Estab

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Estab uses


Recent Major Changes

WARNINGS AND PRECAUTIONS 08/2010

Bone Fracture (5.3)

1 INDICATIONS AND USAGE

Estab is a proton pump inhibitor indicated for the following:

1.1 Treatment of Gastroesophageal Reflux Disease (GERD)

Healing of Erosive Esophagitis

Estab is indicated for the short-term treatment (4 to 8 weeks) in the healing and symptomatic resolution of diagnostically confirmed erosive esophagitis. For those patients who have not healed after 4 to 8 weeks of treatment, an additional 4 to 8 week course of Estab may be considered.

Maintenance of Healing of Erosive Esophagitis

Estab is indicated to maintain symptom resolution and healing of erosive esophagitis. Controlled studies do not extend beyond 6 months.

Symptomatic Gastroesophageal Reflux Disease

Estab is indicated for short-term treatment (4 to 8 weeks) of heartburn and other symptoms associated with GERD in adults and children 1 year or older.

1.2 Risk Reduction of NSAID-Associated Gastric Ulcer

Estab is indicated for the reduction in the occurrence of gastric ulcers associated with continuous NSAID therapy in patients at risk for developing gastric ulcers. Patients are considered to be at risk due to their age and/or documented history of gastric ulcers. Controlled studies do not extend beyond 6 months.

1.3 H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence

Triple Therapy (NEXIUM plus amoxicillin and clarithromycin): Estab, in combination with amoxicillin and clarithromycin, is indicated for the treatment of patients with H. pylori infection and duodenal ulcer disease (active or history of within the past 5 years) to eradicate H. pylori. Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence [see Clinical Studies (14) and Dosage and Administration. (2)].

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 (12.4) and the clarithromycin package insert, Clinical Pharmacology, Microbiology].

1.4 Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome

Estab is indicated for the long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison Syndrome.

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2 DOSAGE AND ADMINISTRATION

Estab is supplied as delayed-release capsules for oral administration or in packets for preparation of delayed-release oral suspensions. The recommended dosages are outlined in the table below. Estab should be taken at least one hour before meals.

The duration of proton pump inhibitor administration should be based on available safety and efficacy data specific to the defined indication and dosing frequency, as described in the Prescribing Information, and individual patient medical needs. Proton pump inhibitor treatment should only be initiated and continued if the benefits outweigh the risks of treatment.

Table 1


Indication


Dose


Frequency


Gastroesophageal Reflux Disease (GERD)


Healing of Erosive Esophagitis


20 mg or 40 mg


Once Daily for 4 to 8 Weeks


Maintenance of Healing of Erosive Esophagitis


20 mg


Once DailyControlled studies did not extend beyond six months.


Symptomatic Gastroesophageal Reflux Disease


20 mg


Once Daily for 4 Weeks


Pediatric GERD


12 to 17 Year Olds

Short-term Treatment of GERD


20 mg or 40 mg


Once Daily for up to 8 Weeks


1 to 11 Year Olds Short-term Treatment of Symptomatic GERD


10 mg


Once Daily for up to 8 Weeks


Healing of Erosive Esophagitis


weight < 20 kg


10 mg


Once Daily for 8 Weeks


weight ≥ 20 kg


10 mg or 20 mg


Once Daily for 8 Weeks


Risk Reduction of NSAID-Associated Gastric Ulcer


20 mg or 40 mg


Once Daily for up to 6 months


H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence


Triple Therapy:


Estab


40 mg


Once Daily for 10 Days


Amoxicillin


1000 mg


Twice Daily for 10 Days


Clarithromycin


500 mg


Twice Daily for 10 Days


Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome


40 mg


Twice Daily


Please refer to amoxicillin and clarithromycin full prescribing information for Contraindications, Warnings, and dosing in elderly and renally-impaired patients.

Special Populations

Geriatric

No dosage adjustment is necessary [see Clinical Pharmacology (12.3)].

Renal Insufficiency

No dosage adjustment is necessary [see Clinical Pharmacology (12.3)].

Hepatic Insufficiency

In patients with mild to moderate liver impairment (Child Pugh Classes A and B), no dosage adjustment is necessary. For patients with severe liver impairment (Child Pugh Class C), a dose of 20 mg of Estab should not be exceeded [see Clinical Pharmacology (12.3)].

Gender

No dosage adjustment is necessary [see Clinical Pharmacology (12.3)].

Administration Options

Directions for use specific to the route and available methods of administration for each of these dosage forms are presented below.

Table 2


Administration Options


Type Route Options

Delayed-Release Capsule


Oral


Capsule can be swallowed whole.

-or-

Capsule can be opened and mixed with applesauce.


Delayed-Release Capsule


Nasogastric Tube


Capsule can be opened and the intact granules emptied into a syringe and delivered through the nasogastric tube.


For Delayed-Release Oral Suspension


Oral


Mix contents of packet with 1 tablespoon (15 mL) of water, leave 2 to 3 minutes to thicken, stir and drink within 30 minutes.


For Delayed-Release Oral Suspension


Nasogastric or Gastric Tube


Add 15 mL of water to a syringe and then add contents of packet. Shake the syringe; leave 2 to 3 minutes to thicken. Shake the syringe and inject through the nasogastric or gastric tube within 30 minutes.


Estab Delayed-Release Capsules

Estab Delayed-Release Capsules should be swallowed whole.

Alternatively, for patients who have difficulty swallowing capsules, one tablespoon of applesauce can be added to an empty bowl and the Estab Delayed-Release Capsule can be opened, and the granules inside the capsule carefully emptied onto the applesauce. The granules should be mixed with the applesauce and then swallowed immediately. The applesauce used should not be hot and should be soft enough to be swallowed without chewing. The granules should not be chewed or crushed. The granules/applesauce mixture should not be stored for future use.

For patients who have a nasogastric tube in place, Estab Delayed-Release Capsules can be opened and the intact granules emptied into a 60 mL catheter tipped syringe and mixed with 50 mL of water. It is important to only use a catheter tipped syringe when administering Estab through a nasogastric tube. Replace the plunger and shake the syringe vigorously for 15 seconds. Hold the syringe with the tip up and check for granules remaining in the tip. Attach the syringe to a nasogastric tube and deliver the contents of the syringe through the nasogastric tube into the stomach. After administering the granules, the nasogastric tube should be flushed with additional water. Do not administer the granules if they have dissolved or disintegrated.

The suspension must be used immediately after preparation.

Estab For Delayed-Release Oral Suspension

Estab For Delayed-Release Oral Suspension should be administered as follows:


For patients who have a nasogastric or gastric tube in place, Estab For Delayed-Release Oral Suspension can be administered as follows:

Indication Dose Frequency

Gastroesophageal Reflux Disease (GERD)


Adults


20 mg or 40 mg


Once daily for 4 to 8 weeks


12 to 17 years


20 mg or 40 mg


Once daily for up to 8 weeks


1 to 11 years


10 mg or 20 mg


Once daily for up to 8 weeks


Risk Reduction of NSAID-Associated Gastric Ulcer


20 mg or 40 mg


Once daily for up to 6 months


H. pylori Eradication (Triple Therapy):


Estab


40 mg


Once daily for 10 days


Amoxicillin


1000 mg


Twice daily for 10 days


Clarithromycin


500 mg


Twice daily for 10 days


Pathological Hypersecretory Conditions


40 mg


Twice daily


See full prescribing information for administration options (2)

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3 DOSAGE FORMS AND STRENGTHS

Estab Delayed-Release Capsules, 20 mg - opaque, hard gelatin, amethyst colored capsules with two radial bars in yellow on the cap and Estab 20 mg in yellow on the body.

Estab Delayed-Release Capsules, 40 mg - opaque, hard gelatin, amethyst colored capsules with three radial bars in yellow on the cap and Estab 40 mg in yellow on the body.

Estab For Delayed-Release Oral Suspension, 10 mg, 20 mg or 40 mg - unit dose packet containing a fine yellow powder, consisting of white to pale brownish Estab granules and pale yellow inactive granules.

4 CONTRAINDICATIONS

Estab is contraindicated in patients with known hypersensitivity to any component of the formulation [see Description (11) ] or to substituted benzimidazoles. Hypersensitivity reactions, e.g., angioedema and anaphylactic shock, have been reported with Estab use.

