|
DEXILANT (dexlansoprazole) delayed-release capsules
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use DEXILANT safely and effectively. See full prescribing information for DEXILANT.
DEXILANT (dexlansoprazole) delayed-release capsules, for oral use
Initial U.S. Approval: 1995 (lansoprazole)
RECENT MAJOR CHANGES
|
Indications and Usage |
|
-
-
Maintenance of Healed Erosive Esophagitis ( 1.2)
|
06/2011 |
|
Warnings and Precautions |
|
-
-
Bone Fracture ( 5.2)
|
09/2010
05/2011 |
INDICATIONS AND USAGE
DEXILANT is a proton pump inhibitor (PPI) indicated for:
-
Healing of all grades of erosive esophagitis (EE). (1.1)
-
Maintaining healing of EE and relief of heartburn. (1.2)
-
Treating heartburn associated with symptomatic non-erosive gastroesophageal reflux disease (GERD). (1.3)
DOSAGE AND ADMINISTRATION
-
Healing of EE: 60 mg once daily for up to 8 weeks. (2.1)
-
Maintenance of healed EE: 30 mg once daily for up to 6 months. (2.1)
-
Symptomatic non-erosive GERD: 30 mg once daily for 4 weeks. (2.1)
-
Hepatic impairment: Consider 30 mg maximum daily dose for patients with moderate hepatic impairment (Child-Pugh Class B). No studies were conducted in patients with severe hepatic impairment (Child-Pugh Class C). (2.2, 8.7)
-
DEXILANT can be taken without regard to food. (2.3)
-
DEXILANT should be swallowed whole. Alternatively, capsules can be opened, sprinkled on one tablespoon of applesauce, and swallowed immediately. (2.3)
DOSAGE FORMS AND STRENGTHS
-
Delayed-Release Capsules: 30 mg and 60 mg. (3)
CONTRAINDICATIONS
Patients with known hypersensitivity to any component of the formulation. (4)
WARNINGS AND PRECAUTIONS
-
Gastric malignancy: Symptomatic response with DEXILANT does not preclude the presence of gastric malignancy. (5.1)
-
Bone Fracture: Long-term and multiple daily dose PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist or spine. (5.2)
-
Hypomagnesemia: Hypomagnesemia has been reported rarely with prolonged treatment with PPIs. (5.3)
ADVERSE REACTIONS
Most commonly reported adverse reactions (≥2%): diarrhea, abdominal pain, nausea, upper respiratory tract infection, vomiting, and flatulence. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals America, Inc. at 1-877-TAKEDA-7 (1-877-825-3327) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
-
Atazanavir: Do not co-administer with DEXILANT because atazanavir systemic concentrations may be substantially decreased. (7.1)
-
Drugs with pH-dependent absorption (e.g., ampicillin esters, digoxin, iron salts, ketoconazole): DEXILANT may interfere with absorption of drugs for which gastric pH is important for bioavailability. (7.1)
-
Warfarin: Patients taking concomitant warfarin may require monitoring for increases in international normalized ratio (INR) and prothrombin time. (7.2)
-
Tacrolimus: Concomitant tacrolimus use may increase tacrolimus whole blood concentrations. (7.3)
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
Revised: 2/2012
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
1.1 Healing of Erosive Esophagitis
DEXILANT is indicated for healing of all grades of erosive esophagitis (EE) for up to 8 weeks.
1.2 Maintenance of Healed Erosive Esophagitis
DEXILANT is indicated to maintain healing of EE and relief of heartburn for up to 6 months.
1.3 Symptomatic Non-Erosive Gastroesophageal Reflux Disease
DEXILANT is indicated for the treatment of heartburn associated with symptomatic non-erosive gastroesophageal reflux disease (GERD) for 4 weeks.
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dose
DEXILANT is available as capsules in 30 mg and 60 mg strengths for adult use. Directions for use in each indication are summarized in Table 1.
2.2 Hepatic Impairment
No adjustment for DEXILANT is necessary for patients with mild hepatic impairment (Child-Pugh Class A). Consider a maximum daily dose of 30 mg for patients with moderate hepatic impairment (Child-Pugh Class B). No studies have been conducted in patients with severe hepatic impairment (Child-Pugh Class C) [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].
2.3 Important Administration Information
DEXILANT can be taken without regard to food.
DEXILANT should be swallowed whole.
-
Alternatively, DEXILANT capsules can be administered as follows:
-
–Open capsule;
-
–Sprinkle intact granules on one tablespoon of applesauce;
-
– Swallow immediately. Granules should not be chewed.
3 DOSAGE FORMS AND STRENGTHS
-
30 mg delayed-release capsules are opaque, blue and gray with TAP and "30" imprinted on the capsule.
