加拿大_dexilant-说明书

PRODUCT MONOGRAPH

Pr DEXILANT?

Dexlansoprazole

delayed release capsules 30 mg and 60 mg H+, K+ - ATPase Inhibitor

Takeda Canada Inc. Oakville, Ontario, L6M 4X8 Date of Preparation: September 2, 2014

Submission Control No: 176596

Table of Contents

PART I: HEALTH PROFESSIONAL INFORMATION (3)

SUMMARY PRODUCT INFORMATION (3)

INDICATIONS AND CLINICAL USE (3)

CONTRAINDICATIONS (3)

WARNINGS AND PRECAUTIONS (4)

ADVERSE REACTIONS (6)

DRUG INTERACTIONS (9)

DOSAGE AND ADMINISTRATION (11)

OVERDOSAGE (12)

ACTION AND CLINICAL PHARMACOLOGY (12)

STORAGE AND STABILITY (16)

DOSAGE FORMS, COMPOSITION AND PACKAGING (16)

PART II: SCIENTIFIC INFORMATION (17)

PHARMACEUTICAL INFORMATION (17)

CLINICAL TRIALS (17)

DETAILED PHARMACOLOGY (21)

TOXICOLOGY (23)

REFERENCES (26)

PART III: CONSUMER INFORMATION (28)

Pr DEXILANT?

Dexlansoprazole delayed release capsules, 30 mg and 60 mg

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

DEXILANT? is indicated for the following in adults 18 years of age and older:

Healing of Erosive Esophagitis

DEXILANT? is indicated for healing of all grades of erosive esophagitis for up to 8 weeks. Maintenance of Healed Erosive Esophagitis

DEXILANT? is indicated for maintaining healing of erosive esophagitis for up to 6 months. 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.

Geriatrics (> 65 years of age):

No dosage adjustment is necessary for elderly patients.

Pediatrics (< 18 years of age):

Safety and effectiveness of DEXILANT? in pediatric patients have not been established. CONTRAINDICATIONS

Patients who are hypersensitive to this drug or to any ingredient in the formulation. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING. DEXILANT? should not be concomitantly administered with atazanavir (see DRUG INTERACTIONS, Drugs with pH-Dependent Absorption Pharmacokinetics).

WARNINGS AND PRECAUTIONS

General

Symptomatic response with DEXILANT? does not preclude the presence of gastric malignancy.

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including clarithromycin and amoxicillin, and may range in severity from mild to life threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.

Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of Clostridia. Studies indicate that a toxin produced by Clostridium difficile is a primary cause of “antibiotic-associated colitis”.

After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to discontinuation of the drug alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against Clostridium difficile colitis.

Decreased gastric acidity due to any means, including proton pump inhibitors, increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with proton pump inhibitors (PPIs) may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter and possibly Clostridium difficile.

Literature suggests that concomitant use of PPIs with methotrexate (primarily at high dose) may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities. A temporary withdrawal of the PPI may be considered in some patients receiving treatments with high dose methotrexate.

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 and ADVERSE REACTIONS). Carcinogenesis and Mutagenesis

Dexlansoprazole was positive in the Ames test for mutagenicity in bacteria. In an in vitro chromosome aberration test using Chinese hamster lung cells, dexlansoprazole was considered positive based on equivocal data in which the percentage of cells with aberrant chromosomes increased slightly but did not reach the preset criteria for a positive response. Dexlansoprazole was negative in the in vivo mouse micronucleus test.

Lansoprazole is a racemic mixture of R- and S-enantiomers. Following administration of lansoprazole in humans and animals, the major component circulating in plasma is dexlansoprazole, the R-enantiomer of lansoprazole. Therefore, the carcinogenic potential of dexlansoprazole was assessed using existing lansoprazole studies (see TOXICOLOGY). Lansoprazole treatment for 2-years was associated with hyperplasia and neoplasms (carcinoids) of enterochromaffin-like cells (ECL cells) in the stomach of conventional rats and mice. These proliferations are related to prolonged hypergastrinemia secondary to gastric acid suppression. Benign tumors of the testis (interstitial cell adenomas in rats and rete testis adenomas in mice) were secondary to an inhibitory effect on testosterone synthesis at high doses in these species. Hepatocellular adenomas and carcinomas were increased in the livers of mice related to induction of CYP enzymes leading to increased liver weights.

Endocrine and Metabolism

Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias, and seizures. 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).

The chronic use of PPIs may lead to hypomagnesaemia. Moreover, hypokalemia and hypocalcemia have been reported in the literature as accompanying electrolyte disorders. Cyanocobalamin (Vitamin B12) Deficiency

The prolonged use of proton pump inhibitors may impair the absorption of protein-bound Vitamin B12 and may contribute to the development of cyanocobalamin (Vitamin B12) deficiency.

Genitourinary

Testicular interstitial cell adenoma occurred in 1 of 30 rats treated with 50 mg/kg/day of lansoprazole (13 times the recommended human dose based on body surface area) in a one-year toxicity study (see TOXICOLOGY, Carcinogenicity).

These changes are associated with endocrine alterations which have not been, to date, observed in humans.

Special Populations

Pregnant Women:

There are no adequate or well-controlled studies in pregnant women with DEXILANT?. Exposure in clinical trials was very limited. DEXILANT? should not be administered to pregnant women unless the expected benefits outweigh the potential risks. See TOXICOLOGY, Reproduction and Teratology.

Nursing Women:

It is not known whether dexlansoprazole is excreted in human milk. However, lansoprazole (the racemate) and its metabolites are excreted in the milk of rats. As many drugs are excreted in human milk, DEXILANT? should not be given to nursing mothers unless its use is considered essential.

Pediatrics (< 18 years of age):

Safety and effectiveness of DEXILANT? in pediatric patients have not been established. Geriatrics (> 65 years of age):

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. No dosage adjustment is necessary for elderly patients. See ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions.

Benefits of use of PPIs should be weighed against the increased risk of fractures as patients in this category (> 71 years of age) may already be at high risk for osteoporosis-related fractures. If the use of PPIs is required, they should be managed carefully according to established treatment guidelines (see DOSAGE AND ADMINISTRATION and ADVERSE REACTIONS) Hepatic Impairment:

No dosage adjustment is necessary for patients with mild hepatic impairment (Child-Pugh Class A). A maximum daily dose of 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. See ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions.

Renal Impairment

No dosage adjustment is necessary for patients with renal impairment. See ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions.

ADVERSE REACTIONS

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

The safety of DEXILANT? was evaluated in 4548 patients in controlled and uncontrolled clinical studies (30 mg, 60 mg, and 90 mg), including 863 patients treated for at least 6 months and 282 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 erosive esophagitis, maintenance of

healed erosive esophagitis, and symptomatic GERD, which included 896 patients on placebo, 2621 patients on DEXILANT? 30 mg or 60 mg and 1363 patients on lansoprazole 30 mg.

