For the use of a Registered Medical Practitioner only

 

Qualitative and Quantitative Composition

DEXLANZOL-30

Each capsule contains:

Dexlansoprazole IP......................30 mg

(as delayed release pellets)

Color: Titanium Dioxide

DEXLANZOL-60

Each capsule contains:

Dexlansoprazole IP.......................60 mg

(as delayed release pellets)

Color: Titanium Dioxide

Dosage Form and Strength

Delayed-release capsules: 30 mg and 60 mg.

Clinical Particulars

Therapeutic Indications

Healing of all grades of erosive esophagitis (EE)

Maintaining healing of EE and relief of heartburn

Treating heartburn associated with symptomatic non-erosive gastroesophageal reflux disease (NERD)

Posology and Method of Administration

Recommended Dosage

DEXLANZOL is available in 30 mg and 60 mg strengths for adult use. Directions for use in each indication are summarized in Table 1.

Table 1: DexlansoprazoleCapsules Dosing Recommendations in adult patients
Indication	Recommended Dose	Frequency
Healing of EE	60 mg	Once daily for up to 8 weeks
Maintaining healing of EE and relief of heartburn	30 mg	Once daily*
Heartburn associated with symptomatic non-erosive gastroesophageal reflux disease (NERD)	30 mg	Once daily for 4 weeks

*Controlled studies did not extend beyond 6 months in adults

Pediatric Population

Safety and effectiveness of DEXLANZOL in pediatric patients have not been established

Dosage Adjustment in Patients with Hepatic Impairment for the Healing of EE

For patients with moderate hepatic impairment (Child-Pugh Class B), the recommended dosage is 30 mg dexlansoprazole once daily for up to eight weeks. Dexlansoprazole is not recommended in patients with severe hepatic impairment (Child-Pugh Class C).

Important Administration Information

• 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.
• Dexlansoprazole capsulescan be taken without regard to food. Dexlansoprazole should be swallowed whole. Dexlansoprazole should not be chewed.

Contraindications

Dexlansoprazole capsulesare contraindicated in patients with known hypersensitivity to any component of the formulation. Hypersensitivity and anaphylaxis have been reported with dexlansoprazole use. Acute interstitial nephritis (AIN) has been reported with other proton pump inhibitors (PPIs), including lansoprazole of which dexlansoprazole is the R-enantiomer.

PPIs, including dexlansoprazole, are contraindicated with rilpivirine-containing products.

Special Warnings and Precautions for Use

Gastric Malignancy

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.

Acute Interstitial Nephritis

Acute interstitial nephritis has been observed in patients taking PPIs including lansoprazole. Acute interstitial nephritis may occur at any point during PPI therapy and is generally attributed to an idiopathic hypersensitivity reaction. Discontinue dexlansoprazole if acute interstitial nephritis develops.

Cyanocobalamin (Vitamin B-12) 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 B-12) 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.

Clostridiumdifficile-associated Diarrhea

Published observational studies suggest that PPI therapy such as dexlansoprazole may be associated with an increased risk of Clostridium difficile-associated diarrhea (CDAD), especially in hospitalized patients. This diagnosis should be considered for diarrhea that does not improve.

Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.

Hypomagnesemia

Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least 3 months, in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias, and seizures. 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), healthcare professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically thereafter. 

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, long-term PPI therapy (a year or longer). Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Patients at risk for osteoporosis-related fractures should be managed according to the established treatment guidelines.

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 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 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, 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.

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.

Concomitant Use of Dexlansoprazole with Methotrexate

Literature suggests that concomitant use of PPIs with methotrexate (primarily at high dose; see methotrexate prescribing information) 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.

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.

Drug Interactions

Tables 2 and 3include drugs with clinically important drug interactions and interaction with diagnostics when administered concomitantly with dexlansoprazole and instructions for preventing or managing them.Consult the labeling of concomitantly used drugs to obtain further information about interactions with PPIs.

