phenytoin given as a

single intravenous dose

(with supplemental oral dosing). Steady state

interactions of rabeprazole

and other drugs metabolized by this enzyme system have not been studied in patients

Warfarin:
There have been reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including rabeprazole and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death

Cyclosporine:
In vitro incubations employing human liver microsomes indicated that rabeprazole inhibited cyclosporine metabolism with an IC50 of 62 micromolar; a concentration that is over 50 times higher than the Cmax in healthy volunteers following 14 days of dosing with

20 mg of rabeprazole

. This degree of inhibition is similar to that by omeprazole at equivalent concentrations

Compounds Dependent on Gastric pH for Absorption:
Due to its effects on gastric acid secretion; rabeprazole can reduce the absorption of drugs where gastric pH is an important determinant of their bioavailability. Like with other drugs that decrease the intragastric acidity; the absorption of drugs such as ketoconazole; atazanavir; iron salts; erlotinib; and mycophenolate mofetil (MMF) can decrease, while the absorption of drugs such as digoxin can increase during treatment with rabeprazole
Concomitant treatment with rabeprazole (20 mg daily) and ketoconazole in healthy subjects decreased the bioavailability of ketoconazole by 30% and increased the AUC and Cmax for digoxin by 19% and 29% respectively. Therefore; patients may need to be monitored when such drugs are taken concomitantly with rabeprazole.

Co-administration of rabeprazole

and antacids produced no clinically relevant changes in plasma rabeprazole concentrations.
Concomitant use of atazanavir and PPIs is not recommended. Co- administration of atazanavir with PPIs is expected to substantially decrease atazanavir plasma concentrations and thereby reduce its therapeutic effect.
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 PPIs and MMF.

Use rabeprazole

with caution in transplant patients receiving MMF

Drugs Metabolized by CYP2C19:
In a clinical study in Japan evaluating rabeprazole in adult patients categorized by CYP2C19 genotype (n=6 per genotype category); gastric acid suppression was higher in poor metabolizers as compared to extensive metabolizers. This could be due to higher rabeprazole plasma levels in poor metabolizers. Whether or not interactions of rabeprazole sodium with other drugs metabolized by CYP2C19 would be different between extensive metabolizers and poor metabolizers has not been studied

Combined Administration with Clarithromycin:
Combined administration consisting of rabeprazole; amoxicillin; and clarithromycin resulted in increases in

plasma concentrations of rabeprazole

and 14-hydroxyclarithromycin Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions due to drug interactions Because of these drug interactions; clarithromycin is contraindicated for co-administration with certain drugs

Methotrexate:
Case reports; published population pharmacokinetic studies; and retrospective analyses suggest that concomitant administration of PPIs and methotrexate (primarily at

high dose

; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate. However, no formal drug interaction studies of methotrexate with PPIs have been conducted

Clopidogrel:
Concomitant

administration of rabeprazole

and clopidogrel in healthy subjects had no clinically meaningful effect on exposure to the active metabolite of clopidogrel. No dose adjustment of clopidogrel is necessary when administered with an approved

dose of rabeprazole



Phamacokinetics
Absorption:
Time for Maximum Plasma Concentration (Tmax):
Oral; delayed-release

tablet

: 2 to 5 hours
10mg granules empty stomach: 2.5 hours

Bioavailability:
Oral; delayed-release tablet: approximately 52%

Effect of food (delayed-release tablet):
Maximum Plasma concentration (Cmax) and AUC not significantly altered; Tmax may be delayed up to 4 hours with high-fat meal; may be taken with or without meals

Effect of food (delayed-release granules):
Decreased Maximum serum concentration (Cmax) and AUC; Tmax delayed; should be taken 30 minutes before a meal

Distribution:
Plasma Protein Binding: 96.3%

Metabolism:
Hepatic: extensive via CYP3A; CYP2C19; and systemic nonenzymatic reduction
Metabolites: desmethyl rabeprazole; thioether; and sulphone
Substrate of CYP2C19

Excretion:
Fecal: approximately 10% primarily as metabolites
Renal: approximately 90% primarily as metabolites
Dialyzable: No
Total body clearance (adult): 4 to 8 mL/min/kg
Total body clearance (1 to 11 years): 8 to 13.5 L/hr

Elimination:
1 to 2 hours
Cirrhosis (mild to moderate): 2- to 3-fold longer

Precaution
Beers Criteria:
Avoid scheduled

use in older adults

for longer than 8 weeks due to risk of Clostridium difficile infection and bone loss and fractures; unless needed for high-risk patients (e.g.; oral corticosteroids; chronic NSAID use) erosive esophagitis; pathological hypersecretory condition; or need for maintenance treatment (e.g.; due to failure of drug discontinuation or histamine-2 blockers).