Patients with known hypersensitivity to any component of the formulation or to substituted benzimidazoles (angioedema and anaphylaxis have occurred) (4)

5 WARNINGS AND PRECAUTIONS

5.1 Concurrent Gastric Malignancy

Symptomatic response to therapy with Estab does not preclude the presence of gastric malignancy.

5.2 Atrophic Gastritis

Atrophic gastritis has been noted occasionally in gastric corpus biopsies from patients treated long-term with omeprazole, of which Estab is an enantiomer.

5.3 Bone Fracture

Several published observational studies suggest that proton pump inhibitor 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 (2) and Adverse Reactions (6.3)]

5.4 Risks of Amoxicillin (as Part of H. pylori Triple Therapy)

[See Warnings and Precautions in the prescribing information for amoxicillin for complete information.]

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients on penicillin therapy. These reactions are more apt to occur in individuals with a history of penicillin hypersensitivity and/or a history of sensitivity to multiple allergens.

There have been well documented reports of individuals with a history of penicillin hypersensitivity reactions that have experienced severe hypersensitivity reactions when treated with a cephalosporin. Before initiating therapy with any penicillin, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, and other allergens. If an allergic reaction occurs, amoxicillin should be discontinued and the appropriate therapy instituted.

Serious anaphylactic reactions require immediate emergency treatment with epinephrine. Oxygen, intravenous steroids, and airway management, including intubation, should also be administered as indicated.

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including clarithromycin and amoxicillin, and may range in severity from mild to life threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.

Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is a primary cause of “antibiotic-associated colitis”.

After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to discontinuation of the drug alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against Clostridium difficile colitis.

5.5 Risks of Clarithromycin

[See Warnings and Precautions in the prescribing information for clarithromycin for complete information.]

Clarithromycin should not be used in pregnant women except in clinical circumstances where no alternative therapy is appropriate. If pregnancy occurs while taking clarithromycin, the patient should be apprised of the potential hazard to the fetus.

Concomitant administration of clarithromycin with cisapride, pimozide, astemizole, terfenadine, ergotamine, or dihydroergotamine is contraindicated.

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6 ADVERSE REACTIONS

Most common adverse reactions:

Adult use (incidence > 1%):


Pediatric (1 - 17 years) use (incidence > 1–2%):


To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely 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 safety of Estab was evaluated in over 15,000 patients (aged 18 to 84 years) in clinical trials worldwide including over 8,500 patients in the United States and over 6,500 patients in Europe and Canada. Over 2,900 patients were treated in long-term studies for up to 6-12 months. In general, Estab was well tolerated in both short and long-term clinical trials.

The safety of Estab was evaluated in 316 pediatric and adolescent patients aged 1 to 17 years in four clinical trials for the treatment of symptomatic GERD [see Clinical Studies (14.2)]. In 109 pediatric patients aged 1 to 11 years, the most frequently reported (at least 1%) treatment-related adverse reactions in these patients were diarrhea (2.8%), headache (1.9%) and somnolence (1.9%). In 149 pediatric patients aged 12 to 17 years the most frequently reported (at least 2%) treatment-related adverse reactions in these patients were headache (8.1%), abdominal pain (2.7%), diarrhea (2%), and nausea (2%). No new safety concerns were identified in pediatric patients.

The safety in the treatment of healing of erosive esophagitis was assessed in four randomized comparative clinical trials, which included 1,240 patients on Estab 20 mg, 2,434 patients on Estab 40 mg, and 3,008 patients on omeprazole 20 mg daily. The most frequently occurring adverse reactions (≥1%) in all three groups were headache (5.5, 5.0, and 3.8, respectively) and diarrhea (no difference among the three groups). Nausea, flatulence, abdominal pain, constipation, and dry mouth occurred at similar rates among patients taking Estab or omeprazole.

Additional adverse reactions that were reported as possibly or probably related to Estab with an incidence < 1% are listed below by body system:

Body as a Whole: abdomen enlarged, allergic reaction, asthenia, back pain, chest pain, substernal chest pain, facial edema, peripheral edema, hot flushes, fatigue, fever, flu-like disorder, generalized edema, leg edema, malaise, pain, rigors;

Cardiovascular: flushing, hypertension, tachycardia;

Endocrine: goiter;

Gastrointestinal: bowel irregularity, constipation aggravated, dyspepsia, dysphagia, dysplasia GI, epigastric pain, eructation, esophageal disorder, frequent stools, gastroenteritis, GI hemorrhage, GI symptoms not otherwise specified, hiccup, melena, mouth disorder, pharynx disorder, rectal disorder, serum gastrin increased, tongue disorder, tongue edema, ulcerative stomatitis, vomiting;

Hearing: earache, tinnitus;

Hematologic: anemia, anemia hypochromic, cervical lymphadenopathy, epistaxis, leukocytosis, leukopenia, thrombocytopenia;

Hepatic: bilirubinemia, hepatic function abnormal, SGOT increased, SGPT increased;

Metabolic/Nutritional: glycosuria, hyperuricemia, hyponatremia, increased alkaline phosphatase, thirst, vitamin B12 deficiency, weight increase, weight decrease;

Musculoskeletal: arthralgia, arthritis aggravated, arthropathy, cramps, fibromyalgia syndrome, hernia, polymyalgia rheumatica;

Nervous System/Psychiatric: anorexia, apathy, appetite increased, confusion, depression aggravated, dizziness, hypertonia, nervousness, hypoesthesia, impotence, insomnia, migraine, migraine aggravated, paresthesia, sleep disorder, somnolence, tremor, vertigo, visual field defect;

Reproductive: dysmenorrhea, menstrual disorder, vaginitis;

Respiratory: asthma aggravated, coughing, dyspnea, larynx edema, pharyngitis, rhinitis, sinusitis;

Skin and Appendages: acne, angioedema, dermatitis, pruritus, pruritus ani, rash, rash erythematous, rash maculo-papular, skin inflammation, sweating increased, urticaria;

Special Senses: otitis media, parosmia, taste loss, taste perversion;

Urogenital: abnormal urine, albuminuria, cystitis, dysuria, fungal infection, hematuria, micturition frequency, moniliasis, genital moniliasis, polyuria;

Visual: conjunctivitis, vision abnormal.

The following potentially clinically significant laboratory changes in clinical trials, irrespective of relationship to Estab, were reported in ≤ 1% of patients: increased creatinine, uric acid, total bilirubin, alkaline phosphatase, ALT, AST, hemoglobin, white blood cell count, platelets, serum gastrin, potassium, sodium, thyroxine and thyroid stimulating hormone [see Clinical Pharmacology (12) for further information on thyroid effects]. Decreases were seen in hemoglobin, white blood cell count, platelets, potassium, sodium, and thyroxine.

Endoscopic findings that were reported as adverse reactions include: duodenitis, esophagitis, esophageal stricture, esophageal ulceration, esophageal varices, gastric ulcer, gastritis, hernia, benign polyps or nodules, Barrett’s esophagus, and mucosal discoloration.

The incidence of treatment-related adverse reactions during 6-month maintenance treatment was similar to placebo. There were no differences in types of related adverse reactions seen during maintenance treatment up to 12 months compared to short-term treatment.

Two placebo-controlled studies were conducted in 710 patients for the treatment of symptomatic gastroesophageal reflux disease. The most common adverse reactions that were reported as possibly or probably related to Estab were diarrhea (4.3%), headache (3.8%), and abdominal pain (3.8%).

6.2 Combination Treatment with Amoxicillin and Clarithromycin

In clinical trials using combination therapy with Estab plus amoxicillin and clarithromycin, no additional adverse reactions specific to these drug combinations were observed. Adverse reactions that occurred were limited to those observed when using Estab, amoxicillin, or clarithromycin alone.

The most frequently reported drug-related adverse reactions for patients who received triple therapy for 10 days were diarrhea, taste perversion (6.6%), and abdominal pain (3.7%). No treatment-emergent adverse reactions were observed at higher rates with triple therapy than were observed with Estab alone.

