NEXIUM (esomeprazole magnesium 40 mg) Dailymed

Recent Major Changes

Indications and Usage, Treatment of GERD (1.1) 12/2011

Dosage and Administration (2) 12/2011

Warnings and Precautions 06/2011

Hypomagnesemia (5.6)

Warnings and Precautions 06/2011

Concomitant use of NEXIUM with St John’s Wort or Rifampin (5.7)

Interactions with Diagnostic Investigations for Neuroendocrine Tumors (5.8)

1 Indications And Usage

NEXIUM is a proton pump inhibitor indicated for the following:

• 
  Treatment of gastroesophageal reflux disease (GERD) (1.1)
  
• 
  Risk reduction of NSAID-associated gastric ulcer (1.2)
  
• 
  H. pylori eradication to reduce the risk of duodenal ulcer recurrence (1.3)
  
• 
  Pathological hypersecretory conditions, including Zollinger-Ellison syndrome (1.4)
  

1.1 Treatment of Gastroesophageal Reflux Disease (GERD)

Healing of Erosive Esophagitis

NEXIUM 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 NEXIUM may be considered.

In infants 1 month to less than 1 year, NEXIUM is indicated for short-term treatment (up to 6 weeks) of erosive esophagitis due to acid-mediated GERD.

Maintenance of Healing of Erosive Esophagitis

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

Symptomatic Gastroesophageal Reflux Disease

NEXIUM 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

NEXIUM 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 (≥ 60) and/or documented history of gastric ulcers. Controlled studies do not extend beyond 6 months.

1.3 Eradication to Reduce the Risk of Duodenal Ulcer Recurrence

Triple Therapy (NEXIUM plus amoxicillin and clarithromycin): NEXIUM, 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 Dosage and Administration (2) and Clinical Studies (14) ].

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 prescribing information for clarithromycin].

1.4 Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome

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

2 Dosage And Administration

NEXIUM 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 Table 1. NEXIUM 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: Recommended Dosage Schedule of NEXIUM

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
1 month to < 1 year old
Erosive esophagitis due to acidmediated GERD
weight 3 kg to 5 kg	2.5 mg	Once Daily for up to 6 Weeks
weight > 5 kg to 7.5 kg	5 mg	Once Daily for up to 6 Weeks
weight >7.5 kg to 12 kg	10 mg	Once Daily for up to 6 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:
NEXIUM	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 prescribing information for Contraindications, Warnings, and dosing in elderly and renally-impaired patients.

Special Populations

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 NEXIUM should not be exceeded [see Clinical Pharmacology (12.3)].

Directions for use specific to the route and available methods of administration for each of these dosage forms are presented in Table 2.

Table 2: Administration Options

Administration Options (See text following table for additional instructions.)
Type	Route	Options
Delayed-Release Capsules	Oral	Capsule can be swallowed whole. -or- Capsule can be opened and mixed with applesauce.
Delayed-Release Capsules	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	For the 2.5 mg and 5 mg strengths, mix the contents of packet with 5 mL of water, leave 2 to 3 minutes to thicken, stir and drink within 30 minutes. For the 10 mg, 20 mg and 40 mg strengths, mix contents of packet with 15 mL of water, and follow the instructions above.
For Delayed-Release Oral Suspension	Nasogastric or Gastric Tube	For the 2.5 mg and 5 mg strengths, add 5 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. For the 10 mg, 20 mg and 40 mg strengths, add 15 mL of water, and follow the instructions above.

NEXIUM Delayed-Release Capsules

NEXIUM 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 NEXIUM 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: do not store for future use. 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. If the granules/applesauce mixture is not used in its entirety, the remaining mixture should be discarded immediately.

For patients who have a nasogastric tube in place, NEXIUM 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 NEXIUM 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 mixture must be used immediately after preparation.

NEXIUM For Delayed-Release Oral Suspension

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

• 
  Empty the contents of a 2.5 mg or 5 mg packet into a container containing 5 mL of water. For the 10 mg, 20 mg, and 40 mg strengths, the contents of a packet should be emptied into a container containing 15 mL of water.
  
