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新类降糖药INVOKANA(canagliflozin)-为第一个治疗糖尿病的药物
2013年3月29日，美国食品和药物管理局FDA批准Invokana（canagliflozin）片剂与饮食和运动配合，用于成人2型糖尿病患者控制血糖。
2型糖尿病是最常见疾病，在美国患者约24万人且确诊糖尿病患者占90％以上。长期高血糖会增大出现严重并发症的风险，包括心脏病、失明、神经和肾脏损害。
“Invokana是钠-葡萄糖共转运体2（SGLT2）抑制剂类新糖尿病药物中第一个被批准的”FDA药物评价和研究中心代谢和内分泌产品部主任、医学博士Mary Parks说，“我们将继续通过批准为影响公众健康的慢性疾病提供新治疗方法的新一类药物来推动药物创新。”
Invokana可阻断肾脏对葡萄糖再吸收、增加葡萄糖排泄并降低糖尿病患者血糖水平的升高。涉及超过10,285例2型糖尿病患者的9个临床试验，对Invokana的安全性和有效性进行了评估。试验表明糖化血红蛋白水平（血糖控制指标）和空腹血糖水平得到改善。
以Invokana作为单独治疗药物以及与其他2型糖尿病治疗药物包括二甲双胍、磺酰脲类、吡格列酮和胰岛素类的药物组合开展了研究。Invokana不能用于1型糖尿病、血尿酮增高（糖尿病酮症酸中毒）或严重肾功能不全、终末期肾脏病或在透析患者。
FDA要求Invokana开展五个上市后研究：心血管预后试验；加强药物警戒计划，以监控为恶性肿瘤、严重胰腺炎、严重的过敏反应、光敏反应、肝脏异常与不良妊娠结局；骨安全性研究；根据儿童研究公平法案（PREA）进行两个儿科研究包括药代动力学和药效学研究以及安全性和有效性研究。
Invokana最常见不良反应是阴道酵母菌感染（念珠菌性外阴阴道炎）和泌尿道感染。因为Invokana兼有利尿作用，可能会因血容量减少导致直立性或体位性低血压（站立时血压突然下降）。体位性低血压可能会导致头晕或昏厥，这在治疗的头3个月内最常见。
Invokana由美国新泽西州泰特斯维尔的杨森制药公司制造。
美国包装
INVOKANA TAB 100MG 30 CANAGLIFLOZIN NDC 50458-0140-30
INVOKANA TAB 100MG 90 CANAGLIFLOZIN NDC 50458-0140-90
INVOKANA TAB 300MG 30 CANAGLIFLOZIN NDC 50458-0141-30
INVOKANA TAB 300MG 90 CANAGLIFLOZIN NDC 50458-0141-90
HIGHLIGHTS OF PRESCRIBING INFORMATION
德国包装
100mgx100片
100mgx30
300mgx100
300mgx30
生产厂家中英文参考译名:
杨森（Janssen Research & Development）
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use INVOKANA ® safely and effectively. See full prescribing information for INVOKANA.
INVOKANA (canagliflozin) tablets, for oral use
Initial U.S. Approval: 2013
RECENT MAJOR CHANGES
Warnings and Precautions (5.2) 12/2015
Warnings and Precautions (5.5) 12/2015
Warnings and Precautions (5.9) 09/2015
INDICATIONS AND USAGE
INVOKANA is a sodium-glucose co-transporter 2 (SGLT2) inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (1)
Limitation of Use:
Not for treatment of type 1 diabetes mellitus or diabetic ketoacidosis (1)
DOSAGE AND ADMINISTRATION
The recommended starting dose is 100 mg once daily, taken before the first meal of the day (2.1)
Dose can be increased to 300 mg once daily in patients tolerating INVOKANA 100 mg once daily who have an eGFR of 60 mL/min/1.73 m2 or greater and require additional glycemic control (2.1)
INVOKANA is limited to 100 mg once daily in patients who have an eGFR of 45 to less than 60 mL/min/1.73 m2 (2.2)
Assess renal function before initiating INVOKANA. Do not initiate INVOKANA if eGFR is below 45 mL/min/1.73 m2 (2.2)
Discontinue INVOKANA if eGFR falls persistently below 45 mL/min/1.73 m2 (2.2)
DOSAGE FORMS AND STRENGTHS
Tablets: 100 mg, 300 mg (3)
CONTRAINDICATIONS
History of serious hypersensitivity reaction to INVOKANA (4)
Severe renal impairment, ESRD, or on dialysis (4)
WARNINGS AND PRECAUTIONS
Hypotension: Before initiating INVOKANA, assess volume status and correct hypovolemia in patients with renal impairment, the elderly, in patients with low systolic blood pressure, or if on diuretics, ACEi, or ARB. Monitor for signs and symptoms during therapy (5.1)
Ketoacidosis: Assess patients who present with signs and symptoms of metabolic acidosis for ketoacidosis, regardless of blood glucose level. If suspected, discontinue INVOKANA, evaluate and treat promptly. Before initiating INVOKANA, consider risk factors for ketoacidosis. Patients on INVOKANA may require monitoring and temporary discontinuation of therapy in clinical situations known to predispose to ketoacidosis (5.2)
Impairment in renal function: Monitor renal function during therapy. More frequent monitoring is recommended in patients with eGFR below 60 mL/min/1.73 m2 (5.3)
Hyperkalemia: Monitor potassium levels in patients with impaired renal function and in patients predisposed to hyperkalemia (2.2, 5.4, 6.1, 8.6)
Urosepsis and Pyelonephritis: Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated (5.5)
Hypoglycemia: Consider a lower dose of insulin or the insulin secretagogue to reduce the risk of hypoglycemia when used in combination with INVOKANA (5.6)
Genital mycotic infections: Monitor and treat if indicated (5.7)
Hypersensitivity reactions: Discontinue INVOKANA and monitor until signs and symptoms resolve (5.8)
Bone fracture: Consider factors that contribute to fracture risk before initiating INVOKANA (5.9)
Increased LDL-C: Monitor LDL-C and treat if appropriate (5.10)
ADVERSE REACTIONS
Most common adverse reactions associated with INVOKANA (5% or greater incidence): female genital mycotic infections, urinary tract infection, and increased urination (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Janssen Pharmaceuticals, Inc. at 1-800-526-7736 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
DRUG INTERACTIONS
UGT inducers (e.g., rifampin): Canagliflozin exposure is reduced. Consider increasing dose from 100 mg to 300 mg (2.3, 7.1)
Digoxin: Monitor digoxin levels (7.2)
USE IN SPECIFIC POPULATIONS
Pregnancy: No adequate and well-controlled studies in pregnant women. Use during pregnancy only if the potential benefit justifies the potential risk to the fetus (8.1)
Nursing mothers: Discontinue drug or nursing (8.3)
Geriatrics: Higher incidence of adverse reactions related to reduced intravascular volume (5.1, 8.5)
Renal impairment: Higher incidence of adverse reactions related to reduced intravascular volume and renal function (2.2, 5.3, 8.6)
Hepatic impairment: Not recommended with severe hepatic impairment (8.7)
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
Revised: 12/2015
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
INVOKANA® (canagliflozin) is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus [see Clinical Studies (14)].
Limitation of Use
INVOKANA is not recommended in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dosage
The recommended starting dose of INVOKANA (canagliflozin) is 100 mg once daily, taken before the first meal of the day. In patients tolerating INVOKANA 100 mg once daily who have an eGFR of 60 mL/min/1.73 m2 or greater and require additional glycemic control, the dose can be increased to 300 mg once daily [see Warnings and Precautions (5.3), Clinical Pharmacology (12.2), and Patient Counseling Information (17)].
In patients with volume depletion, correcting this condition prior to initiation of INVOKANA is recommended [see Warnings and Precautions (5.1), Use in Specific Populations (8.5 and 8.6), and Patient Counseling Information (17)].
2.2 Patients with Renal Impairment
No dose adjustment is needed in patients with mild renal impairment (eGFR of 60 mL/min/1.73 m2 or greater).
The dose of INVOKANA is limited to 100 mg once daily in patients with moderate renal impairment with an eGFR of 45 to less than 60 mL/min/1.73 m2.
INVOKANA should not be initiated in patients with an eGFR less than 45 mL/min/1.73 m2.
Assessment of renal function is recommended prior to initiation of INVOKANA therapy and periodically thereafter. INVOKANA should be discontinued when eGFR is persistently less than 45 mL/min/1.73 m2 [see Warnings and Precautions (5.3) and Use in Specific Populations (8.6)].
2.3 Concomitant Use with UDP-Glucuronosyl Transferase (UGT) Enzyme Inducers
If an inducer of UGTs (e.g., rifampin, phenytoin, phenobarbital, ritonavir) is co-administered with INVOKANA, consider increasing the dosage to 300 mg once daily in patients currently tolerating INVOKANA 100 mg once daily who have an eGFR of 60 mL/min/1.73 m2 or greater and require additional glycemic control [see Drug Interactions (7.1)].
Consider another antihyperglycemic agent in patients with an eGFR of 45 to less than 60 mL/min/1.73 m2 receiving concurrent therapy with a UGT inducer.
3 DOSAGE FORMS AND STRENGTHS
INVOKANA 100 mg tablets are yellow, capsule-shaped, film-coated tablets with "CFZ" on one side and "100" on the other side.
INVOKANA 300 mg tablets are white, capsule-shaped, film-coated tablets with "CFZ" on one side and "300" on the other side.
4 CONTRAINDICATIONS
History of a serious hypersensitivity reaction to INVOKANA [see Warnings and Precautions (5.8)].
Severe renal impairment (eGFR less than 30 mL/min/1.73 m2), end stage renal disease (ESRD), or patients on dialysis [see Warnings and Precautions (5.3) and Use in Specific Populations (8.6)].
5 WARNINGS AND PRECAUTIONS
5.1 Hypotension
INVOKANA causes intravascular volume contraction. Symptomatic hypotension can occur after initiating INVOKANA [see Adverse Reactions (6.1)] particularly in patients with impaired renal function (eGFR less than 60 mL/min/1.73 m2), elderly patients, patients on either diuretics or medications that interfere with the renin-angiotensin-aldosterone system (e.g., angiotensin-converting-enzyme [ACE] inhibitors, angiotensin receptor blockers [ARBs]), or patients with low systolic blood pressure. Before initiating INVOKANA in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy.
5.2 Ketoacidosis
Reports of ketoacidosis, a serious life-threatening condition requiring urgent hospitalization have been identified in postmarketing surveillance in patients with type 1 and type 2 diabetes mellitus receiving sodium glucose co-transporter-2 (SGLT2) inhibitors, including INVOKANA. INVOKANA is not indicated for the treatment of patients with type 1 diabetes mellitus [see Indications and Usage (1)].
Patients treated with INVOKANA who present with signs and symptoms consistent with severe metabolic acidosis should be assessed for ketoacidosis regardless of presenting blood glucose levels, as ketoacidosis associated with INVOKANA may be present even if blood glucose levels are less than 250 mg/dL. If ketoacidosis is suspected, INVOKANA should be discontinued, patient should be evaluated, and prompt treatment should be instituted. Treatment of ketoacidosis may require insulin, fluid and carbohydrate replacement.