For more information on adverse reactions with amoxicillin or clarithromycin, refer to their package inserts, Adverse Reactions sections.

In clinical trials using combination therapy with Estab plus amoxicillin and clarithromycin, no additional increased laboratory abnormalities particular to these drug combinations were observed.

For more information on laboratory changes with amoxicillin or clarithromycin, refer to their package inserts, Adverse Reactions section.

6.3 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Estab. 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. These reports are listed below by body system:

Blood And Lymphatic: agranulocytosis, pancytopenia;

Eye: blurred vision;

Gastrointestinal: pancreatitis; stomatitis;

Hepatobiliary: hepatic failure, hepatitis with or without jaundice;

Immune System: anaphylactic reaction/shock;

Infections and Infestations: GI candidiasis;

Metabolism and nutritional disorders: hypomagnesemia

Musculoskeletal and Connective Tissue: muscular weakness, myalgia, bone fracture;

Nervous System: hepatic encephalopathy, taste disturbance;

Psychiatric: aggression, agitation, depression, hallucination;

Renal and Urinary: interstitial nephritis;

Reproductive System and Breast: gynecomastia;

Respiratory, Thoracic, and Mediastinal: bronchospasm;

Skin and Subcutaneous Tissue: alopecia, erythema multiforme, hyperhidrosis, photosensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis (some fatal).

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7 DRUG INTERACTIONS

7.1 Interference with Antiretroviral Therapy

Concomitant use of atazanavir and nelfinavir with proton pump inhibitors is not recommended. Co-administration of atazanavir with proton pump inhibitors is expected to substantially decrease atazanavir plasma concentrations and may result in a loss of therapeutic effect and the development of drug resistance. Co-administration of saquinavir with proton pump inhibitors is expected to increase saquinavir concentrations, which may increase toxicity and require dose reduction.

Omeprazole, of which Estab is an enantiomer, has been reported to interact with some antiretroviral drugs. The clinical importance and the mechanisms behind these interactions are not always known. Increased gastric pH during omeprazole treatment may change the absorption of the antiretroviral drug. Other possible interaction mechanisms are via CYP 2C19.

Reduced concentrations of atazanavir and nelfinavir

For some antiretroviral drugs, such as atazanavir and nelfinavir, decreased serum levels have been reported when given together with omeprazole. Following multiple doses of nelfinavir (1250 mg, twice daily) and omeprazole (40 mg daily), AUC was decreased by 36% and 92%, Cmax by 37% and 89% and Cmin by 39% and 75% respectively for nelfinavir and M8. Following multiple doses of atazanavir (400 mg, daily) and omeprazole (40 mg, daily, 2 hr before atazanavir), AUC was decreased by 94%, Cmax by 96%, and Cmin by 95%. Concomitant administration with omeprazole and drugs such as atazanavir and nelfinavir is therefore not recommended.

Increased concentrations of saquinavir

For other antiretroviral drugs, such as saquinavir, elevated serum levels have been reported, with an increase in AUC by 82%, in Cmax by 75%, and in Cmin by 106%, following multiple dosing of saquinavir/ritonavir (1000/100 mg) twice daily for 15 days with omeprazole 40 mg daily co-administered days 11 to 15. Therefore, clinical and laboratory monitoring for saquinavir toxicity is recommended during concurrent use with Estab. Dose reduction of saquinavir should be considered from the safety perspective for individual patients.

There are also some antiretroviral drugs of which unchanged serum levels have been reported when given with omeprazole.

7.2 Drugs for Which Gastric pH Can Affect Bioavailability

Estab inhibits gastric acid secretion. Therefore, Estab may interfere with the absorption of drugs where gastric pH is an important determinant of bioavailability.

7.3 Effects on Hepatic Metabolism/Cytochrome P-450 Pathways

Estab is extensively metabolized in the liver by CYP 2C19 and CYP 3A4. In vitro and in vivo studies have shown that Estab is not likely to inhibit CYPs 1A2, 2A6, 2C9, 2D6, 2E1, and 3A4. No clinically relevant interactions with drugs metabolized by these CYP enzymes would be expected. Drug interaction studies have shown that Estab does not have any clinically significant interactions with phenytoin, warfarin, quinidine, clarithromycin, or amoxicillin.

However, post-marketing reports of changes in prothrombin measures have been received among patients on concomitant warfarin and Estab therapy. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly may need to be monitored for increases in INR and prothrombin time.

Estab may potentially interfere with CYP 2C19, the major Estab metabolizing enzyme. Coadministration of Estab 30 mg and diazepam, a CYP 2C19 substrate, resulted in a 45% decrease in clearance of diazepam.

Concomitant administration of Estab and a combined inhibitor of CYP 2C19 and CYP 3A4, such as voriconazole, may result in more than doubling of the Estab exposure. Dose adjustment of Estab is not normally required. However, in patients with Zollinger-Ellison’s Syndrome, who may require higher doses up to 240 mg/day, dose adjustment may be considered.

Omeprazole acts as an inhibitor of CYP 2C19. Omeprazole, given in doses of 40 mg daily for one week to 20 healthy subjects in cross-over study, increased Cmax and AUC of cilostazol by 18% and 26% respectively. Cmax and AUC of one of its active metabolites, 3,4-dihydrocilostazol, which has 4-7 times the activity of cilostazol, were increased by 29% and 69% respectively. Co-administration of cilostazol with Estab is expected to increase concentrations of cilostazol and its above mentioned active metabolite. Therefore a dose reduction of cilostazol from 100 mg b.i.d. to 50 mg b.i.d. should be considered.

7.4 Combination Therapy with Clarithromycin

Co-administration of Estab, clarithromycin, and amoxicillin has resulted in increases in the plasma levels of Estab and 14-hydroxyclarithromycin [see Clinical Pharmacology (12.4) ].

Concomitant administration of clarithromycin with cisapride, pimozide, astemizole, terfenadine, ergotamine, or dihydroergotamine is contraindicated [see prescribing information for clarithromycin].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B

Reproductive studies in rats and rabbits with Estab (esomeprazole) and multiple cohort studies in pregnant women with omeprazole use during the first trimester do not show an increased risk of congenital anomalies or adverse pregnancy outcomes. There are, however, no adequate and well controlled studies of Estab use in pregnancy. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Estab is the s-isomer of omeprazole. In four population-based cohort studies that included 1226 women exposed during the first trimester of pregnancy to omeprazole there was no increased risk of congenital anomalies.

Reproductive studies with Estab have been performed in rats at doses up to 57 times the human dose and in rabbits at doses up to 35 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus. See Animal Toxicology and/or Pharmacology (13.2).

Reproductive studies conducted with omeprazole on rats at oral doses up to 56 times the human dose and in rabbits at doses up to 56 times the human dose did not show any evidence of teratogenicity. In pregnant rabbits, omeprazole at doses about 5.5 to 56 times the human dose produced dose-related increases in embryo-lethality, fetal resorptions, and pregnancy loss. In rats treated with omeprazole at doses about 5.6 to 56 times the human dose, dose-related embryo/fetal toxicity and postnatal developmental toxicity occurred in offspring.

8.3 Nursing Mothers

Omeprazole concentrations have been measured in breast milk of one woman taking omeprazole 20 mg per day. However, the excretion of Estab in milk has not been studied. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for tumorigenicity shown for Estab in rat carcinogenicity studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

The safety and effectiveness of Estab have been established in pediatric patients 1 to 17 years of age for short-term treatment of GERD. However, effectiveness has not been demonstrated in patients less than 1 year of age.

1 to 17 years of age

Use of Estab in pediatric and adolescent patients 1 to 17 years of age for short-term treatment (up to eight weeks) of GERD is supported by: a) extrapolation of results, already included in the currently approved labeling, from adequate and well-controlled studies that supported the approval of Estab for adults, and b) safety and pharmacokinetic studies performed in pediatric and adolescent patients [see Clinical Pharmacology (12.3), Dosage and Administration (2), Adverse Reactions (6.1), and Clinical Studies, (14.3) ]. The safety and effectiveness of Estab for other pediatric uses have not been established.