Concomitant use:
Use with nelfinavir should be avoided.
Dermatologic:
New or worsening cutaneous lupus erythematosus has been reported within weeks to years after continuous drug therapy; avoid using for longer than medically indicated and discontinue use if suspected.

Endocrine and metabolic:
Vitamin B12 deficiency may occur with prolonged use (eg greater than 1 to 2 years); monitoring recommended.

Endocrine and metabolic:
Hypomagnesemia has been reported in patients treated with proton pump inhibitors for at least 3 months; tetany; arrhythmias; and seizures may occur; monitoring recommended with prolonged use or concomitant drugs that may cause hypomagnesemia; discontinuation may be required.

Gastrointestinal:
Symptomatic response does not preclude the presence of gastric malignancy in adults
Clostridium difficile-associated diarrhea may occur; especially in hospitalized patients; use

lowest dose

and shortest duration.

Immunologic:
New or worsening systemic lupus erythematosus has been reported within days to years of treatment initiation; avoid using for longer than medically indicated and discontinue use if suspected.

Musculoskeletal:
Osteoporosis-related bone fracture of hip; wrist; or spine may occur; especially with higher (multiple daily)

doses

or longer duration of therapy (1 year or longer); use lowest dose and shortest treatment duration

Renal:
Acute interstitial nephritis; generally considered an idiopathic hypersensitivity reaction; has been reported; discontinuation required.

Pregnancy Category
Fetal Risk cannot br ruled out
Breast Feeding
Infant Risk cannot be Ruled out
Monitoring
GERD:
Decreased abdominal and gastroesophageal discomfort may indicate efficacy.

Peptic ulcer:
Endoscopic improvement may indicate efficacy.

Serum magnesium:
Routine screening is not necessary; consider screening prior to initiation and periodically during prolonged therapy.

Serum vitamin B12:
Although no routine screening is needed; may consider screening every 1 to 2 years for deficiency in patients receiving prolonged therapy.

How to Take or Administration
Oral:
(Delayed-release tablet) may be taken with or without food; swallow whole; do not chew, crush, or split For duodenal ulcers, tablet should be taken after the morning meal; for Helicobacter pylori eradication, the 3-drug combination should be taken together with the morning and evening meals

(Delayed-release capsule)
In children 1 to 11 years of age, administer 30 minutes prior to meal
Open capsule and sprinkle entire contents on small amount of soft food or liquid that is at or below room temperature; take within 15 minutes
Do not chew or crush granules
Do not store prepared mixture for future use
Dosage Form
Oral Tablet (Enteric Coated):
20mg

Oral Capsule, Delayed Release:
5 mg
10 mg
Treatment
MANAGEMENT OF MILD TO MODERATE TOXICITY:
Treatment is symptomatic and supportive. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting.

MANAGEMENT OF SEVERE TOXICITY:
Treatment is symptomatic and supportive. Significant toxicity is not expected after an

overdose

.

Toxicology
Doses up to 2400mg (120 times the usual Recommended

clinical dose

)resulted in transient effects (e.g.; drowsiness;confusion and tachycardia);with no serious events reported when taken alone.
Patient Counselling or Clinical Teaching
Warn patient to report diarrhea that does not improve and consult healthcare professional prior to taking antidiarrheal medicine
Counsel patient to report symptoms of cutaneous or systemic lupus erythematosus
Advise patient using multiple

daily doses

for longer than a year to report symptoms of osteoporosis-related fractures (e.g.; hip; wrist; spine)

Side effects

may include abdominal pain; diarrhea; nausea; vomiting; flatulence; constipation; pharyngitis; and headaches
Counsel patient to report symptoms of hypomagnesemia
Delayed-release capsules: Advise patient not to swallow capsule whole. Contents of capsule must be sprinkled on small amount of soft food or in liquid and consumed within 15 minutes after mixing and 30 minutes before a meal
Delayed-release

tablets

: Instruct patient with a duodenal ulcer to take drug after a meal. A patient with Helicobacter pylori infection should take drug with food
Category of Rabeprazole Sodium :
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