Esomep-EZS

The active ingredient in the proton pump inhibitor Esomeprazole Magnesium Delayed-Release Capsules USP for oral administration is bis(5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole-1-yl) magnesium dihydrate. Esomeprazole is the S-isomer of omeprazole, which is a mixture of the S- and R- isomers. (Initial U.S. approval of esomeprazole magnesium: 2001.) It has a molecular weight of 749.2 as a dihydrate and 713.1 on an anhydrous basis. The structural formula is:

(C17H18N3O3S)2 Mg • 2 H2O M.W. 749.2

The magnesium salt is an off-white to pale yellow colored crystalline powder. It contains 2 moles of water of solvation and is slightly soluble in water. The stability of esomeprazole magnesium is a function of pH; it rapidly degrades in acidic media, but it has acceptable stability under alkaline conditions. At pH 6.8 (buffer), the half-life of the magnesium salt is about 19 hours at 25°C and about 8 hours at 37°C.

Each Esomeprazole Magnesium Delayed-Release Capsule USP contains either 20 mg or 40 mg of esomeprazole (present as 21.69 mg or 43.38 mg esomeprazole magnesium dihydrate) in the form of enteric-coated granules. In addition, each delayed-release capsule contains the following inactive ingredients: FD&C blue #1, gelatin, hypromellose, methacrylic acid copolymer dispersion, polysorbate 80, propylene glycol, shellac, sugar spheres, talc, titanium dioxide, triethyl citrate, and yellow iron oxide.

Carcinogenesis, Mutagenesis, Impairment of Fertility

The carcinogenic potential of esomeprazole magnesium was assessed using studies of omeprazole, of which esomeprazole is an enantiomer. In two 24 month oral carcinogenicity studies in rats, omeprazole at daily doses of 1.7, 3.4, 13.8, 44, and 140.8 mg/kg/day (about 0.4 to 34 times the human dose of 40 mg/day expressed on a body surface area basis) produced gastric ECL cell carcinoids in a dose-related manner in both male and female rats; the incidence of this effect was markedly higher in female rats, which had higher blood levels of omeprazole. Gastric carcinoids seldom occur in the untreated rat. In addition, ECL cell hyperplasia was present in all treated groups of both sexes. In one of these studies, female rats were treated with 13.8 mg omeprazole/kg/day (about 3.4 times the human dose of 40 mg/day on a body surface area basis) for 1 year, then followed for an additional year without the drug. No carcinoids were seen in these rats. An increased incidence of treatment-related ECL cell hyperplasia was observed at the end of 1 year (94% treated vs. 10% controls). By the second year the difference between treated and control rats was much smaller (46% vs. 26%) but still showed more hyperplasia in the treated group. Gastric adenocarcinoma was seen in one rat (2%). No similar tumor was seen in male or female rats treated for 2 years. For this strain of rat no similar tumor has been noted historically, but a finding involving only one tumor is difficult to interpret. A 78 week mouse carcinogenicity study of omeprazole did not show increased tumor occurrence, but the study was not conclusive.

Esomeprazole was negative in the Ames mutation test, in the in vivo rat bone marrow cell chromosome aberration test, and the in vivo mouse micronucleus test. Esomeprazole, however, was positive in the in vitro human lymphocyte chromosome aberration test. Omeprazole was positive in the in vitro human lymphocyte chromosome aberration test, the in vivo mouse bone marrow cell chromosome aberration test, and the in vivo mouse micronucleus test.

The potential effects of esomeprazole on fertility and reproductive performance were assessed using omeprazole studies. Omeprazole at oral doses up to 138 mg/kg/day in rats (about 34 times the human dose of 40 mg/day on a body surface area basis) was found to have no effect on reproductive performance of parental animals.

Animal Toxicology and/or Pharmacology

Reproduction Studies

Reproduction studies have been performed in rats at oral doses up to 280 mg/kg/day (about 68 times an oral human dose of 40 mg on a body surface area basis) and in rabbits at oral doses up to 86 mg/kg/day (about 42 times an oral human dose of 40 mg on a body surface area basis) and have revealed no evidence of impaired fertility or harm to the fetus due to esomeprazole [see Use in Specific Populations (8.1)].

