PRESCRIBING INFORMATION
1 NAME OF THE MEDICINAL PRODUCTDEXILANT (dexlansoprazole) modified-release capsules, for oral use. DEXILANT isavailable as capsules in 30 mg and 60 mg strengths.
2 THERAPEUTIC INDICATIONS
Dexilant 30 mg is indicated in adults and in adolescents aged 12 to 17 years for thefollowing:• Maintenance of healed erosive reflux oesophagitis and maintenance of relief ofheartburn• Short-term treatment of heartburn and acid regurgitation associated withsymptomatic non-erosive gastro-oesophageal reflux disease (GORD).
Dexilant 60 mg is indicated in adults and in adolescents aged 12 to 17 years for thefollowing:• Treatment of erosive reflux oesophagitis
3

DOSAGE AND ADMINISTRATION

3.1 Recommended Dosage in Adults and adolescents aged 12 to 17 years
DEXILANT is available as capsules in 30 mg and 60 mg strengths for adult andadolescents aged 12 to 17 years use. Directions for use in each indication aresummarized in Table 1.
Table 1. Recommended DEXILANT Capsules dosage regimen byindication in Adults and adolescents aged 12 to 17 years
Indication

Dosage of DEXILANT
CapsulesDuration

Treatment oferosive reflux
oesophagitis

One 60 mg capsule once
daily.

Up to 8 weeks.

Maintenance ofhealed erosive
refluxoesophagitis
andmaintenance ofrelief ofheartburnOne 30 mg capsule once
daily.

Symptomatic
non-erosive
gastrooesophageal
reflux disease(GORD)

One 30 mg capsule once
daily.

Controlled studies did notextend beyond 6 months inadults and 16 weeks inpatients 12 to 17 years ofage.

4 weeks.

3.2 Dosage Adjustment in Patients with Hepatic Impairment
For the treatment of erosive reflux oesophagitis
For patients with moderate hepatic impairment (Child-Pugh Class B), therecommended dosage is 30 mg DEXILANT once daily for up to eight weeks.
DEXILANT is not recommended in patients with severe hepatic impairment (ChildPugh Class C) [see Use in Specific Populations (9.5)].
3.3 Important Administration Information• Take without regard to food.
••Missed doses: If a dose is missed, administer as soon as possible. However, if
the next scheduled dose is due, do not take the missed dose, and take the next
dose on time. Do not take two doses at one time to make up for a missed dose.
• Swallow whole; do not chew.
• For patients who have trouble swallowing capsules, DEXILANT capsules canbe opened and administered with applesauce as follows:
1. Place one tablespoonful of applesauce into a clean container.
2. Open capsule.
3. Sprinkle intact granules on applesauce.
4. Swallow applesauce and granules immediately. Do not chew granules. Do
not save the applesauce and granules for later use.
Alternatively, the capsule can be administered with water via oral syringe or
nasogastric (NG) tube.

Administration with Water in an Oral Syringe
1. Open the capsule and empty the granules into a clean container with 20 mL
of water.
2. Withdraw the entire mixture into a syringe.
3. Gently swirl the syringe in order to keep granules from settling.
4. Administer the mixture immediately into the mouth. Do not save the waterand granule mixture for later use.
5. Refill the syringe with 10 mL of water, swirl gently, and administer.
6. Refill the syringe again with 10 mL of water, swirl gently, and administer.
Administration with Water via a NG Tube (≥16 French)
1. Open the capsule and empty the granules into a clean container with 20 mL
of water.
2. Withdraw the entire mixture into a catheter-tip syringe.
3. Swirl the catheter-tip syringe gently in order to keep the granules fromsettling, and immediately inject the mixture through the NG tube into thestomach. Do not save the water and granule mixture for later use.
4. Refill the catheter-tip syringe with 10 mL of water, swirl gently, and flush
the tube.
5. Refill the catheter-tip syringe again with 10 mL of water, swirl gently, andadminister.

4

DOSAGE FORMS AND STRENGTHSDEXILANT modified-release capsules• 30 mg: strength is an opaque, blue and gray capsule imprinted with “TAP” and“30”.
• 60 mg: strength is an opaque, blue capsule imprinted with “TAP” and “60”.
5
•

•

6

CONTRAINDICATIONSDEXILANT is contraindicated in patients with known hypersensitivity to any
component of the formulation [see Description (11)]. Hypersensitivity reactions
may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, acutetubulointerstitial nephritis and urticaria [see Warnings and Precautions (6.2),
Adverse Reactions (7)]PPIs, including DEXILANT, are contraindicated with rilpivirine-containing
products [see Drug Interactions (8)].
WARNINGS AND PRECAUTIONS

6.1 Presence of Gastric Malignancy
In adults, symptomatic response to therapy with DEXILANT does not preclude thepresence of gastric malignancy. Consider additional follow-up and diagnostic testingin 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.
6.2 Acute Tubulointerstitial Nephritis
Acute tubulointerstitial nephritis (TIN) has been observed in patients taking PPIs andmay 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 caseseries, some patients were diagnosed on biopsy and in the absence of extra-renalmanifestations (e.g., fever, rash or arthralgia).
Discontinue DEXILANT and evaluate patients with suspected acute TIN [seeContraindications (5)].
6.3 Clostridium difficile - Associated Diarrhea
Published observational studies suggest that PPI therapy like DEXILANT 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 [see Adverse Reactions (7.2)].
Patients should use the lowest dose and shortest duration of PPI therapy appropriate
to the condition being treated.
6.4 Bone Fracture
Several published observational studies suggest that PPI therapy may be associatedwith 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 thelowest 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 [see Dosage and Administration (3),Adverse Reactions (7.2)].

6.5 Severe Cutaneous Adverse Reactions
Severe cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS) andtoxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic
symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) havebeen reported in association with the use of PPIs [see Adverse Reactions (7.2)].
Discontinue DEXILANT at the first signs or symptoms of severe cutaneous adverse
reactions or other signs of hypersensitivity and consider further evaluation.
6.6 Cutaneous and Systemic Lupus Erythematosus
Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) havebeen 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 inpatients ranging from infants to the elderly. Generally, histological findings wereobserved without organ involvement.
Systemic lupus erythematosus (SLE) is less commonly reported than CLE in patients
receiving PPIs. PPI associated SLE is usually milder than non-drug 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 ofpatients 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 DEXILANT,
discontinue the drug and refer the patient to the appropriate specialist for evaluation.
Most patients improve with discontinuation of the PPI alone in four to 12 weeks.
Serological testing (e.g., ANA) may be positive and elevated serological test results
may take longer to resolve than clinical manifestations.
6.7 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 (VitaminB12) caused by hypo- or achlorhydria. Rare reports of cyanocobalamin deficiency
occurring with acid-suppressing therapy have been reported in the literature. Thisdiagnosis should be considered if clinical symptoms consistent with cyanocobalamin
deficiency are observed in patients treated with DEXILANT.
6.8 Hypomagnesemia and Mineral Metabolism
Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely inpatients treated with PPIs for at least three months, in most cases after a year oftherapy. 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 withmedications 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 [see Adverse Reactions (7.2)].
Consider monitoring magnesium and calcium levels prior to initiation of
DEXILANT 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.
6.9 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 indiagnostic investigations for neuroendocrine tumors. Healthcare providers should
temporarily stop dexlansoprazole treatment at least 14 days before assessing CgAlevels 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 fortesting, as reference ranges between tests may vary [see Drug Interactions (8),Clinical Pharmacology (12.2)].
6.10 Interaction with Methotrexate
Literature suggests that concomitant use of PPIs with methotrexate (primarily at highdose) 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 [see Drug
Interactions (8)].
6.11 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.
7