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 is contraindicated. Atazanavir: See prescribing information for atazanavir for dosing information. Nelfinavir: Avoid concomitant use with dexlansoprazole. 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.
Intervention:	A temporary withdrawal of dexlansoprazole 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): Co-administration 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 and MMF. Use dexlansoprazole 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.
Intervention:	Temporarily stop dexlansoprazole treatment for 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 treatment at least 30 days before assessing to allow gastrin levels to return to baseline.
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 3. Clinically Relevant Interactions Affecting Dexlansoprazole When Co-Administered with Other Drugs and Substances
CYP2C19 or CYP3A4 Inducers
Clinical Impact:	Decreased exposure of dexlansoprazole when used concomitantly with strong inducers.
Intervention:	St. John’s Wort, rifampin: Avoid concomitant use with dexlansoprazole. Ritonavir-containing products: See prescribing information.
CYP2C19 or CYP3A4 Inhibitors
Clinical Impact:	Increased exposure of dexlansoprazole is expected when used concomitantly with strong inhibitors.
Intervention:	Voriconazole: See prescribing information.

Use in Special Populations

Patients with Renal Impairment

No dosage adjustment of dexlansoprazole is necessary for patients with renal impairment. The pharmacokinetics of dexlansoprazole in patients with renal impairment is not expected to be altered since dexlansoprazole is extensively metabolized in the liver to inactive metabolites, and no parent drug is recovered in the urine following an oral dose of dexlansoprazole.

Patients with Hepatic Impairment

No dosage adjustment for dexlansoprazole 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 dexlansoprazole, there was a significant increase in systemic exposure of dexlansoprazole compared to healthy subjects with normal hepatic function. Therefore, for patients with moderate hepatic impairment (Child-Pugh Class B), dosage reduction is recommended for the healing of EE.

No studies have been conducted in patients with severe hepatic impairment (Child-Pugh Class C); the use of dexlansoprazole is not recommended for these patients.

Pregnant Women

Risk Summary

There are no studies with dexlansoprazole use in pregnant women to inform a drug-associated risk. Dexlansoprazole is the R-enantiomer of lansoprazole, and published observational studies of lansoprazole use during pregnancy did not demonstrate an association of adverse pregnancy-related outcomes with lansoprazole.

Human Data

Dexlansoprazole is the R-enantiomer of lansoprazole. Available data from published observational studies failed to demonstrate an association of adverse pregnancy-related outcomes and lansoprazole use. Methodological limitations of these observational 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 of major malformations between women exposed to PPIs and the control group, corresponding to a Relative Risk (RR)=1.04, . 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 meta-analysis that compared 1,530 pregnant women exposed to PPIs in at least the first trimester with 133,410 unexposed pregnant women showed no significant increases in risk for congenital malformations or spontaneous abortion with exposure to PPIs (for major malformations Odds Ratio (OR)=1.12, and for spontaneous abortions OR=1.29, ).

Lactating Women

Risk Summary

There is no information regarding the presence of dexlansoprazole in human milk, the effects on the breastfed infant, or the effects on milk production. However, lansoprazole and its metabolites are present in rat milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for dexlansoprazole and any potential adverse effects on the breastfed child from dexlansoprazole or from the underlying maternal condition.

Geriatric Patients

In clinical studies of dexlansoprazole, 11% of patients were aged 65 years and over. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified significant differences in responses between geriatric and younger patients, but the greater sensitivity of some elderly individuals cannot be ruled out.

Pediatric Population

Safety and effectiveness of DEXLANZOL in pediatric patients have not been established.

Effects on Ability to Drive and Use Machines

Not applicable

Undesirable Effects

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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of dexlansoprazole was evaluated in 4,548 patients in controlled and uncontrolled clinical studies, including 863 patients treated for at least 6 months and 203 patients treated for 1 year. Patients ranged in age from 18 to 90 years (median age: 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 of EE, maintenance of healed EE, and symptomatic GERD, which included 896 patients on placebo, 455 patients on dexlansoprazole 30 mg, 2,218 patients on dexlansoprazole 60 mg, and 1,363 patients on lansoprazole 30 mg once daily.