Juvenile Animal Study

A 28 day toxicity study with a 14 day recovery phase was conducted in juvenile rats with esomeprazole magnesium at doses of 70 to 280 mg/kg/day (about 17 to 68 times a daily oral human dose of 40 mg on a body surface area basis). An increase in the number of deaths at the high dose of 280 mg/kg/day was observed when juvenile rats were administered esomeprazole magnesium from postnatal day 7 through postnatal day 35. In addition, doses equal to or greater than 140 mg/kg/day (about 34 times a daily oral human dose of 40 mg on a body surface area basis), produced treatment-related decreases in body weight (approximately 14%) and body weight gain, decreases in femur weight and femur length, and affected overall growth. Comparable findings described above have also been observed in this study with another esomeprazole salt, esomeprazole strontium, at equimolar doses of esomeprazole.

Applies to esomeprazole: intravenous powder for injection, oral delayed release capsule, oral powder for reconstitution delayed release

General

The most frequently occurring adverse reactions were headache and diarrhea.
The most frequently reported adverse reactions for patients who received triple therapy for 10 days were diarrhea, taste perversion, and abdominal pain.[Ref]

Nervous system

Very Common (10% or more): Headache (up to 10.9%)
Common (1% to 10%): Dizziness, somnolence, vertigo
Uncommon (0.1% to 1%): Paresthesia
Rare (0.01% to 0.1%): Taste disturbance
Very rare (less than 0.01%): Hepatic encephalopathy
Frequency not reported: Hypertonia, hypoesthesia, migraine/aggravated migraine, parosmia, taste loss/perversion, tremor[Ref]

Gastrointestinal

Very common (10% or more): Flatulence (up to 10.3%)
Common (1% to 10%): Abdominal pain, benign fundic gland polyps, constipation, diarrhea, dry mouth, duodenal ulcer hemorrhage, epigastric pain/aggravated epigastric pain, gastritis/aggravated gastritis, nausea/aggravated nausea, regurgitation, tooth disorder, vomiting/aggravated vomiting
Rare (0.01% to 0.1%): GI candidiasis, stomatitis
Very rare (less than 0.01%): Microscopic colitis
Frequency not reported: Barrett's esophagus, benign polyps or nodules, bowel irregularity, constipation aggravated, duodenitis, dyspepsia, dysphagia, dysplasia gastrointestinal (GI), enlarged abdomen, eructation, esophagitis, esophageal disorder, esophageal stricture, esophageal ulceration, esophageal varices, frequent stools, gastric ulcer, gastroenteritis, GI hemorrhage, GI symptoms not otherwise specified, hernia, hiccup, melena, mouth disorder, mucosal discoloration, pharynx disorder, rectal disorder, tongue disorder, tongue edema, ulcerative stomatitis
Postmarketing reports: Clostridium difficile associated diarrhea, hemorrhagic necrotic gastritis, pancreatitis[Ref]

Respiratory

Common (1% to 10%): Cough, respiratory infection, sinusitis, tachypnea (in pediatrics)
Uncommon (0.1% to 1%): Epistaxis
Rare (0.01% to 0.1%): Bronchospasm
Frequency not reported: Asthma aggravated, dyspnea, larynx edema, pharyngitis, rhinitis[Ref]

Other

Common (1% to 10%): Accident or injury, fever/pyrexia
Rare (0.01% to 0.1%): Malaise
Frequency not reported: Asthenia, earache, facial edema, fatigue, flu-like disorder, leg edema, otitis media, pain, rigors, thirst, tinnitus[Ref]

Dermatologic

Common (1% to 10%): Pruritus
Uncommon (0.1% to 1%): Dermatitis, rash, urticaria
Rare (0.01% to 0.1%): Alopecia, increased sweating, photosensitivity
Very rare (less than 0.01): Erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN)/ fatal TEN
Frequency not reported: Acne, pruritus ani, rash erythematous, rash maculopapular, skin inflammation, subacute cutaneous lupus erythematosus, sweating increased/hyperhidrosis
Postmarketing reports: Cutaneous lupus erythematosus, systemic lupus erythematosus[Ref]

Cardiovascular

Common (1% to 10%): Hypertension/aggravated hypertension
Uncommon (0.1% to 1%): Peripheral edema
Frequency not reported: Chest pain, flushing, generalized edema, hot flush, hypertension, irregular heartbeat, substernal chest pain, tachycardia[Ref]

Musculoskeletal

Common (1% to 10%): Back pain
Uncommon (0.1% to 1%): Fracture of the hip, wrist or spine
Rare (0.01% to 0.1%): Arthralgia, myalgia
Very rare (less than 0.01%): Muscular weakness
Frequency not reported: Arthritis aggravated, arthropathy, cramps, fibromyalgia syndrome, hernia, hyperuricemia/increased uric acid, increased alkaline phosphatase, polymyalgia rheumatic
Postmarketing reports: Bone fracture[Ref]

