繁体中文
设为首页
加入收藏
当前位置:药品说明书与价格首页 >> 糖尿病 >> 新药推荐 >> 卡格列净片|INVOKANA(canagliflozin film-coated tablets)

卡格列净片|INVOKANA(canagliflozin film-coated tablets)

2015-02-02 02:50:35  作者:新特药房  来源:互联网  浏览次数:892  文字大小:【】【】【
简介: 英文药名:INVOKANA(canagliflozin film-coated tablets) 中文药名:卡格列净片 生产厂家:杨森制药药品介绍英文名称:Canagliflozin;商品名Invokana剂型规格:片剂,100mg,300mg适应症:用于治疗 ...

英文药名:INVOKANA(canagliflozin film-coated tablets)

中文药名:卡格列净片

生产厂家:杨森制药
药品介绍
英文名称:Canagliflozin;
商品名Invokana
剂型规格:片剂,100mg,300mg
适应症:
用于治疗成年患者的II型糖尿病,不适用于I型糖尿病或糖尿病酮症酸中毒。
用法用量:推荐开始剂量是100 mg每天1次服药天第一餐前服。耐受INVOKANA 100mg每天1次eGFR 60 mL/min/1.73 m2或更大和需要增加血糖控制患者,剂量可以增加至300 mg每天1次。
药理作用:
钠-葡萄糖共转运体(SGLT)是一种葡萄糖转运蛋白,有两种亚型即SGLT1和SGLT2,分别分布于小肠粘膜和肾小管,能够将葡萄糖转运进血液。Canagliflozin能抑制SGLT2,使肾小管中的葡萄糖不能顺利重吸收进入血液而随尿液排出,从而降低血糖浓度。
2013年3月29日,美国FDA批准了强生Invokana片(canagliflozin)结合饮食与锻炼,用于治疗2型糖尿病成人患者。Invokana由强生旗下杨森制药公司生产。
Invokana 100 mg film-coated tablets
Invokana 300 mg film-coated tablets