Most Commonly Reported Adverse Reactions

The most common adverse reactions (≥2%) that occurred at a higher incidence for dexlansoprazole than placebo in the controlled studies are presented in Table 4.

	Placebo	Dexlansoprazole	Dexlansoprazole	Dexlansoprazole	Lansoprazole
		30 mg	60 mg	Total	30 mg
	(N=896)	(N=455)	(N=2218)	(N=2621)	(N=1363)
Adverse Reaction	%	%	%	%	%
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

Adverse Reactions Resulting in Discontinuation

In controlled clinical studies, the most common adverse reaction leading to discontinuation from dexlansoprazole therapy was diarrhea (0.7%).

Other Adverse Reactions

Other adverse reactions that were reported in controlled studies at an incidence of less than 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, breath odor, colitis microscopic, colonic polyp, constipation, dry mouth, duodenitis, dyspepsia, dysphagia, enteritis, eructation, esophagitis, gastric polyp, gastritis, gastroenteritis, gastrointestinal disorders, gastrointestinal hypermotility disorders, GERD, gastrointestinal ulcers and perforation, hematemesis, hematochezia, hemorrhoids, impaired gastric emptying, irritable bowelsyndrome, 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: Candidainfections, influenza, nasopharyngitis, oral herpes, pharyngitis, sinusitis, viral infection, vulvo-vaginal infection

Injury, Poisoning, and Procedural Complications:falls, fractures, joint sprains, overdose, procedural pain, sunburn

Laboratory Investigations:ALP increased, ALT increased, AST increased, bilirubin decreased/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 uncontrolled study and were considered related to dexlansoprazole 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, and tonsillitis.

Post-marketing Experience

The following adverse reactions have been identified during post-approval of dexlansoprazole. As 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, toxic epidermal necrolysis (some fatal)

Infections and Infestations: Clostridium difficile-associated diarrhea

Metabolism and Nutrition Disorders:hypomagnesemia, hyponatremia

Musculoskeletal System Disorders:bone fracture

Nervous System Disorders:cerebrovascular accident, transient ischemic attack

Renal and Urinary Disorders:acute renal failure, acute kidney injury

Respiratory, Thoracic and Mediastinal Disorders:pharyngeal edema, throat tightness

Skin and Subcutaneous Tissue Disorders:generalized rash, leukocytoclastic vasculitis

If you experience any side-effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the national pharmacovigilance program of India by calling on 1800 180 3024 or you can report to Cipla Ltd on 1800 267 7779. By reporting side-effects, you can help provide more information on the safety of this product.

Overdose

There have been no reports of significant overdose of dexlansoprazole. Multiple doses of dexlansoprazole 120 mg and a single dose of dexlansoprazole 300 mg did not result in death or other severe adverse events. However, serious adverse events of hypertension have been reported in association with twice-daily doses of dexlansoprazole 60 mg. Non-serious adverse reactions observed with twice-daily doses of dexlansoprazole 60 mg include hot flashes, contusion, oropharyngeal pain, and weight loss. Dexlansoprazole is not expected to be removed from the circulation by hemodialysis.

If an overdose occurs, treatment should be symptomatic and supportive.

Pharmacological Properties

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 of acid production.

Pharmacodynamic Properties

Antisecretory ActivityThe effects of dexlansoprazole 60 mg (n=20) or lansoprazole 30 mg (n=23) once daily for 5 days on 24-hour intragastric pH were assessed in healthy subjects in a multiple-dose crossover study. The results are summarized in Table 5.

Dexlansoprazole 60 mg	Lansoprazole 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 in approximately 3,460 patients in clinical trials up to eight weeks and in 1023 patients for up to 6 to 12 months. The mean fasting gastrin concentrations increased from baseline during treatment with dexlansoprazole 30 mg and 60 mg doses. In patients treated for more than 6 months, mean serum gastrin levels increased during approximately the first 3 months of treatment and were stable for the remainder of treatment. Mean serum gastrin levels returned to pre-treatment levels within 1 month of discontinuation of treatment.