Neonates to less than one year of age

There was no statistically significant difference between Estab and placebo in the rate of discontinuation in a multicenter, randomized, double-blind, controlled, treatment-withdrawal study of patients ages 1 to 11 months, inclusive. Patients were enrolled if they had either a clinical diagnosis of suspected GERD, symptomatic GERD, or endoscopically proven GERD. All patients received Estab Delayed-Release Oral Suspension once daily during a two-week, open-label phase of the study. There were 80 patients who attained a pre-specified level of symptom improvement and who entered the double-blind phase, in which they were randomized in equal proportions to receive Estab or placebo for the next four weeks. Efficacy was assessed by observing the time from randomization to study discontinuation due to symptom worsening during the four-week, treatment-withdrawal phase.

The following pharmacokinetic and pharmacodynamic information was obtained in pediatric patients with GERD aged birth to less than one year of age. In neonates (< 1 month old) given Estab 0.5 mg/kg once daily, the percent time with intragastric pH > 4 over the 24-hour dosing period increased from 44% at baseline to 83% on Day 7. In infants (1 to 11 months old, inclusive) given Estab 1.0 mg/kg once daily, the percent time with intragastric pH > 4 increased from 29% at baseline to 69% on Day 7, which is similar to the pharmacodynamic effect in adults [see Clinical Pharmacology (12.2)]. Apparent clearance (CL/F) increases with age in pediatric patients from birth to 2 years of age.

Because Estab was not shown to be effective in the randomized, placebo-controlled study for this age group, the use of Estab in patients less than 1 year of age is not indicated.

8.5 Geriatric Use

Of the total number of patients who received Estab in clinical trials, 1459 were 65 to 74 years of age and 354 patients were ≥ 75 years of age.

No overall differences in safety and efficacy were observed between the elderly and younger individuals, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

10 OVERDOSAGE

A single oral dose of Estab at 510 mg/kg (about 103 times the human dose on a body surface area basis), was lethal to rats. The major signs of acute toxicity were reduced motor activity, changes in respiratory frequency, tremor, ataxia, and intermittent clonic convulsions.

The symptoms described in connection with deliberate Estab overdose (limited experience of doses in excess of 240 mg/day) are transient. Single doses of 80 mg of Estab were uneventful. Reports of overdosage with omeprazole in humans may also be relevant. Doses ranged up to 2,400 mg (120 times the usual recommended clinical dose). Manifestations were variable, but included confusion, drowsiness, blurred vision, tachycardia, nausea, diaphoresis, flushing, headache, dry mouth, and other adverse reactions similar to those seen in normal clinical experience (see omeprazole package insert - Adverse Reactions). No specific antidote for Estab is known. Since Estab is extensively protein bound, it is not expected to be removed by dialysis. In the event of overdosage, treatment should be symptomatic and supportive.

As with the management of any overdose, the possibility of multiple drug ingestion should be considered. For current information on treatment of any drug overdose contact a Poison Control Center at 1–800–222–1222.

11 DESCRIPTION

The active ingredient in Estab® (esomeprazole magnesium) Delayed-Release Capsules and Estab (esomeprazole magnesium) For Delayed-Release Oral Suspension is bis(5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole-1-yl) magnesium trihydrate. Estab is the S-isomer of omeprazole, which is a mixture of the S- and R- isomers. (Initial U.S. approval of Estab magnesium: 2001). Its molecular formula is (C17H18N3O3S)2Mg x 3 H2O with molecular weight of 767.2 as a trihydrate and 713.1 on an anhydrous basis. The structural formula is:

Figure 1

The magnesium salt is a white to slightly colored crystalline powder. It contains 3 moles of water of solvation and is slightly soluble in water. The stability of Estab 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.

Estab is supplied in delayed-release capsules and in packets for a delayed-release oral suspension. Each delayed-release capsule contains 20 mg, or 40 mg of Estab (present as 22.3 mg, or 44.5 mg Estab magnesium trihydrate) in the form of enteric-coated granules with the following inactive ingredients: glyceryl monostearate 40-55, hydroxypropyl cellulose, hypromellose, magnesium stearate, methacrylic acid copolymer type C, polysorbate 80, sugar spheres, talc, and triethyl citrate. The capsule shells have the following inactive ingredients: gelatin, FD&C Blue #1, FD&C Red #40, D&C Red #28, titanium dioxide, shellac, ethyl alcohol, isopropyl alcohol, n-butyl alcohol, propylene glycol, sodium hydroxide, polyvinyl pyrrolidone, and D&C Yellow #10.

Each packet of Estab For Delayed-Release Oral Suspension contains 10 mg, 20 mg, or 40 mg of Estab, in the form of the same enteric-coated granules used in Estab Delayed-Release Capsules, and also inactive granules. The inactive granules are composed of the following ingredients: dextrose, xanthan gum, crospovidone, citric acid, iron oxide, and hydroxypropyl cellulose. The Estab granules and inactive granules are constituted with water to form a suspension and are given by oral, nasogastric, or gastric administration.

Figure 1 - Chemiical Structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Estab is a proton pump inhibitor that suppresses gastric acid secretion by specific inhibition of the H+/K+-ATPase in the gastric parietal cell. The S- and R-isomers of omeprazole are protonated and converted in the acidic compartment of the parietal cell forming the active inhibitor, the achiral sulphenamide. By acting specifically on the proton pump, Estab blocks the final step in acid production, thus reducing gastric acidity. This effect is dose-related up to a daily dose of 20 to 40 mg and leads to inhibition of gastric acid secretion.

12.2 Pharmacodynamics

Antisecretory Activity

The effect of Estab on intragastric pH was determined in patients with symptomatic gastroesophageal reflux disease in two separate studies. In the first study of 36 patients, Estab 40 mg and 20 mg capsules were administered over 5 days. The results are shown in the following table:

Table 3

Effect on Intragastric pH on Day 5


Parameter


Estab

40 mg


Estab

20 mg


% Time Gastric pH >4(Hours)


70%p< 0.01 Estab 40 mg vs. Estab 20 mg

(16.8 h)


53%

(12.7 h)


Coefficient of variation


26%


37%


Median 24 Hour pH


4.9


4.1


Coefficient of variation


16%


27%


In a second study, the effect on intragastric pH of Estab 40 mg administered once daily over a five day period was similar to the first study, (% time with pH > 4 was 68% or 16.3 hours).

Serum Gastrin Effects

The effect of Estab on serum gastrin concentrations was evaluated in approximately 2,700 patients in clinical trials up to 8 weeks and in over 1,300 patients for up to 6 to 12 months. The mean fasting gastrin level increased in a dose-related manner. This increase reached a plateau within two to three months of therapy and returned to baseline levels within four weeks after discontinuation of therapy.

Enterochromaffin-like (ECL) Cell Effects

In 24-month carcinogenicity studies of omeprazole in rats, a dose-related significant occurrence of gastric ECL cell carcinoid tumors and ECL cell hyperplasia was observed in both male and female animals [see Nonclinical Toxicology (13.1) ]. Carcinoid tumors have also been observed in rats subjected to fundectomy or long-term treatment with other proton pump inhibitors or high doses of H2-receptor antagonists.

Human gastric biopsy specimens have been obtained from more than 3,000 patients treated with omeprazole in long-term clinical trials. The incidence of ECL cell hyperplasia in these studies increased with time; however, no case of ECL cell carcinoids, dysplasia, or neoplasia has been found in these patients.

In over 1,000 patients treated with Estab (10, 20 or 40 mg/day) up to 6 to 12 months, the prevalence of ECL cell hyperplasia increased with time and dose. No patient developed ECL cell carcinoids, dysplasia, or neoplasia in the gastric mucosa.

Endocrine Effects

Estab had no effect on thyroid function when given in oral doses of 20 or 40 mg for 4 weeks. Other effects of Estab on the endocrine system were assessed using omeprazole studies. Omeprazole given in oral doses of 30 or 40 mg for 2 to 4 weeks had no effect on carbohydrate metabolism, circulating levels of parathyroid hormone, cortisol, estradiol, testosterone, prolactin, cholecystokinin, or secretin.