ADVERSE REACTIONS
The following serious adverse reactions are described below and elsewhere inlabeling:• Acute Tubulointerstitial Nephritis [see Warnings and Precautions (6.2)]• Clostridium difficile - Associated Diarrhea [see Warnings and Precautions(6.3)]• Bone Fracture [see Warnings and Precautions (6.4)]• Severe Cutaneous Adverse Reactions [see Warnings and Precautions (6.5)]•Cutaneous and Systemic Lupus Erythematosus [see Warnings andPrecautions (6.6)]•Cyanocobalamin (Vitamin B12) Deficiency [see Warnings and Precautions(6.7)]• Hypomagnesemia and Mineral Metabolism [see Warnings and Precautions(6.8)]• Fundic Gland Polyps [see Warnings and Precautions (6.11)]

7.1 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 torates in the clinical trials of another drug and may not reflect the rates observed inpractice.
Adults
The safety of DEXILANT was evaluated in 4548 adult patients in controlled andsingle-arm clinical trials, including 863 patients treated for at least six months and203 patients treated for one year. Patients ranged in age from 18 to 90 years (medianage 48 years), with 54% female, 85% Caucasian, 8% Black, 4% Asian, and 3% Other
races. Six randomized controlled clinical trials were conducted for the treatment oferosive reflux oesophagitis, maintenance of healed erosive reflux oesophagitis, andsymptomatic GORD, which included 896 patients on placebo, 455 patients on
DEXILANT 30 mg, 2218 patients on DEXILANT 60 mg, and 1363 patients on
lansoprazole 30 mg once daily.
Common Adverse Reactions
The most common adverse reactions (≥2%) that occurred at a higher incidence for
DEXILANT than placebo in the controlled studies are presented in Table 2.
Table 2. Common Adverse Reactions in Controlled Studies in Adults(N=896)%

DEXILANT
30 mg(N=455)%

DEXILANT
60 mg(N=2218)%

DEXILANT
Total(N=2621)%

Lansoprazole30 mg(N=1363)%

Diarrhea

2.9

5.1

4.7

4.8

3.2

Abdominal
Pain

3.5

3.5

4.0

4.0

2.6

Nausea

2.6

3.3

2.8

2.9

1.8

Upper
Respiratory Tract
Infection

0.8

2.9

1.7

1.9

0.8

Vomiting

0.8

2.2

1.4

1.6

1.1

Flatulence

0.6

2.6

1.4

1.6

1.2

Placebo
AdverseReaction

Adverse Reactions Resulting in Discontinuation
In controlled clinical studies, the most common adverse reaction leading todiscontinuation from DEXILANT was diarrhea (0.7%).
Less Common Adverse Reactions
Other adverse reactions that were reported in controlled studies at an incidence of lessthan 2% are listed below by body system:
Blood and Lymphatic System Disorders: anemia, lymphadenopathy
Cardiac Disorders: angina, arrhythmia, bradycardia, chest pain, edema, myocardial
infarction, palpitation, tachycardia
Ear and Labyrinth Disorders: ear pain, tinnitus, vertigo

Endocrine Disorders: goiter
Eye Disorders: eye irritation, eye swelling
Gastrointestinal Disorders: abdominal discomfort, abdominal tenderness, abnormal
feces, anal discomfort, Barrett’s esophagus, bezoar, bowel sounds abnormal, breathodor, colitis microscopic, colonic polyp, constipation, dry mouth, duodenitis,
dyspepsia, dysphagia, enteritis, eructation, oesophagitis, gastric polyp, gastritis,
gastroenteritis, gastrointestinal disorders, gastrointestinal hypermotility disorders,
GORD, GI ulcers and perforation, hematemesis, hematochezia, hemorrhoids,
impaired gastric emptying, irritable bowel syndrome, mucus stools, oral mucosal
blistering, painful defecation, proctitis, paresthesia oral, rectal hemorrhage, retching
General Disorders and Administration Site Conditions: adverse drug reaction,asthenia, chest pain, chills, feeling abnormal, inflammation, mucosal inflammation,
nodule, pain, pyrexia
Hepatobiliary Disorders: biliary colic, cholelithiasis, hepatomegaly
Immune System Disorders: hypersensitivity
Infections and Infestations: candida infections, influenza, nasopharyngitis, oral
herpes, pharyngitis, sinusitis, viral infection, vulvo-vaginal infection
Injury, Poisoning and Procedural Complications: falls, fractures, joint sprains,
overdose, procedural pain, sunburnLaboratory Investigations: ALP increased, ALT increased, AST increased, bilirubindecreased/increased, blood creatinine increased, blood gastrin increased, blood
glucose increased, blood potassium increased, liver function test abnormal, platelet
count decreased, total protein increased, weight increase
Metabolism and Nutrition Disorders: appetite changes, hypercalcemia, hypokalemia
Musculoskeletal and Connective Tissue Disorders: arthralgia, arthritis, muscle
cramps, musculoskeletal pain, myalgia
Nervous System Disorders: altered taste, convulsion, dizziness, headaches, migraine,
memory impairment, paresthesia, psychomotor hyperactivity, tremor, trigeminal
neuralgia
Psychiatric Disorders: abnormal dreams, anxiety, depression, insomnia, libido
changes
Renal and Urinary Disorders: dysuria, micturition urgency
Reproductive System and Breast Disorders: dysmenorrhea, dyspareunia, menorrhagia,
menstrual disorder
Respiratory, Thoracic and Mediastinal Disorders: aspiration, asthma, bronchitis,
cough, dyspnea, hiccups, hyperventilation, respiratory tract congestion, sore throat
Skin and Subcutaneous Tissue Disorders: acne, dermatitis, erythema, pruritus, rash,skin lesion, urticaria
Vascular Disorders: deep vein thrombosis, hot flush, hypertension
Additional adverse reactions that were reported in a long-term single-arm trial andwere considered related to DEXILANT by the treating physician included:
anaphylaxis, auditory hallucination, B-cell lymphoma, bursitis, central obesity,cholecystitis acute, dehydration, diabetes mellitus, dysphonia, epistaxis, folliculitis,
gout, herpes zoster, hyperlipidemia, hypothyroidism, increased neutrophils, MCHC
decrease, neutropenia, rectal tenesmus, restless legs syndrome, somnolence, tonsillitis.