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.

Enterochromaffin-like Cell (ECL) Effects

There were no reports of ECL cell hyperplasia in gastric biopsy specimens obtained from 653 patients treated with dexlansoprazole 30 mg, 60 mg, 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 cell proliferation and formation of carcinoid tumors, especially in female rats.

Cardiac Electrophysiology

At a dose five times the maximum recommended dose, dexlansoprazole does not prolong the QT interval to any clinically relevant extent.

Pharmacokinetic Properties

The dual delayed-release formulation of dexlansoprazole results in a dexlansoprazole plasma concentration–time profile with two distinct peaks: the first peak occurs 1 to 2 hours after administration, followed by a second peak within 4 to 5 hours. Dexlansoprazole is eliminated with a half-life of approximately 1 to 2 hours in healthy subjects and in patients with symptomatic gastroesophageal reflux disease (GERD). No accumulation of dexlansoprazole occurs after multiple, once-daily doses of dexlansoprazole 30 mg or 60 mg, although mean AUC_t and C_max values of dexlansoprazole were slightly higher (less than 10%) on Day 5 than on Day 1.

The pharmacokinetics of dexlansoprazole is highly variable, with the percent coefficient of variation (CV %) values for C_max, AUC, and CL/F of greater than 30% (see Table 6).

Table 6: Mean (CV %) Pharmacokinetic Parameters for Subjects on Day 5 after Administration of Dexlansoprazole
Dose (mg)	Cmax (ng/mL)	AUC24 (ng.h/mL)	CL/F (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 dexlansoprazole 30 mg or 60 mg to healthy subjects and symptomatic GERD patients, mean C_max and AUC values of dexlansoprazole increased approximately dose-proportionally.

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 volume of distribution (Vz/F) after multiple doses in symptomatic GERD patients was 40 L.

Metabolism

Dexlansoprazole is extensively metabolized in the liver by oxidation, reduction, and subsequent 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 the sulfone by CYP3A4.

CYP2C19 is a polymorphic liver enzyme that exhibits three phenotypes in the metabolism of CYP2C19 substrates; extensive metabolizers (*1/*1), intermediate metabolizers (*1/mutant) and poor metabolizers (mutant/mutant). Dexlansoprazole is the major circulating component in plasma regardless of CYP2C19 metabolizer status. In CYP2C19 intermediate and extensive metabolizers, the major plasma metabolites are 5­hydroxy dexlansoprazole and its glucuronide conjugate while in CYP2C19, poor metabolizers, dexlansoprazole sulfone is the major plasma metabolite.

Elimination

Following the administration of dexlansoprazole, no unchanged dexlansoprazole is excreted in urine. Following the administration of dexlansoprazole to 6 healthy male subjects, approximately 50.7% (standard deviation : 9.0%) of the administered 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/h, respectively, after 5 days of 30 or 60 mg once-daily administration.

Effect of Food on Pharmacokinetics and Pharmacodynamics

In food-effect studies in healthy subjects receiving dexlansoprazole under various fed conditions compared with fasting, increases in C_max ranged from 12% to 55%, increases in AUC ranged from 9% to 37%, and the t_max varied (ranging from a decrease of 0.7 hours to an increase of 3 hours). No significant differences in mean intragastric pH were observed between fasted and various fed conditions. However, the percentage of time intragastric pH exceeded four over the 24-hour dosing interval decreased slightly when dexlansoprazole was administered after a meal (57%) relative to fasting (64%), primarily due to a decreased response in intragastric pH during the first 4 hours after dosing. Because of this, while dexlansoprazole can be taken without regard to food, some patients may benefit from administering the dose prior to a meal if post-meal symptoms do not resolve under post-fed conditions.

Special Populations

Geriatric

The terminal elimination half-life of dexlansoprazole is significantly increased in geriatric 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.