---------------------------------------------------
Invokana 100 mg film-coated tablets
1. Name of the medicinal product
Invokana 100 mg film-coated tablets
2. Qualitative and quantitative composition
Each tablet contains canagliflozin hemihydrate, equivalent to 100 mg canagliflozin.
Excipient(s) with known effect:
Each tablet contains 39.2 mg lactose.
For the full list of excipients, see section 6.1.
3. Pharmaceutical form
Film-coated tablet (tablet).
- The tablet is yellow, capsule-shaped, approximately 11 mm in length, immediate-release and film-coated, with “CFZ” on one side and “100” on the other side.
4. Clinical particulars
4.1 Therapeutic indications
Invokana is indicated in adults aged 18 years and older with type 2 diabetes mellitus to improve glycaemic control as:
Monotherapy
When diet and exercise alone do not provide adequate glycaemic control in patients for whom the use of metformin is considered inappropriate due to intolerance or contraindications.
Add-on therapy
Add-on therapy with other glucose-lowering medicinal products including insulin, when these, together with diet and exercise, do not provide adequate glycaemic control (see sections 4.4, 4.5, and 5.1 for available data on different add-on therapies).
4.2 Posology and method of administration
Posology
The recommended starting dose of canagliflozin is 100 mg once daily. In patients tolerating canagliflozin 100 mg once daily who have an eGFR ≥ 60 mL/min/1.73 m2 or CrCl ≥ 60 mL/min and need tighter glycaemic control, the dose can be increased to 300 mg once daily orally (see below and section 4.4).
Care should be taken when increasing the dose in patients ≥ 75 years of age, patients with known cardiovascular disease, or other patients for whom the initial canagliflozin-induced diuresis poses a risk (see section 4.4). In patients with evidence of volume depletion, correcting this condition prior to initiation of canagliflozin is recommended (see section 4.4).
When canagliflozin is used as add-on therapy with insulin or an insulin secretagogue (e.g., sulphonylurea), a lower dose of insulin or the insulin secretagogue may be considered to reduce the risk of hypoglycaemia (see sections 4.5 and 4.8).
Elderly (≥ 65 years old)
Renal function and risk of volume depletion should be taken into account (see section 4.4).
Patients with renal impairment
For patients with an eGFR 60 mL/min/1.73 m2 to < 90 mL/min/1.73 m2 or CrCl 60 mL/min to < 90 mL/min, no dose adjustment is needed.
Canagliflozin should not be initiated in patients with an eGFR < 60 mL/min/1.73 m2 or CrCl < 60 mL/min. In patients tolerating canagliflozin whose eGFR falls persistently below 60 mL/min/1.73 m2 or CrCl 60 mL/min, the dose of canagliflozin should be adjusted to or maintained at 100 mg once daily. Canagliflozin should be discontinued when eGFR is persistently below 45 mL/min/1.73 m2 or CrCl persistently below 45 mL/min (see sections 4.4, 4.8, 5.1, and 5.2).
Canagliflozin should also not be used in patients with end stage renal disease (ESRD) or in patients on dialysis as it is not expected to be effective in such populations (see sections 4.4 and 5.2).
Patients with hepatic impairment
For patients with mild or moderate hepatic impairment, no dose adjustment is required.
Canagliflozin has not been studied in patients with severe hepatic impairment and is not recommended for use in these patients (see section 5.2).
Paediatric population
The safety and efficacy of canagliflozin in children under 18 years of age have not yet been established. No data are available.
Method of administration
For oral use
Invokana should be taken orally once a day, preferably before the first meal of the day. Tablets should be swallowed whole.
If a dose is missed, it should be taken as soon as the patient remembers; however, a double dose should not be taken on the same day.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
4.4 Special warnings and precautions for use
General
Invokana has not been studied in patients with type 1 diabetes and is therefore not recommended for use in these patients.
Invokana should not be used for the treatment of diabetic ketoacidosis as it is not effective in this setting.
Use in patients with renal impairment
The efficacy of canagliflozin is dependent on renal function, and efficacy is reduced in patients who have moderate renal impairment and likely absent in patients with severe renal impairment (see section 4.2).
In patients with an eGFR < 60 mL/min/1.73 m2 or CrCl < 60 mL/min, a higher incidence of adverse reactions associated with volume depletion (e.g., postural dizziness, orthostatic hypotension, hypotension) was reported, particularly with the 300 mg dose. In addition, in such patients more events of elevated potassium and greater increases in serum creatinine and blood urea nitrogen (BUN) were reported (see section 4.8).
Therefore, the canagliflozin dose should be limited to 100 mg once daily in patients with eGFR < 60 mL/min/1.73 m2 or CrCl < 60 mL/min and canagliflozin should not be used in patients with an eGFR < 45 mL/min/1.73 m2 or CrCl < 45 mL/min (see section 4.2). Canagliflozin has not been studied in severe renal impairment (eGFR < 30 mL/min/1.73 m2 or CrCl < 30 mL/min) or ESRD.
Monitoring of renal function is recommended as follows:
- Prior to initiation of canagliflozin and at least annually, thereafter (see sections 4.2, 4.8, 5.1, and 5.2)
- Prior to initiation of concomitant medicinal products that may reduce renal function and periodically thereafter
- For renal function approaching moderate renal impairment, at least 2 times to 4 times per year. If renal function falls persistently below eGFR 45 mL/min/1.73 m2 or CrCl < 45 mL/min, canagliflozin treatment should be discontinued.
Use in patients at risk for adverse reactions related to volume depletion
Due to its mechanism of action, canagliflozin, by increasing urinary glucose excretion (UGE) induces an osmotic diuresis, which may reduce intravascular volume and decrease blood pressure (see section 5.1). In controlled clinical studies of canagliflozin, increases in adverse reactions related to volume depletion (e.g., postural dizziness, orthostatic hypotension, or hypotension) were seen more commonly with the 300 mg dose and occurred most frequently in the first three months (see section 4.8).
Caution should be exercised in patients for whom a canagliflozin-induced drop in blood pressure could pose a risk, such as patients with known cardiovascular disease, patients with an eGFR < 60 mL/min/1.73 m2, patients on anti-hypertensive therapy with a history of hypotension, patients on diuretics, or elderly patients (≥ 65 years of age) (see sections 4.2 and 4.8).
Due to volume depletion, generally small mean decreases in eGFR were seen within the first 6 weeks of treatment initiation with canagliflozin. In patients susceptible to greater reductions in intravascular volume as described above, larger decreases in eGFR (> 30%) were sometimes seen, which subsequently improved, and infrequently required interruption of treatment with canagliflozin (see section 4.8).
Patients should be advised to report symptoms of volume depletion. Canagliflozin is not recommended for use in patients receiving loop diuretics (see section 4.5) or who are volume depleted, e.g., due to acute illness (such as gastrointestinal illness).
For patients receiving canagliflozin, in case of intercurrent conditions that may lead to volume depletion (such as a gastrointestinal illness), careful monitoring of volume status (e.g., physical examination, blood pressure measurements, laboratory tests including renal function tests), and serum electrolytes is recommended. Temporary interruption of treatment with canagliflozin may be considered for patients who develop volume depletion while on canagliflozin therapy until the condition is corrected. If interrupted, consideration should be given to more frequent glucose monitoring.
Elevated haematocrit
Haematocrit increase was observed with canagliflozin treatment (see section 4.8); therefore, caution in patients with already elevated haematocrit is warranted.
Elderly (≥ 65 years old)
Elderly patients may be at a greater risk for volume depletion, are more likely to be treated with diuretics, and to have impaired renal function. In patients ≥ 75 years of age, a higher incidence of adverse reactions associated with volume depletion (e.g., postural dizziness, orthostatic hypotension, hypotension) was reported. In addition, in such patients greater decreases in eGFR were reported (see sections 4.2 and 4.8).
Genital mycotic infections
Consistent with the mechanism of sodium glucose co-transporter 2 (SGLT2) inhibition with increased UGE, vulvovaginal candidiasis in females and balanitis or balanoposthitis in males were reported in clinical trials (see section 4.8). Male and female patients with a history of genital mycotic infections were more likely to develop an infection. Balanitis or balanoposthitis occurred primarily in uncircumcised male patients. In rare instances, phimosis was reported and sometimes circumcision was performed. The majority of genital mycotic infections were treated with topical antifungal treatments, either prescribed by a healthcare professional or self-treated while continuing therapy with Invokana.
Cardiac failure
Experience in New York Heart Association (NYHA) class III is limited, and there is no experience in clinical studies with canagliflozin in NYHA class IV.
Urine laboratory assessments
Due to its mechanism of action, patients taking canagliflozin will test positive for glucose in their urine.
Lactose intolerance
The tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.
4.5 Interaction with other medicinal products and other forms of interaction
Pharmacodynamic interactions
Diuretics
Canagliflozin may add to the effect of diuretics and may increase the risk of dehydration and hypotension (see section 4.4).
Insulin and insulin secretagogues
Insulin and insulin secretagogues, such as sulphonylureas, can cause hypoglycaemia. Therefore, a lower dose of insulin or an insulin secretagogue may be required to reduce the risk of hypoglycaemia when used in combination with canagliflozin (see sections 4.2 and 4.8).
Pharmacokinetic interactions
Effects of other medicinal products on canagliflozin
The metabolism of canagliflozin is primarily via glucuronide conjugation mediated by UDP glucuronosyl transferase 1A9 (UGT1A9) and 2B4 (UGT2B4). Canagliflozin is transported by P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP).
Enzyme inducers (such as St. John's wort [Hypericum perforatum], rifampicin, barbiturates, phenytoin, carbamazepine, ritonavir, efavirenz) may give rise to decreased exposure of canagliflozin. Following co-administration of canagliflozin with rifampicin (an inducer of various active transporters and drug-metabolising enzymes), 51% and 28% decreases in canagliflozin systemic exposure (AUC) and peak concentration (Cmax) were observed. These decreases in exposure to canagliflozin may decrease efficacy.
If a combined inducer of these UGT enzymes and transport proteins must be co-administered with canagliflozin, monitoring of glycaemic control to assess response to canagliflozin is appropriate. If an inducer of these UGT enzymes must be co-administered with canagliflozin, increasing the dose to 300 mg once daily may be considered if patients are currently tolerating canagliflozin 100 mg once daily, have an eGFR ≥ 60 mL/min/1.73 m2 or CrCl ≥ 60 mL/min, and require additional glycaemic control. In patients with an eGFR 45 mL/min/1.73 m2 to < 60 mL/min/1.73 m2 or CrCl 45 mL/min to < 60 mL/min taking canagliflozin 100 mg who are receiving concurrent therapy with a UGT enzyme inducer and who require additional glycaemic control, other glucose-lowering therapies should be considered (see sections 4.2 and 4.4).
Cholestyramine may potentially reduce canagliflozin exposure. Dosing of canagliflozin should occur at least 1 hour before or 4-6 hours after administration of a bile acid sequestrant to minimise possible interference with their absorption.
Interaction studies suggest that the pharmacokinetics of canagliflozin are not altered by metformin, hydrochlorothiazide, oral contraceptives (ethinyl estradiol and levonorgestrol), ciclosporin, and/or probenecid.
Effects of canagliflozin on other medicinal products
Digoxin: The combination of canagliflozin 300 mg once daily for 7 days with a single dose of digoxin 0.5 mg followed by 0.25 mg daily for 6 days resulted in a 20% increase in AUC and a 36% increase in Cmax of digoxin, probably due to inhibition of P-gp. Canagliflozin has been observed to inhibit P-gp in vitro. Patients taking digoxin or other cardiac glycosides (e.g., digitoxin) should be monitored appropriately.
Dabigatran: The effect of concomitant administration of canagliflozin (a weak P-gp inhibitor) on dabigatran etexilate (a P-gp substrate) has not been studied. As dabigatran concentrations may be increased in the presence of canagliflozin, monitoring (looking for signs of bleeding or anaemia) should be exercised when dabigatran is combined with canagliflozin.
Simvastatin: The combination of canagliflozin 300 mg once daily for 6 days with a single dose of simvastatin (CYP3A4 substrate) 40 mg resulted in a 12% increase in AUC and a 9% increase in Cmax of simvastatin and an 18% increase in AUC and a 26% increase in Cmax of simvastatin acid. The increases in simvastatin and simvastatin acid exposures are not considered clinically relevant.
Inhibition of BCRP by canagliflozin cannot be excluded at an intestinal level and increased exposure may therefore occur for medicinal products transported by BCRP, e.g. certain statins like rosuvastatin and some anti-cancer medicinal products.
In interaction studies, canagliflozin at steady-state had no clinically relevant effect on the pharmacokinetics of metformin, oral contraceptives (ethinyl estradiol and levonorgestrol), glibenclamide, paracetamol, hydrochlorothiazide, or warfarin.
Drug/Laboratory test interference
1,5-AG assay
Increases in urinary glucose excretion with Invokana can falsely lower 1,5-anhydroglucitol (1,5-AG) levels and make measurements of 1,5-AG unreliable in assessing glycemic control. Therefore, 1,5-AG assays should not be used for assessment of glycemic control in patients on canagliflozin. For further detail, it may be advisable to contact the specific manufacturer of the 1,5-AG assay.
4.6 Fertility, pregnancy and lactation
Pregnancy
There are no data from the use of canagliflozin in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3).
Canagliflozin should not be used during pregnancy. When pregnancy is detected, treatment with canagliflozin should be discontinued.
Breast-feeding
It is unknown whether canagliflozin and/or its metabolites are excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of canagliflozin/metabolites in milk, as well as pharmacologically mediated effects in breast-feeding offspring and juvenile rats exposed to canagliflozin (see section 5.3). A risk to newborns/infants cannot be excluded. Canagliflozin should not be used during breast-feeding.
Fertility
The effect of canagliflozin on fertility in humans has not been studied. No effects on fertility were observed in animal studies (see section 5.3).
4.7 Effects on ability to drive and use machines
Canagliflozin has no or negligible influence on the ability to drive and use machines. However, patients should be alerted to the risk of hypoglycaemia when canagliflozin is used as add-on therapy with insulin or an insulin secretagogue, and to the elevated risk of adverse reactions related to volume depletion, such as postural dizziness (see sections 4.2, 4.4 and 4.8).
4.8 Undesirable effects
Summary of the safety profile
The safety of canagliflozin was evaluated in 10,285 patients with type 2 diabetes, including 3,139 patients treated with canagliflozin 100 mg and 3,506 patients treated with canagliflozin 300 mg, who received medicinal product in nine double-blind, controlled phase 3 clinical studies.
The primary assessment of safety and tolerability was conducted in a pooled analysis (n=2,313) of four 26-week placebo-controlled clinical studies (monotherapy and add-on therapy with metformin, metformin and a sulphonylurea, and metformin and pioglitazone). The most commonly reported adverse reactions during treatment were hypoglycaemia in combination with insulin or a sulphonylurea, vulvovaginal candidiasis, urinary tract infection, and polyuria or pollakiuria (i.e., urinary frequency). Adverse reactions leading to discontinuation of ≥ 0.5% of all canagliflozin-treated patients in these studies were vulvovaginal candidiasis (0.7% of female patients) and balanitis or balanoposthitis (0.5% of male patients). Additional safety analyses (including long-term data) from data across the entire canagliflozin programme (placebo- and active-controlled studies) were conducted to assess reported adverse reactions in order to identify adverse reactions (see table 1) (see sections 4.2 and 4.4).
Tabulated list of adverse reactions
Adverse reactions in table 1 are based on the pooled analysis of the four 26-week placebo-controlled studies (n=2,313) described above. Adverse reactions listed below are classified according to frequency and system organ class (SOC). Frequency categories are defined according to the following convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data).
Table 1: Frequency of adverse reactions (MedDRA) in placebo-controlled studiesa