12.3 Pharmacokinetics

Absorption

Estab Delayed-Release Capsules and Estab For Delayed-Release Oral Suspension contain a bioequivalent enteric-coated granule formulation of Estab magnesium. Bioequivalency is based on a single dose (40 mg) study in 94 healthy male and female volunteers under fasting condition. After oral administration peak plasma levels (Cmax) occur at approximately 1.5 hours (Tmax). The Cmax increases proportionally when the dose is increased, and there is a three-fold increase in the area under the plasma concentration-time curve (AUC) from 20 to 40 mg. At repeated once-daily dosing with 40 mg, the systemic bioavailability is approximately 90% compared to 64% after a single dose of 40 mg. The mean exposure (AUC) to Estab increases from 4.32 µmol*hr/L on Day 1 to 11.2 µmol*hr/L on Day 5 after 40 mg once daily dosing.

The AUC after administration of a single 40 mg dose of Estab is decreased by 43% to 53% after food intake compared to fasting conditions. Estab should be taken at least one hour before meals.

The pharmacokinetic profile of Estab was determined in 36 patients with symptomatic gastroesophageal reflux disease following repeated once daily administration of 20 mg and 40 mg capsules of Estab over a period of five days. The results are shown in the following table:

Table 4


Parameter * (CV)


Estab

40 mg


Estab

20 mg


AUC (μmol*h/L)


12.6 (42%)


4.2 (59%)


Cmax (μmol/L)


4.7 (37%)


2.1 (45%)


Tmax (h)


1.6


1.6


t1/2 (h)


1.5


1.2


* Values represent the geometric mean, except the Tmax, which is the arithmetic mean; CV = Coefficient of variation

Distribution

Estab is 97% bound to plasma proteins. Plasma protein binding is constant over the concentration range of 2 to 20 μmol/L. The apparent volume of distribution at steady state in healthy volunteers is approximately 16 L.

Metabolism

Estab is extensively metabolized in the liver by the cytochrome P450 (CYP) enzyme system. The metabolites of Estab lack antisecretory activity. The major part of esomeprazole’s metabolism is dependent upon the CYP 2C19 isoenzyme, which forms the hydroxy and desmethyl metabolites. The remaining amount is dependent on CYP 3A4 which forms the sulphone metabolite. CYP 2C19 isoenzyme exhibits polymorphism in the metabolism of Estab, since some 3% of Caucasians and 15 to 20% of Asians lack CYP 2C19 and are termed Poor Metabolizers. At steady state, the ratio of AUC in Poor Metabolizers to AUC in the rest of the population (Extensive Metabolizers) is approximately 2.

Following administration of equimolar doses, the S- and R-isomers are metabolized differently by the liver, resulting in higher plasma levels of the S- than of the R-isomer.

Excretion

The plasma elimination half-life of Estab is approximately 1 to 1.5 hours. Less than 1% of parent drug is excreted in the urine. Approximately 80% of an oral dose of Estab is excreted as inactive metabolites in the urine, and the remainder is found as inactive metabolites in the feces.

Pharmacokinetics: Combination Therapy with Antimicrobials

Estab magnesium 40 mg once daily was given in combination with clarithromycin 500 mg twice daily and amoxicillin 1000 mg twice daily for 7 days to 17 healthy male and female subjects. The mean steady state AUC and Cmax of Estab increased by 70% and 18%, respectively during triple combination therapy compared to treatment with Estab alone. The observed increase in Estab exposure during co-administration with clarithromycin and amoxicillin is not expected to produce significant safety concerns.

The pharmacokinetic parameters for clarithromycin and amoxicillin were similar during triple combination therapy and administration of each drug alone. However, the mean AUC and Cmax for 14-hydroxyclarithromycin increased by 19% and 22%, respectively, during triple combination therapy compared to treatment with clarithromycin alone. This increase in exposure to 14-hydroxyclarithromycin is not considered to be clinically significant.

Special Populations

Geriatric

The AUC and Cmax values were slightly higher (25% and 18%, respectively) in the elderly as compared to younger subjects at steady state. Dosage adjustment based on age is not necessary.

Pediatric

1 to 11 Years of Age

The pharmacokinetics of Estab were studied in pediatric patients with GERD aged 1 to 11 years. Following once daily dosing for 5 days, the total exposure (AUC) for the 10 mg dose in patients aged 6 to 11 years was similar to that seen with the 20 mg dose in adults and adolescents aged 12 to 17 years. The total exposure for the 10 mg dose in patients aged 1 to 5 years was approximately 30% higher than the 10 mg dose in patients aged 6 to 11 years. The total exposure for the 20 mg dose in patients aged 6 to 11 years was higher than that observed with the 20 mg dose in 12 to 17 year-olds and adults, but lower than that observed with the 40 mg dose in 12 to 17 year-olds and adults.

Table 5


1 to 5 Year Olds


6 to 11 Year Olds


Parameter


10 mg (N=8)


10 mg (N=7)


20 mg (N=6)


AUC (μmol*h/L)Geometric mean;


4.83


3.70


6.28


Cmax (μmol/L)


2.98


1.77


3.73


tmax (h)


1.44


1.79


1.75


t½λz (h)


0.74


0.88


0.73


Cl/F (L/h)


5.99


7.84


9.22


12 to 17 Years of Age

The pharmacokinetics of Estab were studied in 28 adolescent patients with GERD aged 12 to 17 years inclusive, in a single center study. Patients were randomized to receive Estab 20 mg or 40 mg once daily for 8 days. Mean Cmax and AUC values of Estab were not affected by body weight or age; and more than dose-proportional increases in mean Cmax and AUC values were observed between the two dose groups in the study. Overall, Estab pharmacokinetics in adolescent patients aged 12 to 17 years were similar to those observed in adult patients with symptomatic GERD.

Table 6


12 to 17 Year Olds (N=28)


Adults (N=36)


Parameter


20 mg


40 mg


20 mg


40 mg


AUC (μmol*h/L)


3.65


13.86


4.2


12.6


Cmax (μmol/L)


1.45


5.13


2.1


4.7


tmax (h)


2.00


1.75


1.6


1.6


t½λz (h)


0.82


1.22


1.2


1.5


Data presented are geometric means for AUC, Cmax and t½λz, and median value for tmax.


Gender

The AUC and Cmax values were slightly higher (13%) in females than in males at steady state. Dosage adjustment based on gender is not necessary.

Hepatic Insufficiency

The steady state pharmacokinetics of Estab obtained after administration of 40 mg once daily to 4 patients each with mild (Child Pugh A), moderate (Child Pugh Class B), and severe (Child Pugh Class C) liver insufficiency were compared to those obtained in 36 male and female GERD patients with normal liver function. In patients with mild and moderate hepatic insufficiency, the AUCs were within the range that could be expected in patients with normal liver function. In patients with severe hepatic insufficiency the AUCs were 2 to 3 times higher than in the patients with normal liver function. No dosage adjustment is recommended for patients with mild to moderate hepatic insufficiency (Child Pugh Classes A and B). However, in patients with severe hepatic insufficiency (Child Pugh Class C) a dose of 20 mg once daily should not be exceeded [see Dosage and Administration (2)].

Renal Insufficiency

The pharmacokinetics of Estab in patients with renal impairment are not expected to be altered relative to healthy volunteers as less than 1% of Estab is excreted unchanged in urine.

Other pharmacokinetic observations

Coadministration of oral contraceptives, diazepam, phenytoin, or quinidine did not seem to change the pharmacokinetic profile of Estab.

Studies evaluating concomitant administration of Estab and either naproxen (non-selective NSAID) or rofecoxib (COX-2 selective NSAID) did not identify any clinically relevant changes in the pharmacokinetic profiles of Estab or these NSAIDs.

12.4 Microbiology

Estab, amoxicillin, and clarithromycin triple therapy has been shown to be active against most strains of Helicobacter pylori (H. pylori) in vitro and in clinical infections as described in the Clinical Studies (14) and Indications and Usage (1) sections.

Helicobacter pylori: Susceptibility testing of H. pylori isolates was performed for amoxicillin and clarithromycin using agar dilution methodology, and minimum inhibitory concentrations (MICs) were determined.