Pediatric population

Safety and effectiveness of DEXLANZOL in pediatric patients have not been established.

Gender

In a study of 12 male and 12 female healthy subjects who received a single oral dose of dexlansoprazole 60 mg, females had a higher systemic exposure (AUC) (43% higher) than males. This difference in exposure between males and female does not represent a significant safety concern.

Hepatic Impairment

In a study of 12 patients with moderately impaired hepatic function (Child-Pugh Class B) who received a single oral dose of dexlansoprazole 60 mg, plasma exposure (AUC) of bound and unbound dexlansoprazole in the hepatic impairment group was approximately two times greater compared to subjects with normal hepatic function. This difference in exposure was not due to a difference in protein binding between the two liver function groups. No studies have been conducted in patients with severe hepatic impairment (Child-Pugh Class C).

Renal Impairment

Dexlansoprazole is extensively metabolized in the liver to inactive metabolites, and no parent drug is recovered in the urine following an oral dose of dexlansoprazole. Therefore, the pharmacokinetics of dexlansoprazole is not expected to be altered in patients with renal impairment, and no studies were conducted in subjects with renal impairment. In addition, the pharmacokinetics of lansoprazole were not clinically different in patients with mild, moderate or severe renal impairment compared to healthy subjects with normal renal function.

Effect of Dexlansoprazole on Other Drugs

Cytochrome P 450 Interactions

Dexlansoprazole is metabolized, in part, by CYP2C19 and CYP3A4.

Clopidogrel

Clopidogrel is metabolized to its active metabolite in part by CYP2C19. A study of healthy subjects who were CYP2C19 extensive metabolizers, receiving once daily administration of clopidogrel 75 mg alone or concomitantly with dexlansoprazole 60 mg (n=40), for nine days was conducted. The mean AUC of the active metabolite of clopidogrel was reduced by approximately 9% (mean AUC ratio was 91%, with 90% CI of 86 to 97%) when dexlansoprazole was co-administered compared to administration of clopidogrel alone. Pharmacodynamic parameters were also measured and demonstrated that the change in inhibition of platelet aggregation (induced by 5 mcM ADP) 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.

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 dexlansoprazole 30 mg or 60 mg (N=2 to 6 subjects/group), mean dexlansoprazole C_max and AUC values were up to two times higher in intermediate metabolizers compared to extensive metabolizers; in poor metabolizers, mean C_max was up to four times higher and mean AUC was up to twelve times higher compared to extensive metabolizers. Though such a study was not conducted in Caucasians and African-Americans, it is expected that dexlansoprazole exposure in these races will be affected by CYP2C19 phenotypes as well.

Nonclinical Properties

Animal Toxicology or Pharmacology

Carcinogenesis, Mutagenesis, Impairment of Fertility

The carcinogenic potential of dexlansoprazole was assessed using lansoprazole studies. In two 24-month carcinogenicity studies, Sprague-Dawley rats were treated orally 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 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 andfemale rats (see sectionPharmacodynamic Properties).

In rats, lansoprazole also increased the incidence of intestinal metaplasia of the gastric epithelium in both sexes. In male rats, lansoprazole produced a dose-related increase of 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 human lansoprazole 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 of gastric ECL cell hyperplasia. It also produced an increased incidence of liver tumors (hepatocellular adenoma plus carcinoma). The tumor incidences in male mice treated with 300 and 600 mg lansoprazole/kg/day (40 to 80 times the recommended human lansoprazole 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 based on BSA) exceeded the ranges of background incidences in historical controls for this strain of mice. Lansoprazole treatment produced adenoma of rete testis in male mice receiving 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 the in 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.

Description

The active ingredient in DEXLANZOL (dexlansoprazole) delayed-release capsules, a proton pump inhibitor, is (+)-2- methyl} sulfinyl]-1H-benzimidazole, a compound that inhibits gastric acid secretion. Dexlansoprazole is the R-enantiomer of lansoprazole (a racemic mixture of the R-and S-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 with decomposition 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 in neutral and alkaline conditions than acidic conditions.

