DEXLANSOPRAZOLE Drug Interactions: What You Need to Know

INTERACTIONS Tables 3 and 4 include drugs with clinically important drug interactions and interaction with diagnostics when administered concomitantly with dexlansoprazole delayed-release capsules 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 Dexlansoprazole Delayed-Release Capsules and Interactions 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 dexlansoprazole may reduce antiviral effect and promote the development of drug resistance . Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with dexlansoprazole may increase toxicity of the antiretroviral drugs. There are other antiretroviral drugs which do not result in clinically relevant interactions with dexlansoprazole. Intervention: Rilpivirine-containing products : Concomitant use with dexlansoprazole delayed-release capsules is contraindicated [see Contraindications (4) ] . See prescribing information. Atazanavir : See prescribing information for atazanavir for dosing information. Nelfinavir : Avoid concomitant use with dexlansoprazole delayed-release capsules. See prescribing information for nelfinavir. Saquinavir : See the prescribing information for saquinavir and monitor for potential saquinavir toxicities. Other antiretrovirals : See prescribing information.

Warfarin Clinical

Impact: Increased INR and prothrombin time in patients receiving PPIs and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Intervention: Monitor INR and prothrombin time. Dose adjustment of warfarin may be needed to maintain target INR range. See prescribing information for warfarin.

Methotrexate Clinical

Impact: Concomitant use of PPIs 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 (5.10) ] . Intervention: A temporary withdrawal of dexlansoprazole delayed-release capsules may be considered in some patients receiving high-dose methotrexate.

Digoxin Clinical

Impact: Potential for increased exposure of digoxin. Intervention: Monitor digoxin concentrations. Dose adjustment of digoxin may be needed to maintain therapeutic drug concentrations. See prescribing information for digoxin.

Drugs

Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)

Clinical

Impact: Dexlansoprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity. Intervention: Mycophenolate mofetil (MMF): Coadministration of PPIs in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving dexlansoprazole delayed-release capsules and MMF. Use dexlansoprazole delayed-release capsules with caution in transplant patients receiving MMF. 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 trough concentrations. Dose adjustment of tacrolimus may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus. Interactions with Investigations of Neuroendocrine Tumors Clinical Impact: 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 (5.9) , Clinical Pharmacology (12.2) ] . Intervention: Temporarily stop dexlansoprazole delayed-release capsules treatment 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: Temporarily stop dexlansoprazole delayed-release capsules treatment at least 30 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology (12.2) ] .

False Positive Urine

Tests for THC Clinical Impact: There have been reports of false positive urine screening tests 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 Dexlansoprazole

Delayed-Release Capsules When Co-Administered with Other Drugs and Substances CYP2C19 or CYP3A4 Inducers Clinical Impact: Decreased exposure of dexlansoprazole when used concomitantly with strong inducers [see Clinical Pharmacology (12.3) ] . Intervention: St. John's Wort, rifampin : Avoid concomitant use with dexlansoprazole delayed-release capsules. Ritonavir-containing products : See prescribing information. CYP2C19 or CYP3A4 Inhibitors Clinical Impact: Increased exposure of dexlansoprazole is expected when used concomitantly with strong inhibitors [see Clinical Pharmacology (12.3) ] . Intervention: Voriconazole : See prescribing information. See full prescribing information for a list of clinically important drug interactions. ( 7 )

4 CONTRAINDICATIONS

• Dexlansoprazole delayed-release capsules are contraindicated in patients with known hypersensitivity to any component of the formulation [see Description (11)] . Hypersensitivity reactions may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, acute tubulointerstitial nephritis and urticaria [see Warnings and Precautions (5.2), Adverse Reactions (6)].
• PPIs, including dexlansoprazole delayed-release capsules, are contraindicated with rilpivirine-containing products [see Drug Interactions (7)].
• Patients with known hypersensitivity to any component of the formulation. ( 4 )
• Patients receiving rilpivirine-containing products. ( 4 , 7 )

AND PRECAUTIONS Dexlansoprazole Delayed-Release Capsules, 60 mg contain FD&C Yellow # 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow # 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.