-
60 mg delayed-release capsules are opaque, blue with TAP and "60" imprinted on the capsule.
4 CONTRAINDICATIONS
DEXILANT is contraindicated in patients with known hypersensitivity to any component of the formulation [see Description (11)]. Hypersensitivity and anaphylaxis have been reported with DEXILANT use [see Adverse Reactions (6.1)].
5 WARNINGS AND PRECAUTIONS
5.1 Gastric Malignancy
Symptomatic response with DEXILANT does not preclude the presence of gastric malignancy.
5.2 Bone Fracture
Several published observational studies suggest that proton pump inhibitor (PPI) therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist or spine. The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long-term PPI therapy (a year or longer). Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Patients at risk for osteoporosis-related fractures should be managed according to established treatment guidelines [see Dosage and Administration (2) and Adverse Reactions (6)].
5.3 Hypomagnesemia
Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias, and seizures. In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuation of the PPI.
For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), health care professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically [see Adverse Reactions (6.2)].
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The safety of DEXILANT was eva luated in 4548 patients in controlled and uncontrolled clinical studies, including 863 patients treated for at least 6 months and 203 patients treated for one 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 DEXILANT 30 mg, 2218 patients on DEXILANT 60 mg, and 1363 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 DEXILANT than placebo in the controlled studies are presented in Table 2.
Adverse Reactions Resulting in Discontinuation
In controlled clinical studies, the most common adverse reaction leading to discontinuation from DEXILANT 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, 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, 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, dyspnoea, hiccups, hyperventilation, respiratory tract congestion, sore throat
Skin and Subcutaneous Tissue Disorders: acne, dermatitis, erythema, pruritis, 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 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.
Other adverse reactions not observed with DEXILANT, but occurring with the racemate lansoprazole can be found in the lansoprazole prescribing information, ADVERSE REACTIONS section.
6.2 Postmarketing Experience
The following adverse reactions have been identified during post-approval of DEXILANT. 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
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)
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
Respiratory, Thoracic and Mediastinal Disorders: pharyngeal edema, throat tightness
Skin and Subcutaneous Tissue Disorders: generalized rash, leucocytoclastic vasculitis
7 DRUG INTERACTIONS
7.1 Drugs with pH-Dependent Absorption Pharmacokinetics
DEXILANT causes inhibition of gastric acid secretion. DEXILANT is likely to substantially decrease the systemic concentrations of the HIV protease inhibitor atazanavir, which is dependent upon the presence of gastric acid for absorption, and may result in a loss of therapeutic effect of atazanavir and the development of HIV resistance. Therefore, DEXILANT should not be co-administered with atazanavir.
DEXILANT may interfere with the absorption of other drugs where gastric pH is an important determinant of oral bioavailability (e.g., ampicillin esters, digoxin, iron salts, ketoconazole).
7.2 Warfarin
Co-administration of DEXILANT 90 mg and warfarin 25 mg did not affect the pharmacokinetics of warfarin or INR [see Clinical Pharmacology (12.3)]. However, there have been reports of 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. Patients treated with DEXILANT and warfarin concomitantly may need to be monitored for increases in INR and prothrombin time.
7.3 Tacrolimus
Concomitant administration of dexlansoprazole and tacrolimus may increase whole blood levels of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.
7.4 Clopidogrel
Concomitant administration of dexlansoprazole and clopidogrel in healthy subjects had no clinically important effect on exposure to the active metabolite of clopidogrel or clopidogrel-induced platelet inhibition [see Clinical Pharmacology (12.3)]. No dose adjustment of clopidogrel is necessary when administered with an approved dose of DEXILANT.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Teratogenic Effects
Pregnancy Category B. There are no adequate and well-controlled studies with dexlansoprazole in pregnant women. There were no adverse fetal effects in animal reproduction studies of dexlansoprazole in rabbits. Because animal reproduction studies are not always predictive of human response, DEXILANT should be used during pregnancy only if clearly needed.
A reproduction study conducted in rabbits at oral dexlansoprazole doses up to approximately 9 times the maximum recommended human dexlansoprazole dose (60 mg per day) revealed no evidence of impaired fertility or harm to the fetus due to dexlansoprazole. In addition, reproduction studies performed in pregnant rats with oral lansoprazole at doses up to 40 times the recommended human lansoprazole dose and in pregnant rabbits at oral lansoprazole doses up to 16 times the recommended human lansoprazole dose revealed no evidence of impaired fertility or harm to the fetus due to lansoprazole [see Nonclinical Toxicology (13.2)].