Dexlansoprazole is supplied for oral administration as a dual delayed-release formulation in capsules. The capsules contain dexlansoprazole in a mixture of two types of enteric-coated granules with different pH-dependent dissolution profiles (see section Pharmacodynamic Properties).

DEXLANZOL delayed-release capsules are available in two dosage strengths: 30 and 60 mg, per capsule. Each capsule contains enteric-coated granules consisting of dexlansoprazole.

Pharmaceutical Particulars

Incompatibilities

Not applicable.

Shelf-life

As on the pack.

Packaging Information

DEXLANZOLCapsules30 mg …….Strip pack of 10 capsules

DEXLANZOLCapsules60 mg ……. Strip pack of 10 capsules

Storage and Handling Instructions

Store below 25^oC.

Patient Counselling Information

Medication Guide

Read this Medication Guide before you start taking DEXLANZOL and each time you get a refill. There may be new information. This information does not take the place of talking to your doctor about your medical condition or your treatment.

What is the most important information that I should know about DEXLANZOL?

DEXLANZOL may help your acid-related symptoms, but you could still have serious stomach problems. Talk with your doctor. DEXLANZOL can cause serious side effects, including:

• A type of kidney problem (acute interstitial nephritis). Some people who take proton pump inhibitor (PPI) medicines, including DEXLANZOL, may develop a kidney problem called acute interstitial nephritis, that can happen at any time during treatment with PPI medicines. Call your doctor right away if you have a decrease in the amount that you urinate or if you have blood in your urine.
• Diarrhea. DEXLANZOL may increase your risk of getting severe diarrhea. This diarrhea may be caused by an infection (Clostridium difficile) in your intestines. Call your doctor right away if you have watery stool, stomach pain, and fever that does not go away.
• Bone fractures. People who take multiple daily doses of PPI medicines for a long period of time (a year or longer) may have an increased risk of fractures of the hip, wrist or spine. You should take DEXLANZOL exactly as prescribed, at the lowest dose possible for your treatment and for the shortest time needed. Talk to your doctor about your risk of bone fracture if you take DEXLANZOL.
• Certain types of lupus erythematosus. Lupus erythematosus is an autoimmune disorder (the body’s immune cells attack other cells or organs in the body). Some people who take PPI medicines may develop certain types of lupus erythematosus or have worsening of the lupus they already have. Call your doctor right away if you have new or worsening joint pain or a rash on your cheeks or arms that gets worse in the sun. DEXLANZOL can have other serious side effects. See “What are the possible side effects of DEXLANZOL?”

What is DEXLANZOL?

DEXLANZOL is a prescription medicine called a proton pump inhibitor (PPI). DEXLANZOL reduces the amount of acid in your stomach. DEXLANZOL is used:

• for up to 8 weeks to heal acid-related damage to the lining of the esophagus (called erosive esophagitis or EE)
• for up to 6 months in adults to continue healing of erosive esophagitis and relief of heartburn
• for 4 weeks to treat heartburn related to gastroesophageal reflux disease (GERD) GERD happens when acid from your stomach enters the tube (esophagus) that connects your mouth to your stomach. This may cause a burning feeling in your chest or throat, sour taste or burping. It is not known if DEXLANZOL is safe and effective in children under 12 years of age. DEXLANZOL is not effective for symptoms of GERD in children under 1 year of age.

Who should not take DEXLANZOL?

Do not take DEXLANZOL if you:

• are allergic to dexlansoprazole or any of the other ingredients in DEXLANZOL. See the end of this Medication Guide for a complete list of ingredients in DEXLANZOL.
• are taking a medicine that contains rilpivirine used to treat HIV-1 (Human Immunodeficiency Virus)

What should I tell my doctor before taking DEXLANZOL?