System organ class

Frequency

Adverse reaction

Metabolism and nutrition disorders

very common

Hypoglycaemia in combination with insulin or sulphonylurea

uncommon

Dehydration*

Nervous system disorders

uncommon

Dizziness postural*, Syncope*

Vascular disorders

uncommon

Hypotension*, Orthostatic hypotension*

Gastrointestinal disorders

common

Constipation, Thirstb, Nausea

Skin and subcutaneous tissue disorders

uncommon

Rashc, Urticaria

Musculoskeletal and connective tissue disorders

uncommon

Bone fractured

Renal and urinary disorders

common

Polyuria or Pollakiuriae, Urinary tract infectionf

Reproductive system and breast disorders

very common

Vulvovaginal candidiasis**, g

common

Balanitis or balanoposthitis**, h

Investigations

common

Dyslipidemiai, Haematocrit increased**, j

uncommon

Blood creatinine increased**, k, Blood urea increased **, l, Blood potassium increased**, m, Blood phosphate increasedn

Related to volume depletion; see section 4.4.
See section 4.4.
a Safety data profiles from individual pivotal studies (including studies in moderately renally impaired patients; older patients [≥ 55 years of age to ≤ 80 years of age]; patients with increased CV-risk) were generally consistent with the adverse reactions identified in this table.
b Thirst includes the terms thirst, dry mouth, and polydipsia.
c Rash includes the terms rash erythematous, rash generalised, rash macular, rash maculopapular, rash papular, rash pruritic, rash pustular, and rash vesicular.
d Bone fracture was reported in 0.7% and 0.6% for canagliflozin 100 mg and 300 mg, respectively, compared to 0.3% for placebo. See bone fracture section below for additional information.
e Polyuria or pollakiuria includes the terms polyuria, pollakiuria, micturition urgency, nocturia, and urine output increased.
f Urinary tract infection includes the terms urinary tract infection, cystitis, kidney infection, and urosepsis. There was no imbalance among canagliflozin 100 mg, canagliflozin 300 mg, and placebo for kidney infection or urosepsis.
g Vulvovaginal candidiasis includes the terms vulvovaginal candidiasis, vulvovaginal mycotic infection, vulvovaginitis, vaginal infection, vulvitis, and genital infection fungal.
h Balanitis or balanoposthitis includes the terms balanitis, balanoposthitis, balanitis candida, and genital infection fungal.
i Mean percent increases from baseline for canagliflozin 100 mg and 300 mg versus placebo, respectively, were total cholesterol 3.4% and 5.2% versus 0.9%; HDL-cholesterol 9.4% and 10.3% versus 4.0%; LDL-cholesterol 5.7% and 9.3% versus 1.3%; non-HDL-cholesterol 2.2% and 4.4% versus 0.7%; triglycerides 2.4% and 0.0% versus 7.6%.
j Mean changes from baseline in haematocrit were 2.4% and 2.5% for canagliflozin 100 mg and 300 mg, respectively, compared to 0.0% for placebo.
k Mean percent changes from baseline in creatinine were 2.8% and 4.0% for canagliflozin 100 mg and 300 mg, respectively, compared to 1.5% for placebo.
l Mean percent changes from baseline in blood urea nitrogen were 17.1% and 18.0% for canagliflozin 100 mg and 300 mg, respectively, compared to 2.7% for placebo.
m Mean percent changes from baseline in blood potassium were 0.5% and 1.0% for canagliflozin 100 mg and 300 mg, respectively, compared to 0.6% for placebo.
n Mean percent changes from baseline in serum phosphate were 3.6% and 5.1% for canagliflozin 100 mg and 300 mg, compared to 1.5% for placebo.
Description of selected adverse reactions
Adverse reactions related to volume depletion
In the pooled analysis of the four 26-week, placebo-controlled studies, the incidence of all adverse reactions related to volume depletion (e.g., postural dizziness, orthostatic hypotension, hypotension, dehydration, and syncope) was 1.2% for canagliflozin 100 mg, 1.3% for canagliflozin 300 mg, and 1.1% for placebo. The incidence with canagliflozin treatment in the two active-controlled studies was similar to comparators.
In the dedicated cardiovascular study, where patients were generally older with a higher rate of diabetes complications, the incidences of adverse reactions related to volume depletion were 2.8% with canagliflozin 100 mg, 4.6% with canagliflozin 300 mg, and 1.9% with placebo.
To assess risk factors for these adverse reactions, a larger pooled analysis (N=9,439) of patients from eight controlled phase 3 studies including both doses of canagliflozin was conducted. In this pooled analysis, patients on loop diuretics, patients with a baseline eGFR 30 mL/min/1.73 m2 to < 60 mL/min/1.73 m2, and patients ≥ 75 years of age had generally higher incidences of these adverse reactions. For patients on loop diuretics, the incidences were 3.2% on canagliflozin 100 mg and 8.8% on canagliflozin 300 mg compared to 4.7% in the control group. For patients with a baseline eGFR 30 mL/min/1.73 m2 to < 60 mL/min/1.73 m2, the incidences were 4.8% on canagliflozin 100 mg and 8.1% on canagliflozin 300 mg compared to 2.6% in the control group. In patients ≥ 75 years of age, the incidences were 4.9% on canagliflozin 100 mg and 8.7% on canagliflozin 300 mg compared to 2.6% in the control group (see sections 4.2 and 4.4).
In the dedicated cardiovascular study and the larger pooled analysis, discontinuations due to adverse reactions related to volume depletion and serious adverse reactions related to volume depletion were not increased with canagliflozin.
Hypoglycaemia in add-on therapy with insulin or insulin secretagogues
The frequency of hypoglycaemia was low (approximately 4%) among treatment groups, including placebo, when used as monotherapy or as an add-on to metformin. When canagliflozin was added to insulin therapy, hypoglycaemia was observed in 49.3%, 48.2%, and 36.8% of patients treated with canagliflozin 100 mg, canagliflozin 300 mg, and placebo, respectively, and severe hypoglycaemia occurred in 1.8%, 2.7%, and 2.5% of patients treated with canagliflozin 100 mg, canagliflozin 300 mg, and placebo, respectively. When canagliflozin was added to a sulphonylurea therapy, hypoglycaemia was observed in 4.1%, 12.5%, and 5.8% of patients treated with canagliflozin 100 mg, canagliflozin 300 mg, and placebo, respectively (see sections 4.2 and 4.5).
Genital mycotic infections
Vulvovaginal candidiasis (including vulvovaginitis and vulvovaginal mycotic infection) was reported in 10.4% and 11.4% of female patients treated with canagliflozin 100 mg and canagliflozin 300 mg, respectively, compared to 3.2% in placebo-treated female patients. Most reports of vulvovaginal candidiasis occurred during the first four months of treatment with canagliflozin. Among female patients taking canagliflozin, 2.3% experienced more than one infection. Overall, 0.7% of all female patients discontinued canagliflozin due to vulvovaginal candidiasis (see section 4.4).
Candidal balanitis or balanoposthitis was reported in 4.2% and 3.7% of male patients treated with canagliflozin 100 mg and canagliflozin 300 mg, respectively, compared to 0.6% in placebo-treated male patients. Among male patients taking canagliflozin, 0.9% had more than one infection. Overall, 0.5% of male patients discontinued canagliflozin due to candidial balanitis or balanoposthitis. In rare instances, phimosis was reported and sometimes circumcision was performed (see section 4.4).
Urinary tract infections
Urinary tract infections were more frequently reported for canagliflozin 100 mg and 300 mg (5.9% versus 4.3%, respectively) compared to 4.0% with placebo. Most infections were mild to moderate with no increase in the occurrence of serious adverse reactions. Subjects responded to standard treatments while continuing canagliflozin treatment. The incidence of recurrent infections was not increased with canagliflozin.
Bone fracture
In a cardiovascular study of 4,327 patients with known or at high risk for cardiovascular disease, the incidence rates of bone fracture were 1.6, 1.6, and 1.1 per 100 patient years of exposure to canagliflozin 100 mg, canagliflozin 300 mg, and placebo, respectively, with the fracture imbalance initially occurring within the first 26 weeks of therapy. In other type 2 diabetes studies with canagliflozin, which enrolled a general diabetes population of approximately 5,800 patients, no difference in fracture risk was observed relative to control. After 104 weeks of treatment, canagliflozin did not adversely affect bone mineral density.
Special populations
Elderly (≥ 65 years old)
In a pooled analysis of eight placebo-controlled and active-controlled studies, the safety profile in elderly patients was generally consistent with younger patients. Patients ≥ 75 years of age had a higher incidence of adverse reactions related to volume depletion (such as postural dizziness, orthostatic hypotension, hypotension) with incidences of 4.9%, 8.7%, and 2.6% on canagliflozin 100 mg, canagliflozin 300 mg, and in the control group, respectively. Decreases in eGFR (-3.6% and -5.2%) were reported with canagliflozin 100 mg and canagliflozin 300 mg, respectively, compared to the control group (-3.0%) (see sections 4.2 and 4.4).
Patients with renal impairment (eGFR < 60 mL/min/1.73 m2 or CrCl < 60 mL/min)
Patients with a baseline eGFR < 60 mL/min/1.73 m2 or CrCl < 60 mL/min had a higher incidence of adverse reactions associated with volume depletion (e.g., postural dizziness, orthostatic hypotension, hypotension) with incidences of 4.7%, 8.1%, and 1.5% on canagliflozin 100 mg, canagliflozin 300 mg, and placebo, respectively (see sections 4.2 and 4.4).
The overall incidence of elevated serum potassium was higher in patients with moderate renal impairment with incidences of 7.5%, 12.3%, and 8.1% on canagliflozin 100 mg, canagliflozin 300 mg, and placebo, respectively. In general, elevations were transient and did not require specific treatment.
Increases in serum creatinine of 10-11% and BUN of approximately 12% were observed with both doses of canagliflozin. The proportion of patients with larger decreases in eGFR (> 30%) at any time during treatment was 9.3%, 12.2%, and 4.9% with canagliflozin 100 mg, canagliflozin 300 mg, and placebo, respectively. At study endpoint, 3.0% of patients treated with canagliflozin 100 mg, 4.0% with canagliflozin 300 mg, and 3.3% with placebo had such decreases (see section 4.4).
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:
United Kingdom
Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard
Ireland
IMB Pharmacovigilance
Earlsfort Terrace
IRL - Dublin 2
Tel: +353 1 6764971
Fax: +353 1 6762517
Website: www.imb.ie
e-mail: imbpharmacovigilance@imb.ie
4.9 Overdose
Single doses up to 1,600 mg of canagliflozin in healthy subjects and canagliflozin 300 mg twice daily for 12 weeks in patients with type 2 diabetes were generally well-tolerated.
Therapy
In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute clinical measures if required. Canagliflozin was negligibly removed during a 4-hour haemodialysis session. Canagliflozin is not expected to be dialysable by peritoneal dialysis.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Drugs used in diabetes, other blood glucose lowering drugs, excluding insulins. ATC code: A10BX11.
Mechanism of action
The SGLT2 transporter, expressed in the proximal renal tubules, is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen. Patients with diabetes have been shown to have elevated renal glucose reabsorption which may contribute to persistent elevated blood glucose concentrations. Canagliflozin is an orally-active inhibitor of SGLT2. By inhibiting SGLT2, canagliflozin reduces reabsorption of filtered glucose and lowers the renal threshold for glucose (RTG), and thereby increases UGE, lowering elevated plasma glucose concentrations by this insulin-independent mechanism in patients with type 2 diabetes. The increased UGE with SGLT2 inhibition also translates to an osmotic diuresis, with the diuretic effect leading to a reduction in systolic blood pressure; the increase in UGE results in a loss of calories and therefore a reduction in body weight, as has been demonstrated in studies of patients with type 2 diabetes.
Canagliflozin's action to increase UGE directly lowering plasma glucose is independent of insulin. Improvement in homeostasis model assessment for beta-cell function (HOMA beta-cell) and improved beta-cell insulin secretion response to a mixed-meal challenge has been observed in clinical studies with canagliflozin.
In phase 3 studies, pre-meal administration of canagliflozin 300 mg provided a greater reduction in postprandial glucose excursion than observed with the 100 mg dose. This effect at the 300 mg dose of canagliflozin may, in part, be due to local inhibition of intestinal SGLT1 (an important intestinal glucose transporter) related to transient high concentrations of canagliflozin in the intestinal lumen prior to medicinal product absorption (canagliflozin is a low potency inhibitor of the SGLT1 transporter). Studies have shown no glucose malabsorption with canagliflozin.
Pharmacodynamic effects
Following single and multiple oral doses of canagliflozin to patients with type 2 diabetes, dose-dependent decreases in RTG and increases in UGE were observed. From a starting value of RTG of approximately 13 mmol/L, maximal suppression of 24-hour mean RTG was seen with the 300 mg daily dose to approximately 4 mmol/L to 5 mmol/L in patients with type 2 diabetes in phase 1 studies, suggesting a low risk for treatment-induced hypoglycaemia. The reductions in RTG led to increased UGE in subjects with type 2 diabetes treated with either 100 mg or 300 mg of canagliflozin ranging from 77 g/day to 119 g/day across the phase 1 studies; the UGE observed translates to a loss of 308 kcal/day to 476 kcal/day. The reductions in RTG and increases in UGE were sustained over a 26-week dosing period in patients with type 2 diabetes. Moderate increases (generally < 400 mL to 500 mL) in daily urine volume were seen that attenuated over several days of dosing. Urinary uric acid excretion was transiently increased by canagliflozin (increased by 19% compared to baseline on day 1 and then attenuating to 6% on day 2 and 1% on day 13). This was accompanied by a sustained reduction in serum uric acid concentration of approximately 20%.
In a single-dose study in patients with type 2 diabetes, treatment with 300 mg before a mixed meal delayed intestinal glucose absorption and reduced postprandial glucose through both a renal and a non-renal mechanism.
Clinical efficacy and safety
A total of 10,285 patients with type 2 diabetes participated in nine double-blind, controlled clinical efficacy and safety studies conducted to evaluate the effects of Invokana on glycaemic control. The racial distribution was 72% White, 16% Asian, 4% Black, and 8% other groups. 16% of patients were Hispanic. Approximately 58% of patients were male. Patients had an overall mean age of 59.6 years (range 21 years to 96 years), with 3,082 patients ≥ 65 years of age and 510 patients ≥ 75 years of age. 58% of patients had a body mass index (BMI) ≥ 30 kg/m2. In the clinical development programme, 1,085 patients with a baseline eGFR 30 mL/min/1.73 m2 to < 60 mL/min/1.73 m2 were evaluated.
Placebo-controlled studies
Canagliflozin was studied as monotherapy, dual therapy with metformin, dual therapy with a sulphonylurea, triple therapy with metformin and a sulphonylurea, triple therapy with metformin and pioglitazone, and as an add-on therapy with insulin (table 2). In general, canagliflozin produced clinically and statistically significant (p<0.001) results relative to placebo in glycaemic control, including HbA1c, the percentage of patients achieving HbA1c < 7%, change from baseline fasting plasma glucose (FPG), and 2-hour postprandial glucose (PPG). In addition, reductions in body weight and systolic blood pressure relative to placebo were observed.
Table 2: Efficacy results from placebo-controlled clinical studiesa

