ESOMEPRAZOLE MAGNESIUM DR

The active ingredient in the proton pump inhibitor esomeprazole magnesium delayed-release capsules USP for oral administration is bis(5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole-1-yl) magnesium dihydrate. Esomeprazole is the S-isomer of omeprazole, which is a mixture of the S- and R- isomers. (Initial U.S. approval of esomeprazole magnesium: 2001). Its molecular formula is (C17H18N3O3S)2 Mg x 2 H2O with molecular weight of 749.15 as a dihydrate and 713.12 on an anhydrous basis. The structural formula is: The magnesium salt is a white to slightly colored powder. It contains 2 moles of water of solvation and is practically insoluble in water. The stability of esomeprazole magnesium is a function of pH; it rapidly degrades in acidic media, but it has acceptable stability under alkaline conditions. At pH 6.8 (buffer), the half-life of the magnesium salt is about 19 hours at 25°C and about 8 hours at 37°C. Esomeprazole magnesium is supplied in delayed-release capsules. Each delayed-release capsule contains 20 mg, or 40 mg of esomeprazole (present as 21.75 mg, or 43.5 mg esomeprazole magnesium dihydrate USP) in the form of enteric-coated granules with the following inactive ingredients: colloidal silicon dioxide, hydroxypropyl cellulose, hypromellose, magnesium carbonate, magnesium oxide, methacrylic acid and ethyl acrylate copolymer dispersion, mono and di glycerides, polysorbate 80, sugar spheres (which contains liquid glucose, starch (maize) and sucrose), talc, titanium dioxide, and triethyl citrate. In addition, the empty hard gelatin capsule shells contain gelatin and sodium lauryl sulfate. The capsule shells are imprinted with edible ink containing butyl alcohol, dehydrated alcohol, isopropyl alcohol, propylene glycol, shellac, strong ammonia solution and yellow iron oxide. Meets USP Dissolution Test 2. Structure

Section 1 INDICATIONS AND USAGE 1.1 Treatment of Gastroesophageal Reflux Disease (GERD) Healing of Erosive Esophagitis Esomeprazole magnesium delayed-release capsules are 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 esomeprazole magnesium delayed-release capsules may be considered. Maintenance of Healing of Erosive Esophagitis Esomeprazole magnesium delayed-release capsules are indicated to maintain symptom resolution and healing of erosive esophagitis. Controlled studies do not extend beyond 6 months. Symptomatic Gastroesophageal Reflux Disease Esomeprazole magnesium delayed-release capsules are 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 Esomeprazole magnesium delayed-release capsules are 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 H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence Triple Therapy (esomeprazole magnesium delayed-release capsules plus amoxicillin and clarithromycin): Esomeprazole magnesium delayed-release capsules, 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 Esomeprazole magnesium delayed-release capsules are indicated for the long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison Syndrome.