The following adverse events were reported to have a possible or definite treatment-relationship to DEXILANT? in 1% or more of the treated patients in placebo and positive-controlled clinical trials (Tables 1 and 2, respectively). Numbers in parentheses indicate the percentage of the adverse events reported.

In placebo-controlled studies, gastrointestinal adverse reactions other than constipation occurred at a higher incidence for DEXILANT? than placebo. In active-controlled studies, diarrhea occurred at a higher incidence for DEXILANT? than lansoprazole. The incidence of other common adverse reactions for DEXILANT? were similar to or lower than placebo or lansoprazole.

Less Common Clinical Trial Adverse Drug Reactions(<1%)

Other adverse reactions that were reported for DEXILANT? (30 mg, 60 mg or 90 mg) in controlled studies at an incidence of less than 1% are listed below by body system:

Blood and Lymphatic System Disorders: anemia, lymphadenopathy

Cardiac Disorders: acute myocardial infarction, angina, arrhythmia, bradycardia, edema, palpitations, 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, 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, paresthesia oral, proctitis, rectal hemorrhage, vomiting

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, upper respiratory tract infection, viral infection, vulvo-vaginal infection Injury, Poisoning and Procedural Complications: 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 increased

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, memory impairment, migraine, 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, pruritus, rash, skin lesion, urticaria

Vascular Disorders: deep vein thrombosis, hot flush, hypertension

Additional adverse reactions that were reported for DEXILANT? (60 mg or 90 mg) in a long-term uncontrolled study included: anaphylaxis, auditory hallucination, B-cell lymphoma, bursitis, central obesity, cholecystitis acute, decreased hemoglobin, dehydration, diabetes mellitus, dysphonia, epistaxis, folliculitis, gout, herpes zoster, hyperglycemia, hyperlipidemia, hypothyroidism, increased neutrophils, MCHC decreased, neutropenia, oral soft tissue disorder, rectal tenesmus, restless legs syndrome, somnolence, thrombocythemia, tonsillitis.

Post-Market Adverse Drug Reactions

Adverse reactions have been identified during post-marketing surveillance 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 Nutritional Disorders: hypomagnesemia, hyponatremia

Musculoskeletal and Connective Tissue: Osteoporosis and osteoporosis-related fractures Nervous System Disorders: cerebrovascular accident, transient ischaemic 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 Withdrawal of long-term PPI therapy can lead to aggravation of acid related symptoms and may result in rebound acid hypersecretion.

DRUG INTERACTIONS

Drug-Drug Interactions

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.

It is theoretically possible that 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).

Cytochrome P 450 Interactions

DEXILANT? is metabolized, in part, by CYP2C19 and CYP3A4 (see ACTION AND CLINICAL PHARMACOLOGY, Metabolism).

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 relevant interactions with drugs metabolized by these CYP enzymes would be expected. Furthermore, in vivo studies showed that DEXILANT? did not have an impact on the pharmacokinetics of, coadministered phenytoin (CYP2C9 substrate) or theophylline (CYP1A2 substrate).1 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-drug interaction study in mainly CYP2C19 extensive and intermediate metabolizers has shown that DEXILANT? does not affect the pharmacokinetics of diazepam (CYP2C19 substrate). Warfarin

In a study of 20 healthy subjects, co-administration of DEXILANT? 90 mg once daily for 11 days with a single 25 mg oral dose of warfarin on day 6 did not result in any significant differences in the pharmacokinetics of warfarin or INR compared to administration of warfarin with placebo.1 However, there have been reports of increased INR and prothrombin time in patients receiving PPIs and warfarin concomitantly. Patients treated with PPIs and warfarin concomitantly may need to be monitored for increases in INR and prothrombin time. Concomitant Use of Antacids with DEXILANT?

No formal drug-drug interaction studies were conducted with DEXILANT? and antacids. Drug-drug interactions studies were performed with the racemate lansoprazole and antacids. Simultaneous administration of lansoprazole with aluminum and magnesium hydroxide or magaldrate results in lower peak plasma levels, but does not significantly reduce bioavailability. Antacids may be used concomitantly if required. In clinical trials, antacids were administered concomitantly with lansoprazole delayed-release capsules. In a single-dose crossover study when 30 mg of lansoprazole was administered concomitantly with one gram of sucralfate in healthy volunteers, absorption of lansoprazole was delayed and its bioavailability was reduced. The value of lansoprazole AUC was reduced by 17% and that for C max was reduced by 21%. In a similar study when 30 mg of lansoprazole was administered concomitantly with 2 grams of sucralfate, lansoprazole AUC and C max were reduced by 32% and 55%, respectively. When lansoprazole dosing occurred 30 minutes prior to sucralfate administration, C max was reduced by only 28% and there was no statistically significant difference in lansoprazole AUC. Therefore, lansoprazole should be administered at least 30 minutes prior to sucralfate. It would be expected that similar results would be seen with DEXILANT?.

Theophylline

Although a study of the use of concomitant theophylline and dexlansoprazole did not reveal any changes in the pharmacokinetics or pharmacodynamics of theophylline, individual patients should monitor their theophylline level while taking the two drugs concomitantly.

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.

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 DETAILED PHARMACOLOGY).No dose adjustment of clopidogrel is necessary when administered with an approved dose of DEXILANT?. Methotrexate

Case reports, published population pharmacokinetic studies, and retrospective analyses suggest that concomitant administration of PPIs and methotrexate (primarily at high dose) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate. However, no formal drug interaction studies of methotrexate with PPIs have been conducted.

Drug-Food Interactions

DEXILANT? can be taken without regard to food or timing of food (see ACTION AND CLINICAL PHARMACOLOGY).

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Tests

Interactions with laboratory tests have not been established.

DOSAGE AND ADMINISTRATION

Recommended Dose and Dosage Adjustment

b Controlled studies did not extend beyond 6 months.

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).

No dosage adjustment is necessary for elderly patients or for patients with renal impairment. Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.

Missed Dose

If a capsule is missed at its usual time, it should be taken as soon as possible. But if it is too close to the time of the next dose, only the prescribed dose should be taken at the appointed time. A double dose should not be taken.

Administration

DEXILANT? can be taken without regard to food or the timing of food.

DEXILANT? should be swallowed whole with plenty of water.

?Alternatively, DEXILANT? capsules can be opened and administered as follows: Open capsule;

Sprinkle intact granules on one tablespoon of applesauce;

Swallow immediately. Granules should not be chewed.

OVERDOSAGE

There have been no reports of significant overdose of DEXILANT?. Dexlansoprazole is not expected to be removed from the circulation by hemodialysis.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

DEXILANT? 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, DEXILANT?blocks the final step of acid production.

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.2 The results are summarized in Table 3.

Table 3:Effect on 24-Hour Intragastric pH on Day 5 After

?