An increased risk of hip fracture has been reported in a cohort study. The risk was significantly increased among patients prescribed long-term high PPIs.[Ref]

Endocrine

Common (1% to 10%): Increased serum gastrin
Very rare (less than 0.01%): Gynecomastia
Frequency not reported: Decreased/increased thyroxine, goiter, increased thyroid stimulating hormone[Ref]

Local

Common (1% to 10%): Administration/injection site reactions
Postmarketing reports: Tissue inflammatory reaction[Ref]

Immunologic

Common (1% to 10%): Viral infection[Ref]

Hepatic

Uncommon (0.1% to 1%): Increased liver enzymes,
Rare (0.01% to 0.1%): Hepatitis with/without jaundice
Very rare (less than 0.01%): Hepatic failure
Frequency not reported: Abnormal hepatic function, ALT/AST increased, bilirubinemia, increased total bilirubin[Ref]

Ocular

Uncommon (0.1% to 1%): Blurred vision
Rare (0.01% to 0.1%): Visual accommodation disorder, visual field defect
Frequency not reported: Abnormal vision, conjunctivitis
Postmarketing reports: Irreversible visual impairment, loss of vision[Ref]

Psychiatric

Uncommon (0.1% to 1%): Insomnia
Rare (0.01% to 0.1%): Agitation, confusion, depression/aggravated depression
Very rare (less than 0.01%): Aggression, hallucinations
Frequency not reported: Apathy, irritability, nervousness, sleep disorder[Ref]

Hematologic

Rare (0.01% to 0.1%): Leukopenia, thrombocytopenia
Very rare (less than 0.01%): Agranulocytosis, pancytopenia
Frequency not reported: Anemia, anemia hypochromic, cervical lymphadenopathy, decreased/increased hemoglobin, decreased/increased platelets, decreased/increased white blood cell count, leukocytosis[Ref]

Metabolic

Rare (0.01% to 0.1%): Hyponatremia
Very rare (less than 0.01%): Hypomagnesemia with or without hypocalcemia and/or hypokalemia, severe hypomagnesemia
Frequency not reported: Anorexia, decreased/increased potassium, decreased/increased sodium, increased appetite, vitamin B12 deficiency, weight decrease/increase[Ref]

Hypersensitivity

Rare (0.01% to 0.1%): Anaphylactic reaction/shock, angioedema, hypersensitivity reactions
Frequency not reported: Allergic reaction[Ref]

Renal

Very rare (less than 0.01%): Interstitial nephritis with/without renal failure
Frequency not reported: Glycosuria
Postmarketing reports: Impaired renal function, increased creatinine, nephrosis[Ref]

Genitourinary

Frequency not reported: Abnormal urine, albuminuria, cystitis, dysmenorrhea, dysuria, fungal infection, genital moniliasis, hematuria, menstrual disorder, micturition frequency, moniliasis, polyuria, vaginitis
Postmarketing reports: Impotence[Ref]

Some side effects of esomeprazole may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Esomeprazole Magnesium: 20 mg to 40 mg orally once daily
-Duration of therapy: Up to 6 months

Esomeprazole Strontium: 24.65 mg to 49.3 mg orally once a day
-Duration of therapy: Up to 6 months

Comments:
-Patients older than 60 years and/or with history of gastric ulcers are considered to be at risk for developing gastric ulcers.
-Controlled studies do not extend beyond 6 months.

Use: Reduction in the occurrence of gastric ulcers associated with continuous NSAID therapy in patients at risk for developing gastric ulcers

Esomeprazole Magnesium: 40 mg orally twice a day

Esomeprazole Strontium: 49.3 mg orally twice a day

Comments:
-Doses up to 240 mg daily have been used.
-The dosage in patients with pathological hypersecretory conditions varies with the individual patient; regimens should be adjusted to individual patient needs.

Use: Long term treatment of pathological hypersecretory conditions, including Zollinger-Ellison Syndrome

Esomeprazole Sodium:
-Initial dose: 80 mg IV infusion over 30 minutes
-Maintenance dose: 8 mg/hr IV continuous infusion for a total of 72 hours (includes initial 30 minute dose plus 71.5 hours of continuous infusion)

Comments:
-Intravenous therapy is aimed solely at the acute initial management of bleeding gastric or duodenal ulcers and does not constitute full treatment.
-IV therapy should be followed by oral acid-suppressive therapy.