Monotherapy (26 weeks)

 

Canagliflozin

 

100 mg

300 mg

Placebo

(N=195)

(N=197)

(N=192)

HbA1c (%)

Baseline (mean)

8.06

8.01

7.97

Change from baseline (adjusted mean)

-0.77

-1.03

0.14

Difference from placebo (adjusted mean) (95% CI)

-0.91b

(-1.09; -0.73)

-1.16b

(-1.34; -0.98)

N/Ac

Patients (%) achieving HbA1c < 7%

44.5b

62.4b

20.6

Body weight

Baseline (mean) in kg

85.9

86.9

87.5

% change from baseline (adjusted mean)

-2.8

-3.9

-0.6

Difference from placebo (adjusted mean) (95% CI)

-2.2b

(-2.9; -1.6)

-3.3b

(-4.0; -2.6)

N/Ac

Dual therapy with metformin (26 weeks)

 

Canagliflozin + metformin

 

100 mg

300 mg

Placebo + metformin

(N=368)

(N=367)

(N=183)

HbA1c (%)

Baseline (mean)

7.94

7.95

7.96

Change from baseline (adjusted mean)

-0.79

-0.94

-0.17

Difference from placebo (adjusted mean) (95% CI)

-0.62b

(-0.76; -0.48)

-0.77b

(-0.91; -0.64)

N/Ac

Patients (%) achieving HbA1c < 7%

45.5b

57.8b

29.8

Body weight

Baseline (mean) in kg

88.7

85.4

86.7

% change from baseline (adjusted mean)

-3.7

-4.2

-1.2

Difference from placebo (adjusted mean) (95% CI)

-2.5b

(-3.1; -1.9)

-2.9b

(-3.5; -2.3)

N/Ac

Triple therapy with metformin and sulphonylurea (26 weeks)

 

Canagliflozin + metformin and sulphonylurea

 

100 mg

300 mg

Placebo + metformin and sulphonylurea

(N=157)

(N=156)

(N=156)

HbA1c (%)

Baseline (mean)

8.13

8.13

8.12

Change from baseline (adjusted mean)

-0.85

-1.06

-0.13

Difference from placebo (adjusted mean) (95% CI)

-0.71b

(-0.90; -0.52)

-0.92b

(-1.11; -0.73)

N/Ac

Patients (%) achieving HbA1c < 7%

43.2b

56.6b

18.0

Body weight

Baseline (mean) in kg

93.5

93.5

90.8

% change from baseline (adjusted mean)

-2.1

-2.6

-0.7

Difference from placebo (adjusted mean) (95% CI)

-1.4b

(-2.1; -0.7)

-2.0b

(-2.7; -1.3)

N/Ac

Add-on therapy with insulind (18 weeks)

 

Canagliflozin + insulin

 

100 mg

300 mg

Placebo + insulin

(N=566)

(N=587)

(N=565)

HbA1c (%)

Baseline (mean)

8.33

8.27

8.20

Change from baseline (adjusted mean)

-0.63

-0.72

0.01

Difference from placebo (adjusted mean)

(97.5% CI)

-0.65b

(-0.73; -0.56)

-0.73b

(-0.82; -0.65)

N/Ac

Patients (%) achieving HbA1c < 7%

19.8b

24.7b

7.7

Body weight

Baseline (mean) in kg

96.9

96.7

97.7

% change from baseline (adjusted mean)

-1.8

-2.3

0.1

Difference from placebo (adjusted mean) (97.5% CI)

-1.9b

(-2.2; -1.5)

-2.4b

(-2.8; -2.0)

N/Ac

a Intent-to-treat population using last observation in study prior to glycaemic rescue therapy.
b p<0.001 compared to placebo.
c Not applicable.
d Canagliflozin as add-on therapy to insulin (with or without other glucose-lowering medicinal products).
In addition to the studies presented above, glycaemic efficacy results observed in an 18-week dual therapy sub-study with a sulphonylurea and a 26-week triple therapy study with metformin and pioglitazone were generally comparable with those observed in other studies.
Active-controlled studies
Canagliflozin was compared to glimepiride as dual therapy with metformin and compared to sitagliptin as triple therapy with metformin and a sulphonylurea (table 3). Canagliflozin 100 mg as dual therapy with metformin produced similar reductions in HbA1c from baseline and 300 mg produced superior (p<0.05) reductions in HbA1c compared to glimepiride, thus demonstrating non-inferiority. A lower proportion of patients treated with canagliflozin 100 mg (5.6%) and canagliflozin 300 mg (4.9%) experienced at least one episode/event of hypoglycaemia over 52 weeks of treatment compared to the group treated with glimepiride (34.2%). In a study comparing canagliflozin 300 mg to sitagliptin 100 mg in triple therapy with metformin and a sulphonylurea, canagliflozin demonstrated non-inferior (p<0.05) and superior (p<0.05) reduction in HbA1c relative to sitagliptin. The incidence of hypoglycaemia episodes/events with canagliflozin 300 mg and sitagliptin 100 mg was 40.7% and 43.2%, respectively. Significant improvements in body weight and reductions in systolic blood pressure compared to both glimepiride and sitagliptin were also observed.
Table 3: Efficacy results from active-controlled clinical studiesa

Compared to glimepiride as dual therapy with metformin (52 weeks)

 