• 
  Stir.
  
• 
  Leave 2 to 3 minutes to thicken.
  
• 
  Stir and drink within 30 minutes.
  
• 
  If any medicine remains after drinking, add more water, stir, and drink immediately.
  
• 
  In cases where there is a need to use two packets, they may be mixed in a similar way by adding twice the required amount of water or follow the mixing instructions provided by your pharmacist or doctor.
  

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

• 
  Add 5 mL of water to a catheter tipped syringe and then add the contents of a 2.5 mg or 5 mg NEXIUM packet. For the 10 mg, 20 mg, and 40 mg strengths, the volume of water in the syringe should be 15 mL. It is important to only use a catheter tipped syringe when administering NEXIUM through a nasogastric tube or gastric tube.
  
• 
  Immediately shake the syringe and leave 2 to 3 minutes to thicken.
  
• 
  Shake the syringe and inject through the nasogastric or gastric tube, French size 6 or larger, into the stomach within 30 minutes.
  
• 
  Refill the syringe with an equal amount of water (5 mL or 15 mL).
  
• 
  Shake and flush any remaining contents from the nasogastric or gastric tube into the stomach.
  

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
1 month to less than 1 year: 2.5 mg, 5 mg or 10 mg (based on weight). Once daily, up to 6 weeks for erosive esophagitis (EE) due to acid-mediated GERD only.
Risk Reduction of NSAID-Associated Gastric Ulcer
	20 mg or 40 mg	Once daily for up to 6 months
H. pylori Eradication (Triple Therapy):
NEXIUM	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)

Patients with severe liver impairment-do not exceed dose of 20 mg (2)

Most common adverse reactions (6.1):

• 
  Adults (≥ 18 years) (incidence ≥ 1%) are headache, diarrhea, nausea, flatulence, abdominal pain, constipation, and dry mouth
  
• 
  Pediatric (≤ 17 years) (incidence ≥ 2%) are headache, diarrhea, abdominal pain, nausea, and somnolence
  
• 
  Pediatric (1 month to < 1 year) (incidence 1%) are abdominal pain, regurgitation, tachypnea, and increased ALT
  

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.

Adults

The safety of NEXIUM 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, NEXIUM was well tolerated in both short and long-term clinical trials.

The safety in the treatment of healing of erosive esophagitis was assessed in four randomized comparative clinical trials, which included 1,240 patients on NEXIUM 20 mg, 2,434 patients on NEXIUM 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, 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 NEXIUM or omeprazole.

Additional adverse reactions that were reported as possibly or probably related to NEXIUM with an incidence < 1% are uled 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 NEXIUM, 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)]. 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 NEXIUM were diarrhea (4.3%), headache (3.8%), and abdominal pain (3.8%).

Pediatrics

The safety of NEXIUM 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%).

The safety of NEXIUM was evaluated in 167 pediatric patients from birth to <1 year of age in three clinical trials. [See Clinical Studies (14.6) ] In a study that included 26 pediatric patients aged birth to 1 month there were no treatment related adverse reactions. In a study that included 43 pediatric patients age 1 to 11 months, inclusive the most frequently reported (at least 5%) adverse reactions, irrespective of causality, were irritability and vomiting. In a study that included 98 pediatric patients, age 1 to 11 months, inclusive exposed to esomeprazole for up to 6 weeks (including 39 patients randomized to the withdrawal phase), there were 4 treatment-related adverse reactions: abdominal pain (1%), regurgitation (1%), tachypnea (1%), and increased ALT (1%).

No new safety concerns were identified in pediatric patients.

Combination Treatment with Amoxicillin and Clarithromycin

In clinical trials using combination therapy with NEXIUM 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 NEXIUM, amoxicillin, or clarithromycin alone.

The most frequently reported drug-related adverse reactions for patients who received triple therapy for 10 days were diarrhea (9.2%), 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 NEXIUM 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 NEXIUM 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.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of NEXIUM. 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 uled 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).