Use: Risk reduction of rebleeding of gastric or duodenal ulcers following therapeutic endoscopy

Esomeprazole Magnesium:
1 to 11 years: 10 mg once a day
-Duration of therapy: Up to 8 weeks

12 to 17 years: 20 mg once a day
-Duration of therapy: 4 weeks

Esomeprazole Sodium:
GERD with Erosive Esophagitis:
1 month to less than 1 year: 0.5 mg/kg IV infused over 10 to 30 minutes

1 to 17 years:
-Less than 55 kg: 10 mg IV infused over 10 to 30 minutes
-55 kg or more: 20 mg IV infused over 10 to 30 minutes

-Comment: Esomeprazole magnesium doses over 1 mg/kg/day have not been studied in patients 1 to 11 years of age.

Uses:
-Short term treatment of symptomatic GERD
-Alternative to oral therapy for the short-term treatment of GERD with erosive esophagitis in patients unable to use oral route

Data not available

Administration advice:
Oral Formulations:
-This drug should be taken at least one hour before meals.
-Capsules and tablets should not be chewed or crushed.
-Delayed-release capsules can be opened and mixed with 1 tablespoon of applesauce and swallowed immediately. Any unused mixture should be discarded. Mixing with other foods has not been evaluated and is not recommended. Do not store for future use.

Intravenous:
-The intravenous injection of esomeprazole should be administered over at least 3 minutes. The intravenous infusion should be administered over 10 to 30 minutes.
-Treatment with esomeprazole injection is intended for short-term treatment (up to 10 days).

Storage requirements:
-Keep the delayed-release capsules in a tightly closed container.
-The reconstituted IV solution should be stored at temperatures up to 30C (86F) and administered within 12 hours after reconstitution OR within 6 hours if 5% dextrose injection is used after reconstitution. No refrigeration is required.

Reconstitution/preparation techniques:
Delayed-release capsule:
-For patients with a nasogastric tube (NG), the delayed-release capsule can be opened, emptied into a 60 mL catheter tipped syringe, and mixed with 50 mL of water. Shake for 15 seconds, check for granules remaining in the tip, deliver contents through the NG tube, and flush the NG tube with water. Use mixture immediately after preparing. Rinse syringe with water after each use.

Oral suspension:
-Oral administration: Empty contents of 2.5 mg or 5 mg packet into 5 mL of water. Use 15 mL of water for the 10 mg, 20 mg and 40 mg packets. Stir, let thicken for 2 to 3 minutes, stir again, and drink within 30 minutes. Mix any remaining medicine with more water, stir, and drink.
-Nasogastric (NG) or gastric tube: Add 5 mL water to a catheter tipped syringe and add contents of a 2.5 mg or 5 mg packet. Use 10 mL water for the 10 mg, 20 mg and 40 mg packets. Shake the syringe and let thicken for 2 to 3 minutes. Shake syringe prior to injecting through the NG or gastric tube using a French size 6 or larger. Use mixture within 30 minutes. Refill the syringe with equal amount of water originally used, shake, and flush any remaining contents from NG or gastric tube.

General:
-Proton pump inhibitor treatment should only be initiated and continued if the benefits outweigh the risks of treatment.
-Triple therapy: Refer to amoxicillin and clarithromycin prescribing information for contraindications, warnings, and dosing in elderly and renally impaired patients.
-Antacids can be used during treatment.
-Patients receiving long-term therapy should be monitored for adverse events and the need for continued use.
-Esomeprazole strontium 44.6 mg is equivalent to 40 mg esomeprazole.

Monitoring:
-Magnesium levels, especially in patients at risk of hypomagnesemia

Patient advice:
-Patients should communicate if they are taking, or begin taking, other medications, because this drug can interfere with antiretroviral drugs and drugs that are affected by gastric pH changes.
-Patients should be told that full effect may take 1 to 4 days.
-Patients should be instructed to immediately report and seek care for signs/symptoms of cutaneous reactions and/or diarrhea that does not improve.

• Usually taken once daily.
• Take at least an hour before a meal.
• Swallow delayed-release capsules whole. In people who have difficulty swallowing, the capsule may be opened and the contents mixed with applesauce and swallowed immediately.
• See your doctor if you develop any unexplained fever, rash (particularly one that gets worse after you have been in the sun), new or worsening joint pain, persistent diarrhea or generalized aches and pains.
• Also see your doctor if you develop any muscle cramps, spasms, or weakness; jitteriness; abnormal heartbeat; dizziness; seizures; or any other symptoms of concern.