In many of the postmarketing reports, and particularly in patients with type 1 diabetes, the presence of ketoacidosis was not immediately recognized and institution of treatment was delayed because presenting blood glucose levels were below those typically expected for diabetic ketoacidosis (often less than 250 mg/dL). Signs and symptoms at presentation were consistent with dehydration and severe metabolic acidosis and included nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. In some but not all cases, factors predisposing to ketoacidosis such as insulin dose reduction, acute febrile illness, reduced caloric intake due to illness or surgery, pancreatic disorders suggesting insulin deficiency (e.g., type 1 diabetes, history of pancreatitis or pancreatic surgery), and alcohol abuse were identified.
Before initiating INVOKANA, consider factors in the patient history that may predispose to ketoacidosis including pancreatic insulin deficiency from any cause, caloric restriction, and alcohol abuse. In patients treated with INVOKANA consider monitoring for ketoacidosis and temporarily discontinuing INVOKANA in clinical situations known to predispose to ketoacidosis (e.g., prolonged fasting due to acute illness or surgery).
5.3 Impairment in Renal Function
INVOKANA increases serum creatinine and decreases eGFR. Patients with hypovolemia may be more susceptible to these changes. Renal function abnormalities can occur after initiating INVOKANA [see Adverse Reactions (6.1)]. More frequent renal function monitoring is recommended in patients with an eGFR below 60 mL/min/1.73 m2.
5.4 Hyperkalemia
INVOKANA can lead to hyperkalemia. Patients with moderate renal impairment who are taking medications that interfere with potassium excretion, such as potassium-sparing diuretics, or medications that interfere with the renin-angiotensin-aldosterone system are at an increased risk of developing hyperkalemia [see Dosage and Administration (2.2) and Adverse Reactions (6.1)].
Monitor serum potassium levels periodically after initiating INVOKANA in patients with impaired renal function and in patients predisposed to hyperkalemia due to medications or other medical conditions.
5.5 Urosepsis and Pyelonephritis
There have been postmarketing reports of serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization in patients receiving SGLT2 inhibitors, including INVOKANA. Treatment with SGLT2 inhibitors increases the risk for urinary tract infections. Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated [see Adverse Reactions (6)].
5.6 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues
Insulin and insulin secretagogues are known to cause hypoglycemia. INVOKANA can increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue [see Adverse Reactions (6.1)]. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with INVOKANA.
5.7 Genital Mycotic Infections
INVOKANA increases the risk of genital mycotic infections. Patients with a history of genital mycotic infections and uncircumcised males were more likely to develop genital mycotic infections [see Adverse Reactions (6.1)]. Monitor and treat appropriately.
5.8 Hypersensitivity Reactions
Hypersensitivity reactions (e.g., generalized urticaria), some serious, were reported with INVOKANA treatment; these reactions generally occurred within hours to days after initiating INVOKANA. If hypersensitivity reactions occur, discontinue use of INVOKANA; treat and monitor until signs and symptoms resolve [see Contraindications (4) and Adverse Reactions (6.1)].
5.9 Bone Fracture
An increased risk of bone fracture, occurring as early as 12 weeks after treatment initiation, was observed in patients using INVOKANA. Consider factors that contribute to fracture risk prior to initiating INVOKANA [see Adverse Reactions (6.1)].
5.10 Increases in Low-Density Lipoprotein (LDL-C)
Dose-related increases in LDL-C occur with INVOKANA [see Adverse Reactions (6.1)]. Monitor LDL-C and treat if appropriate after initiating INVOKANA.
5.11 Macrovascular Outcomes
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with INVOKANA or any other antidiabetic drug.
6 ADVERSE REACTIONS
The following important adverse reactions are described below and elsewhere in the labeling:
Hypotension [see Warnings and Precautions (5.1)]
Ketoacidosis [see Warnings and Precautions (5.2)]
Impairment in Renal Function [see Warnings and Precautions (5.3)]
Hyperkalemia [see Warnings and Precautions (5.4)]
Urosepsis and Pyelonephritis [see Warnings and Precautions (5.5)]
Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see Warnings and Precautions (5.6)]
Genital Mycotic Infections [see Warnings and Precautions (5.7)]
Hypersensitivity Reactions [see Warnings and Precautions (5.8)]
Bone Fracture [see Warnings and Precautions (5.9)]
Increases in Low-Density Lipoprotein (LDL-C) [see Warnings and Precautions (5.10)]
6.1 Clinical Studies Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Pool of Placebo-Controlled Trials
The data in Table 1 is derived from four 26-week placebo-controlled trials. In one trial INVOKANA was used as monotherapy and in three trials INVOKANA was used as add-on therapy [see Clinical Studies (14)]. These data reflect exposure of 1667 patients to INVOKANA and a mean duration of exposure to INVOKANA of 24 weeks. Patients received INVOKANA 100 mg (N=833), INVOKANA 300 mg (N=834) or placebo (N=646) once daily. The mean age of the population was 56 years and 2% were older than 75 years of age. Fifty percent (50%) of the population was male and 72% were Caucasian, 12% were Asian, and 5% were Black or African American. At baseline the population had diabetes for an average of 7.3 years, had a mean HbA1C of 8.0% and 20% had established microvascular complications of diabetes. Baseline renal function was normal or mildly impaired (mean eGFR 88 mL/min/1.73 m2).
Table 1 shows common adverse reactions associated with the use of INVOKANA. These adverse reactions were not present at baseline, occurred more commonly on INVOKANA than on placebo, and occurred in at least 2% of patients treated with either INVOKANA 100 mg or INVOKANA 300 mg.
Table 1: Adverse Reactions From Pool of Four 26–Week Placebo-Controlled Studies Reported in ≥ 2% of INVOKANA-Treated Patients*
| Adverse Reaction |
Placebo
N=646 |
INVOKANA 100 mg
N=833 |
INVOKANA 300 mg
N=834 |
|
| Female genital mycotic infections |
3.2% |
10.4% |
11.4% |
| Urinary tract infections |
4.0% |
5.9% |
4.3% |
| Increased urination |
0.8% |
5.3% |
4.6% |
| Male genital mycotic infections |
0.6% |
4.2% |
3.7% |
| Vulvovaginal pruritus |
0.0% |
1.6% |
3.0% |
| Thirst |
0.2% |
2.8% |
2.3% |
| Constipation |
0.9% |
1.8% |
2.3% |
| Nausea |
1.5% |
2.2% |
2.3% | The four placebo-controlled trials included one monotherapy trial and three add-on combination trials with metformin, metformin and sulfonylurea, or metformin and pioglitazone.
Female genital mycotic infections include the following adverse reactions: Vulvovaginal candidiasis, Vulvovaginal mycotic infection, Vulvovaginitis, Vaginal infection, Vulvitis, and Genital infection fungal. Percentages calculated with the number of female subjects in each group as denominator: placebo (N=312), INVOKANA 100 mg (N=425), and INVOKANA 300 mg (N=430).
Urinary tract infections include the following adverse reactions: Urinary tract infection, Cystitis, Kidney infection, and Urosepsis.
Increased urination includes the following adverse reactions: Polyuria, Pollakiuria, Urine output increased, Micturition urgency, and Nocturia.
Male genital mycotic infections include the following adverse reactions: Balanitis or Balanoposthitis, Balanitis candida, and Genital infection fungal. Percentages calculated with the number of male subjects in each group as denominator: placebo (N=334), INVOKANA 100 mg (N=408), and INVOKANA 300 mg (N=404).
Thirst includes the following adverse reactions: Thirst, Dry mouth, and Polydipsia.
Abdominal pain was also more commonly reported in patients taking INVOKANA 100 mg (1.8%), 300 mg (1.7%) than in patients taking placebo (0.8%).
Pool of Placebo- and Active-Controlled Trials
The occurrence of adverse reactions for canagliflozin was evaluated in a larger pool of patients participating in placebo- and active-controlled trials.
The data combined eight clinical trials [see Clinical Studies (14)] and reflect exposure of 6177 patients to INVOKANA. The mean duration of exposure to INVOKANA was 38 weeks with 1832 individuals exposed to INVOKANA for greater than 50 weeks. Patients received INVOKANA 100 mg (N=3092), INVOKANA 300 mg (N=3085) or comparator (N=3262) once daily. The mean age of the population was 60 years and 5% were older than 75 years of age. Fifty-eight percent (58%) of the population was male and 73% were Caucasian, 16% were Asian, and 4% were Black or African American. At baseline, the population had diabetes for an average of 11 years, had a mean HbA1C of 8.0% and 33% had established microvascular complications of diabetes. Baseline renal function was normal or mildly impaired (mean eGFR 81 mL/min/1.73 m2).
The types and frequency of common adverse reactions observed in the pool of eight clinical trials were consistent with those listed in Table 1. In this pool, INVOKANA was also associated with the adverse reactions of fatigue (1.7% with comparator, 2.2% with INVOKANA 100 mg, and 2.0% with INVOKANA 300 mg) and loss of strength or energy (i.e., asthenia) (0.6% with comparator, 0.7% with INVOKANA 100 mg, and 1.1% with INVOKANA 300 mg).
In the pool of eight clinical trials, the incidence rate of pancreatitis (acute or chronic) was 0.9, 2.7, and 0.9 per 1000 patient-years of exposure to comparator, INVOKANA 100 mg, and INVOKANA 300 mg, respectively.
In the pool of eight clinical trials, hypersensitivity-related adverse reactions (including erythema, rash, pruritus, urticaria, and angioedema) occurred in 3.0%, 3.8%, and 4.2% of patients receiving comparator, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Five patients experienced serious adverse reactions of hypersensitivity with INVOKANA, which included 4 patients with urticaria and 1 patient with a diffuse rash and urticaria occurring within hours of exposure to INVOKANA. Among these patients, 2 patients discontinued INVOKANA. One patient with urticaria had recurrence when INVOKANA was re-initiated.
Photosensitivity-related adverse reactions (including photosensitivity reaction, polymorphic light eruption, and sunburn) occurred in 0.1%, 0.2%, and 0.2% of patients receiving comparator, INVOKANA 100 mg, and INVOKANA 300 mg, respectively.
Other adverse reactions occurring more frequently on INVOKANA than on comparator were:
Volume Depletion-Related Adverse Reactions
INVOKANA results in an osmotic diuresis, which may lead to reductions in intravascular volume. In clinical studies, treatment with INVOKANA was associated with a dose-dependent increase in the incidence of volume depletion-related adverse reactions (e.g., hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration). An increased incidence was observed in patients on the 300 mg dose. The three factors associated with the largest increase in volume depletion-related adverse reactions were the use of loop diuretics, moderate renal impairment (eGFR 30 to less than 60 mL/min/1.73 m2), and age 75 years and older (Table 2) [see Dosage and Administration (2.2), Warnings and Precautions (5.1), and Use in Specific Populations (8.5 and 8.6)].
Table 2: Proportion of Patients With at Least One Volume Depletion-Related Adverse Reaction (Pooled Results from 8 Clinical Trials)
| Baseline Characteristic |
Comparator Group
% |
INVOKANA 100 mg
% |
INVOKANA 300 mg
% |
|
|
| Overall population |
1.5% |
2.3% |
3.4% |
| 75 years of age and older |
2.6% |
4.9% |
8.7% |
| eGFR less than 60 mL/min/1.73 m2 |
2.5% |
4.7% |
8.1% |
| Use of loop diuretic |
4.7% |
3.2% |
8.8% | Includes placebo and active-comparator groups
Patients could have more than 1 of the listed risk factors
In a pool of nine clinical trials with mean duration of exposure to INVOKANA of 85 weeks, the proportion of patients who experienced falls was 1.3%, 1.5%, and 2.1% with comparator, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. The higher risk of falls for patients treated with INVOKANA was observed within the first few weeks of treatment.