Pediatrics
The safety of DEXILANT was evaluated in controlled and single-arm clinical trials
including 166 pediatric patients, 12 to 17 years of age for the treatment ofsymptomatic non-erosive GORD, treatment of erosive reflux oesophagitis,
maintenance of healed erosive reflux oesophagitis and maintenance of relief ofheartburn [see Clinical Studies (14.4)].
The adverse reaction profile was similar to that of adults. The most common adverse
reactions that occurred in ≥ 5% of patients were headache, abdominal pain, diarrhea,
nasopharyngitis and oropharyngeal pain.
Other Adverse Reactions
See the full prescribing information for lansoprazole for other adverse reactions notobserved with DEXILANT.
7.2 Postmarketing Experience
The following adverse reactions have been identified during post-approval use of
DEXILANT. 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.
Blood and Lymphatic System Disorders: autoimmune hemolytic anemia, idiopathic
thrombocytopenic purpura
Ear and Labyrinth Disorders: deafness
Eye Disorders: blurred vision
Gastrointestinal Disorders: oral edema, pancreatitis, fundic gland polyps
General Disorders and Administration Site Conditions: facial edema
Hepatobiliary Disorders: drug-induced hepatitis
Immune System Disorders: anaphylactic shock (requiring emergency intervention),
exfoliative dermatitis, Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis(TEN) (some fatal), DRESS, AGEP, erythema multiforme.
Infections and Infestations: Clostridium difficile associated diarrhea
Metabolism and Nutrition Disorders: hypomagnesemia, hypocalcemia, hypokalemia,
hyponatremia
Musculoskeletal System Disorders: bone fracture
Nervous System Disorders: cerebrovascular accident, transient ischemic attack
Renal and Genitourinary Disorders: acute renal failure, erectile dysfunction.
Respiratory, Thoracic and Mediastinal Disorders: pharyngeal edema, throat tightness
Skin and Subcutaneous Tissue Disorders: generalized rash, leukocytoclastic vasculitis
Reporting suspected adverse reactions after authorization of the medicinal product isimportant. It allows continued monitoring of the benefit/risk balance of the medicinal
product.
Any suspected adverse events should be reported to the Ministry of Health according
to the National Regulation by using an online form
https://sideeffects.health.gov.il

8
DRUG INTERACTIONS
Tables 3 and 4 include drugs with clinically important drug interactions andinteraction with diagnostics when administered concomitantly with DEXILANT 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 DEXILANT
and Interactions with Diagnostics
Antiretrovirals
Clinical
Impact:Intervention:

The effect of PPIs on antiretroviral drugs is variable. The clinical importanceand the mechanisms behind these interactions are not always known.
• Decreased exposure of some antiretroviral drugs (e.g., rilpivirine,
atazanavir, and nelfinavir) when used concomitantly withdexlansoprazole may reduce antiviral effect and promote thedevelopment of drug resistance.
•

Increased exposure of other antiretroviral drugs (e.g., saquinavir) whenused concomitantly with dexlansoprazole may increase toxicity of theantiretroviral drugs.

•

There are other antiretroviral drugs which do not result in clinically
relevant interactions with dexlansoprazole.

Rilpivirine-containing products: Concomitant use with DEXILANT iscontraindicated [see Contraindications (5)]. See prescribing information.
Atazanavir: See prescribing information for atazanavir for dosing information.
Nelfinavir: Avoid concomitant use with DEXILANT. 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:Intervention:

Methotrexate

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

Clinical
Impact:Intervention:

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 havebeen conducted [see Warnings and Precautions (6.10)].
A temporary withdrawal of DEXILANT may be considered in somepatients receiving high-dose methotrexate.

DigoxinClinical
Impact:Intervention:

Potential for increased exposure of digoxin.
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,
mycophenoloate mofetil, ketoconazole/itraconazole)
Clinical
Impact:Intervention:

Dexlansoprazole can reduce the absorption of other drugs due to its effect on
reducing intragastric acidity.
Mycophenolate mofetil (MMF): Co-administration of PPIs in healthy
subjects and in transplant patients receiving MMF has been reported toreduce 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 DEXILANT and MMF. Use
DEXILANT 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.

Monitor tacrolimus whole blood trough concentrations. Dose adjustment
Intervention: of tacrolimus may be needed to maintain therapeutic drugconcentrations. 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(6.9), Clinical Pharmacology (12.2)].

Temporarily stop DEXILANT treatment at least 14 days before assessing CgAIntervention: 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.

Temporarily stop DEXILANT treatment at least 30 days before assessing toIntervention: 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 fortetrahydrocannabinol (THC) in patients receiving PPIs.

Intervention: An alternative confirmatory method should be considered to verify positive
results.

Table 4. Clinically Relevant Interactions Affecting DEXILANT When Co-administered with
Other Drugs and Substances
CYP2C19 or CYP3A4 Inducers
Clinical
Impact:Decreased exposure of dexlansoprazole when used concomitantly withstrong inducers [see Clinical Pharmacology (12.3)].

St. John’s Wort, rifampin: Avoid concomitant use with
Intervention: DEXILANT. Ritonavir-containing products: See prescribing
information.
CYP2C19 or CYP3A4 Inhibitors
Clinical
Impact:Increased exposure of dexlansoprazole is expected when used concomitantlywith strong inhibitors [see Clinical Pharmacology (12.3)].

Intervention: Voriconazole: See prescribing information.
9 USE IN SPECIFIC POPULATIONS
9.1 Pregnancy
Risk Summary
There are no studies with dexlansoprazole use in pregnant women to inform a drugassociated risk.
Dexlansoprazole is the R-enantiomer of lansoprazole, and published observational
studies of lansoprazole use during pregnancy did not demonstrate an association ofadverse pregnancy-related outcomes with lansoprazole (see Data).

In animal reproduction studies, oral administration of lansoprazole to rats duringorganogenesis through lactation at 1.8 times the maximum recommended humandexlansoprazole dose produced reductions in the offspring in femur weight, femur
length, crown-rump length and growth plate thickness (males only) on postnatal Day
21 (see Data). These effects were associated with reduction in body weight gain.
Advise pregnant women of the potential risk to the fetus.