Pretreatment Resistance: Clarithromycin pretreatment resistance rate (MIC ≥ 1 mcg/mL) to H. pylori was 15% (66/445) at baseline in all treatment groups combined. A total of > 99% (394/395) of patients had H. pylori isolates that were considered to be susceptible (MIC ≤ 0.25 mcg/mL) to amoxicillin at baseline. One patient had a baseline H. pylori isolate with an amoxicillin MIC = 0.5 mcg/mL.

Clarithromycin Susceptibility Test Results and Clinical/Bacteriologic Outcomes: The baseline H. pylori clarithromycin susceptibility results and the H. pylori eradication results at the Day 38 visit are shown in the table below:

Table 7


Clarithromycin Pretreatment Results


H. pylori negative (Eradicated)


H. pylori positive

(Not Eradicated)

Post-treatment susceptibility results


S Susceptible (S) MIC ≤ 0.25 mcg/mL, Intermediate (I) MIC = 0.5 mcg/mL, Resistant (R) MIC ≥ 1.0 mcg/mL


I


R


No MIC


Susceptible 182


162


4


0


2


14


Intermediate 1


1


0


0


0


0


Resistant 29


13


1


0


13


2


Patients not eradicated of H. pylori following NEXIUM/amoxicillin/clarithromycin triple therapy will likely have clarithromycin resistant H. pylori isolates. Therefore, clarithromycin susceptibility testing should be done, when possible. Patients with clarithromycin resistant H. pylori should not be re-treated with a clarithromycin-containing regimen.

Amoxicillin Susceptibility Test Results and Clinical/Bacteriological Outcomes:

In the NEXIUM/amoxicillin/clarithromycin clinical trials, 83% (176/212) of the patients in the NEXIUM/amoxicillin/clarithromycin treatment group who had pretreatment amoxicillin susceptible MICs (≤ 0.25 mcg/mL) were eradicated of H. pylori, and 17% (36/212) were not eradicated of H. pylori. Of the 36 patients who were not eradicated of H. pylori on triple therapy, 16 had no post-treatment susceptibility test results and 20 had post-treatment H. pylori isolates with amoxicillin susceptible MICs. Fifteen of the patients who were not eradicated of H. pylori on triple therapy also had post-treatment H. pylori isolates with clarithromycin resistant MICs. There were no patients with H. pylori isolates who developed treatment emergent resistance to amoxicillin.

Susceptibility Test for Helicobacter pylori: The reference methodology for susceptibility testing of H. pylori is agar dilution MICs. One to three microliters of an inoculum equivalent to a No. 2 McFarland standard (1 x 107 - 1 x 108 CFU/mL for H. pylori) are inoculated directly onto freshly prepared antimicrobial containing Mueller-Hinton agar plates with 5% aged defibrinated sheep blood (≥ 2 weeks old). The agar dilution plates are incubated at 35°C in a microaerobic environment produced by a gas generating system suitable for Campylobacter. After 3 days of incubation, the MICs are recorded as the lowest concentration of antimicrobial agent required to inhibit growth of the organism. The clarithromycin and amoxicillin MIC values should be interpreted according to the following criteria:

Table 8


Clarithromycin MIC (mcg/mL)These are breakpoints for the agar dilution methodology and they should not be used to interpret results obtained using alternative methods.


Interpretation


≤ 0.25


Susceptible (S)


0.5


Intermediate (I)


≥1.0


Resistant (R)


Amoxicillin MIC (mcg/mL)


Interpretation


≤ 0.25


Susceptible (S)


Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard clarithromycin and amoxicillin powders should provide the following MIC values:

Table 9


Microorganism


Antimicrobial Agent


MIC (mcg/mL)


H. pylori ATCC 43504


Clarithromycin


0.016 − 0.12 (mcg/mL)


H. pylori ATCC 43504


Amoxicillin


0.016 − 0.12 (mcg/mL)


Effects on Gastrointestinal Microbial Ecology: Decreased gastric acidity due to any means, including proton pump inhibitors, increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with proton pump inhibitors may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter and possibly Clostridium difficile in hospitalized patients.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

The carcinogenic potential of Estab was assessed using studies of omeprazole, of which Estab 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 141 mg/kg/day 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 5.6 times the human dose 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.

Estab 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. Estab, 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 Estab on fertility and reproductive performance were assessed using omeprazole studies. Omeprazole at oral doses up to 138 mg/kg/day in rats (about 56 times the human dose on a body surface area basis) was found to have no effect on reproductive performance of parental animals.

13.2 Animal Toxicology and/or Pharmacology

Reproductive Toxicology Studies

Reproductive studies have been performed in rats at oral doses up to 280 mg/kg/day (about 57 times the human dose on a body surface area basis) and in rabbits at oral doses up to 86 mg/kg/day (about 35 times the human dose on a body surface area basis) and have revealed no evidence of impaired fertility or harm to the fetus due to Estab.

Reproductive studies conducted with omeprazole in rats at oral doses up to 138 mg/kg/day (about 56 times the human dose on a body surface area basis) and in rabbits at doses up to 69 mg/kg/day (about 56 times the human dose on a body surface area basis) did not disclose any evidence for a teratogenic potential of omeprazole. In rabbits, omeprazole in a dose range of 6.9 to 69.1 mg/kg/day (about 5.5 to 56 times the human dose on a body surface area basis) produced dose-related increases in embryo-lethality, fetal resorptions, and pregnancy disruptions. In rats, dose-related embryo/fetal toxicity and postnatal developmental toxicity were observed in offspring resulting from parents treated with omeprazole at 13.8 to 138.0 mg/kg/day (about 5.6 to 56 times the human dose on a body surface area basis).

14 CLINICAL STUDIES

14.1 Healing of Erosive Esophagitis

The healing rates of Estab 40 mg, Estab 20 mg, and omeprazole 20 mg were evaluated in patients with endoscopically diagnosed erosive esophagitis in four multicenter, double-blind, randomized studies. The healing rates at Weeks 4 and 8 were evaluated and are shown in the table below:

Table 10


Study


No. of Patients


Treatment Groups


Week 4


Week 8


Significance Level


1


588


Estab 20 mg


68.7%


90.6%


N.S.N.S. = not significant (p > 0.05)


588


Omeprazole 20 mg


69.5%


88.3%


2


654


Estab 40 mg


75.9%


94.1%


p < 0.001


656


Estab 20 mg


70.5%


89.9%


p < 0.05


650


Omeprazole 20 mg


64.7%


86.9%


3


576


Estab 40 mg


71.5%


92.2%


N.S.


572


Omeprazole 20 mg


68.6%


89.8%


4


1216


Estab 40 mg


81.7%


93.7%


p < 0.001


1209


Omeprazole 20 mg


68.7%


84.2%


In these same studies of patients with erosive esophagitis, sustained heartburn resolution and time to sustained heartburn resolution were evaluated and are shown in the table below:

Table 11


Cumulative Percent with Sustained Resolution


Study


No. of Patients


Treatment Groups


Day 14


Day 28


Significance Level


1


573


Estab 20 mg


64.3%


72.7%


N.S.N.S. = not significant (p > 0.05)


555


Omeprazole 20 mg


64.1%


70.9%


2


621


Estab 40 mg


64.8%


74.2%


p <0.001


620


Estab 20 mg


62.9%


70.1%


N.S.


626


Omeprazole 20 mg


56.5%


66.6%


3


568


Estab 40 mg


65.4%


73.9%


N.S.


551


Omeprazole 20 mg


65.5%


73.1%


4


1187


Estab 40 mg


67.6%


75.1%


p <0.001


1188


Omeprazole 20 mg


62.5%


70.8%


In these four studies, the range of median days to the start of sustained resolution (defined as 7 consecutive days with no heartburn) was 5 days for Estab 40 mg, 7 to 8 days for Estab 20 mg and 7 to 9 days for omeprazole 20 mg.

There are no comparisons of 40 mg of Estab with 40 mg of omeprazole in clinical trials assessing either healing or symptomatic relief of erosive esophagitis.

Long-Term Maintenance of Healing of Erosive Esophagitis

Two multicenter, randomized, double-blind placebo-controlled 4-arm trials were conducted in patients with endoscopically confirmed, healed erosive esophagitis to evaluate Estab 40 mg (n=174), 20 mg (n=180), 10 mg (n=168) or placebo (n=171) once daily over six months of treatment.