Impairment in Renal Function
INVOKANA is associated with a dose-dependent increase in serum creatinine and a concomitant fall in estimated GFR (Table 3). Patients with moderate renal impairment at baseline had larger mean changes.
Table 3: Changes in Serum Creatinine and eGFR Associated with INVOKANA in the Pool of Four Placebo-Controlled Trials and Moderate Renal Impairment Trial
Placebo
N=646 |
INVOKANA 100 mg
N=833 |
INVOKANA 300 mg
N=834 |
| Pool of Four Placebo-Controlled Trials |
Baseline |
Creatinine (mg/dL) |
0.84 |
0.82 |
0.82 |
| eGFR (mL/min/1.73 m2) |
87.0 |
88.3 |
88.8 |
| Week 6 Change |
Creatinine (mg/dL) |
0.01 |
0.03 |
0.05 |
| eGFR (mL/min/1.73 m2) |
-1.6 |
-3.8 |
-5.0 |
| End of Treatment Change |
Creatinine (mg/dL) |
0.01 |
0.02 |
0.03 |
| eGFR (mL/min/1.73 m2) |
-1.6 |
-2.3 |
-3.4 |
|
Placebo
N=90 |
INVOKANA 100 mg
N=90 |
INVOKANA 300 mg
N=89 |
| Moderate Renal Impairment Trial |
Baseline |
Creatinine (mg/dL) |
1.61 |
1.62 |
1.63 |
| eGFR (mL/min/1.73 m2) |
40.1 |
39.7 |
38.5 |
| Week 3 Change |
Creatinine (mg/dL) |
0.03 |
0.18 |
0.28 |
| eGFR (mL/min/1.73 m2) |
-0.7 |
-4.6 |
-6.2 |
| End of Treatment Change |
Creatinine (mg/dL) |
0.07 |
0.16 |
0.18 |
| eGFR (mL/min/1.73 m2) |
-1.5 |
-3.6 |
-4.0 | Week 26 in mITT LOCF population
In the pool of four placebo-controlled trials where patients had normal or mildly impaired baseline renal function, the proportion of patients who experienced at least one event of significant renal function decline, defined as an eGFR below 80 mL/min/1.73 m2 and 30% lower than baseline, was 2.1% with placebo, 2.0% with INVOKANA 100 mg, and 4.1% with INVOKANA 300 mg. At the end of treatment, 0.5% with placebo, 0.7% with INVOKANA 100 mg, and 1.4% with INVOKANA 300 mg had a significant renal function decline.
In a trial carried out in patients with moderate renal impairment with a baseline eGFR of 30 to less than 50 mL/min/1.73 m2 (mean baseline eGFR 39 mL/min/1.73 m2) [see Clinical Studies (14.3)], the proportion of patients who experienced at least one event of significant renal function decline, defined as an eGFR 30% lower than baseline, was 6.9% with placebo, 18% with INVOKANA 100 mg, and 22.5% with INVOKANA 300 mg. At the end of treatment, 4.6% with placebo, 3.4% with INVOKANA 100 mg, and 2.2% with INVOKANA 300 mg had a significant renal function decline.
In a pooled population of patients with moderate renal impairment (N=1085) with baseline eGFR of 30 to less than 60 mL/min/1.73 m2 (mean baseline eGFR 48 mL/min/1.73 m2), the overall incidence of these events was lower than in the dedicated trial but a dose-dependent increase in incident episodes of significant renal function decline compared to placebo was still observed.
Use of INVOKANA has been associated with an increased incidence of renal-related adverse reactions (e.g., increased blood creatinine, decreased glomerular filtration rate, renal impairment, and acute renal failure), particularly in patients with moderate renal impairment.
In the pooled analysis of patients with moderate renal impairment, the incidence of renal-related adverse reactions was 3.7% with placebo, 8.9% with INVOKANA 100 mg, and 9.3% with INVOKANA 300 mg. Discontinuations due to renal-related adverse events occurred in 1.0% with placebo, 1.2% with INVOKANA 100 mg, and 1.6% with INVOKANA 300 mg [see Warnings and Precautions (5.3)].
Genital Mycotic Infections
In the pool of four placebo-controlled clinical trials, female genital mycotic infections (e.g., vulvovaginal mycotic infection, vulvovaginal candidiasis, and vulvovaginitis) occurred in 3.2%, 10.4%, and 11.4% of females treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Patients with a history of genital mycotic infections were more likely to develop genital mycotic infections on INVOKANA. Female patients who developed genital mycotic infections on INVOKANA were more likely to experience recurrence and require treatment with oral or topical antifungal agents and anti-microbial agents. In females, discontinuation due to genital mycotic infections occurred in 0% and 0.7% of patients treated with placebo and INVOKANA, respectively [see Warnings and Precautions (5.7)].
In the pool of four placebo-controlled clinical trials, male genital mycotic infections (e.g., candidal balanitis, balanoposthitis) occurred in 0.6%, 4.2%, and 3.7% of males treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Male genital mycotic infections occurred more commonly in uncircumcised males and in males with a prior history of balanitis or balanoposthitis. Male patients who developed genital mycotic infections on INVOKANA were more likely to experience recurrent infections (22% on INVOKANA versus none on placebo), and require treatment with oral or topical antifungal agents and anti-microbial agents than patients on comparators. In males, discontinuations due to genital mycotic infections occurred in 0% and 0.5% of patients treated with placebo and INVOKANA, respectively. In the pooled analysis of 8 controlled trials, phimosis was reported in 0.3% of uncircumcised male patients treated with INVOKANA and 0.2% required circumcision to treat the phimosis [see Warnings and Precautions (5.7)].
Hypoglycemia
In all clinical trials, hypoglycemia was defined as any event regardless of symptoms, where biochemical hypoglycemia was documented (any glucose value below or equal to 70 mg/dL). Severe hypoglycemia was defined as an event consistent with hypoglycemia where the patient required the assistance of another person to recover, lost consciousness, or experienced a seizure (regardless of whether biochemical documentation of a low glucose value was obtained). In individual clinical trials [see Clinical Studies (14)], episodes of hypoglycemia occurred at a higher rate when INVOKANA was co-administered with insulin or sulfonylureas (Table 4) [see Warnings and Precautions (5.6)].
Table 4: Incidence of Hypoglycemia* in Controlled Clinical Studies
Monotherapy
(26 weeks) |
Placebo
(N=192) |
INVOKANA 100 mg
(N=195) |
INVOKANA 300 mg
(N=197) |
|
|
| Overall [N (%)] |
5 (2.6) |
7 (3.6) |
6 (3.0) |
In Combination with Metformin
(26 weeks) |
Placebo + Metformin
(N=183) |
INVOKANA 100 mg + Metformin
(N=368) |
INVOKANA 300 mg + Metformin
(N=367) |
| Overall [N (%)] |
3 (1.6) |
16 (4.3) |
17 (4.6) |
| Severe [N (%)] |
0 (0) |
1 (0.3) |
1 (0.3) |
In Combination with Metformin
(52 weeks) |
Glimepiride + Metformin
(N=482) |
INVOKANA 100 mg + Metformin
(N=483) |
INVOKANA 300 mg + Metformin
(N=485) |
| Overall [N (%)] |
165 (34.2) |
27 (5.6) |
24 (4.9) |
| Severe [N (%)] |
15 (3.1) |
2 (0.4) |
3 (0.6) |
In Combination with Sulfonylurea
(18 weeks) |
Placebo + Sulfonylurea
(N=69) |
INVOKANA 100 mg + Sulfonylurea
(N=74) |
INVOKANA 300 mg + Sulfonylurea
(N=72) |
| Overall [N (%)] |
4 (5.8) |
3 (4.1) |
9 (12.5) |
In Combination with Metformin + Sulfonylurea
(26 weeks) |
Placebo + Metformin + Sulfonylurea
(N=156) |
INVOKANA 100 mg + Metformin + Sulfonylurea
(N=157) |
INVOKANA 300 mg + Metformin + Sulfonylurea
(N=156) |
| Overall [N (%)] |
24 (15.4) |
43 (27.4) |
47 (30.1) |
| Severe [N (%)] |
1 (0.6) |
1 (0.6) |
0 |
In Combination with Metformin + Sulfonylurea
(52 weeks) |
Sitagliptin + Metformin + Sulfonylurea
(N=378) |
|
INVOKANA 300 mg + Metformin + Sulfonylurea
(N=377) |
| Overall [N (%)] |
154 (40.7) |
|
163 (43.2) |
| Severe [N (%)] |
13 (3.4) |
|
15 (4.0) |
In Combination with Metformin + Pioglitazone
(26 weeks) |
Placebo + Metformin + Pioglitazone
(N=115) |
INVOKANA 100 mg + Metformin + Pioglitazone
(N=113) |
INVOKANA 300 mg + Metformin + Pioglitazone
(N=114) |
| Overall [N (%)] |
3 (2.6) |
3 (2.7) |
6 (5.3) |
In Combination with Insulin
(18 weeks) |
Placebo
(N=565) |
INVOKANA 100 mg
(N=566) |
INVOKANA 300 mg
(N=587) |
| Overall [N (%)] |
208 (36.8) |
279 (49.3) |
285 (48.6) |
| Severe [N (%)] |
14 (2.5) |
10 (1.8) |
16 (2.7) | Number of patients experiencing at least one event of hypoglycemia based on either biochemically documented episodes or severe hypoglycemic events in the intent-to-treat population
Severe episodes of hypoglycemia were defined as those where the patient required the assistance of another person to recover, lost consciousness, or experienced a seizure (regardless of whether biochemical documentation of a low glucose value was obtained)
Bone Fracture
The occurrence of bone fractures was evaluated in a pool of nine clinical trials with a mean duration of exposure to INVOKANA of 85 weeks. The incidence rates of adjudicated bone fractures were 1.1, 1.4, and 1.5 per 100 patient-years of exposure in the comparator, INVOKANA 100 mg, and INVOKANA 300 mg groups, respectively. Fractures were observed as early as 12 weeks after treatment initiation and were more likely to be low trauma (e.g., fall from no more than standing height), and affect the upper extremities [see Warnings and Precautions (5.9)].
Laboratory and Imaging Tests
Increases in Serum Potassium
In a pooled population of patients (N=723) with moderate renal impairment (eGFR 45 to less than 60 mL/min/1.73 m2), increases in serum potassium to greater than 5.4 mEq/L and 15% above baseline occurred in 5.3%, 5.0%, and 8.8% of patients treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Severe elevations (greater than or equal to 6.5 mEq/L) occurred in 0.4% of patients treated with placebo, no patients treated with INVOKANA 100 mg, and 1.3% of patients treated with INVOKANA 300 mg.