8.3 Nursing Mothers
It is not known whether dexlansoprazole is excreted in human milk. However, lansoprazole and its metabolites are present in rat milk following the administration of lansoprazole. As many drugs are excreted in human milk, and because of the potential for tumorigenicity shown for lansoprazole in rat carcinogenicity studies [see Nonclinical Toxicology (13.1)], a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
8.4 Pediatric Use
Safety and effectiveness of DEXILANT in pediatric patients (less than 18 years of age) have not been established.
8.5 Geriatric Use
In clinical studies of DEXILANT, 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 greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology (12.3)].
8.6 Renal Impairment
No dosage adjustment of DEXILANT is necessary in patients with renal impairment. The pharmacokinetics of dexlansoprazole in patients with renal impairment are 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 [see Clinical Pharmacology (12.3)].
8.7 Hepatic Impairment
No dosage adjustment for DEXILANT is necessary for patients with mild hepatic impairment (Child-Pugh Class A). DEXILANT 30 mg should be considered for patients with moderate hepatic impairment (Child-Pugh Class B). No studies have been conducted in patients with severe hepatic impairment (Child-Pugh Class C) [see Clinical Pharmacology (12.3)].
10 OVERDOSAGE
There have been no reports of significant overdose of DEXILANT. Multiple doses of DEXILANT 120 mg and a single dose of DEXILANT 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 DEXILANT 60 mg. Non-serious 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. If an overdose occurs, treatment should be symptomatic and supportive.
11 DESCRIPTION
The active ingredient in DEXILANT (dexlansoprazole) delayed-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- and S-enantiomers). Its empirical formula is: C16H14F3N3O2S, with a molecular weight of 369.36. The structural formula is:
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.
DEXILANT is supplied as a dual delayed-release formulation in capsules for oral administration. The capsules contain dexlansoprazole in a mixture of two types of enteric-coated granules with different pH-dependent dissolution profiles [see Clinical Pharmacology (12.3)].
DEXILANT is available in two dosage strengths: 30 mg and 60 mg, per capsule. Each capsule contains enteric-coated granules consisting of dexlansoprazole (active ingredient) and the following inactive ingredients: sugar spheres, magnesium carbonate, sucrose, low-substituted hydroxypropyl cellulose, titanium dioxide, hydroxypropyl cellulose, hypromellose 2910, talc, methacrylic acid copolymers, polyethylene glycol 8000, triethyl citrate, polysorbate 80, and colloidal silicon dioxide. The components of the capsule shell include the following inactive ingredients: hypromellose, carrageenan and potassium chloride. Based on the capsule shell color, blue contains FD&C Blue No. 2 aluminum lake; gray contains black ferric oxide; and both contain titanium dioxide.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Dexlansoprazole is a PPI that suppresses gastric acid secretion by specific inhibition of the (H+,K+)-ATPase in the gastric parietal cell. By acting specifically on the proton pump, dexlansoprazole blocks the final step of acid production.
12.2 Pharmacodynamics
Antisecretory Activity
The effects of DEXILANT 60 mg (n=20) or lansoprazole 30 mg (n=23) once daily for five days on 24-hour intragastric pH were assessed in healthy subjects in a multiple-dose crossover study. The results are summarized in Table 3.
Serum Gastrin Effects
The effect of DEXILANT on serum gastrin concentrations was eva luated in approximately 3460 patients in clinical trials up to 8 weeks and in 1023 patients for up to 6 to 12 months. The mean fasting gastrin concentrations increased from baseline during treatment with DEXILANT 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 one month of discontinuation of treatment.
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 mg, 60 mg or 90 mg for up to 12 months.
During lifetime exposure of rats dosed daily with up to 150 mg per kg per day of lansoprazole, marked hypergastrinemia was observed followed by ECL cell proliferation and formation of carcinoid tumors, especially in female rats [see Nonclinical Toxicology (13.1)].
Effect on Cardiac Repolarization
A study was conducted to assess the potential of DEXILANT to prolong the QT/QTc interval in healthy adult subjects. DEXILANT doses of 90 mg or 300 mg did not delay cardiac repolarization compared to placebo. The positive control (moxifloxacin) produced statistically significantly greater mean maximum and time-averaged QT/QTc intervals compared to placebo.
12.3 Pharmacokinetics
The dual delayed release formulation of DEXILANT 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 (see Figure 1). Dexlansoprazole is eliminated with a half-life of approximately 1 to 2 hours in healthy subjects and in patients with symptomatic GERD. No accumulation of dexlansoprazole occurs after multiple, once daily doses of DEXILANT 30 mg or 60 mg, although mean AUC
| 以下是“全球医药”详细资料 |
|
|
| |