Canagliflozin + metformin

 

100 mg

300 mg

Glimepiride (titrated) + metformin

(N=483)

(N=485)

(N=482)

HbA1c (%)

Baseline (mean)

7.78

7.79

7.83

Change from baseline (adjusted mean)

-0.82

-0.93

-0.81

Difference from glimepiride (adjusted mean) (95% CI)

-0.01b

(−0.11; 0.09)

-0.12b

(−0.22; −0.02)

N/Ac

Patients (%) achieving HbA1c < 7%

53.6

60.1

55.8

Body weight

Baseline (mean) in kg

86.8

86.6

86.6

% change from baseline (adjusted mean)

-4.2

-4.7

1.0

Difference from glimepiride (adjusted mean) (95% CI)

-5.2b

(−5.7; −4.7)

-5.7b

(−6.2; −5.1)

N/Ac

Compared to sitagliptin as triple therapy with metformin and sulphonylurea (52 weeks)

 

Canagliflozin 300 mg + metformin and sulphonylurea

Sitagliptin 100 mg + metformin and sulphonylurea

(N=377)

(N=378)

HbA1c (%)

Baseline (mean)

8.12

8.13

Change from baseline (adjusted mean)

-1.03

-0.66

Difference from sitagliptin (adjusted mean) (95% CI)

-0.37b

(-0.50; -0.25)

N/Ac

Patients (%) achieving HbA1c < 7%

47.6

35.3

Body weight

Baseline (mean) in kg

87.6

89.6

% change from baseline (adjusted mean)

-2.5

0.3

Difference from sitagliptin (adjusted mean) (95% CI)

-2.8d

(-3.3; -2.2)