Pharmacokinetics

The formulation of DEXILANT? utilizing Dual Delayed Release technology 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).2,3 Figure 1: Mean Plasma Dexlansoprazole Concentration – Time Profile Following Oral Administration of 60 mg DEXILANT? or 30 mg Lansoprazole Once Daily for

Dexlansoprazole is eliminated with a half-life of approximately 1 to 2 hours in healthy subjects (see Table 4) and in patients with symptomatic GERD. No accumulation of dexlansoprazole occurs after multiple, once daily doses of DEXILANT? 30 mg or 60 mg.

Table 4: Mean (CV %) Pharmacokinetic Parameters for Healthy

?

After oral administration of DEXILANT? 30 mg or 60 mg to healthy subjects , mean C max and AUC values of dexlansoprazole increased approximately dose proportionally (see Figure 2).

Figure 2: Mean Plasma Dexlansoprazole Concentration –

Time Profile Following Oral Administration of DEXILANT? on Day 5

Distribution:

Plasma protein binding of dexlansoprazole ranged from 96.1% to 98.8% 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 40.3 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 which exhibits three phenotypes in the metabolism of CYP2C19 substrates; extensive metabolizers (*1/*1), intermediate metabolizers (*1/mutant) and poor metabolizers (mutant/mutant). Systemic exposure of dexlansoprazole is generally higher in intermediate and poor metabolizers. Dexlansoprazole is the major circulating component in plasma4, 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 is excreted in urine. Following the administration of [14C]dexlansoprazole to 6 healthy male subjects, approximately 50.7% (standard deviation (SD): 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:

DEXILANT? can be taken without regard to food or the timing of food. In food-effect studies in healthy subjects receiving DEXILANT?, increases in C max ranged from 12% to 55% and increases in AUC ranged from 9% to 37% under various fed conditions compared to fasting. However, no relevant differences with regard to intragastric pH were observed.5 An additional study showed that administration of 60 mg DEXILANT? prior to consumption of breakfast, lunch, dinner or an evening snack did not have an effect on dexlansoprazole exposure, or a clinically relevant effect on 24-hour intragastric pH control.6

Special Populations and Conditions

Pediatrics:

The pharmacokinetics of dexlansoprazole in patients under the age of 18 years have not been studied.

Geriatrics:

In a study of 12 male and 12 female healthy subjects who received a single oral dose of DEXILANT? 60 mg, the terminal elimination half-life of dexlansoprazole was statistically significantly longer in geriatric subjects compared to younger subjects (2.23 and 1.5 hours, respectively). In addition, dexlansoprazole exhibited higher systemic exposure (AUC) in geriatric subjects (34.5% higher) than younger subjects. These differences were not clinically relevant.No dosage adjustment is necessary in geriatric patients (see WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Gender:

In a study of 12 male and 12 female healthy subjects who received a single oral dose of DEXILANT? 60 mg, females had higher systemic exposure (AUC) (42.8% higher) than males. No dosage adjustment is necessary in patients based on gender.

Hepatic Insufficiency:

In a study of 12 patients with moderately impaired hepatic function who received a single oral dose of DEXILANT? 60 mg, plasma exposure (AUC) of bound and unbound dexlansoprazole in the hepatic impairment group was approximately 2 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 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 WARNINGS AND PRECAUTIONS).

Renal Insufficiency:

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 are not expected to be altered in patients with renal impairment, and no studies were conducted in subjects with renal impairment (see WARNINGS AND PRECAUTIONS).

STORAGE AND STABILITY

Store at room temperature (15° to 30°C).

DOSAGE FORMS, COMPOSITION AND PACKAGING

DEXILANT? is supplied as a dual delayed release formulation in capsules for oral administration using Dual Delayed Release technology. The capsules contain dexlansoprazole in a mixture of two types of enteric-coated granules with different pH-dependent dissolution profiles. One type of granule is designed to release dexlansoprazole after the granules reach the proximal small intestine; the second type of granule is designed to release dexlansoprazole in the distal region of the small intestine, generally several hours later.

DEXILANT? is available in two dosage strengths: 30 mg and 60 mg, per capsule. Each capsule contains enteric-coated granules consisting of dexlansoprazole and the following non-medicinal ingredients: colloidal silicon dioxide, hydroxypropyl cellulose, hypromellose 2910, low-substituted hydroxypropyl cellulose, magnesium carbonate, methacrylic acid copolymer, polyethylene glycol 8000, polysorbate 80, sucrose, sugar spheres, talc, titanium dioxide, and triethyl citrate.

The components of the capsule shell include the following non-medicinal ingredients: carrageenan, hypromellose 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.

DEXILANT? is provided in high-density polyethylene (HDPE) bottles in 90 count configurations. Each 30 mg capsule is opaque, blue and gray with TAP and “30” imprinted on the capsule and e ach 60 mg capsule is opaque, blue with TAP and “60” imprinted on the capsule.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance Common name: Dexlansoprazole Chemical name: (+)-2-[(R )-{[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]

methyl} sulfinyl]-1H -benzimidazole

Molecular formula and molecular mass: C 16H 14F 3N 3O 2S 369.36 Structural formula:

N

H

N S

O

N

CH 3

O

CF 3

Physicochemical properties:

Dexlansoprazole is a white to nearly white crystalline powder which melts with decomposition at 140°C. Dexlansoprazole is the R-enantiomer of lansoprazole (a racemic mixture of the R- and S-enantiomers).

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.

CLINICAL TRIALS

Healing of Erosive Esophagitis

Two multi-center, double-blind, active-controlled, randomized, 8-week studies were conducted in patients with endoscopically confirmed erosive esophagitis.7 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 daily,

DEXILANT ? 90 mg daily or lansoprazole 30 mg daily. 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 Grades A and B erosive esophagitis (mild) and 29% of patients had Grades C and D erosive esophagitis (moderate to severe) before treatment.

By the life-table method of analysis DEXILANT? 60 mg healed 92.3% to 93.1% of patients versus 86.1% to 91.5% for lansoprazole 30 mg after 8 weeks of treatment. Non-inferiority was demonstrated in both studies. Statistical superiority was not established using log-rank tests. The crude rate estimates considered patients who did not have endoscopically documented healed erosive esophagitis and who discontinued prematurely as not healed. Based on crude rate estimates, healing rates at Week 4 (secondary) or Week 8 (primary) were higher for DEXILANT? than lansoprazole (Table 5). Treatment with DEXILANT? 60 mg was non-inferior to lansoprazole 30 mg at Week 8 in both studies. Statistical superiority of DEXILANT? 60 mg over lansoprazole 30 mg was established in the first study but was not replicated in the second study.

Table 5: Erosive Esophagitis Healing Rates – All Grades

The life-table healing rates at Week 8 for patients with moderate to severe erosive esophagitis were 88.9% and 74.5% for DEXILANT? 60 mg and lansoprazole 30 mg, respectively, in the first study. The difference was statistically significant (p=0.011). In the second study, the Week 8 life-table healing rates were 87.6% and 87.7% for DEXILANT? 60 mg and lansoprazole 30 mg, respectively, and were not statistically significantly different.