Before you take DEXLANZOL, tell your doctor if you:

• have been told that you have low magnesium levels in your blood
• have liver problems
• have any other medical conditions
• are pregnant or plan to become pregnant. DEXLANZOL may harm your unborn baby. Talk to your doctor about the possible risks to an unborn baby if DEXLANZOL is taken during pregnancy.
• are breastfeeding or plan to breastfeed. It is not known if DEXLANZOL passes into your breast milk or if it will affect your baby or your breast milk. Talk to your doctor about the best way to feed your baby if you take DEXLANZOL. Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. DEXLANZOL may affect how other medicines work, and other medicines may affect how DEXLANZOL works. Especially tell your doctor if you take methotrexate. Know the medicines that you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.

How should I take DEXLANZOL?

• Take DEXLANZOL exactly as prescribed by your doctor.
• Do not change your dose or stop taking DEXLANZOL without talking to your doctor first.
• Take DEXLANZOL with or without food.
• Swallow DEXLANZOL whole. Do not chew the capsules or the granules that are in the capsules.
• If you miss a dose of DEXLANZOL, take it as soon as you remember. If it is almost time for your next dose, do not take the missed dose. Take your next dose at your regular time. Do not take 2 doses at the same time to make up for the missed dose.
• If you get any side effects, talk to your doctor, pharmacist, or nurse or write to drugsafety@cipla.com. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national pharmacovigilance program of India by calling on 1800 180 3024 or you can report to Cipla Ltd on 1800 267 7779. By reporting side-effects, you can help provide more information on the safety of this product.

What are the possible side effects of DEXLANZOL?

DEXLANZOL may cause serious side effects, including:

• See “What is the most important information I should know about DEXLANZOL?”
• Vitamin B12 deficiency. DEXLANZOL reduces the amount of acid in your stomach. Stomach acid is needed to absorb Vitamin B12 properly. Talk with your doctor about the possibility of Vitamin B12 deficiency if you have been on DEXLANZOL for a long time (more than 3 years).
• Low magnesium levels in your body. This problem can be serious. Low magnesium can happen in some people who take a PPI medicine for at least 3 months. If low magnesium levels happen, it is usually after a year of treatment. You may or may not have symptoms of low magnesium. Tell your doctor right away if you develop any of these symptoms:
  
  • seizures
  • dizziness
  • abnormal or fast heartbeat
  • jitteriness
  • jerking movements or shaking (tremors)
  • muscle weakness
  • spasms of the hands and feet
  • cramps or muscle aches
  • spasm of the voice box.

Your doctor may check the level of magnesium in your body before you start taking DEXLANZOL, or during treatment, if you will be taking DEXLANZOL for a long period of time.

• Stomach growths (fundic gland polyps). People who take PPI medicines for a long time have an increased risk of developing a certain type of stomach growth called fundic gland polyps, especially after taking PPI medicines for more than 1 year.

The most common side effects of DEXLANZOL in adults include:

• diarrhea
• stomach pain
• nausea
• common cold
• vomiting
• gas.

Other side effects:

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

• rash
• face swelling
• throat tightness
• difficulty breathing

Your doctor may stop DEXLANZOL if these symptoms happen. Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of DEXLANZOL. For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. If you get any side effects, talk to your doctor, pharmacist, or nurse or write to drugsafety@cipla.com. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national pharmacovigilance program of India by calling on 1800 180 3024 or you can report to Cipla Ltd on 1800 267 7779. By reporting side-effects, you can help provide more information on the safety of this product.

General information about the safe and effective use of DEXLANZOL

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

This Medication Guide summarizes the most important information about DEXLANZOL. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about DEXLANZOL that is written for health professionals.

How should I store DEXLANZOL?

Store DEXLANZOLbelow 25°C.

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

Details of Manufacturer

Mfd. By Cipla Ltd.

Registered Office:

Cipla House, Peninsula Business Park,

Ganpatrao Kadam Marg

Lower Parel

Mumbai – 400 013, India

Details of Permission or License Number with Date

25/2/2010 dated 09/01/2019

Date of Revision

28/02/2020