N/Ac

a Intent-to-treat population using last observation in study prior to glycaemic rescue therapy.
b p<0.05.
c Not applicable.
d p<0.001.
Special populations
In three studies conducted in special populations (older patients, patients with an eGFR of 30 mL/min/1.73 m2 to < 50 mL/min/1.73 m2 and patients with or at high risk for cardiovascular disease), canagliflozin was added to patients' current stable diabetes treatments (diet, monotherapy, or combination therapy).
Older patients
A total of 714 patients ≥ 55 years of age to ≤ 80 years of age (227 patients 65 years of age to < 75 years of age and 46 patients 75 years of age to ≤ 80 years of age) with inadequate glycaemic control on current diabetes treatment (glucose-lowering medicinal products and/or diet and exercise) participated in a double-blind, placebo-controlled study over 26 weeks. Statistically significant (p<0.001) changes from baseline HbA1c relative to placebo of -0.57% and -0.70% were observed for 100 mg and 300 mg, respectively (see sections 4.2 and 4.8).
Patients with eGFR 45 mL/min/1.73 m2 to < 60 mL/min/1.73 m2
In a pooled analysis of patients (N=721) with a baseline eGFR 45 mL/min/1.73 m2 to < 60 mL/min/1.73 m2, canagliflozin provided clinically meaningful reduction in HbA1c compared to placebo, with -0.47% for canagliflozin 100 mg and -0.52% for canagliflozin 300 mg. Patients with a baseline eGFR 45 mL/min/1.73 m2 to < 60 mL/min/1.73 m2 treated with canagliflozin 100 mg and 300 mg exhibited mean improvements in percent change in body weight relative to placebo of -1.8% and -2.0%, respectively.
The majority of patients with a baseline eGFR 45 mL/min/1.73 m2 to < 60 mL/min/1.73 m2 were on insulin and/or a sulphonylurea (85% [614/721]). Consistent with the expected increase of hypoglycaemia when a medicinal product not associated with hypoglycaemia is added to insulin and/or sulphonylurea, an increase in hypoglycaemia episodes/events was seen when canagliflozin was added to insulin and/or a sulphonylurea (see section 4.8).
Fasting plasma glucose
In four placebo-controlled studies, treatment with canagliflozin as monotherapy or add-on therapy with one or two oral glucose-lowering medicinal products resulted in mean changes from baseline relative to placebo in FPG of -1.2 mmol/L to -1.9 mmol/L for canagliflozin 100 mg and -1.9 mmol/L to -2.4 mmol/L for canagliflozin 300 mg, respectively. These reductions were sustained over the treatment period and near maximal after the first day of treatment.
Postprandial glucose
Using a mixed-meal challenge, canagliflozin as monotherapy or add-on therapy with one or two oral glucose-lowering medicinal products reduced postprandial glucose (PPG) from baseline relative to placebo by -1.5 mmol/L to -2.7 mmol/L for canagliflozin 100 mg and -2.1 mmol/L to -3.5 mmol/L for 300 mg, respectively, due to reductions in the pre-meal glucose concentration and reduced postprandial glucose excursions.
Body weight
Canagliflozin 100 mg and 300 mg as monotherapy and as dual or triple add-on therapy resulted in statistically significant reductions in the percentage of body weight at 26 weeks relative to placebo. In two 52-week active-controlled studies comparing canagliflozin to glimepiride and sitagliptin, sustained and statistically significant mean reductions in the percentage of body weight for canagliflozin as add-on therapy to metformin were -4.2% and -4.7% for canagliflozin 100 mg and 300 mg, respectively, compared to the combination of glimepiride and metformin (1.0%) and -2.5% for canagliflozin 300 mg in combination with metformin and a sulphonylurea compared to sitagliptin in combination with metformin and a sulphonylurea (0.3%).
A subset of patients (N=208) from the active-controlled dual therapy study with metformin who underwent dual energy X-ray densitometry (DXA) and abdominal computed tomography (CT) scans for evaluation of body composition demonstrated that approximately two-thirds of the weight loss with canagliflozin was due to loss of fat mass with similar amounts of visceral and abdominal subcutaneous fat being lost. Two hundred eleven (211) patients from the clinical study in older patients participated in a body composition substudy using DXA body composition analysis. This demonstrated that approximately two-thirds of the weight loss associated with canagliflozin was due to loss of fat mass relative to placebo. There were no meaningful changes in bone density in trabecular and cortical regions.
Cardiovascular safety
A pre-specified interim meta-analysis was conducted of adjudicated major cardiovascular events in the phase 2 and 3 clinical studies in 9,632 patients with type 2 diabetes, including 4,327 patients (44.9%) with cardiovascular disease or at high risk for cardiovascular disease who are participating in an ongoing cardiovascular study. The hazard ratio for the composite primary endpoint (time to event of cardiovascular death, non-fatal stroke, non-fatal myocardial infarction, and unstable angina requiring hospitalisation) for canagliflozin (both doses pooled) versus combined active and placebo comparators was 0.91 (95% CI: 0.68; 1.22); therefore, there was no evidence of an increase in cardiovascular risk with canagliflozin relative to comparators. The hazard ratios for the 100 mg and 300 mg doses were similar.
Blood pressure
In placebo-controlled studies, treatment with canagliflozin 100 mg and 300 mg resulted in mean reductions in systolic blood pressure of -3.9 mmHg and -5.3 mmHg, respectively, compared to placebo (-0.1 mmHg) and a smaller effect on diastolic blood pressure with mean changes for canagliflozin 100 mg and 300 mg of -2.1 mmHg and -2.5 mmHg, respectively, compared to placebo (-0.3 mmHg). There was no notable change in heart rate.
Patients with baseline HbA1c > 10% to ≤ 12%
A substudy of patients with baseline HbA1c > 10% to ≤ 12% with canagliflozin as monotherapy resulted in reductions from baseline in HbA1c (not placebo-adjusted) of -2.13% and -2.56% for canagliflozin 100 mg and 300 mg, respectively.
Paediatric population
The European Medicines Agency has deferred the obligation to submit the results of studies with canagliflozin in one or more subsets of the paediatric population in type 2 diabetes (see section 4.2 for information on paediatric use).
5.2 Pharmacokinetic properties
The pharmacokinetics of canagliflozin are essentially similar in healthy subjects and patients with type 2 diabetes. After single-dose oral administration of 100 mg and 300 mg in healthy subjects, canagliflozin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1 hour to 2 hours post-dose. Plasma Cmax and AUC of canagliflozin increased in a dose-proportional manner from 50 mg to 300 mg. The apparent terminal half-life (t1/2) (expressed as mean ± standard deviation) was 10.6 ± 2.13 hours and 13.1 ± 3.28 hours for the 100 mg and 300 mg doses, respectively. Steady-state was reached after 4 days to 5 days of once-daily dosing with canagliflozin 100 mg to 300 mg. Canagliflozin does not exhibit time-dependent pharmacokinetics, and accumulated in plasma up to 36% following multiple doses of 100 mg and 300 mg.
Absorption
The mean absolute oral bioavailability of canagliflozin is approximately 65%. Co-administration of a high-fat meal with canagliflozin had no effect on the pharmacokinetics of canagliflozin; therefore, Invokana may be taken with or without food. However, based on the potential to reduce postprandial plasma glucose excursions due to delayed intestinal glucose absorption, it is recommended that Invokana be taken before the first meal of the day (see sections 4.2 and 5.1).
Distribution
The mean steady-state volume of distribution of canagliflozin following a single intravenous infusion in healthy subjects was 119 litres, suggesting extensive tissue distribution. Canagliflozin is extensively bound to proteins in plasma (99%), mainly to albumin. Protein binding is independent of canagliflozin plasma concentrations. Plasma protein binding is not meaningfully altered in patients with renal or hepatic impairment.
Biotransformation
O-glucuronidation is the major metabolic elimination pathway for canagliflozin, which is mainly glucuronidated by UGT1A9 and UGT2B4 to two inactive O-glucuronide metabolites. CYP3A4-mediated (oxidative) metabolism of canagliflozin is minimal (approximately 7%) in humans.