Gastric

Malignancy : In adults, symptomatic response with dexlansoprazole does not preclude the presence of gastric malignancy. Consider additional follow-up and diagnostic testing. ( 5.1 )

Acute Tubulointerstitial

Nephritis: Discontinue treatment and evaluate patients. ( 5.2 ) Clostridium difficile- Associated Diarrhea : PPI therapy may be associated with increased risk. ( 5.3 )

Bone

Fracture : Long-term and multiple daily dose PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist or spine. ( 5.4 )

Severe Cutaneous Adverse

Reactions : Discontinue at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation. ( 5.5 ) Cutaneous and Systemic Lupus Erythematosus : Mostly cutaneous; new onset or exacerbation of existing disease; discontinue dexlansoprazole delayed-release capsules and refer to specialist for evaluation. ( 5.6 ) Cyanocobalamin (Vitamin B12) Deficiency : Daily long-term use (e.g., longer than 3 years) may lead to malabsorption or a deficiency of cyanocobalamin. ( 5.7 ) Hypomagnesemia and Mineral Metabolism : Reported rarely with prolonged treatment with PPIs. ( 5.8 ) Interactions with Investigations for Neuroendocrine Tumors: Increases in intragastric pH may result in hypergastrinemia and enterochromaffin-like cell hyperplasia and increased chromogranin A levels which may interfere with diagnostic investigations for neuroendocrine tumors. ( 5.9 , 7 ) Interaction with Methotrexate : Concomitant use with PPIs may elevate and/or prolong serum concentrations of methotrexate and/or its metabolite, possibly leading to toxicity. With high-dose methotrexate administration, consider a temporary withdrawal of dexlansoprazole delayed-release capsules. ( 5.10 , 7 )

Fundic Gland

Polyps : Risk increases with long-term use, especially beyond 1 year. Use the shortest duration of therapy. ( 5.11 ) Risk of Heart Valve Thickening in Pediatric Patients Less than Two Years of Age : Dexlansoprazole is not recommended in pediatric patients less than 2 years of age. ( 5.12 , 8.4 )

5.1 Presence of Gastric Malignancy In adults, symptomatic response to therapy with dexlansoprazole does not preclude the presence of gastric malignancy. Consider additional follow-up and diagnostic testing in adult patients who have a suboptimal response or an early symptomatic relapse after completing treatment with a PPI. In older patients, also consider an endoscopy.

5.2 Acute Tubulointerstitial Nephritis Acute tubulointerstitial nephritis (TIN) has been observed in patients taking PPIs and may occur at any point during PPI therapy. Patients may present with varying signs and symptoms from symptomatic hypersensitivity reactions to non-specific symptoms of decreased renal function (e.g., malaise, nausea, anorexia). In reported case series, some patients were diagnosed on biopsy and in the absence of extra-renal manifestations (e.g., fever, rash or arthralgia). Discontinue dexlansoprazole and evaluate patients with suspected acute TIN <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> .

5.3 Clostridium difficile -Associated Diarrhea Published observational studies suggest that PPI therapy like dexlansoprazole may be associated with an increased risk of Clostridium difficile- associated diarrhea, especially in hospitalized patients. This diagnosis should be considered for diarrhea that does not improve <span class="opacity-50 text-xs">[see Adverse Reactions (6.2) ]</span>. Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.

5.4 Bone Fracture Several published observational studies suggest that PPI 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 conditions being treated. Patients at risk for osteoporosis-related fractures should be managed according to established treatment guidelines <span class="opacity-50 text-xs">[see Dosage and Administration (2) , Adverse Reactions (6.2) ]</span>.

5.5 Severe Cutaneous Adverse Reactions Severe cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported in association with the use of PPIs <span class="opacity-50 text-xs">[see Adverse Reactions (6.2) ]</span> . Discontinue dexlansoprazole delayed-release capsules at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation.