In these patients, increases in potassium were more commonly seen in those with elevated potassium at baseline. Among patients with moderate renal impairment, approximately 84% were taking medications that interfere with potassium excretion, such as potassium-sparing diuretics, angiotensin-converting-enzyme inhibitors, and angiotensin-receptor blockers [see Warnings and Precautions (5.3 and 5.4) and Use in Specific Populations (8.6)].
Increases in Serum Magnesium
Dose-related increases in serum magnesium were observed early after initiation of INVOKANA (within 6 weeks) and remained elevated throughout treatment. In the pool of four placebo-controlled trials, the mean percent change in serum magnesium levels was 8.1% and 9.3% with INVOKANA 100 mg and INVOKANA 300 mg, respectively, compared to -0.6% with placebo. In a trial of patients with moderate renal impairment [see Clinical Studies (14.3)], serum magnesium levels increased by 0.2%, 9.2%, and 14.8% with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively.
Increases in Serum Phosphate
Dose-related increases in serum phosphate levels were observed with INVOKANA. In the pool of four placebo controlled trials, the mean percent change in serum phosphate levels were 3.6% and 5.1% with INVOKANA 100 mg and INVOKANA 300 mg, respectively, compared to 1.5% with placebo. In a trial of patients with moderate renal impairment [see Clinical Studies (14.3)], the mean serum phosphate levels increased by 1.2%, 5.0%, and 9.3% with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively.
Increases in Low-Density Lipoprotein Cholesterol (LDL-C) and non-High-Density Lipoprotein Cholesterol (non-HDL-C)
In the pool of four placebo-controlled trials, dose-related increases in LDL-C with INVOKANA were observed. Mean changes (percent changes) from baseline in LDL-C relative to placebo were 4.4 mg/dL (4.5%) and 8.2 mg/dL (8.0%) with INVOKANA 100 mg and INVOKANA 300 mg, respectively. The mean baseline LDL-C levels were 104 to 110 mg/dL across treatment groups [see Warnings and Precautions (5.10)].
Dose-related increases in non-HDL-C with INVOKANA were observed. Mean changes (percent changes) from baseline in non-HDL-C relative to placebo were 2.1 mg/dL (1.5%) and 5.1 mg/dL (3.6%) with INVOKANA 100 mg and 300 mg, respectively. The mean baseline non-HDL-C levels were 140 to 147 mg/dL across treatment groups.
Increases in Hemoglobin
In the pool of four placebo-controlled trials, mean changes (percent changes) from baseline in hemoglobin were -0.18 g/dL (-1.1%) with placebo, 0.47 g/dL (3.5%) with INVOKANA 100 mg, and 0.51 g/dL (3.8%) with INVOKANA 300 mg. The mean baseline hemoglobin value was approximately 14.1 g/dL across treatment groups. At the end of treatment, 0.8%, 4.0%, and 2.7% of patients treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively, had hemoglobin above the upper limit of normal.
Decreases in Bone Mineral Density
Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry in a clinical trial of 714 older adults (mean age 64 years) [see Clinical Studies (14.3)]. At 2 years, patients randomized to INVOKANA 100 mg and INVOKANA 300 mg had placebo-corrected declines in BMD at the total hip of 0.9% and 1.2%, respectively, and at the lumbar spine of 0.3% and 0.7%, respectively. Additionally, placebo-adjusted BMD declines were 0.1% at the femoral neck for both INVOKANA doses and 0.4% at the distal forearm for patients randomized to INVOKANA 300 mg. The placebo-adjusted change at the distal forearm for patients randomized to INVOKANA 100 mg was 0%.
6.2 Postmarketing Experience
Additional adverse reactions have been identified during postapproval use of INVOKANA. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Ketoacidosis [see Warnings and Precautions (5.2)]
Urosepsis and Pyelonephritis [see Warnings and Precautions (5.5)]
7 DRUG INTERACTIONS
7.1 UGT Enzyme Inducers
Rifampin: Co-administration of canagliflozin with rifampin, a nonselective inducer of several UGT enzymes, including UGT1A9, UGT2B4, decreased canagliflozin area under the curve (AUC) by 51%. This decrease in exposure to canagliflozin may decrease efficacy. If an inducer of these UGTs (e.g., rifampin, phenytoin, phenobarbital, ritonavir) must be co-administered with INVOKANA (canagliflozin), consider increasing the dose to 300 mg once daily if patients are currently tolerating INVOKANA 100 mg once daily, have an eGFR greater than 60 mL/min/1.73 m2, and require additional glycemic control. Consider other antihyperglycemic therapy in patients with an eGFR of 45 to less than 60 mL/min/1.73 m2 receiving concurrent therapy with a UGT inducer and require additional glycemic control [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].
7.2 Digoxin
There was an increase in the AUC and mean peak drug concentration (Cmax) of digoxin (20% and 36%, respectively) when co-administered with INVOKANA 300 mg [see Clinical Pharmacology (12.3)]. Patients taking INVOKANA with concomitant digoxin should be monitored appropriately.
7.3 Positive Urine Glucose Test
Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors as SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests. Use alternative methods to monitor glycemic control.
7.4 Interference with 1,5-anhydroglucitol (1,5-AG) Assay
Monitoring glycemic control with 1,5-AG assay is not recommended as measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Teratogenic Effects
Pregnancy Category C
There are no adequate and well-controlled studies of INVOKANA in pregnant women. Based on results from rat studies, canagliflozin may affect renal development and maturation. In a juvenile rat study, increased kidney weights and renal pelvic and tubular dilatation were evident at greater than or equal to 0.5 times clinical exposure from a 300 mg dose [see Nonclinical Toxicology (13.2)].
These outcomes occurred with drug exposure during periods of animal development that correspond to the late second and third trimester of human development. During pregnancy, consider appropriate alternative therapies, especially during the second and third trimesters. INVOKANA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
8.3 Nursing Mothers
It is not known if INVOKANA is excreted in human milk. INVOKANA is secreted in the milk of lactating rats reaching levels 1.4 times higher than that in maternal plasma. Data in juvenile rats directly exposed to INVOKANA showed risk to the developing kidney (renal pelvic and tubular dilatations) during maturation. Since human kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur, there may be risk to the developing human kidney. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from INVOKANA, a decision should be made whether to discontinue nursing or to discontinue INVOKANA, taking into account the importance of the drug to the mother [see Nonclinical Toxicology (13.2)].
8.4 Pediatric Use
Safety and effectiveness of INVOKANA in pediatric patients under 18 years of age have not been established.
8.5 Geriatric Use
Two thousand thirty-four (2034) patients 65 years and older, and 345 patients 75 years and older were exposed to INVOKANA in nine clinical studies of INVOKANA [see Clinical Studies (14.3)].
Patients 65 years and older had a higher incidence of adverse reactions related to reduced intravascular volume with INVOKANA (such as hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration), particularly with the 300 mg daily dose, compared to younger patients; a more prominent increase in the incidence was seen in patients who were 75 years and older [see Dosage and Administration (2.1) and Adverse Reactions (6.1)]. Smaller reductions in HbA1C with INVOKANA relative to placebo were seen in older (65 years and older; -0.61% with INVOKANA 100 mg and -0.74% with INVOKANA 300 mg relative to placebo) compared to younger patients (-0.72% with INVOKANA 100 mg and -0.87% with INVOKANA 300 mg relative to placebo).
8.6 Renal Impairment
The efficacy and safety of INVOKANA were evaluated in a study that included patients with moderate renal impairment (eGFR 30 to less than 50 mL/min/1.73 m2) [see Clinical Studies (14.3)]. These patients had less overall glycemic efficacy and had a higher occurrence of adverse reactions related to reduced intravascular volume, renal-related adverse reactions, and decreases in eGFR compared to patients with mild renal impairment or normal renal function (eGFR greater than or equal to 60 mL/min/1.73 m2). Dose-related, transient mean increases in serum potassium were observed early after initiation of INVOKANA (i.e., within 3 weeks) in this trial. Increases in serum potassium of greater than 5.4 mEq/L and 15% above baseline occurred in 16.1%, 12.4%, and 27.0% of patients treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Severe elevations (greater than or equal to 6.5 mEq/L) occurred in 1.1%, 2.2%, and 2.2% of patients treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively [see Dosage and Administration (2.2), Warnings and Precautions (5.1, 5.3, and 5.4), and Adverse Reactions (6.1)].
The efficacy and safety of INVOKANA have not been established in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m2), with ESRD, or receiving dialysis. INVOKANA is not expected to be effective in these patient populations [see Contraindications (4) and Clinical Pharmacology (12.3)].
8.7 Hepatic Impairment
No dosage adjustment is necessary in patients with mild or moderate hepatic impairment. The use of INVOKANA has not been studied in patients with severe hepatic impairment and is therefore not recommended [see Clinical Pharmacology (12.3)].
10 OVERDOSAGE
There were no reports of overdose during the clinical development program of INVOKANA (canagliflozin).
In the event of an overdose, contact the Poison Control Center. It is also reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive treatment as dictated by the patient's clinical status. Canagliflozin was negligibly removed during a 4-hour hemodialysis session. Canagliflozin is not expected to be dialyzable by peritoneal dialysis.
11 DESCRIPTION
INVOKANA (canagliflozin) contains canagliflozin, an inhibitor of sodium-glucose co-transporter 2 (SGLT2), the transporter responsible for reabsorbing the majority of glucose filtered by the kidney. Canagliflozin, the active ingredient of INVOKANA, is chemically known as (1S)-1,5-anhydro-1-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol hemihydrate and its molecular formula and weight are C24H25FO5S∙1/2 H2O and 453.53, respectively. The structural formula for canagliflozin is:
Canagliflozin is practically insoluble in aqueous media from pH 1.1 to 12.9.
INVOKANA is supplied as film-coated tablets for oral administration, containing 102 and 306 mg of canagliflozin in each tablet strength, corresponding to 100 mg and 300 mg of canagliflozin (anhydrous), respectively.
Inactive ingredients of the core tablet are croscarmellose sodium, hydroxypropyl cellulose, lactose anhydrous, magnesium stearate, and microcrystalline cellulose. The magnesium stearate is vegetable-sourced. The tablets are finished with a commercially available film-coating consisting of the following excipients: polyvinyl alcohol (partially hydrolyzed), titanium dioxide, macrogol/PEG, talc, and iron oxide yellow, E172 (100 mg tablet only).
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Sodium-glucose co-transporter 2 (SGLT2), expressed in the proximal renal tubules, is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen. Canagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, canagliflozin reduces reabsorption of filtered glucose and lowers the renal threshold for glucose (RTG), and thereby increases urinary glucose excretion (UGE).
12.2 Pharmacodynamics
Following single and multiple oral doses of canagliflozin in patients with type 2 diabetes, dose-dependent decreases in the renal threshold for glucose (RTG) and increases in urinary glucose excretion were observed. From a starting RTG value of approximately 240 mg/dL, canagliflozin at 100 mg and 300 mg once daily suppressed RTG throughout the 24-hour period. Maximal suppression of mean RTG over the 24-hour period was seen with the 300 mg daily dose to approximately 70 to 90 mg/dL in patients with type 2 diabetes in Phase 1 studies. The reductions in RTG led to increases in mean UGE of approximately 100 g/day in subjects with type 2 diabetes treated with either 100 mg or 300 mg of canagliflozin. In patients with type 2 diabetes given 100 mg to 300 mg once daily over a 16-day dosing period, reductions in RTG and increases in urinary glucose excretion were observed over the dosing period. In this study, plasma glucose declined in a dose-dependent fashion within the first day of dosing. In single-dose studies in healthy and type 2 diabetic subjects, treatment with canagliflozin 300 mg before a mixed-meal delayed intestinal glucose absorption and reduced postprandial glucose.