Section 2.1 Recommended Dosage in Adults by Indication Table 1 shows the recommended adult dosage of esomeprazole magnesium delayed-release capsules by indication. The duration of esomeprazole magnesium delayed-release capsules treatment should be based on available safety and efficacy data specific to the defined indication and dosing frequency and individual patient medical needs. Esomeprazole magnesium delayed-release capsules should only be initiated and continued if the benefits outweigh the risks of treatment. Table 1: Recommended Dosage of Esomeprazole Magnesium Delayed-Release Capsules in Adults by Indication Adult Indication Recommended Dosage of Esomeprazole Magnesium Delayed-Release Capsules Treatment Duration Healing of EE 20 mg or 40 mg1 once daily 4 to 8 weeks2 Maintenance of Healing of EE 20 mg once daily Controlled studies do not extend beyond 6 months Treatment of Symptomatic GERD 20 mg once daily 4 weeks; if symptoms do not resolve completely, consider an additional 4 weeks Risk Reduction of NSAID-Associated Gastric Ulcer 20 mg or 40 mg1 once daily Controlled studies do not extend beyond 6 months H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence (Triple Therapy) Esomeprazole magnesium delayed-release capsules 40 mg once daily1 Amoxicillin 1000 mg twice daily3 Clarithromycin 500 mg twice daily3 Starting dosage is 40 mg twice daily4; individualize the regimen to patient needs. 10 days 10 days 10 days Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome Dosages of up to 240 mg/day have been administered [see CLINICAL STUDIES (14.7)]. As long as clinically indicated 1. A maximum dosage of 20 mg once daily is recommended for patients with severe liver impairment (Child-Pugh Class C) [see USE IN SPECIFIC POPULATIONS (8.6)]. 2. Most patients are healed within 4 to 8 weeks. For patients who do not heal after 4 to 8 weeks, an additional 4 to 8 weeks of treatment may be required to achieve healing [see CLINICAL STUDIES (14.1)]. 3. Refer to the amoxicillin and clarithromycin prescribing information for dosage adjustments in elderly and renally-impaired patients. 4. A starting dosage of 20 mg twice daily is recommended for patients with severe liver impairment (Child-Pugh Class C) [see USE IN SPECIFIC POPULATIONS (8.6)]. 2.2 Recommended Dosage in Pediatric Patients by Indication Table 2 shows the recommended dosage of esomeprazole magnesium delayed-release capsules in pediatric patients by indication. Table 2: Recommended Dosage of Esomeprazole Magnesium Delayed-Release Capsules in Pediatric Patients by Indication Indication Patient Age Recommended Dosage Duration Healing of EE 12 years to 17 years Esomeprazole magnesium delayed-release capsules: 20 mg or 40 mg once daily 4 to 8 Weeks Treatment of Symptomatic GERD 12 years to 17 years Esomeprazole magnesium delayed-release capsules: 20 mg once daily 4 weeks 2.3 Preparation and Administration Instructions Take Esomeprazole magnesium delayed-release capsules at least one hour before meals [see CLINICAL PHARMACOLOGY (12.3)]. Antacids may be used concomitantly with esomeprazole magnesium delayed-release capsules. Take a missed dose as soon as possible. If it is almost time for the next dose, skip the missed dose and take the next dose at the regular scheduled time. Do not take 2 doses at the same time. Esomeprazole Magnesium Delayed-Release Capsules Administer esomeprazole magnesium delayed-release capsules orally or via a nasogastric tube, as described below. Oral Administration Swallow esomeprazole magnesium delayed-release capsules whole; do not chew or crush the capsules. For patients who have difficulty swallowing capsules, esomeprazole magnesium delayed-release capsules can be opened, and the contents sprinkled on applesauce. Use with other foods has not been evaluated and is not recommended. Add one tablespoon of applesauce to an empty bowl. The applesauce used should not be hot and should be soft enough to be swallowed without chewing. Open the esomeprazole magnesium delayed-release capsule and carefully empty the granules inside the capsule onto the applesauce. Mix the granules with the applesauce. Administer the mixture immediately. Do not chew or crush the granules Discard any remaining mixture. Do not store the mixture for future use. Administration via Nasogastric Tube Open the esomeprazole magnesium delayed-release capsule and empty the granules into a 60 mL catheter-tipped syringe. Mix the granules with 50 mL of water. Replace the plunger and shake the catheter-tipped syringe vigorously for 15 seconds. Hold the catheter-tipped syringe with the tip up and check for any granules remaining in the tip. Attach the catheter-tipped syringe to a nasogastric tube and deliver the contents of the syringe through the nasogastric tube into the stomach. After administering the granules, flush the nasogastric tube with additional water. Use the mixture immediately after preparation. Do not administer the granules if they have dissolved or disintegrated.

Esomeprazole magnesium delayed-release capsules are contraindicated in patients with known hypersensitivity to substituted benzimidazoles or to any component of the formulation. Hypersensitivity reactions may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, acute tubulointerstitial nephritis, and urticaria [see WARNINGS AND PRECAUTIONS (5.2), ADVERSE REACTIONS (6)]. For information about contraindications of antibacterial agents (clarithromycin and amoxicillin) indicated in combination with esomeprazole magnesium delayed-release capsules, refer to the CONTRAINDICATIONS section of their package inserts.