5.6 Cutaneous and Systemic Lupus Erythematosus Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) have been reported in patients taking PPIs. These events have occurred as both new onset and an exacerbation of existing autoimmune disease. The majority of PPI-induced lupus erythematosus cases were CLE. The most common form of CLE reported in patients treated with PPIs was subacute CLE (SCLE) and occurred within weeks to years after continuous drug therapy in patients ranging from infants to the elderly. Generally, histological findings were observed without organ involvement. Systemic lupus erythematosus (SLE) is less commonly reported than CLE in patients receiving PPIs. PPI-associated SLE is usually milder than nondrug induced SLE. Onset of SLE typically occurred within days to years after initiating treatment primarily in patients ranging from young adults to the elderly. The majority of patients presented with rash; however, arthralgia and cytopenia were also reported. Avoid administration of PPIs for longer than medically indicated. If signs or symptoms consistent with CLE or SLE are noted in patients receiving dexlansoprazole delayed-release capsules, discontinue the drug and refer the patient to the appropriate specialist for evaluation. Most patients improve with discontinuation of the PPI alone in 4 to 12 weeks. Serological testing (e.g., ANA) may be positive and elevated serological test results may take longer to resolve than clinical manifestations.

5.7 Cyanocobalamin (Vitamin B12)

Deficiency

Daily treatment with any acid-suppressing medications over a long period of time (e.g., longer than three years) may lead to malabsorption of cyanocobalamin (Vitamin B12) caused by hypo- or achlorhydria. Rare reports of cyanocobalamin deficiency occurring with acid-suppressing therapy have been reported in the literature. This diagnosis should be considered if clinical symptoms consistent with cyanocobalamin deficiency are observed in patients treated with dexlansoprazole.

5.8 Hypomagnesemia and Mineral Metabolism Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias, and seizures. Hypomagnesemia may lead to hypocalcemia and/or hypokalemia and may exacerbate underlying hypocalcemia in at-risk patients. In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuation of the PPI. For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), health care professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically <span class="opacity-50 text-xs">[see Adverse Reactions (6.2) ]</span> . Consider monitoring magnesium and calcium levels prior to initiation of dexlansoprazole delayed-release capsules and periodically while on treatment in patients with a preexisting risk of hypocalcemia (e.g., hypoparathyroidism). Supplement with magnesium and/or calcium as necessary. If hypocalcemia is refractory to treatment, consider discontinuing the PPI.

5.9 Interactions with Investigations for Neuroendocrine Tumors Serum chromogranin A (CgA) levels increase secondary to drug-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors. Healthcare providers should temporarily stop dexlansoprazole treatment 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 <span class="opacity-50 text-xs">[see Drug Interactions (7) , Clinical Pharmacology (12.2) ]</span>.

5.10 Interaction with Methotrexate Literature suggests that concomitant use of PPIs with methotrexate (primarily at high dose) may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities. In high-dose methotrexate administration, a temporary withdrawal of the PPI may be considered in some patients <span class="opacity-50 text-xs">[see Drug Interactions (7) ]</span>.

5.11 Fundic Gland Polyps PPI use is associated with an increased risk of fundic gland polyps that increases with long-term use, especially beyond one year. Most PPI users who developed fundic gland polyps were asymptomatic and fundic gland polyps were identified incidentally on endoscopy. Use the shortest duration of PPI therapy appropriate to the condition being treated.

5.12 Risk of Heart Valve Thickening in Pediatric Patients Less Than Two Years of Age Dexlansoprazole is not recommended in pediatric patients less than two years of age. Nonclinical studies in juvenile rats with lansoprazole have demonstrated an adverse effect of heart valve thickening. Dexlansoprazole is the R-enantiomer of lansoprazole <span class="opacity-50 text-xs">[see Use in Specific Populations (8.4) ]</span>.