In in vitro studies, canagliflozin neither inhibited cytochrome P450 CYP1A2,CYP2A6, CYP2C19, CYP2D6, or CYP2E1, CYP2B6, CYP2C8, CYP2C9, nor induced CYP1A2, CYP2C19, CYP2B6, CYP3A4 at higher than therapeutic concentrations. No clinically relevant effect on CYP3A4 was observed in vivo (see section 4.5).
Elimination
Following administration of a single oral [14C]canagliflozin dose to healthy subjects, 41.5%, 7.0%, and 3.2% of the administered radioactive dose was recovered in faeces as canagliflozin, a hydroxylated metabolite, and an O-glucuronide metabolite, respectively. Enterohepatic circulation of canagliflozin was negligible.
Approximately 33% of the administered radioactive dose was excreted in urine, mainly as O-glucuronide metabolites (30.5%). Less than 1% of the dose was excreted as unchanged canagliflozin in urine. Renal clearance of canagliflozin 100 mg and 300 mg doses ranged from 1.30 mL/min to 1.55 mL/min.
Canagliflozin is a low-clearance substance, with a mean systemic clearance of approximately 192 mL/min in healthy subjects following intravenous administration.
Special populations
Patients with renal impairment
A single-dose, open-label study evaluated the pharmacokinetics of canagliflozin 200 mg in subjects with varying degrees of renal impairment (classified using CrCl based on the Cockroft-Gault equation) compared to healthy subjects. The study included 8 subjects with normal renal function (CrCl ≥ 80 mL/min), 8 subjects with mild renal impairment (CrCl 50 mL/min to < 80 mL/min), 8 subjects with moderate renal impairment (CrCl 30 mL/min to < 50 mL/min), and 8 subjects with severe renal impairment (CrCl < 30 mL/min) as well as 8 subjects with ESRD on haemodialysis.
The Cmax of canagliflozin was moderately increased by 13%, 29%, and 29% in subjects with mild, moderate, and severe renal failure, respectively, but not in subjects on haemodialysis. Compared to healthy subjects, plasma AUC of canagliflozin was increased by approximately 17%, 63%, and 50% in subjects with mild, moderate, and severe renal impairment, respectively, but was similar for ESRD subjects and healthy subjects.
Canagliflozin was negligibly removed by haemodialysis.
Patients with hepatic impairment
Relative to subjects with normal hepatic function, the geometric mean ratios for Cmax and AUC∞ of canagliflozin were 107% and 110%, respectively, in subjects with Child-Pugh class A (mild hepatic impairment) and 96% and 111%, respectively, in subjects with Child-Pugh class B (moderate) hepatic impairment following administration of a single 300 mg dose of canagliflozin.
These differences are not considered to be clinically meaningful. There is no clinical experience in patients with Child-Pugh class C (severe) hepatic impairment.
Elderly (≥ 65 years old)
Age had no clinically meaningful effect on the pharmacokinetics of canagliflozin based on a population pharmacokinetic analysis (see sections 4.2, 4.4, and 4.8).
Paediatric population
Studies characterising the pharmacokinetics of canagliflozin in paediatric patients have not been conducted.
Other special populations
Pharmacogenetics
Both UGT1A9 and UGT2B4 are subject to genetic polymorphism. In a pooled analysis of clinical data, increases in canagliflozin AUC of 26% were observed in UGT1A9*1/*3 carriers and 18% in UGT2B4*2/*2 carriers. These increases in canagliflozin exposure are not expected to be clinically relevant. The effect of being homozygote (UGT1A9*3/*3, frequency < 0.1%) is probably more marked, but has not been investigated.
Gender, race/ethnicity, or body mass index had no clinically meaningful effect on the pharmacokinetics of canagliflozin based on a population pharmacokinetic analysis.
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, and genotoxicity.
Canagliflozin showed no effects on fertility and early embryonic development in the rat at exposures up to 19 times the human exposure at the maximum recommended human dose (MRHD).
In an embryo-foetal development study in rats, ossification delays of metatarsal bones were observed at systemic exposures 73 times and 19 times higher than the clinical exposures at the 100 mg and 300 mg doses. It is unknown whether ossification delays can be attributed to effects of canagliflozin on calcium homeostasis observed in adult rats. Ossification delays were also observed for the combination of canagliflozin and metformin, which were more prominent than for metformin alone at canagliflozin exposures 43 times and 12 times higher than clinical exposures at 100 mg and 300 mg doses.
In a pre- and postnatal development study, canagliflozin administered to female rats from gestation day 6 to lactation day 20 resulted in decreased body weights in male and female offspring at maternally toxic doses > 30 mg/kg/day (exposures ≥ 5.9 times the human exposure to canagliflozin at the MHRD). Maternal toxicity was limited to decreased body weight gain.
A study in juvenile rats administered canagliflozin from day 1 through day 90 postnatal did not show increased sensitivity compared to effects observed in adults rats. However, dilatation of the renal pelvis was noticed with a No Observed Effect Level (NOEL) at exposures 2.4 times and 0.6 times the clinical exposures at 100 mg and 300 mg doses, respectively, and did not fully reverse within the approximately 1-month recovery period. Persistent renal findings in juvenile rats can most likely be attributed to reduced ability of the developing rat kidney to handle canagliflozin-increased urine volumes, as functional maturation of the rat kidney continues through 6 weeks of age.
Canagliflozin did not increase the incidence of tumours in male and female mice in a 2-year study at doses of 10, 30, and 100 mg/kg. The highest dose of 100 mg/kg provided up to 14 times the clinical dose of 300 mg based on AUC exposure. Canagliflozin increased the incidence of testicular Leydig cell tumours in male rats at all doses tested (10, 30, and 100 mg/kg); the lowest dose of 10 mg/kg is approximately 1.5 times the clinical dose of 300 mg based on AUC exposure. The higher doses of canagliflozin (100 mg/kg) in male and female rats increased the incidence of pheochromocytomas and renal tubular tumours. Based on AUC exposure, the NOEL of 30 mg/kg/day for pheochromocytomas and renal tubular tumours is approximately 4.5 times the exposure at the daily clinical dose of 300 mg. Based on preclinical and clinical mechanistic studies, Leydig cell tumours, renal tubule tumours, and pheochromocytomas are considered to be rat-specific. Canagliflozin-induced renal tubule tumours and pheochromocytomas in rats appear to be caused by carbohydrate malabsorption as a consequence of intestinal SGLT1 inhibitory activity of canagliflozin in the gut of rats; mechanistic clinical studies have not demonstrated carbohydrate malabsorption in humans at canagliflozin doses of up to 2-times the maximum recommended clinical dose. The Leydig cell tumours are associated with an increase in luteinizing hormone (LH), which is a known mechanism of Leydig cell tumour formation in rats. In a 12-week clinical study, unstimulated LH did not increase in male patients treated with canagliflozin.
6. Pharmaceutical particulars
6.1 List of excipients
Tablet core
Lactose anhydrous
Microcrystalline cellulose
Hydroxypropylcellulose
Croscarmellose sodium
Magnesium stearate
Film-coating
Polyvinyl alcohol
Titanium dioxide (E171)
Macrogol 3350
Talc
Iron oxide yellow (E172)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
Polyvinyl chloride/Aluminum (PVC/Alu) perforated unit dose blister.
Pack sizes of 10 x 1, 30 x 1, 90 x 1, and 100 x 1 film-coated tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
No special requirements.
7. Marketing authorisation holder
Janssen-Cilag International NV
Turnhoutseweg 30
B-2340 Beerse
Belgium
8. Marketing authorisation number(s)
EU/1/13/884/001 (10 tablets)
EU/1/13/884/002 (30 tablets)
EU/1/13/884/003 (90 tablets)
EU/1/13/884/004 (100 tablets)
9. Date of first authorisation/renewal of the authorisation
Date of first authorisation: 15 November 2013
10. Date of revision of the text
25 April 2014
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu/.