Cardiac Electrophysiology
In a randomized, double-blind, placebo-controlled, active-comparator, 4-way crossover study, 60 healthy subjects were administered a single oral dose of canagliflozin 300 mg, canagliflozin 1,200 mg (4 times the maximum recommended dose), moxifloxacin, and placebo. No meaningful changes in QTc interval were observed with either the recommended dose of 300 mg or the 1,200 mg dose.
12.3 Pharmacokinetics
The pharmacokinetics of canagliflozin is similar in healthy subjects and patients with type 2 diabetes. Following single-dose oral administration of 100 mg and 300 mg of INVOKANA, peak plasma concentrations (median Tmax) of canagliflozin occurs within 1 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) was 10.6 hours and 13.1 hours for the 100 mg and 300 mg doses, respectively. Steady-state was reached after 4 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 Dosage and Administration (2.1)].
Distribution
The mean steady-state volume of distribution of canagliflozin following a single intravenous infusion in healthy subjects was 119 L, 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.
Metabolism
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.
Excretion
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 feces 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 to 1.55 mL/min.
Mean systemic clearance of canagliflozin was approximately 192 mL/min in healthy subjects following intravenous administration.
Specific Populations
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 the MDRD-eGFR formula) compared to healthy subjects.
Renal impairment did not affect the Cmax of canagliflozin. Compared to healthy subjects (N=3; eGFR greater than or equal to 90 mL/min/1.73 m2), plasma AUC of canagliflozin was increased by approximately 15%, 29%, and 53% in subjects with mild (N=10), moderate (N=9), and severe (N=10) renal impairment, respectively, (eGFR 60 to less than 90, 30 to less than 60 and 15 to less than 30 mL/min/1.73 m2, respectively), but was similar for ESRD (N=8) subjects and healthy subjects.
Increases in canagliflozin AUC of this magnitude are not considered clinically relevant. The pharmacodynamic response to canagliflozin declines with increasing severity of renal impairment [see Contraindications (4) and Warnings and Precautions (5.3)].
Canagliflozin was negligibly removed by hemodialysis.
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 [see Use in Specific Populations (8.7)].
Pharmacokinetic Effects of Age, Body Mass Index (BMI)/Weight, Gender and Race
Based on the population PK analysis with data collected from 1526 subjects, age, body mass index (BMI)/weight, gender, and race do not have a clinically meaningful effect on the pharmacokinetics of canagliflozin [see Use in Specific Populations (8.5)].
Pediatric
Studies characterizing the pharmacokinetics of canagliflozin in pediatric patients have not been conducted.
Drug Interaction Studies
In Vitro Assessment of Drug Interactions
Canagliflozin did not induce CYP450 enzyme expression (3A4, 2C9, 2C19, 2B6, and 1A2) in cultured human hepatocytes. Canagliflozin did not inhibit the CYP450 isoenzymes (1A2, 2A6, 2C19, 2D6, or 2E1) and weakly inhibited CYP2B6, CYP2C8, CYP2C9, and CYP3A4 based on in vitro studies with human hepatic microsomes. Canagliflozin is a weak inhibitor of P-gp.
Canagliflozin is also a substrate of drug transporters P-glycoprotein (P-gp) and MRP2.
In Vivo Assessment of Drug Interactions
Table 5: Effect of Co–Administered Drugs on Systemic Exposures of Canagliflozin
| Co-Administered Drug |
Dose of Co-Administered Drug* |
Dose of Canagliflozin* |
Geometric Mean Ratio
(Ratio With/Without Co-Administered Drug)
No Effect=1.0 |
AUC†
(90% CI) |
Cmax
(90% CI) |
| QD = once daily; BID = twice daily |
|
See Drug Interactions (7.1) for the clinical relevance of the following:
|
| Rifampin |
600 mg QD for 8 days |
300 mg |
0.49
(0.44; 0.54) |
0.72
(0.61; 0.84) |
No dose adjustments of INVOKANA required for the following:
|
| Cyclosporine |
400 mg |
300 mg QD for 8 days |
1.23
(1.19; 1.27) |
1.01
(0.91; 1.11) |
| Ethinyl estradiol and levonorgestrel |
0.03 mg ethinyl estradiol and 0.15 mg levonorgestrel |
200 mg QD for 6 days |
0.91
(0.88; 0.94) |
0.92
(0.84; 0.99) |
| Hydrochlorothiazide |
25 mg QD for 35 days |
300 mg QD for 7 days |
1.12
(1.08; 1.17) |
1.15
(1.06; 1.25) |
| Metformin |
2,000 mg |
300 mg QD for 8 days |
1.10
(1.05; 1.15) |
1.05
(0.96; 1.16) |
| Probenecid |
500 mg BID for 3 days |
300 mg QD for 17 days |
1.21
(1.16; 1.25) |
1.13
(1.00; 1.28 | QD = once daily; BID = twice daily
Single dose unless otherwise noted
AUC inf for drugs given as a single dose and AUC 24h for drugs given as multiple doses
Table 6: Effect of Canagliflozin on Systemic Exposure of Co-Administered Drugs
| Co-Administered Drug |
Dose of Co-Administered Drug |
Dose of Canagliflozin |
Geometric Mean Ratio
(Ratio With/Without Co-Administered Drug)
No Effect = 1.0 |
|
AUC†
(90% CI) |
Cmax
(90% CI) |
| QD = once daily; BID = twice daily; INR = International Normalized Ratio |
|
See Drug Interactions (7.2) for the clinical relevance of the following:
|
| Digoxin |
0.5 mg QD first day followed by 0.25 mg QD for 6 days |
300 mg QD for 7 days |
digoxin |
1.20
(1.12; 1.28) |
1.36
(1.21; 1.53) |
No dose adjustments of co-administered drug required for the following:
|
| Acetaminophen |
1,000 mg |
300 mg BID for 25 days |
acetaminophen |
1.06‡
(0.98; 1.14) |
1.00
(0.92; 1.09) |
| Ethinyl estradiol and levonorgestrel |
0.03 mg ethinyl estradiol and 0.15 mg levonorgestrel |
200 mg QD for 6 days |
ethinyl estradiol |
1.07
(0.99; 1.15) |
1.22
(1.10; 1.35) |
| levonorgestrel |
1.06
(1.00; 1.13) |
1.22
(1.11; 1.35) |
| Glyburide |
1.25 mg |
200 mg QD for 6 days |
glyburide |
1.02
(0.98; 1.07) |
0.93
(0.85; 1.01) |
| 3-cis-hydroxy-glyburide |
1.01
(0.96; 1.07) |
0.99
(0.91; 1.08) |
| 4-trans-hydroxy-glyburide |
1.03
(0.97; 1.09) |
0.96
(0.88; 1.04) |
| Hydrochlorothiazide |
25 mg QD for 35 days |
300 mg QD for 7 days |
hydrochlorothiazide |
0.99
(0.95; 1.04) |
0.94
(0.87; 1.01) |
| Metformin |
2,000 mg |
300 mg QD for 8 days |
metformin |
1.20
(1.08; 1.34) |
1.06
(0.93; 1.20) |
| Simvastatin |
40 mg |
300 mg QD for 7 days |
simvastatin |
1.12
(0.94; 1.33) |
1.09
(0.91; 1.31) |
| simvastatin acid |
1.18
(1.03; 1.35) |
1.26
(1.10; 1.45) |
| Warfarin |
30 mg |
300 mg QD for 12 days |
(R)-warfarin |
1.01
(0.96; 1.06) |
1.03
(0.94; 1.13) |
| (S)-warfarin |
1.06
(1.00; 1.12) |
1.01
(0.90; 1.13) |
| INR |
1.00
(0.98; 1.03) |
1.05
(0.99; 1.12) | Single dose unless otherwise noted
AUC inf for drugs given as a single dose and AUC 24h for drugs given as multiple doses
AUC 0–12h
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Carcinogenicity was evaluated in 2-year studies conducted in CD1 mice and Sprague-Dawley rats. Canagliflozin did not increase the incidence of tumors in mice dosed at 10, 30, or 100 mg/kg (less than or equal to 14 times exposure from a 300 mg clinical dose).
Testicular Leydig cell tumors, considered secondary to increased luteinizing hormone (LH), increased significantly in male rats at all doses tested (10, 30, and 100 mg/kg). In a 12-week clinical study, LH did not increase in males treated with canagliflozin.
Renal tubular adenoma and carcinoma increased significantly in male and female rats dosed at 100 mg/kg, or approximately 12-times exposure from a 300 mg clinical dose. Also, adrenal pheochromocytoma increased significantly in males and numerically in females dosed at 100 mg/kg. Carbohydrate malabsorption associated with high doses of canagliflozin was considered a necessary proximal event in the emergence of renal and adrenal tumors in rats. Clinical studies have not demonstrated carbohydrate malabsorption in humans at canagliflozin doses of up to 2-times the recommended clinical dose of 300 mg.
Mutagenesis
Canagliflozin was not mutagenic with or without metabolic activation in the Ames assay. Canagliflozin was mutagenic in the in vitro mouse lymphoma assay with but not without metabolic activation. Canagliflozin was not mutagenic or clastogenic in an in vivo oral micronucleus assay in rats and an in vivo oral Comet assay in rats.
Impairment of Fertility
Canagliflozin had no effects on the ability of rats to mate and sire or maintain a litter up to the high dose of 100 mg/kg (approximately 14 times and 18 times the 300 mg clinical dose in males and females, respectively), although there were minor alterations in a number of reproductive parameters (decreased sperm velocity, increased number of abnormal sperm, slightly fewer corpora lutea, fewer implantation sites, and smaller litter sizes) at the highest dosage administered.
13.2 Animal Toxicology and/or Pharmacology
In a juvenile toxicity study in which canagliflozin was dosed directly to young rats from postnatal day (PND) 21 until PND 90 at doses of 4, 20, 65, or 100 mg/kg, increased kidney weights and a dose-related increase in the incidence and severity of renal pelvic and renal tubular dilatation were reported at all dose levels. Exposure at the lowest dose tested was greater than or equal to 0.5 times the maximum clinical dose of 300 mg. The renal pelvic dilatations observed in juvenile animals did not fully reverse within the 1-month recovery period. Similar effects on the developing kidney were not seen when canagliflozin was administered to pregnant rats or rabbits during the period of organogenesis or during a study in which maternal rats were dosed from gestation day (GD) 6 through PND 21 and pups were indirectly exposed in utero and throughout lactation.
In embryo-fetal development studies in rats and rabbits, canagliflozin was administered for intervals coinciding with the first trimester period of non-renal organogenesis in humans.
No developmental toxicities were observed at any dose tested other than a slight increase in the number of fetuses with reduced ossification at a dose that was associated with maternal toxicity and that is approximately 19 times the human exposure to canagliflozin at the 300 mg clinical dose.