No additional clinical benefit was seen with Estab 40 mg over Estab 20 mg.

The percentages of patients that maintained healing of erosive esophagitis at the various time points are shown in the figures below:

Figure 2

Maintenance of Healing Rates by Month (Study 177)

s= scheduled visit

Figure 3

Maintenance of Healing Rates by Month (Study 178)

s= scheduled visit

Patients remained in remission significantly longer and the number of recurrences of erosive esophagitis was significantly less in patients treated with Estab compared to placebo.

In both studies, the proportion of patients on Estab who remained in remission and were free of heartburn and other GERD symptoms was well differentiated from placebo.

In a third multicenter open label study of 808 patients treated for 12 months with Estab 40 mg, the percentage of patients that maintained healing of erosive esophagitis was 93.7% for six months and 89.4% for one year.

figureone figuretwo

14.2 Symptomatic Gastroesophageal Reflux Disease (GERD)

Two multicenter, randomized, double-blind, placebo-controlled studies were conducted in a total of 717 patients comparing four weeks of treatment with Estab 20 mg or 40 mg once daily versus placebo for resolution of GERD symptoms. Patients had ≥ 6-month history of heartburn episodes, no erosive esophagitis by endoscopy, and heartburn on at least four of the seven days immediately preceding randomization.

The percentage of patients that were symptom-free of heartburn was significantly higher in the Estab groups compared to placebo at all follow-up visits (Weeks 1, 2, and 4).

No additional clinical benefit was seen with Estab 40 mg over Estab 20 mg.

The percent of patients symptom-free of heartburn by day are shown in the figures below:

Figure 4

Percent of Patients Symptom-Free of Heartburn by Day

(Study 225)

Figure 5

Percent of Patients Symptom-Free of Heartburn by Day

(Study 226)

In three European symptomatic GERD trials, Estab 20 mg and 40 mg and omeprazole 20 mg were evaluated. No significant treatment related differences were seen.

figurethree figurefour

14.3 Pediatric Gastroesophageal Reflux Disease

1 to 11 Years of Age

In a multicenter, parallel-group study, 109 pediatric patients with a history of endoscopically-proven GERD (1 to 11 years of age; 53 female; 89 Caucasian, 19 Black, 1 Other) were treated with Estab once daily for up to 8 weeks to evaluate safety and tolerability. Dosing by patient weight was as follows:

weight < 20 kg: once daily treatment with Estab 5 mg or 10 mg

weight ≥ 20 kg: once daily treatment with Estab 10 mg or 20 mg

Patients were endoscopically characterized as to the presence or absence of erosive esophagitis.

Of the 109 patients, 53 had erosive esophagitis at baseline (51 had mild, 1 moderate, and 1 severe esophagitis). Although most of the patients who had a follow up endoscopy at the end of 8 weeks of treatment healed, spontaneous healing cannot be ruled out because these patients had low grade erosive esophagitis prior to treatment, and the trial did not include a concomitant control.

12 to 17 Years of Age

In a multicenter, randomized, double-blind, parallel-group study, 149 adolescent patients (12 to 17 years of age; 89 female; 124 Caucasian, 15 Black, 10 Other) with clinically diagnosed GERD were treated with either Estab 20 mg or Estab 40 mg once daily for up to 8 weeks to evaluate safety and tolerability. Patients were not endoscopically characterized as to the presence or absence of erosive esophagitis.

14.4 Risk Reduction of NSAID-Associated Gastric Ulcer

Two multicenter, double-blind, placebo-controlled studies were conducted in patients at risk of developing gastric and/or duodenal ulcers associated with continuous use of non-selective and COX-2 selective NSAIDs. A total of 1429 patients were randomized across the 2 studies. Patients ranged in age from 19 to 89 with 70.7% female, 29.3% male, 82.9% Caucasian, 5.5% Black, 3.7% Asian, and 8.0% Others. At baseline, the patients in these studies were endoscopically confirmed not to have ulcers but were determined to be at risk for ulcer occurrence due to their age (≥60 years) and/or history of a documented gastric or duodenal ulcer within the past 5 years. Patients receiving NSAIDs and treated with Estab 20 mg or 40 mg once-a-day experienced significant reduction in gastric ulcer occurrences relative to placebo treatment at 26 weeks. No additional benefit was seen with Estab 40 mg over Estab 20 mg. These studies did not demonstrate significant reduction in the development of NSAID-associated duodenal ulcer due to the low incidence.

Table 12


Study


No. of Patients


Treatment Group


% of Patients Remaining Gastric Ulcer Free


1


191

194

184


Estab 20 mg

Estab 40 mg

Placebo


95.4

96.7

88.2


2


267

271

257


Estab 20 mg

Estab 40 mg

Placebo


94.7

95.3

83.3

14.5 Helicobacter pylori (H.pylori) Eradication in Patients with Duodenal Ulcer Disease

Triple Therapy (NEXIUM/amoxicillin/clarithromycin): Two multicenter, randomized, double-blind studies were conducted using a 10 day treatment regimen. The first study (191) compared Estab 40 mg once daily in combination with amoxicillin 1000 mg twice daily and clarithromycin 500 mg twice daily to Estab 40 mg once daily plus clarithromycin 500 mg twice daily. The second study (193) compared Estab 40 mg once daily in combination with amoxicillin 1000 mg twice daily and clarithromycin 500 mg twice daily to Estab 40 mg once daily. H. pylori eradication rates, defined as at least two negative tests and no positive tests from CLOtest®, histology and/or culture, at 4 weeks post-therapy were significantly higher in the Estab plus amoxicillin and clarithromycin group than in the Estab plus clarithromycin or Estab alone group. The results are shown in the following table:

Table 13


Study


Treatment Group


Per-Protocol


Intent-to-Treat


191


Estab plus amoxicillin and clarithromycin


84%p < 0.05 compared to Estab plus clarithromycin

[78, 89]

(n=196)


77%

[71, 82]

(n=233)


Estab plus clarithromycin


55%

[48, 62]

(n=187)


52%

[45, 59]

(n=215)


193


Estab plus amoxicillin and clarithromycin


85%p < 0.05 compared to Estab alone

[74, 93]

(n=67)


78%

[67, 87]

(n=74)


Estab


5%

[0, 23]

(n=22)


4%

[0, 21]

(n=24)


The percentage of patients with a healed baseline duodenal ulcer by 4 weeks after the 10 day treatment regimen in the Estab plus amoxicillin and clarithromycin group was 75% (n=156) and 57% (n=60) respectively, in the 191 and 193 studies (per-protocol analysis).

14.6 Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome

In a multicenter, open-label dose-escalation study of 21 patients (15 males and 6 females, 18 Caucasian and 3 Black, mean age of 55.5 years) with pathological hypersecretory conditions, such as Zollinger-Ellison Syndrome, Estab significantly inhibited gastric acid secretion. Initial dose was 40 mg twice daily in 19/21 patients and 80 mg twice daily in 2/21 patients. Total daily doses ranging from 80 mg to 240 mg for 12 months maintained gastric acid output below the target levels of 10 mEq/h in patients without prior gastric acid-reducing surgery and below 5 mEq/hr in patients with prior gastric acid-reducing surgery. At the Month 12 final visit, 18/20 (90%) patients had Basal Acid Output (BAO) under satisfactory control (median BAO = 0.17 mmol/hr). Of the 18 patients evaluated with a starting dose of 40 mg twice daily, 13 (72%) had their BAO controlled with the original dosing regimen at the final visit.

Table 14


Estab dose at the Month 12 visit


BAO under adequate control at the Month 12 visit (N=20)


40 mg twice daily


13/15


80 mg twice daily


4/4


80 mg three times daily


1/1

15 REFERENCES

1. National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically. Fifth Edition: Approved Standard NCCLS Document M7-A5, Vol. 20, no. 2, NCCLS, Wayne, PA, January 2000.