The following serious adverse reactions are described below and elsewhere in labeling: Acute Tubulointerstitial Nephritis [see WARNINGS AND PRECAUTIONS (5.2)] Clostridium difficile-Associated Diarrhea [see WARNINGS AND PRECAUTIONS (5.3)] Bone Fracture [see WARNINGS AND PRECAUTIONS (5.4)] Cutaneous and Systemic Lupus Erythematosus [see WARNINGS AND PRECAUTIONS (5.5)] Cyanocobalamin (Vitamin B-12) Deficiency [see WARNINGS AND PRECAUTIONS (5.7)] Hypomagnesemia [see WARNINGS AND PRECAUTIONS (5.8)] Fundic Gland Polyps [see WARNINGS AND PRECAUTIONS (5.12)] 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 esomeprazole magnesium delayed-release capsules 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 to 12 months. In general, esomeprazole magnesium delayed-release capsules were 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 esomeprazole magnesium delayed-release capsules 20 mg, 2,434 patients on esomeprazole magnesium delayed-release capsules 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 esomeprazole magnesium delayed-release capsules or omeprazole. Additional adverse reactions that were reported as possibly or probably related to esomeprazole magnesium delayed-release capsules 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 esomeprazole magnesium delayed-release capsules, 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 esomeprazole magnesium delayed-release capsules were diarrhea (4.3%), headache (3.8%), and abdominal pain (3.8%). Pediatrics The safety of esomeprazole magnesium delayed-release capsules 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%). Combination Treatment with Amoxicillin and Clarithromycin In clinical trials using combination therapy with esomeprazole magnesium delayed-release capsules 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 esomeprazole magnesium delayed-release capsules, 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 esomeprazole magnesium delayed-release capsules 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 esomeprazole magnesium delayed-release capsules 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 esomeprazole magnesium delayed-release capsules. 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; microscopic colitis; fundic gland polyps; Hepatobiliary: hepatic failure, hepatitis with or without jaundice; Immune System: anaphylactic reaction/shock; systemic lupus erythematosus; Infections and Infestations: GI candidiasis; Clostridium difficile-associated diarrhea; Metabolism and nutritional disorders: hypomagnesemia, with or without hypocalcemia and/or hypokalemia; 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), cutaneous lupus erythematosus.

Tables 3 and 4 include drugs with clinically important drug interactions and interaction with diagnostics when administered concomitantly with esomeprazole and instructions for preventing or managing them. Consult the labeling of concomitantly used drugs to obtain further information about interactions with PPIs. Table 3: Clinically Relevant Interactions Affecting Drugs Co-Administered with Esomeprazole and Interaction with Diagnostics Antiretrovirals Clinical Impact: The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. Decreased exposure of some antiretroviral drugs (e.g., rilpivirine atazanavir, and nelfinavir) when used concomitantly with esomeprazole may reduce antiviral effect and promote the development of drug resistance [se e CLINICAL PHARMACOLOGY (12.3)]. Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with esomeprazole may increase toxicity [see CLINICAL PHARMACOLOGY (12.3)]. There are other antiretroviral drugs which do not result in clinically relevant interactions with esomeprazole. Intervention: Rilpivirine-containing products: Concomitant use with esomeprazole magnesium delayed-release capsules are contraindicated [see CONTRAINDICATIONS (4)]. Atazanavir: See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with esomeprazole magnesium delayed-release capsules. See prescribing information for nelfinavir. Saquinavir: See the prescribing information for saquinavir for monitoring of potential saquinavir-related toxicities. Other antiretrovirals: See prescribing information for specific antiretroviral drugs Warfarin Clinical Impact: Increased INR and prothrombin time in patients receiving PPIs, including esomeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Intervention: Monitor INR and prothrombin time and adjust the dose of warfarin, if needed, to maintain the target INR range. Methotrexate Clinical Impact: Concomitant use of esomeprazole with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see WARNINGS AND PRECAUTIONS (5.11)]. Intervention: A temporary withdrawal of esomeprazole magnesium delayed-release capsules may be considered in some patients receiving high-dose methotrexate. 