The crude healing rates at Week 8 for patients with moderate to severe erosive esophagitis are presented in Table 6.

*Statistically significant

DEXILANT? 90 mg was studied and did not provide additional clinical benefit over DEXILANT? 60 mg.

Maintenance of Healed Erosive Esophagitis

A multi-center, double-blind, placebo-controlled, randomized study was conducted in patients who successfully completed a erosive esophagitis study and showed endoscopically confirmed healed erosive esophagitis.8 Maintenance of healing and symptom relief over a six-month period were evaluated with DEXILANT? 30 mg or 60 mg once daily compared to placebo. A total of 445 patients were enrolled and ranged in age from 18 to 85 years (median age 49 years), with 52% female. Race was distributed as follows: 90% Caucasian, 5% Black and 5% other.

By the life-table method, DEXILANT? 30 mg and 60 mg demonstrated statistically significantly higher rates of maintenance of healed erosive esophagitis (74.9% and 82.5%, respectively) than placebo (27.2%) at Month 6 (p<0.00001).

Based on crude rate estimates, 66.4% percent of patients treated with 30 mg or 60 mg of DEXILANT? remained healed over the six-month time period versus 14.3% of placebo patients (p<0.00001) (Table 7).

Table 7: Maintenance Rates a of Healed EE at Month 6

and prematurely discontinued were considered to have relapsed.

b Patients with at least one post baseline endoscopy

* Statistically significant vs. placebo

For patients with more severe grades of erosive esophagitis (Grades C or D) before healing, DEXILANT? 30 mg and 60 mg also achieved statistically significantly higher 6-month maintenance rates than placebo by the life-table method. For the crude rate analysis, the trends in the results were similar to the life-table analysis.

DEXILANT? 30 mg and 60 mg achieved statistically significantly (p<0.00001) greater percentages of heartburn relief during the study treatment period. The median percentages of 24-hour heartburn-free days were 96.1%, 90.9% and 28.6% for DEXILANT? 30 mg, 60 mg and placebo, respectively. The median percentages of nights without heartburn were 98.9%, 96.2% and 71.7% for DEXILANT? 30 mg, 60 mg and placebo, respectively.

In a second study (N=451) of DEXILANT? 60 mg and 90 mg versus placebo, DEXILANT? 60 mg showed similar results to the first study in the maintenance of healed erosive esophagitis and heartburn relief. DEXILANT? 90 mg did not provide additional clinical benefit over DEXILANT? 60 mg.

Symptomatic GERD

A multi-center, double-blind, placebo-controlled, randomized, 4-week study was conducted in patients with a diagnosis of symptomatic GERD made primarily by presentation of symptoms.9 These patients who identified heartburn as their primary symptom, had a history of heartburn for 6 months or longer, had heartburn on at least 4 of 7 days immediately prior to randomization and had no esophageal erosions as confirmed by endoscopy. However, patients with symptoms which were not acid-related may not have been excluded using these inclusion 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 were enrolled 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 with heartburn-free 24-hour periods and percent of nights without heartburn over placebo as assessed by daily diary over 4 weeks (Table 8). DEXILANT? 60 mg was studied and provided no additional clinical benefit over DEXILANT? 30 mg.

Table 8: Median Percentages of Heartburn Relief During the 4 Week

A higher percentage of patients on DEXILANT? 30 mg had heartburn-free 24-hour periods compared to placebo through 4 weeks of treatment.

加拿大签证在职证明

Certificateofemployment 时间（打印日期即可） Date:申请国家 To:Consulate-Generalof Mr/Ms姓名拼音（MR.ZhangSan）职位isThisistocertifythat He/She年月日（2013-01-01）. inourcompany.hasbeenworkingheresince He/She去的日期(Jan012013)回国日期andisallowedtobeoffworkbetween (Jan102013)所申请的国家天数(10)days. ，totaltohaveatripto Weguaranteethat he/she willabidebythelawsinyourcountryandregulationsand returntoChina his/.Weagreeandwillkeep himself/herself ontime.Allofthetra velingexpenseswillbepaidby herhe/she comesbacktoChina. positionafter Yourkindapprovalofthisapplicationwillbehighlyappreciated. Yoursincerely 准假人英文职称 ManagerPosition: 准假人姓名拼音（不一定要法人，准假人拼音即可。） ManagerSignature: 中文签名负责人手写签名 公司盖章公司英文名称Company:（区号）公司电话 Tel：（区号）公司传真：Fax公司英文地址 Address：备注： 所有红色字体请替换内容并删除，建议用公司正规抬头纸打印！

加拿大个人旅游签证申请表

加拿大个人旅游签证申请表 加拿大签证申请表201101(1/5) 姓名性别曾用名国籍婚姻状况结婚日期年月日若离异或再婚，请提供前任配偶姓名及婚姻具体起止日期 身份证号码出生地省市/镇户口所在地出生日期: 年月日家庭电话谁提供费用具体家庭地址(邮编) 申请人单位名称(中、英文) 单位电话单位地址传真职务手机邮政编码护照号码: 签发地签发日期截至日期是否有亲属在加拿大: 是否在加拿大身份: 与本人关系是否有人曾申请过加拿大签证是否若选是请提供申请类型、签发日期以及赴加拿大日期 是否曾被加拿大拒签: 是否次数最后一次时间签证类别过去5年，你是否在国外居住超过6个月, 是否如答是请提供细节，包括国家、身份、居住起止日期 你是否曾经参军, 是否如答是请填写申请补充表 你是否有在任何国家犯罪、被拘捕或因任何刑事犯罪被指控, 是否如答是请填写申请补充表你是否曾任职于政府机构、或司法部门、或政党,是否(如公务员、警察、医院行政人员、法官、议员等) 如答是请填写申请补充表你的护照是否曾经遗失或者被盗, 是否 加拿大联系人的姓名或组织者的名字和地址及与申请人的关系(包括电话号码，如随团旅游可不填写): 你是否有具体的旅行安排, 是否 (如随团旅游可不填写)如选是请填写具体往返时间、航班号、所住酒店名称地址及加拿大联系人或公司姓名地址。

预计抵达加拿大时间: 年月日/ 加拿大停留时间: 在加拿大期间可用资金(加元): 列出过去5年内你曾经进入的所有国家(包括每次访问起始日期) 我谨声明:本表所列各项内容均属事实且详尽。 我明白，所列内容如被发现不实或不详，我的申请将被驳回。 加拿大签证申请表201101(2/5) 关系姓名出生日期及地点现行地址现行职业 签证申请人 申请人配偶 申请人母亲 申请人父亲 申请人之子女(包括正式继养、收养之子女) 姓名关系婚姻状况出生日期及地点现行地址现行职业 申请人之兄弟姐妹(包括同父异母及同母异父之兄弟姐妹) 姓名关系婚姻状况出生日期及地点现行地址现行职业 我谨声明:本表所列各项内容均属事实且详尽。 我明白，所列内容如被发现不实或不详，我的申请将被驳回。 加拿大签证申请表201101(3/5) 教育详情表 日期学校的名称及地址学历/学位课程类别自至 名称: 地址: 名称: 地址:

加拿大签证在线申请

在线申请流程 在线申请加拿大签证需要登陆加拿大移民局官网来申请： 第一步：登陆加拿大移民局官网并填写调查问卷； 第二步：注册GCKey账户并填写帐户的问题； 第三步：在线上传您的申请材料，并在线支付100加元的签证费用。 注：在线申请加拿大签证需要登陆加拿大移民局官网来申请，加拿大签证在线申请的整个过程是全英文的，而且在申请的过程中最好先准备好加拿大签证材料并扫描好，因为上传资料时须用到扫描件。在线申请支持Mastercard、Visa和JCB。如果你满足这些条件，就可以开始看以下的在线申请步骤了： 第一步：登录加拿大移民局网站并选择申请类型； 第二步：注册GCKey账户； 第三步：上传资料。 具体操作 第一步：登录加拿大移民局网站并选择申请类型。 加拿大移民局网站：http://www.cic.gc.ca/english/

点击My Application（我的申请）就可以在线申请签证，你还可以在这里看到签证申请相关的各种信息。如图：

进入页面后，直接点击上图画圈的部分：apply online for a visa,study or work permit.然后进入到在线申请页面。 如果你第一次在线申请，建议你可以先点击Determine your eligibility 下方的Answer a few questions，先填写一套问卷，看您是否有资格申请。官网会自动协助你列出一份准备清单，帮你在线申请！如图：

点击“Check your eligibility ”你将会看到一个调查问卷，分别有5个问题，第一个是你来加拿大的目的，分别有学习（Study）、旅游（Visit）、移居（Move there）、工作（work）、短期过境（Transit only-less than 48 hour）、商务拜访（IEC-Travel and Work）。请根据您的实际情来选择。对于游客来说，应该选择Visit。

加拿大签证须知-GIC担保

Visa Section 19 Dongzhimenwai Dajie Chaoyang District Beijing, PRC 100600 加拿大使馆移民处 朝阳区东直门外大街19号 中国·北京 100600 学习许可申请表格– 具备良好英语水平申请人的简化资金文件之类别 加拿大使馆, 北京 请在递交申请之前仔细阅读此份表格。所有申请文件将用以证明你被获准进入加拿大符合移民及难民保护法之 要求。未能提供完整、真实及准确的文件有可能导致你的申请被拒签。 . 所有学习许可申请将基于申请人递交的文件进行审理。请确保你递交在申请表格中提及的所有相关文件。 所有文件必须与你的申请表及申请受理费同时递交。只有英文或法文的文件可以被接受。所有中文文件必须附有 英文或法文翻译件。 所有申请表均免费，并可以从使馆网站下载: www.beijing.gc.ca 警告:提供不实文件或虚假信息是严重过失行为。如果你或代表你的某人直接或间接的歪曲了与你的学习许可申请相关的事实： 你的申请将被拒绝； 与此拒签相关的信息将被录入加拿大的全球移民数据库；并且 依据移民及难民保护法第40章第2节，你可能在两年内不能被获准进入加拿大。 1. 加拿大学习许可要求 你必须使签证官满意你符合移民及难民保护法之要求，并且你的在加逗留为临时性质。还必须： 使签证官满意你将在被授权的逗留期限结束后离开加拿大； 已经被一教育机构接受并持有有效的接收信函； 证明你有足够资金负担你的在加逗留; 提供所有签证官为评估你的准入性而所需的文件；以及 完成体检. 如果课程或学习项目为期六个月及以下，则不需要学习许可。 2. 学习许可申请的要求–简化资金文件之类别 自2011年5月3日起，符合条件的申请人可递交由加拿大的金融机构参与出具的有效担保投资证(GIC)以取代多数资金文件. 目前, 加拿大皇家银行(RBC) 是唯一参与的加拿大金融机构。更多信息请与RBC中国联系: 加拿大皇家银行有限公司北京分行

加拿大个人旅游签证手册

加拿大个人旅游签证手册 一、心理准备：不签证不知道咱们还是第三世界国家的人民， 想去发达国家花钱都得看别人的脸色。首先我们必须认识到这一点，放低姿态，积极准备、同时也做好签不过的准备。即便签不过也不 要在签证处和人家吵闹呀。我签之前用了10多天的时间准备各种资料，准备签不过加拿大就立刻改签欧洲去法国或德国滑雪。所以我 在准备诸如请假信、在职证明之类的材料的时候没有明确目的国家。否则签不过再找老板、公司HR签字太麻烦。 二、材料准备：我套用之前查到的一个上海MM的加拿大个人 游签证的攻略里说的， “不要以为很容易，我材料准备的真的很辛苦，而且用心良苦 ~ 想到的都准备了~ 而且还要所有材料有条理，有逻辑性~ 整套材 料就是说明了3个问题： 1)，为什么要去那里旅游（旅游的动机） 2)，无滞留可能 3)，足够旅游的资金” A. 以下是加拿大使馆签证处要求的材料清单 申请人每人须提供： 1. 两份用英文或法文填写的“临时居民签证申请表”(可以从加 拿大大使馆网上下载),并签名、注明日期。在每份表格上须亲笔签名。注意：将你雇主的电话和传真号码一并填写在表格第10栏内。 2. 一份用中文及英文，或中文及法文填写的“家属表/教育和就业细节表”(可以从加拿大大使馆网上下载),，并签名、注明日期。 在每份表格上须亲笔签名。 3. 四张在近六个月以内拍摄的护照像尺寸的照片（彩色或黑白 均可），并在每张照片的背面用汉语拼音清晰地注明该申请人的姓 名和出生日期（依照“日/月/年”的顺序）。 4. 护照或旅行证件的原件，其中必须至少有一页空白页，其有 效期至少要持续到你计划从加拿大离境日期后的一个月。 5. 两张写好自己通讯地址的可粘贴标签，将你的姓名、地址和 邮政编码用中文填写在上面。 6. 准确数额的申请费。请注意：持外交或公务护照的申请人无

加拿大 免疫证明

加拿大免疫证明 在职证明 致：签证官 xxx先生/女士自x年x月x日（现单位入职时间某年某月某日）在我们公司工作。他/她计划于xxxx年xx月(出国时间某年某月)赴贵国旅游，所有费用包括：机票费，运输费，住宿费和医疗保险等均由他/她本人承担。他/她将会根据行程按时回国并继续在我公司工作。 姓名出生日期护照号职位年薪 xxxxxxxxgxxxxxxxxxxxxxx 希望您能够予以签证 领导人姓名 领导人职位 领导的签名 公司盖章 公司电话：xxx-xxxxxx 公司地址：xxxxxx 公司名称：xxxxxx 附件一:营员所在学校在读证明(正式文件需以学校专用信笺打印) 在读证明