The estimated background risk of major birth defects and miscarriage for theindicated population is unknown. All pregnancies have a background risk of birthdefect, loss, or other adverse outcomes. In the US general population, the estimatedbackground risk of major birth defects and miscarriage in clinically recognizedpregnancies is 2 to 4% and 15 to 20%, respectively.
Data
Human Data
Dexlansoprazole is the R-enantiomer of lansoprazole. Available data from publishedobservational studies failed to demonstrate an association of adverse pregnancyrelated outcomes and lansoprazole use. Methodological limitations of theseobservational studies cannot definitely establish or exclude any drug-associated risk
during pregnancy. In a prospective study by the European Network of Teratology
Information Services, outcomes from a group of 62 pregnant women administered
median daily doses of 30 mg of lansoprazole were compared to a control group of 868
pregnant women who did not take any PPIs. There was no difference in the rate ofmajor malformations between women exposed to PPIs and the control group,
corresponding to a Relative Risk (RR)=1.04, [95% Confidence Interval (CI) 0.254.21]. In a population-based retrospective cohort study covering all live births in
Denmark from 1996 to 2008, there was no significant increase in major birth defects
during analysis of first trimester exposure to lansoprazole in 794 live births. A metaanalysis that compared 1,530 pregnant women exposed to PPIs in at least the firsttrimester with 133,410 unexposed pregnant women showed no significant increases inrisk for congenital malformations or spontaneous abortion with exposure to PPIs (formajor malformations Odds Ratio (OR)=1.12, [95% CI 0.86-1.45] and for spontaneousabortions OR=1.29, [95% CI 0.84-1.97]).
Animal Data
An embryo-fetal development study conducted in rabbits at oral dexlansoprazole
doses up to 30 mg/kg/day (approximately nine times the maximum recommended
human dexlansoprazole dose [60 mg/day] based on body surface area) duringorganogenesis showed no effects on fetuses due to dexlansoprazole. In addition,embryo-fetal development studies performed in rats with oral lansoprazole at doses up
to 150 mg/kg/day (40 times the recommended human lansoprazole dose based on
body surface area) during organogenesis and in rabbits with oral lansoprazole at doses
up to 30 mg/kg/day (16 times the recommended human lansoprazole dose based on
body surface area) during organogenesis revealed no effects on fetuses due tolansoprazole.
A pre- and postnatal developmental toxicity study in rats with additional endpoints toevaluate bone development was performed with lansoprazole at oral doses of 10 to100 mg/kg/day (0.2 to 1.8 times the maximum recommended human dexlansoprazole
dose of 60 mg based on dexlansoprazole AUC [area under the plasma concentrationtime curve]) administered during organogenesis through lactation. Maternal effects
observed at 100 mg/kg/day (1.8 times the maximum recommended humandexlansoprazole dose of 60 mg based on dexlansoprazole AUC) included increased
gestation period, decreased body weight gain during gestation, and decreased foodconsumption. The number of stillbirths was increased at this dose, which may havebeen secondary to maternal toxicity. Body weight of pups was reduced at 100
mg/kg/day starting on postnatal Day 11. Femur weight, femur length, and crownrump length were reduced at 100 mg/kg/day on postnatal Day 21. Femur weight was
still decreased in the 100 mg/kg/day group at age 17 to 18 weeks. Growth plate
thickness was decreased in the 100 mg/kg/day males on postnatal Day 21, and wasincreased in the 30 and 100 mg/kg/day males at age 17 to 18 weeks. The effects onbone parameters were associated with reduction in body weight gain.
9.2 Lactation
Risk Summary
There is no information regarding the presence of dexlansoprazole in human milk, theeffects on the breastfed infant, or the effects on milk production. However,lansoprazole and its metabolites are present in rat milk. The developmental and healthbenefits of breastfeeding should be considered along with the mother’s clinical needfor DEXILANT and any potential adverse effects on the breastfed child from
DEXILANT or from the underlying maternal condition.
9.3 Pediatric Use
The use of DEXILANT is not recommended for the treatment of symptomatic nonerosive GORD in pediatric patients one month to less than one year of age because
lansoprazole (the racemic mixture) was not shown to be effective in a multicenter,double-blind controlled trial, and nonclinical studies with lansoprazole havedemonstrated an adverse effect of heart valve thickening and bone changes.
The safety and effectiveness of DEXILANT have not been established in pediatricpatients less than 12 years of age. DEXILANT is not recommended in pediatricpatients less than 12 years of age. Nonclinical studies in juvenile rats withlansoprazole have demonstrated an adverse effect of heart valve thickening and bonechanges at lansoprazole doses higher than the maximum recommended equivalent
human dose, as described below in Juvenile Animal Toxicity Data.
The safety and effectiveness of DEXILANT have been established in pediatricpatients 12 to 17 years of age for the healing of all grades of erosive reflux
oesophagitis, the maintenance of healed erosive reflux oesophagitis and maintenanceof relief of heartburn, and treatment of heartburn associated with symptomatic nonerosive GORD.
Use of DEXILANT in this age group is supported by evidence from adequate andwell-controlled studies of DEXILANT in adults with additional safety, efficacy andpharmacokinetic data in pediatric patients 12 to 17 years of age [see Dosage andAdministration (3.1), Adverse Reactions (7.1), Clinical Pharmacology (12.3), andClinical Studies (14.1, 14.2, 14.3, and 14.4)].
The adverse reaction profile in patients 12 to 17 years of age was similar to adults.

Juvenile Animal Toxicity Data
Heart Valve Thickening
In a juvenile rat study, adverse effects on bone growth and development and heart
valves were observed at lansoprazole doses higher than the maximum recommended
equivalent human dose.
An eight-week oral toxicity study with a four-week recovery phase was conducted injuvenile rats with lansoprazole administered from postnatal Day 7 (age equivalent toneonatal humans) through 62 (age equivalent to approximately 14 years in humans) at
doses of 40 to 500 mg/kg/day.
Heart valve thickening occurred at a lansoprazole dose of 500 mg/kg/day(approximately three to five times the expected dexlansoprazole exposure in pediatricpatients less than 12 years of age based on AUC). Heart valve thickening was notobserved at the next lower dose (250 mg/kg/day) and below. The findings trended
towards reversibility after a four-week drug-free recovery period. The relevance ofheart valve thickening in this study to pediatric patients less than 12 years of age is
unknown. These findings are not relevant for patients 12 years of age and older. No
effects on heart valves were observed in a 13-week intravenous toxicity study oflansoprazole in adolescent rats (approximately 12 years human age equivalence) at
systemic exposures similar to those achieved in the eight-week oral toxicity study injuvenile (neonatal) rats.
Bone Changes
In the eight-week oral toxicity study of lansoprazole, doses equal to or greater than
100 mg/kg/day produced delayed growth, with impairment of weight gain observed as
early as postnatal Day 10 (age equivalent to neonatal humans). At the end oftreatment, the signs of impaired growth at 100 mg/kg/day and higher included
reductions in body weight (14 to 44% compared to controls), absolute weight ofmultiple organs, femur weight, femur length and crown-rump length. Femoral growthplate thickness was reduced only in males and only at the 500 mg/kg/day dose. The
effects related to delayed growth persisted through the end of the four-week recovery
period. Longer term data were not collected.
9.4

Geriatric Use

Of the total number of patients (n=4548) in clinical studies of DEXILANT, 11% of
patients were aged 65 years and over, while 2% were 75 years and over. No overall
differences in safety or effectiveness were observed between these patients andyounger patients and other reported clinical experience has not identified significant
differences in responses between geriatric and younger patients, but greater sensitivityof some older individuals cannot be ruled out [see Clinical Pharmacology (12.3)].
9.5 Hepatic Impairment
No dosage adjustment for DEXILANT is necessary for patients with mild hepatic
impairment (Child-Pugh Class A).
In a study of adult patients with moderate hepatic impairment (Child-Pugh Class B)
who received a single dose of 60 mg DEXILANT, there was a significant increase insystemic exposure of dexlansoprazole compared to healthy subjects with normal
hepatic function [see Clinical Pharmacology (12.3)]. Therefore, for patients with

moderate hepatic impairment (Child-Pugh Class B), dosage reduction isrecommended for the treatment of erosive reflux oesophagitis [see Dosage andAdministration (3.2)].
No studies have been conducted in patients with severe hepatic impairment (ChildPugh Class C); the use of DEXILANT is not recommended for these patients [seeDosage and Administration (3.2)].
10 OVERDOSAGE
There have been no reports of significant overdose with DEXILANT. Multiple dosesof DEXILANT 120 mg and a single dose of DEXILANT 300 mg did not result indeath or other severe adverse events. However, serious adverse events of hypertension
have been reported in association with twice daily doses of DEXILANT 60 mg. Nonserious adverse reactions observed with twice daily doses of DEXILANT 60 mg
include hot flashes, contusion, oropharyngeal pain, and weight loss. Dexlansoprazole
is not expected to be removed from the circulation by hemodialysis.
In the event of over-exposure, treatment should be symptomatic and supportive.
11 DESCRIPTION
The active ingredient in DEXILANT (dexlansoprazole modified-release capsules, a
proton pump inhibitor, is (+)-2-[(R)-{[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]
methyl} sulfinyl]-1H-benzimidazole, a compound that inhibits gastric acid secretion.
Dexlansoprazole is the R-enantiomer of lansoprazole (a racemic mixture of the R- andS-enantiomers). Its empirical formula is: C16H14F3N3O2S, with a molecular weight of
369.36. Dexlansoprazole has the following chemical structure:

Dexlansoprazole is a white to nearly white crystalline powder which melts withdecomposition at 140°C. Dexlansoprazole is freely soluble in dimethylformamide,
methanol, dichloromethane, ethanol, and ethyl acetate; and soluble in acetonitrile;slightly soluble in ether; and very slightly soluble in water; and practically insoluble
in hexane.
Dexlansoprazole is stable when exposed to light. Dexlansoprazole is more stable inneutral and alkaline conditions than acidic conditions.
Dexlansoprazole is supplied for oral administration as a dual modified -releaseformulation in capsules. The capsules contain dexlansoprazole in a mixture of two
types of enteric-coated granules with different pH-dependent dissolution profiles [seeClinical Pharmacology (12.3)].
DEXILANT modified-release capsules are available in two dosage strengths: 30 and
60 mg, per capsule. Each capsule contains enteric-coated granules consisting of
dexlansoprazole (active ingredient) and the following inactive ingredients: sucrose,sugar spheres, (sucrose, corn starch),talc, methacrylic acid-methyl methacrylate
copolymer (1:2), magnesium carbonate, methacrylic acid-ethyl acrylate copolymer(1:1) dispersion 30 per cent (methacrylic acid units, ethyl acrylate units, sodium
dodecylsulfate, polysorbate 80), low-substituted hydroxypropyl cellulose ,hypromellose, titanium dioxide (E171), methacrylic acid-methyl methacrylate
copolymer (1:1), triethyl citrate, macrogol 8000, polysorbate 80, hydroxypropyl
cellulose and Silica colloidal anhydrous. The components of the capsule shell include
the following inactive ingredients: hypromellose, carrageenan (E407) , potassium
chloride and purified water. Based on the capsule shell color, blue contains Indigotine(E132) FD&C Blue No.2 aluminum lake; gray contains Iron oxide black (E172); andboth contain titanium dioxide (E171). Printing ink: Iron oxide red (E172), iron oxide
yellow (E172), indigotine (E132), carnauba wax, shellac, glycerol mono-oleate.
12. CLINICAL PHARMACOLOGY
12.1

Mechanism of Action

Dexlansoprazole belongs to a class of antisecretory compounds, the substituted
benzimidazoles, that suppress gastric acid secretion by specific inhibition of the (H+,
K+)-ATPase at the secretory surface of the gastric parietal cell. Because this enzyme
is regarded as the acid (proton) pump within the parietal cell, dexlansoprazole has
been characterized as a gastric proton-pump inhibitor, in that it blocks the final step ofacid production.
12.2 Pharmacodynamics
Antisecretory Activity
The effects of DEXILANT 60 mg (n=20) or lansoprazole 30 mg (n=23) once daily forfive days on 24 hour intragastric pH were assessed in healthy subjects in a multipledose crossover study. The results are summarized in Table 5.

Table 5. Effect on 24 Hour Intragastric pH
on Day 5 After Administration of
DEXILANT or Lansoprazole
DEXILANT
Lansoprazole
60 mg
30 mg
Mean Intragastric pH
4.55

4.13

% Time Intragastric pH >4 (hours)
71(17 hours)

60(14 hours)

Serum Gastrin Effects
The effect of dexlansoprazole on serum gastrin concentrations was evaluated inapproximately 3460 patients in clinical trials up to eight weeks and in 1023 patientsfor up to six to 12 months. The mean fasting gastrin concentrations increased frombaseline during treatment with 30 and 60 mg DEXILANT. In patients treated for morethan six months, mean serum gastrin levels increased during approximately the first
three months of treatment and were stable for the remainder of treatment. Mean serum
gastrin levels returned to pre-treatment levels within one month of discontinuation oftreatment.
Increased gastrin causes enterochromaffin-like cell hyperplasia and increased serum

CgA levels. The increased CgA levels may cause false positive results in diagnostic
investigations for neuroendocrine tumors [see Warnings and Precautions (6.9)].
Enterochromaffin-Like Cell (ECL) Effects
There were no reports of ECL cell hyperplasia in gastric biopsy specimens obtained
from 653 patients treated with DEXILANT 30, 60 or 90 mg for up to 12 months.
During lifetime exposure of rats dosed daily with up to 150 mg/kg/day of
lansoprazole, marked hypergastrinemia was observed followed by ECL cellproliferation and formation of carcinoid tumors, especially in female rats [seeNonclinical Toxicology (13.1)].
Cardiac Electrophysiology
At a dose five times the maximum recommended dose, dexlansoprazole does notprolong the QT interval to any clinically relevant extent.
12.3 Pharmacokinetics
The dual modified-release formulation of DEXILANT results in a dexlansoprazole
plasma concentration-time profile with two distinct peaks; the first peak occurs one totwo hours after administration, followed by a second peak within four to five hours(see Figure 1). Dexlansoprazole is eliminated with a half-life of approximately one totwo hours in healthy subjects and in patients with symptomatic GORD. No
accumulation of dexlansoprazole occurs after multiple, once daily doses of
DEXILANT 30 or 60 mg although mean AUCt and Cmax values of dexlansoprazole
were slightly higher (less than 10%) on Day 5 than on Day 1.
Figure 1: Mean Plasma Dexlansoprazole Concentration –Time Profile Following Oral Administration of 30 or 60 mg DEXILANT
Once Daily for 5 Days in Healthy Adult Subjects

Plasma Concentration (ng/mL)

1200

DEXILANT 30 mg
DEXILANT 60 mg

1000

800

600

400

200

0
0

4

8

12

16

20

24

Time (h)The pharmacokinetics of dexlansoprazole are highly variable, with percent coefficientof variation (%CV) values for Cmax, AUC, and CL/F of greater than 30% (see Table
6).
Table 6. Mean (%CV) Pharmacokinetic Parameters for
Adult Subjects on Day 5 After Administration of
DEXILANT
Dose
Cmax
AUC24
CL/F

(mg)

(ng/mL)(ng·h/mL)

(L/h)

30

658 (40%)(N=44)

3275 (47%)(N=43)

11.4 (48%)(N=43)

60

1397 (51%)(N=79)

6529 (60%)(N=73)

11.6 (46%)(N=41)