2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol) Clopidogrel Clinical Impact: Concomitant use of esomeprazole 40 mg resulted in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see CLINICAL PHARMACOLOGY (12.3)]. There are no adequate combination studies of a lower dose of esomeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel. Intervention: Avoid concomitant use with esomeprazole magnesium delayed-release capsules Consider use of alternative anti-platelet therapy [see WARNINGS AND PRECAUTIONS (5.6)]. Citalopram Clinical Impact: Increased exposure of citalopram leading to an increased risk of QT prolongation [see CLINICAL PHARMACOLOGY (12.3)]. Intervention: Limit the dose of citalopram to a maximum of 20 mg per day. See prescribing information for citalopram. Cilostazol Clinical Impact: Increased exposure of cilostazol and one of its active metabolites (3,4-dihydro-cilostazol) [see CLINICAL PHARMACOLOGY (12.3)]. Intervention: Consider reducing the dose of cilostazol to 50 mg twice daily. See prescribing information for cilostazol. Digoxin Clinical Impact: Potential for increased exposure of digoxin [see CLINICAL PHARMACOLOGY (12.3)]. Intervention: Monitor digoxin concentrations and adjust the dose, if needed, to maintain therapeutic drug concentrations. See prescribing information for digoxin. Combination Therapy with Clarithromycin and Amoxicillin Clinical Impact: Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions. Intervention: See Contraindications, Warnings and Precautions in prescribing information for clarithromycin. See Drug Interactions in prescribing information for amoxicillin. Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole) Clinical Impact: Esomeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity Intervention: Mycophenolate mofetil (MMF): Co-administration of omeprazole, of which esomeprazole is an enantiomer, in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving esomeprazole magnesium delayed-release capsules and MMF. Use esomeprazole magnesium delayed-release capsules with caution in transplant patients receiving MMF [see CLINICAL PHARMACOLOGY (12.3)]. See the prescribing information for other drugs dependent on gastric pH for absorption. Tacrolimus Clinical Impact: Potentially increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19. Intervention: Monitor tacrolimus whole blood concentrations and consider reducing the dose, if needed, to maintain therapeutic drug concentrations. See prescribing information for tacrolimus. Interactions with Investigations of Neuroendocrine Tumors Clinical Impact: Serum chromogranin A (CgA) levels increase secondary to PPI-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors [see WARNINGS AND PRECAUTIONS (5.10), CLINICAL PHARMACOLOGY (12.2)]. Intervention: Discontinue esomeprazole magnesium delayed-release capsules at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g. for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary. Interaction with Secretin Stimulation Test Clinical Impact: Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma. Intervention: Discontinue esomeprazole magnesium delayed-release capsules 4 weeks prior to testing [see CLINICAL PHARMACOLOGY (12.2)] False Positive Urine Tests for THC Clinical Impact: There have been reports of false positive urine screening test for tetrahydrocannabinol (THC) in patients receiving PPIs. Intervention: An alternative confirmatory method should be considered to verify positive results. Table 4: Clinically Relevant Interactions Affecting Esomeprazole When Co-Administered with Other Drugs CYP2C19 or CYP3A4 Inducers Clinical Impact: Decreased exposure of esomeprazole when used concomitantly with strong inducers [see CLINICAL PHARMACOLOGY (12.3)]. Intervention: St. John’s Wort, rifampin: Avoid concomitant use with [see WARNINGS AND PRECAUTIONS (5.9)]. Ritonavir-containing products: see prescribing information for specific drugs Voriconazole Clinical Impact: Increased exposure of esomeprazole [see CLINICAL PHARMACOLOGY (12.3)]. Intervention: Dose adjustment of esomeprazole magnesium delayed-release capsules is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses, dosage adjustment may be considered. See prescribing information for voriconazole.