兹证明_____________，出生日期________________,为我校(校名，年 级)___________________学生，本校在______________________期无课程安排 并对其参加加拿大夏令营无任何反对意见。 特此证明。 日期： 学校盖章 certification weherebyconfirmthat____________,bornon___________,iscurre ntlyastudentofourschool______________________________.andther earenocoursesarrangedduringtheperiodof_______________________ _________.wehavenoobjectiononhis/herattendingofthesummerschoo lprgramincanada.yourkindassistancetohis/hermatterishighlyappr eciated. thankyouforyourkindattention. date： scholnameandseal: 加拿大留学存款证明

加拿大探亲签证办理的注意事项有哪些

加拿大探亲签证办理的注意事项有哪些 加拿大探亲签证办理的注意事项有哪些 加拿大探亲签证是家长对于想要看望国外留学的一种途径办理方法。加拿大探亲访友签证的办理过程中需要填写加拿大探亲申请表。针对每一个环节，申请人应该都有合理的思考和回答能力。以下三 方面是申请人需要思考的问题。 第一，探亲的签证 加拿大没有陪读签证之说，亲友之间的探访必须申请访问加拿大探亲签证(VisitorVisa)。 第二，探亲的对象 加拿大留学专家表示，最好是直系亲属之间的探访，比如父母探子女，夫妻互访，甚至祖父母探孙辈都是可能的，但是加拿大签证 官很少支持对旁系亲属或非亲属(所谓朋友)的探访。亲属之间的探 访以父母探子女最容易，而夫妻互访签证通过率相对比较低。所以，加拿大探亲访友签证的`办理也要针对不同人群进行申请工作。 第三，探亲的时机 最好是学生赴加拿大一段时间之后再申请去探望，如果能赶上节假日就更好了。有些低龄学生的父母如果打算亲自送孩子过去的， 也最好在学生获签之后再递探亲申请，这样的签证比之学生去后再 签虽然难度大一些，但大多数情况下还是可能成功的。 第四，探亲的时间 大部分探亲申请签证官一次性给半年的签证，到达加拿大以后可以申请续签，但通常只能申请一次，这一次签证官一般也给半年， 也就是说探亲时间最长为一年。 第五，探亲的申请

探亲申请周期比留学要短，通常5个工作日即可出结果，同时，除非是70岁以上的老人，申请人无需体检。 第六，探亲的条件 第七，探亲的限制 持探亲签证不能在加拿大申请转为学生签证，探亲签证也只有一次往返的机会(学生签证是多次往返的)。 综合上述的内容，加拿大探亲签证的办理只要满足上述的7条内容，相信申请人的加拿大探亲访友签证一定能够顺利的签下。另外 留学要提醒您的是：加拿大探亲申请表的填写内容一定要属实，不 可造假。 加拿大高等教育主要在大学和学院里开展，也就是我们常说的university和college。和我们传统印象中的大学、大专不同，加 拿大学院偏重培养就业人才，课程更偏向就业;大学更偏重培养研究 性人才，课程更偏向教授学生研究和创新。加拿大以其良好的国民 福利待遇、高水平的教学质量，受到了越来越多家长和学生的青睐。申请加拿大本科留学关键申请因素包括： 高中在读证明原件，或高中毕业证书复印件及翻译件(加盖学校 公章)，或高中毕业证书公证件; 高中成绩单原件或公证文件; 一份书面个人陈述(视申请学校而定); 完整的学校申请表; 其它对申请有利的材料; 护照扫描或者复印件; 申请费。

加拿大官网旅游签证_在职收入证明(中英文)

（在职收入证明，给加拿大官网网签用的是英文版。下面附的中文翻译是不需要的，大家使用的时候请删除。在职证明由本人亲自撰写，白本获签8年多次往返，如有其他疑问可以与我联系，新浪微博：神马菜菜籽） DATE:****/**/** 翻译：时间：****年**月**日 Visa Section 翻译：签证部门 Ms./Mr. **** (ID No.******************) is an employee of the *** department in our company since ****. Her/His annual income is about RMB **,***, incloding salary, bonus, and subsidies. We have approved her/his annual leave from ****/**/** to ****/**/** for her/his holiday to *******. All the expenses during the travel will be borne by herself/himself. We hereby guarantee Ms./Mr. **** will obey the laws in outbound and we shall retain her/his position till the end of the holiday. 翻译：****女士/先生（身份证号：******************）自****年起在我公司***部门开始工作。她/他的年收入大约为***元人民币，包括基本工资、年终奖金和其他补贴。我们已经批准了她/他去***国家的假期，从****年**月**日到****年**月**日。所有旅行开支由她/他本人负担，我公司兹证明**女士/先生将遵守一切贵国法律，我公司将在她/他旅行期间保留她/他的职位直到回国。 Signature：（给你出证明的领导的签名、加盖公司公章） Position: **********（给你出证明的领导的职位） Company：**********（公司名） Add：**************（公司地址） Tel：***********（公司电话） Fax：***********（公司传真）

加拿大签证基本材料

加拿大留学签证部分基本材料： 寸白底免冠彩照 个人陈述 、加拿大大使馆收取的签证费 加拿大工作签证所需材料 一、国外邀请方应提供以下材料： 二、国内申请人应提供以下材料：

护照原件及复印件，有效期至少要持续到申请人计划从加拿大离境后的一个月三张两寸的白色背景的彩色照片 护照的原件及首页和尾页的复印件！！！！。 两份用中文写有申请姓名，地址及邮编的粘性贴纸 两份申请表格（英文/法文） 一份家属表及教育和就业细节表格（中文及英文/法文） 加拿大旅游签证所需材料 一、加拿大办理旅游签证，您需要配合提供以下材料：

二、注意事项：以上文件尽量提供原件！ 加拿大探亲访友所需材料 一、国外邀请方应提供以下材料：

、说明访问目的的邀请函（原件或复印件均可）！！ 、邀请人在加拿大的身份证件复印件（例如：永久居民卡的正反面复印件、学习许、尽量提供由加拿大海关或税务署出具的邀请人及其配偶的税收状况证明（原件或二、国内申请人应提供以下材料： （例如：户口本或结婚证或往来信件等） 地址及邮编的粘性贴纸 表）。(我单位填写) 三、以上材料尽量提供原件和复印件；签证大约需要7天；

加拿大过境签证所需材料 教育和就业细节表”，并在表格上须亲笔签名。 、两张写好通讯地址的可粘贴标签，将你的姓名、地址和邮编用中文填写在上面。 加拿大商务签证所需材料 一、国外邀请方应提供以下材料： 二、国内申请人应提供以下材料：