Absorption
After oral administration of DEXILANT 30 or 60 mg to healthy subjects andsymptomatic GORD patients, mean Cmax and AUC values of dexlansoprazole
increased approximately dose proportionally (see Figure 1).
When granules of DEXILANT 60 mg are mixed with water and dosed via NG tube ororally via syringe, the bioavailability (Cmax and AUC) of dexlansoprazole was similar
to that when DEXILANT 60 mg was administered as an intact capsule [see Dosage
and Administration (3.3)].
Effect on Food
In food-effect studies in healthy subjects receiving DEXILANT under various fed
conditions compared to fasting, increases in Cmax ranged from 12 to 55%, increases
in AUC ranged from 9 to 37%, and Tmax varied (ranging from a decrease of 0.7
hours to an increase of three hours) [see Dosage and Administration (3.3)].
Distribution
Plasma protein binding of dexlansoprazole ranged from 96 to 99% in healthy subjects
and was independent of concentration from 0.01 to 20 mcg/mL. The apparent volumeof distribution (Vz/F) after multiple doses in symptomatic GORD patients was 40 L.
Elimination
Metabolism
Dexlansoprazole is extensively metabolized in the liver by oxidation, reduction, andsubsequent formation of sulfate, glucuronide and glutathione conjugates to inactive
metabolites. Oxidative metabolites are formed by the cytochrome P450 (CYP)
enzyme system including hydroxylation mainly by CYP2C19, and oxidation to thesulfone by CYP3A4.
CYP2C19 is a polymorphic liver enzyme which exhibits three phenotypes in themetabolism of CYP2C19 substrates: extensive metabolizers (*1/*1), intermediate
metabolizers (*1/mutant) and poor metabolizers (mutant/mutant). Dexlansoprazole isthe major circulating component in plasma regardless of CYP2C19 metabolizer
status. In CYP2C19 intermediate and extensive metabolizers, the major plasma
metabolites are 5-hydroxy dexlansoprazole and its glucuronide conjugate, while in
CYP2C19 poor metabolizers dexlansoprazole sulfone is the major plasma metabolite.
Excretion
Following the administration of DEXILANT, no unchanged dexlansoprazole isexcreted in urine. Following the administration of [14C] dexlansoprazole to six
healthy male subjects, approximately 50.7% (standard deviation (SD): 9.0%) of theadministered radioactivity was excreted in urine and 47.6% (SD: 7.3%) in the feces.
Apparent clearance (CL/F) in healthy subjects was 11.4 to 11.6 L/hour, respectively,

after five days of 30 or 60 mg once daily administration.
Specific Populations
Age: Pediatric Population
The pharmacokinetics of dexlansoprazole in patients under the age of 12 years havenot been studied.
Patients 12 to 17 Years of Age
The pharmacokinetics of dexlansoprazole were studied in 36 patients 12 to 17 yearsof age with symptomatic GORD in a multi-center trial. Patients were randomized toreceive DEXILANT 30 or 60 mg once daily for seven days. The dexlansoprazolemean Cmax and AUC in patients 12 to 17 years of age were 105 and 88%,
respectively, compared to those observed in adults at the 30 mg dose, and were 81 and
78%, respectively, at the 60 mg dose (see Tables 6 and 7).
Table 7. Mean (%CV) Pharmacokinetic Parameters in Patients 12 to 17
Years of Age with Symptomatic GORD on Day 7 After Administration of
DEXILANTOnce Daily for 7 Days
Dose
Cmax
AUCtauCL/F(ng/mL)(ng·h/mL)
(L/h)
30 mg
(N=17)

691
(53)

2886
(47)

12.8
(48)

60 mg
(N=18)

1136
(51)

5120
(58)

15.3
(49)

Age: Geriatric Population
The terminal elimination half-life of dexlansoprazole is significantly increased ingeriatric subjects compared to younger subjects (2.2 and 1.5 hours, respectively).
Dexlansoprazole exhibited higher systemic exposure (AUC) in geriatric subjects(34% higher) than younger subjects [see Use in Specific Populations (9.4)].
Sex
In a study of 12 male and 12 female healthy subjects who received a single dose of
DEXILANT 60 mg, females had higher systemic exposure (AUC) (43% higher) thanmales. This difference in exposure between males and females does not represent asignificant safety concern.
Renal Impairment
Dexlansoprazole is extensively metabolized in the liver to inactive metabolites, andno parent drug is recovered in the urine following an oral dose of dexlansoprazole.
Therefore, the pharmacokinetics of dexlansoprazole are not expected to be altered inpatients with renal impairment, and no studies were conducted in patients with renal
impairment. In addition, the pharmacokinetics of lansoprazole were not clinicallydifferent in patients with mild, moderate or severe renal impairment compared tohealthy subjects with normal renal function.
Hepatic Impairment
In a study of 12 patients with moderate hepatic impairment (Child-Pugh Class B) who
received a single dose of 60 mg DEXILANT, the systemic exposure (AUC) of boundand unbound dexlansoprazole was approximately two times greater compared tosubjects with normal hepatic function. This difference in exposure was not due to adifference in protein binding. No studies have been conducted in patients with severe
hepatic impairment (Child-Pugh Class C) [see Dosage and Administration (3.2), Usein Specific Populations (9.5)].
Drug-Drug Interactions
Effect of Dexlansoprazole on Other Drugs
Cytochrome P 450 Interactions
Dexlansoprazole is metabolized, in part, by CYP2C19 and CYP3A4 [see ClinicalPharmacology (12.3)].
In vitro studies have shown that dexlansoprazole is not likely to inhibit CYP isoforms
1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2D6, 2E1 or 3A4. As such, no clinically relevantinteractions with drugs metabolized by these CYP enzymes would be expected.
Furthermore, in vivo studies showed that DEXILANT did not have an impact on thepharmacokinetics of co-administered phenytoin (CYP2C9 substrate) or theophylline(CYP1A2 substrate). The subjects’ CYP1A2 genotypes in the drug-drug interaction
study with theophylline were not determined. Although in vitro studies indicated that
DEXILANT has the potential to inhibit CYP2C19 in vivo, an in vivo drug-druginteraction study in mainly CYP2C19 extensive and intermediate metabolizers has
shown that DEXILANT does not affect the pharmacokinetics of diazepam (CYP2C19
substrate).
Clopidogrel
Clopidogrel is metabolized to its active metabolite in part by CYP2C19. A study ofhealthy subjects who were CYP2C19 extensive metabolizers, receiving once dailyadministration of clopidogrel 75 mg alone or concomitantly with DEXILANT 60 mg(n=40), for nine days was conducted. The mean AUC of the active metabolite ofclopidogrel was reduced by approximately 9% (mean AUC ratio was 91%, with 90%
CI of 86 to 97%) when DEXILANT was co-administered compared to administrationof clopidogrel alone. Pharmacodynamic parameters were also measured anddemonstrated that the change in inhibition of platelet aggregation (induced by 5 mcMADP) was related to the change in the exposure to clopidogrel active metabolite. The
effect on exposure to the active metabolite of clopidogrel and on clopidogrel-induced
platelet inhibition is not considered clinically important.
Effect of Other Drugs on Dexlansoprazole
Because dexlansoprazole is metabolized by CYP2C19 and CYP3A4, inducers andinhibitors of these enzymes may potentially alter exposure of dexlansoprazole.
12.4

Pharmacogenomics

Effect of CYP2C19 Polymorphism on Systemic Exposure of Dexlansoprazole
Systemic exposure of dexlansoprazole is generally higher in intermediate and poor
metabolizers. In male Japanese subjects who received a single dose of DEXILANT
30 or 60 mg (N=2 to 6 subjects/group), mean dexlansoprazole Cmax and AUC values
were up to two times higher in intermediate compared to extensive metabolizers; inpoor metabolizers, mean Cmax was up to four times higher and mean AUC was up to
12 times higher compared to extensive metabolizers. Though such study was notconducted in Caucasians and African Americans, it is expected dexlansoprazole
exposure in these races will be affected by CYP2C19 phenotypes as well.
13
13.1

NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility

The carcinogenic potential of dexlansoprazole was assessed using lansoprazole
studies. In two, 24month carcinogenicity studies, Sprague-Dawley rats were treatedorally with lansoprazole at doses of 5 to 150 mg/kg/day, about one to 40 times the
exposure on a body surface (mg/m2) basis of a 50 kg person of average height [1.46m2 body surface area (BSA)] given the recommended human dose of lansoprazole 30
mg/day.
Lansoprazole produced dose-related gastric ECL cell hyperplasia and ECL cell
carcinoids in both male and female rats [see Clinical Pharmacology (12.2)].
In rats, lansoprazole also increased the incidence of intestinal metaplasia of the gastricepithelium in both sexes. In male rats, lansoprazole produced a dose-related increaseof testicular interstitial cell adenomas. The incidence of these adenomas in rats
receiving doses of 15 to 150 mg/kg/day (four to 40 times the recommended humanlansoprazole dose based on BSA) exceeded the low background incidence (range =1.4 to 10%) for this strain of rat.
In a 24 month carcinogenicity study, CD-1 mice were treated orally with lansoprazole
doses of 15 to 600 mg/kg/day, two to 80 times the recommended human lansoprazole
dose based on BSA. Lansoprazole produced a dose-related increased incidence ofgastric ECL cell hyperplasia. It also produced an increased incidence of liver tumors(hepatocellular adenoma plus carcinoma). The tumor incidences in male mice treatedwith 300 and 600 mg lansoprazole/kg/day (40 to 80 times the recommended humanlansoprazole dose based on BSA) and female mice treated with 150 to 600 mg
lansoprazole/kg/day (20 to 80 times the recommended human lansoprazole dose basedon BSA) exceeded the ranges of background incidences in historical controls for thisstrain of mice. Lansoprazole treatment produced adenoma of rete testis in male micereceiving 75 to 600 mg/kg/day (10 to 80 times the recommended human lansoprazole
dose based on BSA).
A 26 week p53 (+/-) transgenic mouse carcinogenicity study of lansoprazole was not
positive.

Lansoprazole was positive in the Ames test and the in vitro human lymphocyte
chromosomal aberration assay. Lansoprazole was not genotoxic in the ex vivo rat
hepatocyte unscheduled DNA synthesis (UDS) test, the in vivo mouse micronucleus
test or the rat bone marrow cell chromosomal aberration test.
Dexlansoprazole was positive in the Ames test and in the in vitro chromosome
aberration test using Chinese hamster lung cells. Dexlansoprazole was negative in thein vivo mouse micronucleus test.
The potential effects of dexlansoprazole on fertility and reproductive performance
were assessed using lansoprazole studies. Lansoprazole at oral doses up to 150
mg/kg/day (40 times the recommended human lansoprazole dose based on BSA) was
found to have no effect on fertility and reproductive performance of male and female
rats.
14

CLINICAL STUDIES

14.1

Treatment of erosive reflux oesophagitis in Adults

Two multi-center, double-blind, active-controlled, randomized, eight week studies
were conducted in patients with endoscopically confirmed erosive reflux oesophagitis.
Severity of the disease was classified based on the Los Angeles Classification
Grading System (Grades A-D). Patients were randomized to one of the following
three treatment groups: DEXILANT 60 mg once daily, DEXILANT 90 mg once dailyor lansoprazole 30 mg once daily. Patients who were H. pylori positive or who had
Barrett’s Esophagus and/or definite dysplastic changes at baseline were excluded
from these studies. A total of 4092 patients were enrolled and ranged in age from 18
to 90 years (median age 48 years) with 54% male. Race was distributed as follows:
87% Caucasian, 5% Black and 8% Other. Based on the Los Angeles Classification,
71% of patients had mild erosive reflux oesophagitis (Grades A and B) and 29% of
patients had moderate to severe erosive reflux oesophagitis (Grades C and D) before
treatment.
The studies were designed to test non-inferiority. If non-inferiority was demonstrated
then superiority would be tested. Although non-inferiority was demonstrated in bothstudies, the finding of superiority in one study was not replicated in the other.
The proportion of patients with healed erosive reflux oesophagitis at Week 4 or 8 ispresented below in Table 8.

Table 8. Erosive reflux oesphagitis Healing Rates*: in Adults: All Grades

Study

1

Number ofPatients(N)†

TreatmentGroup(daily)Week 4%
HealedWeek
8‡%
Healed657

DEXILANT
60 mg

70

87

(95% CI) for theTreatment
Difference(DEXILANT–
Lansoprazole)by Week 8(-1.5, 6.1)§

2

648

Lansoprazole
30 mg

65

85

639

DEXILANT
60 mg

66

85

656

Lansoprazole
30 mg

65

79

(2.2, 10.5)§

CI = Confidence interval*
Based on crude rate estimates, patients who did not have endoscopically
documented healed erosive reflux oesphagitis and prematurely discontinued wereconsidered not healed.
†
Patients with at least one post baseline endoscopy‡
Primary efficacy endpoint§
Demonstrated non-inferiority to lansoprazole
DEXILANT 90 mg once daily was studied and did not provide additional clinicalbenefit over DEXILANT 60 mg once daily.
14.2 Maintenance of healed erosive reflux oesophagitis and maintenance ofrelief of heartburn in Adults
A multi-center, double-blind, placebo-controlled, randomized study was conducted inpatients who successfully completed an erosive reflux oesophagitis study and showedendoscopically confirmed healed erosive reflux oesophagitis. Maintenance of healing
and symptom resolution over a six month period was evaluated with DEXILANT 30
or 60 mg once daily compared to placebo. A total of 445 patients were enrolled andranged in age from 18 to 85 years (median age 49 years), with 52% female. Race wasdistributed as follows: 90% Caucasian, 5% Black and 5% Other.
Sixty-six percent of patients treated with 30 mg of DEXILANT remained healed overthe sixmonth time period as confirmed by endoscopy (see Table 9).

Table 9. Maintenance Rates* ofhealed erosive reflux oesophagitis at
Month 6 in Adults
NumberofPatients(N)†
125

TreatmentGroup(daily)Maintenance
Rate
(%)

DEXILANT
30 mg

66.4‡

119
Placebo
14.3*Based on crude rate estimates, patients who did not have endoscopically documented
relapse and prematurely discontinued were considered to have relapsed.
†
Patients with at least one post baseline endoscopy‡
Statistically significant vs placebo

DEXILANT 60 mg once daily was studied and did not provide additional clinicalbenefit over DEXILANT 30 mg once daily.
The effect of DEXILANT 30 mg on maintenance of relief of heartburn was also
evaluated. Upon entry into the maintenance study, a majority of patients’ baseline
heartburn severity was rated as none. DEXILANT 30 mg demonstrated a statisticallysignificantly higher percent of 24 hour heartburn-free periods compared to placebo
over the six month treatment period (see Table 10). The majority of patients treatedwith placebo discontinued due to relapse of erosive reflux oesophagitis between
Month 2 and Month 6.
Table 10. Median Percentage of 24 Hour Heartburn-Free Periodsof the Maintenance of healed erosive reflux oesophagitis Study in Adults
Overall Treatment*

TreatmentGroup(daily)N

HeartburnFree
24hourPeriods(%)

DEXILANT
30 mg

132

96.1†

Placebo141
28.6
Secondary efficacy endpoint†
Statistically significant vs placeboMonth 1Month 6

N

HeartburnFree
24hourPeriods(%)