德国包装
100mgx100片
100mgx30
300mgx100
300mgx30

欧盟批准INVOKANA(卡格列净)用于II型糖尿病成人的治疗
2013年11月25日,杨森糖尿病新药INVOKANA(canagliflozin)获欧盟委员会(EC)批准,用于2型糖尿病成人患者的治疗,以改善血糖控制。
强生公司旗下杨森制药宣布欧盟委员会已经批准INVOKANA(卡格列净)用于欧盟地区II型糖尿病成人的治疗,以改善血糖控制。Canagliflozin(卡格列净)是一种每日一次的口服药物,属于钠-葡萄糖-同向转运体2(SGLT2)抑制剂的一类新型药物。
在欧盟的此项决定之前,今年9月,卡格列净获得了欧洲药品管理局(EMA)人用医药产品委员会(CHMP)建议批准的积极建议。卡格列净被批准用于18岁以上的成人II型糖尿病的治疗,以控制血糖。
用于单药治疗,适用于当单纯控制饮食和适当锻炼已不足以控制血糖且由于不能耐受并发症或有用药禁忌症而不能使用二甲双胍(metformin)者
用于与其他抗胰高血糖素类药物如胰岛素等的联合治疗,适用于抗胰高血糖素药物联合饮食控制和适当锻炼不足以控制血糖时。
奥地利Rudolfstiftung医院第一临床医学系的Guntram Schernthaner教授发表评论,“对于II型糖尿病患者来说,控制血糖水平是一项日常斗争。约半数II型糖尿病成人都没能成功达到或稳定足够的血糖水平,这会导致潜在的致命性并发症。在欧洲,越来越多人罹患II型糖尿病,而此次批准一种新的治疗选择将会很受欢迎。”
肾脏对控制血糖水平起着重要的作用。葡萄糖从血液滤过到肾脏,又重吸收到血流中。重吸收中的重要载体是钠-葡萄糖-同向转运体2(SGLT2)。卡格列净能选择性抑制SGLT2,从而促进尿液排出葡萄糖,降低II型糖尿病成人的血糖水平。大规模调查显示,由于增加了尿液中葡萄糖的排出,卡格列净还与收缩压和体重的下降有关。
“我们很高兴INVOKANA在欧洲被批准使用,因为它为II型糖尿病人提供了一种新的治疗选择,来帮助他们控制这种进展中的疾病。卡格列净的批准也加强了杨森的义务去解决II型糖尿病治疗和管理中未满足的需要。”杨森欧洲集团董事长Jane Griffiths在非洲中东地区说。
欧盟的这项批准是基于一项全球的广泛的临床三期试验项目,这个项目纳入了9个研究的10285个病人,是到目前为止卫生当局发起的用于II型糖尿病治疗的临床药理实验产品最大的后期发展计划之一。
这些研究对比了卡格列净与目前的标准治疗,其中两个分别比较了卡格列净与西格列汀(sitagliptin)、格列美脲(glimepiride)。这个三期项目也纳入了三项特殊人群的大规模研究:年龄大于55岁的II型糖尿病人、伴有中度肾损害的II型糖尿病人和考虑有高心血管病患病风险的II型糖尿病人。
这个项目的结果显示,与基线相比,100mg和300mg的剂量都有助于控制血糖。二级研究显示,与安慰剂(placebo)组相比,卡格列净组体重下降。三期试验结果显示,卡格列净普遍有较好耐受。由SGLT2抑制剂引起的不良药物反应与卡格列净也有关,包括生殖器霉菌感染,尿路感染(UTIs),渗透性利尿(比如尿频、口渴或便秘),血容量减少(比如直立性眩晕)。其副作用偶见皮疹和荨麻疹。当卡格列净作为单药治疗或与二甲双胍联合治疗时,低血糖的发生率较低。
卡格列净早在今年3月被美国食品及药品管理局(FDA)批准,最近在澳大利亚也被批准。

责任编辑:admin


相关文章
FDA批准第4个SGLT-2抑制剂ertugliflozin,用于2型糖尿病
新型长效糖尿病新药semaglutide每周皮下注射一次
Invokamet XR用于2型糖尿病成人患者的一线治疗
INVOKAMET XR TAB(卡格列净和盐酸二甲双胍缓释片)
Invokamet XR(卡格列净和盐酸二甲双胍缓释片)
FDA批准复方新药Invokamet XR用于2型糖尿病
JARDIANCE(Empagliflozin TABLET)
达格列净片|FORXIGA TAB(dapagliflozin)
恩格列净片|JARDIANCE(empagliflozin tablets)
Lusefi tab(Luseogliflozin Hydrate)鲁格列净片
Invokamet(canagliflozin/metformin HCl tablets)
 

最新文章

更多

· Jardiance Filmtablette...
· Synjardy XR(empagliflo...
· 托格列净片|DEBERZA(To...
· Qtern(dapagliflozin/s...
· Galvus Filmtabletten(...
· 那格列奈片|Starlix(nat...
· SOLIQUA 100/33(insulin...
· Insulin Novorapid(门冬...
· NovoRapid(门冬胰岛素注...
· Invokamet XR(卡格列净...

推荐文章

更多

· Jardiance Filmtablette...
· Synjardy XR(empagliflo...
· 托格列净片|DEBERZA(To...
· Qtern(dapagliflozin/s...
· Galvus Filmtabletten(...
· 那格列奈片|Starlix(nat...
· SOLIQUA 100/33(insulin...
· Insulin Novorapid(门冬...
· NovoRapid(门冬胰岛素注...
· Invokamet XR(卡格列净...

热点文章

更多

· Jardiance Filmtablette...