二、注意事项： 接受全国的客人。所有的申请人都可以在北京申请签证。 人。 因加拿大是移民性国家，对申请人的审核较严格，请尽量多的提供有力证据，证

加拿大签证办理流程

加拿大签证办理流程 加拿大商务签证办理流程 个人身份证明 护照 有效期超过6个月的因私护照原件，如有旧护照请提供，如旧护照丢失需公安机关开具丢失证明。 照片 三张2寸白底彩色护照照片(白底)，最近半年内拍摄，背面标上名字拼音和出生日期。 户口本 全家户口本整本复印件(包括迁出、注销页)，若配偶及子女不在同一户口本，请一同提供配偶及子女户口本整本复印件。 资产证明 1. 资产证明原件和复印件 2.如房产证如有请提供，车辆登记证，定期存折，银行存款证明(存款证明最好要5万元以上); 3.最近6个月的银行对账单盖银行章 在职证明： 使用印有公司抬头信笺由中方雇主签发的准假信原件，此信必须包含： 旅行目的;

用中文注明的雇主全称和地址、以及电话和传真号码; 申请人的职务、收入和起聘日期;以及说明此次旅行所有相关费用支付责任的声明。 邀请函 邀请信必须由与申请人进行直接业务往来的一方出具，包含：邀请人的全称及职务、公司地址、电话和传真号码; 被邀请的所有成员的姓名及分别的职务，以及其分别雇主的全称; 邀请缘由的简述，其中包含将要进行的商务或贸易详情; 预期的访问期限及详细行程安排; 说明此次旅行所有相关费用支付责任的声明; 如适用，加拿大邀请方与中方企业签署的合同及/或协议的副本、以及双方贸易往来的证明。 如适用，任何显示与邀请方之间持续性或预期中的商务往来的文件。 学生及儿童 请假证明 1.若申请人为在校学生，需提供学校英文版在读证明原件，内容需包括：学校名称，地址和电话，学生所学专业或所在班级，学校假期时间等. 2.学生证原件及复印件 其他所需材料 表格： 1)英文填写完整的《临时居民签证申请表》(imm5257)

加拿大各类签证办理常识

加拿大签证怎么申请?加拿大签证有哪些分类? 大签 由于加拿大移民部颁发的《学习许可》、《工作许可》、《居留许可》等均是一张大纸，坊间称这一类的身份文件为大签。不过需要特别注意的是，大签是一个外国人在加拿大的身 份确认文件，但不是一个出入境凭证，也就是说只有大签无法入境加拿大! 为了保持你的合法身份，在加拿大境内的外国人(学生、务工者等)，务必在大签过期之 前妥善操作续签手续，确保身份合法有效。 小签 小签就是贴在护照上的签证(Visa)，它的唯一作用就是入境加拿大的门票。如果没有小签，会遭遇以下情况： 1、在搭乘飞机来加拿大时，会被拒绝; 2、在中国出海关时，会以没有签证为由被海关拦下，拒绝出境; 3、由于没有签证，无法入境加拿大。 与此同时，请特别注意： 1、有了小签，意味着你只是有了入境加拿大的可能性，但并不意味着你100%会被允许 入境。因为根据加拿大移民法，加拿大边境服务局(CBSA)，也就是俗话说的加拿大海关才是 有权决定是否允许你入境，并且给予你相应居留时间的人; 2、根据美国-加拿大的特别规约，从加拿大仅前往美国，再从美国返回，只需要出示有 效大签，无需使用小签入境; 3、对于免签入境国家、地区的公民，无需申请小签。但是，原则上需要提前申请 eTA(电子旅行证)乘坐飞机入境，美国公民除外; 4、对于加拿大人(加拿大公民、加拿大永久居民)来说不存在小签的问题，前者持护照入境，后者持枫叶卡入境。 小签过期怎么办? 如果在加拿大境内合法学习工作，拥有《学习许可》、《工作许可》这类的大签，建议 大家直接在加拿大境内完成“小签”申请。当然了，如果情况紧急不得不离开离开加拿大，也 可以选择在境外递交“小签”申请，完成贴签后再返回加拿大。 另外，关于加拿大留学与毕业工签政策，坊间总有各种各样的版本，再来讨论一下这个 热门话题：只要留学，就能有“毕业工签”吗? 来加拿大留学的人，大多希望能够在毕业后有机会留下。这样不仅可以积累加拿大工作 经验并获得一定收入，还能有充分时间考虑是否移民和如何移民的问题。因此，毕业后能不 能获得毕业工签就变成了最关键的问题。那么在什么情况下，留学生才能获得毕业工签呢?综合来说，需要具备以下这四个条件。

加拿大留学签证资金证明材料详解

加拿大留学签证资金证明材料详解 加拿大留学签证资金证明材料详解。在很多同学的心目中，加拿大签证的申请材料非常繁琐，尤其是在资金证明材料方面要求很严格。尽管加拿大使馆在09年初调整了对存款历史的追溯期，从18个月降为12个月，但是对于材料提供的详细程度还是丝毫没有改变。而正因为材料准备的复杂性，很多学生在申请材料准备时有所疏漏而导致拒签。其实，加拿大签证对于材料的要求是非常有逻辑性的，本文将与大家一起分享和中在加拿大签证的材料准备中，对于资金方面材料准备的一些心得。 首先让我们看看加拿大官方列出的资金证明要求： 反映至少十二个月资金累积历史的证明。鉴于此，我们要求如下： ·日期为最近两个月内的显示现有可用资金的存款证明原件； ·存单原件及/或存折原件；以及 ·资金来源的书面说明。 其它形式资产的相关文件，如股市账户、商业交易文件及房地产交易文件；虽然不能替代上述所需文件，但可以附于申请内。若无法提供文件证明，申请人也可以提供一份书面说明。 申请人父母的收入及雇佣证明。要求如下： ·申请人父/母各自的现任雇主出具的雇佣证明信原件，包含父/母各自雇主的全称、地址和电话；父/母在该处就业年限、职务、最近两年的收入、有无任何奖金和额外收入。如果申请人由父母以外的人士资助，请按照以上要求提供相应信息；及/或

·地方税务机关出具的最近十二个月中父/母各自个人收入所得税的缴税单原件，包含缴税人姓名及其名下所缴纳的金额。 如果父/母一方或双方拥有或部分拥有某公司，请递交： ·营业登记证的公证件 ·近期的缴税单据 ·公司上一个财务年度的财务审计报表和验资报告 从使馆给出的资金材料要求，我们不难发现，使馆对于资金来源的解释只有一个要求，即"合理"。 在所有的资金材料中，最中心的就是现金存款，而其他材料无非就是围绕这个存款来说明，这笔钱是"合理"的收入，不可能是通过非法手段获得，也不是借来充数的。存款的金额，一般需要保证能支付学生在加期间所有的学费和生活费用。 对于大部分的同学来说提供这样一笔足额的存款都不算困难，困难的是如何证明其"合理"。根据使馆的要求，我们至少需要证明这笔资金在过去十二个月的存在的状况，即证明在过去至少十二个月里面，担保人都是持有这笔资金的。一般情况下，资金的来源存在以下几种情况： 1.资金一直都存在银行，已经存满12个月； 2.资金由股票或基金账户转来； 3.固定资产买卖所得； 4.股东分红。 如果是资金一直存在银行的，那么担保人一般都是有定期存款的习惯，可以追溯更早以前的定期存款记录，找到资金累积的历史，向签证官说明，这笔资金是为学生留学而专门存下来的。虽然使馆不要求十二个月以前的历史记