14 CLINICAL STUDIES
INVOKANA (canagliflozin) has been studied as monotherapy, in combination with metformin, sulfonylurea, metformin and sulfonylurea, metformin and a thiazolidinedione (i.e., pioglitazone), and in combination with insulin (with or without other antihyperglycemic agents). The efficacy of INVOKANA was compared to a dipeptidyl peptidase-4 (DPP-4) inhibitor (sitagliptin) and a sulfonylurea (glimepiride). INVOKANA was also evaluated in adults 55 to 80 years of age and patients with moderate renal impairment.
In patients with type 2 diabetes, treatment with INVOKANA produced clinically and statistically significant improvements in HbA1C compared to placebo. Reductions in HbA1C were observed across subgroups including age, gender, race, and baseline body mass index (BMI).
14.1 Monotherapy
A total of 584 patients with type 2 diabetes inadequately controlled on diet and exercise participated in a 26-week, double-blind, placebo-controlled study to evaluate the efficacy and safety of INVOKANA. The mean age was 55 years, 44% of patients were men, and the mean baseline eGFR was 87 mL/min/1.73 m2. Patients taking other antihyperglycemic agents (N=281) discontinued the agent and underwent an 8-week washout followed by a 2-week, single-blind, placebo run-in period. Patients not taking oral antihyperglycemic agents (N=303) entered the 2-week, single-blind, placebo run-in period directly. After the placebo run-in period, patients were randomized to INVOKANA 100 mg, INVOKANA 300 mg, or placebo, administered once daily for 26 weeks.
At the end of treatment, INVOKANA 100 mg and 300 mg once daily resulted in a statistically significant improvement in HbA1C (p<0.001 for both doses) compared to placebo. INVOKANA 100 mg and 300 mg once daily also resulted in a greater proportion of patients achieving an HbA1C less than 7%, in significant reduction in fasting plasma glucose (FPG), in improved postprandial glucose (PPG), and in percent body weight reduction compared to placebo (see Table 7). Statistically significant (p<0.001 for both doses) mean changes from baseline in systolic blood pressure relative to placebo were -3.7 mmHg and -5.4 mmHg with INVOKANA 100 mg and 300 mg, respectively.
Table 7: Results from 26-Week Placebo-Controlled Clinical Study with INVOKANA as Monotherapy*
| Efficacy Parameter |
Placebo
(N=192) |
INVOKANA 100 mg
(N=195) |
INVOKANA 300 mg
(N=197) |
|
| HbA1C (%) |
| Baseline (mean) |
7.97 |
8.06 |
8.01 |
| Change from baseline (adjusted mean) |
0.14 |
-0.77 |
-1.03 |
| Difference from placebo (adjusted mean) (95% CI) |
|
-0.91
(-1.09; -0.73) |
-1.16
(-1.34; -0.99) |
| Percent of Patients Achieving HbA1C < 7% |
21 |
45 |
62 |
| Fasting Plasma Glucose (mg/dL) |
| Baseline (mean) |
166 |
172 |
173 |
| Change from baseline (adjusted mean) |
8 |
-27 |
-35 |
| Difference from placebo (adjusted mean) (95% CI) |
|
-36
(-42; -29) |
-43
(-50; -37) |
| 2-hour Postprandial Glucose (mg/dL) |
| Baseline (mean) |
229 |
250 |
254 |
| Change from baseline (adjusted mean) |
5 |
-43 |
-59 |
| Difference from placebo (adjusted mean) (95% CI) |
|
-48
(-59.1; -37.0) |
-64
(-75.0; -52.9) |
| Body Weight |
| Baseline (mean) in kg |
87.5 |
85.9 |
86.9 |
| % change from baseline (adjusted mean) |
-0.6 |
-2.8 |
-3.9 |
| Difference from placebo (adjusted mean) (95% CI) |
|
-2.2
(-2.9; -1.6) |
-3.3
(-4.0; -2.6) | Intent-to-treat population using last observation in study prior to glycemic rescue therapy
Least squares mean adjusted for baseline value and stratification factors
p<0.001
14.2 Combination Therapy
Add-on Combination Therapy with Metformin
A total of 1284 patients with type 2 diabetes inadequately controlled on metformin monotherapy (greater than or equal to 2,000 mg/day, or at least 1,500 mg/day if higher dose not tolerated) participated in a 26-week, double-blind, placebo- and active-controlled study to evaluate the efficacy and safety of INVOKANA in combination with metformin. The mean age was 55 years, 47% of patients were men, and the mean baseline eGFR was 89 mL/min/1.73 m2. Patients already on the required metformin dose (N=1009) were randomized after completing a 2-week, single-blind, placebo run-in period. Patients taking less than the required metformin dose or patients on metformin in combination with another antihyperglycemic agent (N=275) were switched to metformin monotherapy (at doses described above) for at least 8 weeks before entering the 2-week, single-blind, placebo run-in. After the placebo run-in period, patients were randomized to INVOKANA 100 mg, INVOKANA 300 mg, sitagliptin 100 mg, or placebo, administered once daily as add-on therapy to metformin.
At the end of treatment, INVOKANA 100 mg and 300 mg once daily resulted in a statistically significant improvement in HbA1C (p<0.001 for both doses) compared to placebo when added to metformin. INVOKANA 100 mg and 300 mg once daily also resulted in a greater proportion of patients achieving an HbA1C less than 7%, in significant reduction in fasting plasma glucose (FPG), in improved postprandial glucose (PPG), and in percent body weight reduction compared to placebo when added to metformin (see Table 8). Statistically significant (p<0.001 for both doses) mean changes from baseline in systolic blood pressure relative to placebo were -5.4 mmHg and -6.6 mmHg with INVOKANA 100 mg and 300 mg, respectively.
Table 8: Results from 26-Week Placebo-Controlled Clinical Study of INVOKANA in Combination with Metformin*
| Efficacy Parameter |
Placebo + Metformin
(N=183) |
INVOKANA 100 mg + Metformin
(N=368) |
INVOKANA 300 mg + Metformin
(N=367) |
|
| HbA1C (%) |
| Baseline (mean) |
7.96 |
7.94 |
7.95 |
| Change from baseline (adjusted mean) |
-0.17 |
-0.79 |
-0.94 |
| Difference from placebo (adjusted mean) (95% CI)† |
|
-0.62‡
(-0.76; -0.48) |
-0.77‡
(-0.91; -0.64) |
| Percent of patients achieving HbA1C < 7% |
30 |
46‡ |
58‡ |
| Fasting Plasma Glucose (mg/dL) |
| Baseline (mean) |
164 |
169 |
173 |
| Change from baseline (adjusted mean) |
2 |
-27 |
-38 |
| Difference from placebo (adjusted mean) (95% CI)† |
|
-30‡
(-36; -24) |
-40‡
(-46; -34) |
| 2-hour Postprandial Glucose (mg/dL) |
| Baseline (mean) |
249 |
258 |
262 |
| Change from baseline (adjusted mean) |
-10 |
-48 |
-57 |
| Difference from placebo (adjusted mean) (95% CI)† |
|
-38‡
(-49; -27) |
-47‡
(-58; -36) |
| Body Weight |
| Baseline (mean) in kg |
86.7 |
88.7 |
85.4 |
| % change from baseline (adjusted mean) |
-1.2 |
-3.7 |
-4.2 |
| Difference from placebo (adjusted mean) (95% CI)† |
|
-2.5‡
(-3.1; -1.9) |
-2.9‡
(-3.5; -2.3) | Intent-to-treat population using last observation in study prior to glycemic rescue therapy
Least squares mean adjusted for baseline value and stratification factors
p<0.001
INVOKANA Compared to Glimepiride, Both as Add-on Combination With Metformin
A total of 1450 patients with type 2 diabetes inadequately controlled on metformin monotherapy (greater than or equal to 2,000 mg/day, or at least 1,500 mg/day if higher dose not tolerated) participated in a 52-week, double-blind, active-controlled study to evaluate the efficacy and safety of INVOKANA in combination with metformin.
The mean age was 56 years, 52% of patients were men, and the mean baseline eGFR was 90 mL/min/1.73 m2. Patients tolerating maximally required metformin dose (N=928) were randomized after completing a 2-week, single-blind, placebo run-in period. Other patients (N=522) were switched to metformin monotherapy (at doses described above) for at least 10 weeks, then completed a 2-week single-blind run-in period. After the 2-week run-in period, patients were randomized to INVOKANA 100 mg, INVOKANA 300 mg, or glimepiride (titration allowed throughout the 52-week study to 6 or 8 mg), administered once daily as add-on therapy to metformin.
As shown in Table 9 and Figure 1, at the end of treatment, INVOKANA 100 mg provided similar reductions in HbA1C from baseline compared to glimepiride when added to metformin therapy. INVOKANA 300 mg provided a greater reduction from baseline in HbA1C compared to glimepiride, and the relative treatment difference was -0.12% (95% CI: –0.22; –0.02). As shown in Table 9, treatment with INVOKANA 100 mg and 300 mg daily provided greater improvements in percent body weight change, relative to glimepiride.
Table 9: Results from 52–Week Clinical Study Comparing INVOKANA to Glimepiride in Combination with Metformin*
| Efficacy Parameter |
INVOKANA 100 mg + Metformin
(N=483) |
INVOKANA 300 mg + Metformin
(N=485) |
Glimepiride (titrated) + Metformin
(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) |
-0.01
(-0.11; 0.09) |
-0.12
(-0.22; -0.02) |
|
| Percent of patients achieving HbA1C < 7% |
54 |
60 |
56 |
| Fasting Plasma Glucose (mg/dL) |
| Baseline (mean) |
165 |
164 |
166 |
| Change from baseline (adjusted mean) |
-24 |
-28 |
-18 |
| Difference from glimepiride (adjusted mean) (95% CI)† |
-6
(-10; -2) |
-9
(-13; -5) |
|
| 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) |
-5.2
(-5.7; -4.7) |
-5.7
(-6.2; -5.1) | Intent-to-treat population using last observation in study prior to glycemic rescue therapy
Least squares mean adjusted for baseline value and stratification factors
INVOKANA + metformin is considered non-inferior to glimepiride + metformin because the upper limit of this confidence interval is less than the pre-specified non-inferiority margin of < 0.3%.
§ p<0.001
Figure 1: Mean HbA1C Change at Each Time Point (Completers) and at Week 52 Using Last Observation Carried Forward (mITT Population)
Add-on Combination Therapy With Sulfonylurea
A total of 127 patients with type 2 diabetes inadequately controlled on sulfonylurea monotherapy participated in an 18-week, double-blind, placebo-controlled sub-study to evaluate the efficacy and safety of INVOKANA in combination with sulfonylurea. The mean age was 65 years, 57% of patients were men, and the mean baseline eGFR was 69 mL/min/1.73 m2. Patients treated with sulfonylurea monotherapy on a stable protocol-specified dose (greater than or equal to 50% maximal dose) for at least 10 weeks completed a 2-week, single-blind, placebo run-in period. After the run-in period, patients with inadequate glycemic control were randomized to INVOKANA 100 mg, INVOKANA 300 mg, or placebo, administered once daily as add-on to sulfonylurea.
As shown in Table 10, at the end of treatment, INVOKANA 100 mg and 300 mg daily provided statistically significant (p<0.001 for both doses) improvements in HbA1C relative to placebo when added to sulfonylurea. INVOKANA 300 mg once daily compared to placebo resulted in a greater proportion of patients achieving an HbA1C less than 7%, (33% vs 5%), greater reductions in fasting plasma glucose (-36 mg/dL vs +12 mg/dL), and greater percent body weight reduction (-2.0% vs -0.2%).