16 HOW SUPPLIED/STORAGE AND HANDLING

Estab Delayed-Release Capsules, 20 mg, are opaque, hard gelatin, amethyst colored capsules with two radial bars in yellow on the cap and Estab 20 mg in yellow on the body. They are supplied as follows:

NDC 0186-5020-31 unit of use bottles of 30

NDC 0186-5022-28 unit dose packages of 100

NDC 0186-5020-54 bottles of 90

NDC 0186-5020-82 bottles of 1000

Estab Delayed-Release Capsules, 40 mg, are opaque, hard gelatin, amethyst colored capsules with three radial bars in yellow on the cap and Estab 40 mg in yellow on the body. They are supplied as follows:

NDC 0186-5040-31 unit of use bottles of 30

NDC 0186-5042-28 unit dose packages of 100

NDC 0186-5040-54 bottles of 90

NDC 0186-5040-82 bottles of 1000

NDC 0186-5040-35 unit of use bottles of 30

NDC 0186-5042-25 unit dose packages of 100

NDC 0186-5040-55 bottles of 90

NDC 0186-5040-85 bottles of 1000

Estab For Delayed-Release Oral Suspension is supplied as a unit dose packet containing a fine yellow powder, consisting of white to pale brownish Estab granules and pale yellow inactive granules. Estab unit dose packets are supplied as follows:

NDC 0186-4010–01 unit dose packages of 30: 10 mg packets

NDC 0186-4020–01 unit dose packages of 30: 20 mg packets

NDC 0186-4040–01 unit dose packages of 30: 40 mg packets

Store at 25°C (77°F); excursions permitted to 15 to 30°C (59 to 86°F).. Keep Estab Delayed-Release Capsules container tightly closed. Dispense in a tight container if the Estab Delayed-Release Capsules product package is subdivided.

Estab and the color purple as applied to the capsule are registered trademarks of the AstraZeneca group of companies.

©AstraZeneca 2010

17 PATIENT COUNSELING INFORMATION

See FDA-Approved Patient Labeling

- Advise patients to let you know if they are taking, or begin taking, other medications, because Estab can interfere with antiretroviral drugs and drugs that are affected by gastric pH changes [see Drug Interactions (7.1)].

- Let patients know that antacids may be used while taking Estab.

- Advise patients to take Estab at least one hour before a meal.

- For patients who are prescribed Estab Delayed-Release Capsules, advise them not to chew or crush the capsules.

- Advise patients that, if they open Estab Delayed-Release Capsules to mix the granules with food, the granules should only be mixed with applesauce. Use with other foods has not been evaluated and is not recommended.

- For patients who are advised to open the Estab Delayed-Release Capsules before taking them or who are prescribed Estab For Delayed-Release Oral Suspension, instruct them in the proper technique for administration [see Dosage and Administration (2)] and tell them to follow the dosing instructions in the PATIENT INFORMATION insert included in the package.

Distributed by:

AstraZeneca LP

Wilmington, DE 19850

NEXIUM® (nex-e-um) (esomeprazole magnesium)

Delayed-Release Capsules and Delayed-Release Oral Suspension

Read the Patient Information that comes with Estab before you start taking it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your doctor about your medical condition or your treatment.

If you have any questions about Estab, ask your doctor.

WHAT IS Estab?

Estab is a prescription medicine called a proton pump inhibitor (PPI).

Estab is used in adults:

- for 4 to 8 weeks to treat the symptoms of gastroesophageal reflux disease (GERD). Estab may also be prescribed to heal acid-related damage to the lining of the esophagus (erosive esophagitis), and to help continue this healing.

GERD is a chronic condition (lasts a long time) that occurs when acid from the stomach backs up into the esophagus (food pipe) causing symptoms, such as heartburn, or damage to the lining of the esophagus. Common symptoms include frequent heartburn that will not go away, a sour or bitter taste in the mouth, and difficulty swallowing.

- for up to 6 months to reduce the risk of stomach ulcers in some people taking pain medicines called non-steroidal anti-inflammatory drugs (NSAIDs).

- to treat patients with a stomach infection (Helicobacter pylori), along with the antibiotics amoxicillin and clarithromycin.

- for the long-term treatment of Zollinger-Ellison Syndrome. Zollinger-Ellison Syndrome is a rare condition in which the stomach produces a more than normal amount of acid.

For children and adolescents 1 to 17 years of age, Estab may be prescribed for up to 8 weeks for short-term treatment of GERD.

Estab is not recommended for children under the age of 1 year.

WHO SHOULD NOT TAKE Estab?

Do not take Estab if you:

- are allergic to any of the ingredients in Estab. See the end of this leaflet for a complete list of ingredients in Estab.

- are allergic to any other Proton Pump Inhibitor (PPI) medicine.

WHAT SHOULD I TELL MY DOCTOR BEFORE TAKING Estab?

Tell your doctor about all your medical conditions, including if you:


Tell your doctor about all of the medicines you take including prescription and non-prescription drugs, vitamins and herbal supplements. Estab may affect how other medicines work, and other medicines may affect how Estab works. Especially tell your doctor if you take:


HOW SHOULD I TAKE Estab?


WHAT ARE THE POSSIBLE SIDE EFFECTS OF Estab?

Serious allergic reactions. Tell your doctor if you get any of the following symptoms with Estab.


Your doctor may stop Estab if these symptoms happen.

The most common side effects with Estab may include:


People who are taking multiple daily doses of proton pump inhibitor medicines for a long period of time may have an increased risk of fractures of the hip, wrist or spine.

Tell your doctor about any side effects that bother you or that do not go away. These are not all the possible side effects with Estab. Talk with your doctor or pharmacist if you have any questions about side effects.

HOW SHOULD I STORE Estab?


Keep Estab and all medicines out of the reach of children.

GENERAL ADVICE

Medicines are sometimes prescribed for purposes other than those listed in the Patient Information leaflet. Do not use Estab for a condition for which it was not prescribed. Do not give Estab to other people, even if they have the same symptoms you have. It may harm them.

This Patient Information leaflet provides a summary of the most important information about Estab. For more information, ask your doctor. You can ask your doctor or pharmacist for information that is written for healthcare professionals. For more information, go to www.purplepill.com or call toll free 1-800-463-9486.

PATIENT INSTRUCTIONS FOR USE

For instructions on taking Delayed-Release Capsules, please see “HOW SHOULD I TAKE Estab?”

Take Estab Delayed-Release Oral Suspension as follows:


If any medicine remains after drinking, add more water, stir, and drink right away.

Estab Delayed-Release Capsules and Estab for Delayed-Release Oral Suspension may be given through a nasogastric tube (NG tube) or gastric tube, as prescribed by your doctor. Follow the instructions below:

Estab Delayed-Release Capsules:


Estab For Delayed-Release Oral Suspension:


WHAT ARE THE INGREDIENTS IN Estab?

Active ingredient: Estab magnesium trihydrate

Inactive ingredients in Estab Delayed-Release Capsules (including the capsule shells): glyceryl monostearate 40-55, hydroxypropyl cellulose, hypromellose, magnesium stearate, methacrylic acid copolymer type C, polysorbate 80, sugar spheres, talc, triethyl citrate, gelatin, FD&C Blue #1, FD&C Red #40, D&C Red #28, titanium dioxide, shellac, ethyl alcohol, isopropyl alcohol, n-butyl alcohol, propylene glycol, sodium hydroxide, polyvinyl pyrrolidone, and D&C Yellow #10.

Inactive granules in Estab Delayed-Release Oral Suspension: dextrose, xanthan gum, crospovidone, citric acid, iron oxide, and hydroxypropyl cellulose.

Estab is a registered trademark of the AstraZeneca group of companies.

©2010 AstraZeneca Pharmaceuticals LP. All rights reserved.

AstraZeneca Pharmaceuticals LP

Wilmington, DE 19850

August 2010

Estab pharmaceutical active ingredients containing related brand and generic drugs:

Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Estab available forms, composition, doses:

Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Estab destination | category:

Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Estab Anatomical Therapeutic Chemical codes:

A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Estab pharmaceutical companies:

Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. Dailymed."ESOMEPRAZOLE STRONTIUM: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. "Esomeprazole". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).
  3. "Esomeprazole". http://www.drugbank.ca/drugs/DB0073... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Estab?

Depending on the reaction of the Estab after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Estab not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Estab addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sdrugs.com conducted a study on Estab, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Estab consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Rachana Salvi, MD Pharmacology

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