加拿大留学申请签证注意事项

加拿大留学申请签证注意事项 加拿大留学申请签证注意事项 加拿大留学申请签证提前多久办理。去往加拿大留学需要办理签证，那么，办理签证需要提前多久办理才不会耽误留学进度呢？下 面我们一起来看下。 【加拿大留学申请签证提前多久办理】 加拿大留学签证时间在材料准备充分的情况下，递给大使馆审理时间大概是15个工作日，留学期间按常规不能打工的，兼职可以。 留学学费大概在8万-12万人民币之间。 另外在加拿大驻华使馆成立了签证审理中心后，大大提高了申请者的签证速度，原来需要4个月的签证时间，现在已缩短至1.5~2 个月。 根据加拿大使馆最新公布的统计数据显示，目前申请加拿大留学签证的人数以及获得签证的人数都比过去有所上升。同时，加拿大 留学签证的审批时间也有所缩短，以前需要6-8周的审理时间，现 在只需4-6周即可完成。 加拿大留学：首先，要被在加的一所学校录取，方可有资格获得加拿大的学生签证。 其次，申请人必须是被学校无条件地接受。（如果学校要求在签署录取信之前预先交纳费用，则录取信中应包含费用已交纳的说明） 如果学生未满十八岁就开始在加拿大读书，必须有一个法定的已成年的监护人。这个监护人必须是加拿大的公民或者永久性居民， 而且和学生住在一起学生的监护人必须给学生一份经过公证的依照 法律的声明 关于申请程序

开始正式申请学生签证时要递交的文件 1.填写完毕的申请表 2.在申请人计划前往加拿大的日期之后至少还有十八个月有效期的护照 3.学校发给申请人的录取信的原件和一份完善的影印件 4.申请人缴交学费的收据 6.在申请人名下的最少一万元加市的银行支票或汇票（接到的奖学金或研究员薪金可以抵补这一数额），如果申请人是进全日制的寄宿学校，可以用寄宿费己预交的证明来代替 7.如果学生的年龄在十八岁以下，还要有监护人的书面声明 8.一份关于申请人在加拿大就学理由的简要说明 申请人如果计划在魁北克省内的学校学习，在递交申请之前必须从魁北克政府那里得到同意接受的证明。 有关注意事项： 学生签证的申请人必须向签证官员证明 1.他们将只是为了一个临时的目的进入加拿大 3.他们已经被一所加拿大的教育机构录取 另外，申请学生签证的手续费，无论申请是否被批准，都是不退还的，领事馆要求申请人体检，其费用也要由申请人自己负担。

加拿大签证用表(加拿大签证用表,可交互)

1Importer — name, address, and telephone no.

I hereby declare that the goods described herein were: Je certifie par les présentes que les marchandises désignées dans cette déclaration ont été : 18 I declare the information contained to be true and complete. Je déclare que les renseignements contenus dans la présente déclaration sont vrais et complets. 17TOTAL Customs duties Droits de douane Excise tax Taxe d'accise 40 Remarks - Remarques 22 Cargo control no. - N° de contr?le du fret 23 GST collected on transaction no. TPS recueillie sur la transaction n° Importer Importateur Signature The goods described herein are subject to CBSA control while in Canada and must be re-exported under CBSA supervision on or before the expiry date of the permit. On re-exportation both goods and permit must be presented for identification and comparison. Tant qu'elles sont au Canada, les marchandises décrites sur le formulaire sont assujetties au contr?le de l'ASFC et doivent être réexportées sous la surveillance de l'ASFC avant ou à la date d'échéance du permis. Lors de la réexportation, les marchandises et le permis doivent être présentés aux fins d'identification et de comparaison. THIS PORTION TO BE COMPLETED BY THE CBSA FOR ACQUITTAL PURPOSES - CETTE PARTIE DOIT êTRE REMPLIE PAR L'ASFC AUX FINS D'ACQUITTEMENT 28Examined by me and re-exported from Canada Vérifiées par moi et réexportées du Canada 29Duties paid under transaction no. Droits acquittés selon le n° de la transaction 30 Examined by me and shipped in bond to:Vérifiées par moi et expédiées en douane à : CBSA office - Bureau de l'ASFC Under En vertu Cargo control no. - N° de contr?le du fret 31Destroyed under supervision Détruites sous surveillance 33 Deposit accounted for on transaction no. Dép?t comptabilisé sur le n° de la transaction 35 Deposit returned by cheque no. Dép?t retourné par chèque n° 34 Dated - En date du 36 Dated - En date du 37 Accounting centre Centre de comptabilité 38 CBSA office stamp - Timbre du bureau de l'ASFC Agent Mandataire 26 CBSA office stamp - Timbre du bureau de l'ASFC 10 111314 FAILURE TO SURRENDER THIS TEMPORARY PERMIT ON LEAVING CANADA WILL FORFEIT THE DEPOSIT. FOR ADDITIONAL INFORMATION, SEE REVERSE SIDE.LE DéP?T SERA CONFISQUé SI CE PERMIS TEMPORAIRE N'EST PAS PRéSENTé EN QUITTANT LE CANADA. POUR PLUS DE RENSEIGNEMENTS, VOIR AU VERSO. 24 Make refund cheque payable to: émettre le chèque de remboursement à l'ordre de : Postal code - Code postal Name and address - Nom et adresse 25 Deposit - Consignation US $______________ X ________ = CAN $______________Cash Argent Cheque Chèque Bond Cautionnement No. N°___________________________ Where American funds have been tendered, the deposit will be adjusted according to the U.S. exchange rate at the time of banking,and therefore the actual Canadian dollar equivalent of the deposit may differ from the amount indicated. Lorsque des devises américaines sont présentées, le montant sera rajusté pour rendre compte du taux de change en vigueur au moment de la transaction bancaire, et par conséquent, l'équivalent du dép?t en dollars canadiens peut être différent du montant indiqué.All refunds will be made in Canadian currency by means of a Government of Canada cheque. Tous les remboursements seront faits en devises canadiennes au moyen d'un chèque du gouvernement du Canada.é.-U._____________$ X ________ = ______________$ CAN Value for duty Valeur en douane Tariff treatment Traitement tarifaire 15 Value for tax Valeur taxable 16 GST TPS Mandataire — nom, adresse et n° de téléphone Importateur — nom, adresse et n° de téléphone 6Authority - Autorisation 12Rate of duty Taux de droit 9 Classification no.N° de classement 7b Quantity Quantité 7a 8 Description Weight Poids Gross - Brut Net yyyy/mm/dd - aaaa/mm/jj yyyy/mm/dd - aaaa/mm/jj yyyy/mm/dd - aaaa/mm/jj

加拿大旅游签证的条件

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