Table 10: Results from 18-Week Placebo–Controlled Clinical Study of INVOKANA in Combination with Sulfonylurea*
| Efficacy Parameter |
Placebo + Sulfonylurea
(N=45) |
INVOKANA 100 mg + Sulfonylurea
(N=42) |
INVOKANA 300 mg + Sulfonylurea
(N=40) |
|
| HbA1C (%) |
| Baseline (mean) |
8.49 |
8.29 |
8.28 |
| Change from baseline (adjusted mean) |
0.04 |
-0.70 |
-0.79 |
| Difference from placebo (adjusted mean) (95% CI)† |
|
-0.74‡
(-1.15; -0.33) |
-0.83‡
(-1.24; -0.41) | Intent-to-treat population using last observation in study prior to glycemic rescue therapy
Least squares mean adjusted for baseline value
p<0.001
Add-on Combination Therapy With Metformin and Sulfonylurea
A total of 469 patients with type 2 diabetes inadequately controlled on the combination of metformin (greater than or equal to 2,000 mg/day or at least 1,500 mg/day if higher dose not tolerated) and sulfonylurea (maximal or near-maximal effective dose) participated in a 26-week, double-blind, placebo-controlled study to evaluate the efficacy and safety of INVOKANA in combination with metformin and sulfonylurea. The mean age was 57 years, 51% of patients were men, and the mean baseline eGFR was 89 mL/min/1.73 m2. Patients already on the protocol-specified doses of metformin and sulfonylurea (N=372) entered a 2-week, single-blind, placebo run-in period. Other patients (N=97) were required to be on a stable protocol-specified dose of metformin and sulfonylurea for at least 8 weeks before entering the 2-week run-in period. Following the run-in period, patients were randomized to INVOKANA 100 mg, INVOKANA 300 mg, or placebo, administered once daily as add-on to metformin and sulfonylurea.
At the end of treatment, INVOKANA 100 mg and 300 mg once daily resulted in a statistically significant improvement in HbA1C (p<0.001 for both doses) compared to placebo when added to metformin and sulfonylurea. INVOKANA 100 mg and 300 mg once daily also resulted in a greater proportion of patients achieving an HbA1C less than 7%, in a significant reduction in fasting plasma glucose (FPG), and in percent body weight reduction compared to placebo when added to metformin and sulfonylurea (see Table 11).
Table 11: Results from 26–Week Placebo-Controlled Clinical Study of INVOKANA in Combination with Metformin and Sulfonylurea*
| Efficacy Parameter |
Placebo + Metformin and Sulfonylurea
(N=156) |
INVOKANA 100 mg + Metformin and Sulfonylurea
(N=157) |
INVOKANA 300 mg + Metformin and Sulfonylurea
(N=156) |
|
| HbA1C (%) |
| Baseline (mean) |
8.12 |
8.13 |
8.13 |
| Change from baseline (adjusted mean) |
-0.13 |
-0.85 |
-1.06 |
| Difference from placebo (adjusted mean) (95% CI)† |
|
-0.71‡
(-0.90; -0.52) |
-0.92‡
(-1.11; -0.73) |
| Percent of patients achieving A1C < 7% |
18 |
43‡ |
57‡ |
| Fasting Plasma Glucose (mg/dL) |
| Baseline (mean) |
170 |
173 |
168 |
| Change from baseline (adjusted mean) |
4 |
-18 |
-31 |
| Difference from placebo (adjusted mean) (95% CI) |
|
-22‡
(-31; -13) |
-35‡
(-44; -25) |
| Body Weight |
| Baseline (mean) in kg |
90.8 |
93.5 |
93.5 |
| % change from baseline (adjusted mean) |
-0.7 |
-2.1 |
-2.6 |
| Difference from placebo (adjusted mean) (95% CI) |
|
-1.4‡
(-2.1; -0.7) |
-2.0‡
(-2.7; -1.3) | Intent-to-treat population using last observation in study prior to glycemic rescue therapy
Least squares mean adjusted for baseline value and stratification factors
p<0.001
INVOKANA Compared to Sitagliptin, Both as Add-on Combination Therapy With Metformin and Sulfonylurea
A total of 755 patients with type 2 diabetes inadequately controlled on the combination of metformin (greater than or equal to 2,000 mg/day or at least 1,500 mg/day if higher dose not tolerated) and sulfonylurea (near-maximal or maximal effective dose) participated in a 52-week, double-blind, active-controlled study to compare the efficacy and safety of INVOKANA 300 mg versus sitagliptin 100 mg in combination with metformin and sulfonylurea. The mean age was 57 years, 56% of patients were men, and the mean baseline eGFR was 88 mL/min/1.73 m2. Patients already on protocol-specified doses of metformin and sulfonylurea (N=716) entered a 2-week single-blind, placebo run-in period. Other patients (N=39) were required to be on a stable protocol-specified dose of metformin and sulfonylurea for at least 8 weeks before entering the 2-week run-in period. Following the run-in period, patients were randomized to INVOKANA 300 mg or sitagliptin 100 mg as add-on to metformin and sulfonylurea.
As shown in Table 12 and Figure 2, at the end of treatment, INVOKANA 300 mg provided greater HbA1C reduction compared to sitagliptin 100 mg when added to metformin and sulfonylurea (p<0.05). INVOKANA 300 mg resulted in a mean percent change in body weight from baseline of -2.5% compared to +0.3% with sitagliptin 100 mg. A mean change in systolic blood pressure from baseline of -5.06 mmHg was observed with INVOKANA 300 mg compared to +0.85 mmHg with sitagliptin 100 mg.
Table 12: Results from 52–Week Clinical Study Comparing INVOKANA to Sitagliptin in Combination with Metformin and Sulfonylurea*
| Efficacy Parameter |
INVOKANA 300 mg + Metformin and Sulfonylurea
(N=377) |
Sitagliptin 100 mg + Metformin and Sulfonylurea
(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)† |
-0.37‡
(-0.50; -0.25) |
|
| Percent of patients achieving HbA1C < 7% |
48 |
35 |
| Fasting Plasma Glucose (mg/dL) |
| Baseline (mean) |
170 |
164 |
| Change from baseline (adjusted mean) |
-30 |
-6 |
| Difference from sitagliptin (adjusted mean) (95% CI)† |
-24
(-30; -18) |
|
| 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)† |
-2.8§
(-3.3; -2.2) | Intent-to-treat population using last observation in study prior to glycemic rescue therapy
Least squares mean adjusted for baseline value and stratification factors
INVOKANA + metformin + sulfonylurea is considered non-inferior to sitagliptin + metformin + sulfonylurea because the upper limit of this confidence interval is less than the pre-specified non-inferiority margin of < 0.3%.
§ p<0.001
Figure 2: Mean HbA1C Change at Each Time Point (Completers) and at Week 52 Using Last Observation Carried Forward (mITT Population)
Add-on Combination Therapy With Metformin and Pioglitazone
A total of 342 patients with type 2 diabetes inadequately controlled on the combination of metformin (greater than or equal to 2,000 mg/day or at least 1,500 mg/day if higher dose not tolerated) and pioglitazone (30 or 45 mg/day) participated in a 26-week, double-blind, placebo-controlled study to evaluate the efficacy and safety of INVOKANA in combination with metformin and pioglitazone. The mean age was 57 years, 63% of patients were men, and the mean baseline eGFR was 86 mL/min/1.73 m2. Patients already on protocol-specified doses of metformin and pioglitazone (N=163) entered a 2-week, single-blind, placebo run-in period. Other patients (N=181) were required to be on stable protocol-specified doses of metformin and pioglitazone for at least 8 weeks before entering the 2-week run-in period. Following the run-in period, patients were randomized to INVOKANA 100 mg, INVOKANA 300 mg, or placebo, administered once daily as add-on to metformin and pioglitazone.
At the of end of treatment, INVOKANA 100 mg and 300 mg once daily resulted in a statistically significant improvement in HbA1C (p<0.001 for both doses) compared to placebo when added to metformin and pioglitazone. INVOKANA 100 mg and 300 mg once daily also resulted in a greater proportion of patients achieving an HbA1C less than 7%, in significant reduction in fasting plasma glucose (FPG) and in percent body weight reduction compared to placebo when added to metformin and pioglitazone (see Table 13). Statistically significant (p<0.05 for both doses) mean changes from baseline in systolic blood pressure relative to placebo were -4.1 mmHg and -3.5 mmHg with INVOKANA 100 mg and 300 mg, respectively.
Table 13: Results from 26–Week Placebo-Controlled Clinical Study of INVOKANA in Combination with Metformin and Pioglitazone*
| Efficacy Parameter |
Placebo + Metformin and Pioglitazone
(N=115) |
INVOKANA 100 mg + Metformin and Pioglitazone
(N=113) |
INVOKANA 300 mg + Metformin and Pioglitazone
(N=114) |
|
| HbA1C (%) |
| Baseline (mean) |
8.00 |
7.99 |
7.84 |
| Change from baseline (adjusted mean) |
-0.26 |
-0.89 |
-1.03 |
| Difference from placebo (adjusted mean) (95% CI) |
|
-0.62
(-0.81; -0.44) |
-0.76
(-0.95; -0.58) |
| Percent of patients achieving HbA1C < 7% |
33 |
47 |
64 |
| Fasting Plasma Glucose (mg/dL) |
| Baseline (mean) |
164 |
169 |
164 |
| Change from baseline (adjusted mean) |
3 |
-27 |
-33 |
| Difference from placebo (adjusted mean) (95% CI) |
|
-29
(-37; -22) |
-36
(-43; -28) |
| Body Weight |
| Baseline (mean) in kg |
94.0 |
94.2 |
94.4 |
| % change from baseline (adjusted mean) |
-0.1 |
-2.8 |
-3.8 |
| Difference from placebo (adjusted mean) (95% CI) |
|
-2.7
(-3.6; -1.8) |
-3.7
(-4.6; -2.8) | Intent-to-treat population using last observation in study prior to glycemic rescue therapy
Least squares mean adjusted for baseline value and stratification factors
p<0.001
Add-On Combination Therapy With Insulin (With or Without Other Antihyperglycemic Agents)
A total of 1718 patients with type 2 diabetes inadequately controlled on insulin greater than or equal to 30 units/day or insulin in combination with other antihyperglycemic agents participated in an 18-week, double-blind, placebo-controlled substudy of a cardiovascular study to evaluate the efficacy and safety of INVOKANA in combination with insulin. The mean age was 63 years, 66% of patients were men, and the mean baseline eGFR was 75 mL/min/1.73 m2. Patients on basal, bolus, or basal/bolus insulin for at least 10 weeks entered a 2-week, single-blind, placebo run-in period. Approximately 70% of patients were on a background basal/bolus insulin regimen. After the run-in period, patients were randomized to INVOKANA 100 mg, INVOKANA 300 mg, or placebo, administered once daily as add-on to insulin. The mean daily insulin dose at baseline was 83 units, which was similar across treatment groups.