N

HeartburnFree
24hourPeriods
(%)

126

96.7

80

98.3

117

28.6

23

73.3

*

14.3

Treatment of Symptomatic non-erosive GORD in Adults

A multi-center, double-blind, placebo-controlled, randomized, four week study was
conducted in patients with a diagnosis of symptomatic non-erosive GORD madeprimarily by presentation of symptoms. These patients who identified heartburn as
their primary symptom, had a history of heartburn for six months or longer, hadheartburn on at least four of seven days immediately prior to randomization and had
no esophageal erosions as confirmed by endoscopy. However, patients withsymptoms which were not acid-related may not have been excluded using theseinclusion criteria. Patients were randomized to one of the following treatment groups:
DEXILANT 30 mg daily, 60 mg daily, or placebo. A total of 947 patients wereenrolled and ranged in age from 18 to 86 years (median age 48 years) with 71%
female. Race was distributed as follows: 82% Caucasian, 14% Black and 4% Other.
DEXILANT 30 mg provided statistically significantly greater percent of days withheartburn-free 24 hour periods over placebo as assessed by daily diary over fourweeks (see Table 11). DEXILANT 60 mg once daily was studied and provided no
additional clinical benefit over DEXILANT 30 mg once daily.
Table 11. Median Percentages of 24 Hour HeartburnFree Periods During the 4 Week Treatment Period of thesymptomatic non-erosive GORD Study in Adults
N
Treatment
Heartburn-FreeGroup(daily)24 hour Periods(%)

DEXILANT
30 mg

54.9*

310
Placebo*
Statistically significant vs placebo

18.5

312

A higher percentage of patients on DEXILANT 30 mg had heartburn-free 24 hour
periods compared to placebo as early as the first three days of treatment and this was
sustained throughout the treatment period (percentage of patients on Day 3:
DEXILANT 38% vs placebo 15%; on Day 28: DEXILANT 63% vs placebo 40%).
14.4

Pediatric GORD

Use of DEXILANT in patients 12 to 17 years of age is supported by evidence from
adequate and well-controlled studies of DEXILANT capsules in adults, withadditional safety, efficacy, and pharmacokinetic data from studies performed inpediatric patients.
Treatment of erosive reflux oesophagitis, Maintenance of healed erosive reflux
oesophagitis and maintanance of relief of Heartburn
In a multi-center, 36 week trial, 62 patients 12 to 17 years of age with a documented
history of GORD for at least three months and endoscopically-proven erosive
esophagitis (EE) were enrolled to evaluate the healing of erosive reflux esophagitis,
maintenance of healed erosive reflux esophagitis and maintenance of relief ofheartburn, followed by an additional 12 weeks without treatment. The median age was
15 years, with males accounting for 61% of the patients. Based on the Los Angeles
Classification Grading Scale, 97% of patients had mild erosive reflux esophagitis(Grades A and B), and 3% of patients had moderate to severe erosive reflux
esophagitis (Grades C and D) before treatment.
In the first eight weeks, 62 patients were treated with DEXILANT 60 mg once daily
to evaluate the healing of erosive reflux esophagitis. Of the 62 patients, 58 patientscompleted the eight week trial, and 51 (88%) patients achieved healing of erosive
reflux esophagitis, as confirmed by endoscopy, over eight weeks of treatment (seeTable 12).
Table 12. Treatment of erosive reflux esophagitis at Week 8 inPediatric Patients 12 to 17 Years of Age
DEXILANT 60 mg
Proportion of randomized patients
healedn (%)
95% CI

51/62 (82%)(70, 91) †Proportion of evaluable patients healed*n (%)

51/58 (88%)(77, 95) †95% CI*†

Includes only patients who underwent post-baseline endoscopy.
Reported are the exact confidence limits.

After the initial eight weeks of treatment, all 51 patients with healed erosive reflux
esophagitis were randomized to receive treatment with DEXILANT 30 mg orplacebo, once daily for an additional 16 weeks to evaluate maintenance of healing andsymptom resolution. Maintenance of healing was assessed by endoscopy at Week 24.
Of the 51 patients randomized, 13 patients discontinued early. Of these, five patients
did not undergo postbaseline endoscopy. Eighteen of 22 (82%) evaluable patientstreated with DEXILANT 30 mg remained healed over the 16 week treatment period
as confirmed by endoscopy, compared with 14 of 24 (58%) in placebo (see Table 13).

Table 13. Maintenance of Healed erosive reflux
esophagitis at Week 24* in
Pediatric Patients 12 to 17 Years of Age
DEXILANT 30 mg
Placebo
Proportion of randomized
patients who
maintained healing of erosive
reflux esophagitisn (%)
95% Cl18/25 (72%)(51, 88) ‡14/26 (54%)(33, 73) ‡Proportion of evaluable
patients who maintained
healing of erosive reflux
esophagitis†n (%)
95% Cl18/22 (82%)(60, 95) ‡14/24 (58%)(37, 78) ‡*Following eight weeks of initial therapy and 16 weeks of maintenance therapy.
Includes patients with at least one postbaseline endoscopy.
‡
Reported are the exact confidence limits.
†

Relief of heartburn was assessed in randomized patients during the 16 week
maintenance period. The median percentage of 24hour heartburn-free periods was
87% for those receiving DEXILANT 30 mg compared to 68% for those receiving
placebo.
Out of the 32 patients who maintained healing of erosive reflux esophagitis at the endof the 16 week maintenance period, 27 patients (16 treated with DEXILANT and 11
treated with placebo during the double-blind phase) were followed for an additional
12 weeks without therapy. Twenty -four of the 27 patients completed the 12week
follow-up period. One patient required treatment with acid suppression therapy.

Treatment of Symptomatic Non-Erosive GORD
In a single-arm, open-label, multi-center trial, 104 pediatric patients 12 to 17 years ofage with symptomatic non-erosive GORD were treated with DEXILANT 30 mg once
daily, for four weeks to evaluate safety and effectiveness. Patients had a documented
history of GORD symptoms for at least three months prior to screening, reported
heartburn on at least three out of seven days during screening, and had no esophageal
erosions as confirmed by endoscopy. The median age was 15 years, with females
accounting for 70% of the patients. During the four week treatment period, themedian percentage of 24hour heartburn free periods was 47%.
15

HOW SUPPLIED/STORAGE AND HANDLINGDEXILANT modified-release capsules, 30 mg, are opaque, blue and gray with "TAP"and “30” imprinted on the capsule and supplied as:
PVC/PE/polychlorotrifluoroethylene (PCTFE) - aluminium blister packs containing
14 or 28 capsules.
DEXILANT modified-release capsules, 60 mg, are opaque, blue with "TAP" and “60”imprinted on the capsule and supplied as:
PVC/PE/polychlorotrifluoroethylene (PCTFE) - aluminium blister packs containing
14 or 28 capsules.
Not all pack sizes may be marketed.
Do not store above 25°C.
The expiry date of the product is indicated on the packaging materials.
16 REGISTRATION HOLDER AND IMPORTER
Takeda Israel Ltd.
Efal 25,
P.O.B 4140,
Petach Tikva 4951125
18 REGISTRATION NUMBER(S)
Dexilant 30 mg - 155-45-34383
Dexilant 60 mg - 155-46-34387
Revised in August 2023 according to MOHs guidelines
Based on US PI update from July 2023