At the of end of treatment, INVOKANA 100 mg and 300 mg once daily resulted in a statistically significant improvement in HbA1C (p<0.001 for both doses) compared to placebo when added to insulin. INVOKANA 100 mg and 300 mg once daily also resulted in a greater proportion of patients achieving an HbA1C less than 7%, in significant reductions in fasting plasma glucose (FPG), and in percent body weight reductions compared to placebo (see Table 14). Statistically significant (p<0.001 for both doses) mean changes from baseline in systolic blood pressure relative to placebo were -2.6 mmHg and -4.4 mmHg with INVOKANA 100 mg and 300 mg, respectively.
Table 14: Results from 18–Week Placebo-Controlled Clinical Study of INVOKANA in Combination with Insulin ≥ 30 Units/Day (With or Without Other Oral Antihyperglycemic Agents)*
| Efficacy Parameter |
Placebo + Insulin
(N=565) |
INVOKANA 100 mg + Insulin
(N=566) |
INVOKANA 300 mg + Insulin
(N=587) |
|
| HbA1C (%) |
| Baseline (mean) |
8.20 |
8.33 |
8.27 |
| Change from baseline (adjusted mean) |
0.01 |
-0.63 |
-0.72 |
| Difference from placebo (adjusted mean) (95% CI)† |
|
-0.65‡
(-0.73; -0.56) |
-0.73‡
(-0.82; -0.65) |
| Percent of patients achieving HbA1C < 7% |
8 |
20 |
25 |
| Fasting Plasma Glucose (mg/dL) |
| Baseline |
169 |
170 |
168 |
| Change from baseline (adjusted mean) |
4 |
-19 |
-25 |
| Difference from placebo (adjusted mean) (97.5% CI) |
|
-23
(-29; -16) |
-29
(-35; -23) |
| Body Weight |
| Baseline (mean) in kg |
97.7 |
96.9 |
96.7 |
| % change from baseline (adjusted mean) |
0.1 |
-1.8 |
-2.3 |
| Difference from placebo (adjusted mean) (97.5% CI) |
|
-1.9
(-2.2; -1.6) |
-2.4
(-2.7; -2.1) | Intent-to-treat population using last observation in study prior to glycemic rescue therapy
Least squares mean adjusted for baseline value and stratification factors
p<0.001
14.3 Studies in Special Populations
Adults 55 to 80 Years of Age
A total of 714 older patients with type 2 diabetes inadequately controlled on current diabetes therapy (either diet and exercise alone or in combination with oral or parenteral agents) participated in a 26-week, double-blind, placebo-controlled study to evaluate the efficacy and safety of INVOKANA in combination with current diabetes treatment. The mean age was 64 years, 55% of patients were men, and the mean baseline eGFR was 77 mL/min/1.73 m2. Patients were randomized to the addition of INVOKANA 100 mg, INVOKANA 300 mg, or placebo, administered once daily. At the end of treatment, INVOKANA provided statistically significant improvements from baseline relative to placebo in HbA1C (p<0.001 for both doses) of -0.57% (95% CI: -0.71; -0.44) for INVOKANA 100 mg and -0.70% (95% CI: -0.84; -0.57) for INVOKANA 300 mg. Statistically significant (p<0.001 for both doses) reductions from baseline in fasting plasma glucose (FPG) and body weight were also observed in this study relative to placebo [see Use in Specific Populations (8.5)].
Moderate Renal Impairment
A total of 269 patients with type 2 diabetes and a baseline eGFR of 30 mL/min/1.73 m2 to less than 50 mL/min/1.73 m2 inadequately controlled on current diabetes therapy participated in a 26-week, double-blind, placebo-controlled clinical study to evaluate the efficacy and safety of INVOKANA in combination with current diabetes treatment (diet or antihyperglycemic agent therapy, with 95% of patients on insulin and/or sulfonylurea). The mean age was 68 years, 61% of patients were men, and the mean baseline eGFR was 39 mL/min/1.73 m2. Patients were randomized to the addition of INVOKANA 100 mg, INVOKANA 300 mg, or placebo, administered once daily.
At the end of treatment, INVOKANA 100 mg and INVOKANA 300 mg daily provided greater reductions in HbA1C relative to placebo (-0.30% [95% CI: -0.53; -0.07] and -0.40%, [95% CI: -0.64; -0.17], respectively) [see Warnings and Precautions (5.3), Adverse Reactions (6.1), and Use in Specific Populations (8.6)].
16 HOW SUPPLIED/STORAGE AND HANDLING
INVOKANA (canagliflozin) tablets are available in the strengths and packages listed below:
100 mg tablets are yellow, capsule-shaped, film-coated tablets with "CFZ" on one side and "100" on the other side.
| NDC 50458-140-30 |
Bottle of 30 |
| NDC 50458-140-90 |
Bottle of 90 |
| NDC 50458-140-50 |
Bottle of 500 |
| NDC 50458-140-10 |
Blister package containing 100 tablets (10 blister cards containing 10 tablets each) | 300 mg tablets are white, capsule-shaped, film-coated tablets with "CFZ" on one side and "300" on the other side.
| NDC 50458-141-30 |
Bottle of 30 |
| NDC 50458-141-90 |
Bottle of 90 |
| NDC 50458-141-50 |
Bottle of 500 |
| NDC 50458-141-10 |
Blister package containing 100 tablets (10 blister cards containing 10 tablets each) | Storage and Handling
Store at 25°C (77°F); excursions permitted to 15 to 30°C (59 to 86°F).
http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b9057d3b-b104-4f09-8a61-c61ef9d4a3f3
Invokana是一种新类型的钠-葡萄糖协同转运蛋白2(SGLT2)抑制剂药物
Invokana(canagliflozin)为一种新类型强效的口服片剂
批准日期：2013年3月29javascript: 公司：Janssen Research & Development，LLC
适应证和用途
INVOKANA是一种钠-葡萄糖共-转运蛋白2(SGLT2)抑制剂适用作为对食物和运动的一种辅助在有2型糖尿病成年中改善血糖控制。使用的限制：
● 不为1型糖尿病或糖尿病酮症酸中毒的治疗。
剂型和给药方法
（1）推荐开始剂量是100mg每天1次服药天第一餐前服用。
（2）在耐受INVOKANA 100 mg每天1次患者有eGFR为60 mL/min/1.73m2或大于和需要额外的血糖控制剂量可以增加至300 mg每天1次。
（3）在有eGFR为45至小于60 mL/min/1.73m2患者INVOKANA被限制至100 mg每天1次。
（4）开始INVOKANA前评估肾功能。如eGFR低于45 mL/min/1.73 m2不要开始INVOKANA。
（5）终止INVOKANA如eGFR下降低于45 mL/min/1.73m2。剂型和规格片：100mg，300mg。禁忌证（1）对INVOKANA严重超敏性反应史。
（2）严重肾受损，肾病终末期ESRD，或正在透析。
警告和注意事项
（1）低血压：开始INVOKANA前，评估容积状态和在有肾受损患者，老年人，在有低收缩压患者，或如用利尿药，ACEi，或ARB纠正低血容量。治疗期间监视体征和症状。
（2）肾功能受损：治疗期间监视肾功能。有eGFR低于60mL/min/1.73m2患者中建议更频监视。
（3）高钾血症：有肾功能受损患者和易患高钾血症患者中监视钾水平。
（4）低血糖：考虑较低剂量胰岛素[insulin]或胰岛素促分泌素[secretagogue]以减低当与INVOKANA联用低血糖风险。
（5）生殖器真菌感染：如指示监视和治疗。
（6）超敏性反应：终止INVOKANA和监视直至体征和症状解决。
（7）LDL-C增加：监视LDL-C和用标准医护治疗。不良反应伴INVOKANA最常见不良反应(发生率5%或更大)：女性生殖器真菌感染，尿路感染，和排尿增加。
药物相互作用
（1）UGT诱导剂(如，利福平[rifampin])：Canagliflozin暴露减低。考虑增加剂量从100mg至300mg。
（2）地高辛[Digoxin]：监视地高辛水平。
特殊人群中使用
（1）妊娠：在妊娠妇女中没有适当和对照良好研究。妊娠期间使用只有如潜在获益公正地胜于对胎儿潜在风险。
（2）哺乳母亲：终止药物或哺乳。
（3）老年医学：与血管内血容量减少相关不良反应的较高发生率。
（4）肾受损：与血管内血容量减低和肾功能相关不良反应的较高发生率。
（5）肝受损：有严重肝受损不建议使用。
Type 2 diabetes has its warrior – Invokana (canagliflozin) tablets
There has been a lot of buzz around recently regarding new revelation in type 2 diabetes medications. For example, the recent announcement by FDA that it has approved Invokana (canagliflozin) tablets, which enhances glycemic control in adults having type 2 diabetes, has bring in a new lease of life to patient who have type 2 diabetes. Before giving its approval to this tablet FDA was convinced with the result of the tablet through various studies on 10,285 patients. The tablet has been used with diet and exercise and touted as first-of-its-kind diabetes drug employs new method to lower blood sugar i.e. flushing out it through patient’s urine.
But still there are so many questions around about this type 2 drugs. For example, many patients have been wondering whether this tablet can be had for type 1 diabetes also. No according to its manufacturers you can’t take this drug with type 1 diabetes. This tablet has also not found suitable for people with diabetic ketoacidosis i.e. increased ketones in blood or urine.
Before starting this medication, contact your physician as there are side-effects involved. For example, Invokana tablet can result in dehydration. And dehydration may result in dizzy, lightheaded, weakness or faintness. If you have low blood pressure the condition of dehydration may result fatal.
In rare cases this tablet may result in vaginal yeast infection in women. Moreover men may get yeast infection of the penis viz., balanitis or balanoposthitis. After taking this medication if you come across yeast infection your physician may advice you to use over-the-counter antifungal medicine.
If you are just starting to take this medicine talk to your doctor, about any conditions you have like if you have kidney, liver or other problems. If you are pregnant you may take the advice of your physician whether to take this medicine.
According to its manufacturers Invokana varies from other available drugs for type 2 diabetes, as it has been found shrinking the amount of sugar absorbed from food and stored in the liver. This drug has also been found dropping in blood pressure as soon as a patient stands up.
About Type 2 diabetes
Around 26 million Americans have diabetes, reveals U.S. Centers for Disease Control and Prevention and 90 to 95 percent have been suffering from type 2 diabetes, while 60 percent with this type of condition are overweight. That said, this medication will definitely bring a sort of revolution in this type of condition.
强生糖尿病新药INVOKANA获欧盟批准
2013年11月25日,强生（JNJ）旗下杨森（Janssen）宣布，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。
今年9月，canagliflozin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。此外，canagliflozin已于今年3月获FDA批准，并于近期获得了澳大利亚的批准。
Canagliflozin为日服一次的口服糖尿病药物，属于选择性纳葡萄糖共转运体2（sodium glucose co-transporter 2，SGLT2）抑制剂的一类新药，通过阻断肾脏对血糖的重吸收及增加尿液中血糖的排泄，来降低机体血糖水平。
与非糖尿病人群相比，2型糖尿病患者的肾脏能够重吸收大量的葡萄糖进入血液，这可能会推高血糖水平。
Canagliflozin是强生公司最有前途的药物候选者之一。该公司旗下杨森部门具有该药在北美、南美、欧洲、中东、非洲、澳大利亚、新西兰及一些亚洲国家的销售权。
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