Canagliflozin
Therapeutic agent (verify pharmacological class)
What it is used for
1 INDICATIONS AND USAGE INVOKANA (canagliflozin) is indicated: • as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus. • to reduce the risk of major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction and nonfatal stroke) in adults with type 2 diabetes mellitus and established cardiovascular disease (CVD). • to reduce the risk of end-stage kidney disease (ESKD), doubling of serum creatinine, cardiovascular (CV) death, and hospitalization for heart failure in adults with type 2 diabetes mellitus and diabetic nephropathy with albuminuria greater than 300 mg/day. INVOKANA is a sodium-glucose co-transporter 2 (SGLT2) inhibitor indicated: • As an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus ( 1 ). • To reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes mellitus and established cardiovascular disease ( 1 ). • To reduce the risk of end-stage kidney disease, doubling of serum creatinine, cardiovascular death, and hospitalization for heart failure in adults with type 2 diabetes mellitus and diabetic nephropathy with albuminuria ( 1 ). Limitations of Use: • Not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus ( 1 ). • Not recommended for use to improve glycemic control in patients with type 2 diabetes mellitus with an eGFR less than 30 mL/min/1.73 m 2 ( 1 ). Limitations of Use INVOKANA is not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus [see Warnings and Precautions (5.1) ] . INVOKANA is not recommended for use to improve glycemic control in patients with type 2 diabetes mellitus with an eGFR less than 30 mL/min/1.73 m 2 . INVOKANA is likely to be ineffective in this setting based upon its mechanism of action.
Warnings
• Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis : Consider ketone monitoring in patients at risk for ketoacidosis, as indicated. Assess for ketoacidosis regardless of presenting blood glucose levels and discontinue INVOKANA if ketoacidosis is suspected. Monitor patients for resolution of ketoacidosis before restarting ( 5.1 ). • Lower Limb Amputation : Monitor patients for infection or ulcers of lower limb and discontinue if these occur ( 5.2 ). • Volume Depletion : May result in acute kidney injury. Before initiating INVOKANA, assess and correct volume status in patients with renal impairment, elderly patients, or patients on loop diuretics. Monitor for signs and symptoms during therapy ( 5.3 ). • Urosepsis and Pyelonephritis : Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated ( 5.4 ). • Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues : Consider a lower dose of insulin or the insulin secretagogue to reduce the risk of hypoglycemia when used in combination with INVOKANA ( 5.5 ). • Necrotizing Fasciitis of the Perineum (Fournier's Gangrene) : Serious, life-threatening cases have occurred in both females and males. Assess patients presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise. If suspected, institute prompt treatment ( 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 ). 5.1 Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis In patients with type 1 diabetes mellitus, INVOKANA significantly increases the risk of diabetic ketoacidosis, a life-threatening event, beyond the background rate. In placebo-controlled trials of patients with type 1 diabetes mellitus, the risk of ketoacidosis was markedly increased in patients who received sodium glucose transporter 2 (SGLT2) inhibitors compared to patients who received placebo; this risk may be greater with higher doses of INVOKANA. INVOKANA is not indicated for glycemic control in patients with type 1 diabetes mellitus. Type 2 diabetes mellitus and pancreatic disorders (e.g., history of pancreatitis or pancreatic surgery) are also risk factors for ketoacidosis. There have been postmarketing reports of fatal events of ketoacidosis in patients with type 2 diabetes mellitus using SGLT2 inhibitors, including INVOKANA. Precipitating conditions for diabetic ketoacidosis or other ketoacidosis include under-insulinization due to insulin dose reduction or missed insulin doses, acute febrile illness, reduced caloric intake, ketogenic diet, surgery, volume depletion, and alcohol abuse. Signs and symptoms are consistent with dehydration and severe metabolic acidosis and include nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. Blood glucose levels at presentation may be below those typically expected for diabetic ketoacidosis (e.g., less than 250 mg/dL). Ketoacidosis and glucosuria may persist longer than typically expected. Urinary glucose excretion persists for 3 days after discontinuing INVOKANA [see Clinical Pharmacology (12.2) ]; however, there have been postmarketing reports of ketoacidosis and/or glucosuria lasting greater than 6 days and some up to 2 weeks after discontinuation of SGLT2 inhibitors. Consider ketone monitoring in patients at risk for ketoacidosis if indicated by the clinical situation. Assess for ketoacidosis regardless of presenting blood glucose levels in patients who present with signs and symptoms consistent with severe metabolic acidosis. If ketoacidosis is suspected, discontinue INVOKANA, promptly evaluate, and treat ketoacidosis, if confirmed. Monitor patients for resolution of ketoacidosis before restarting INVOKANA. Withhold INVOKANA, if possible, in temporary clinical situations that could predispose patients to ketoacidosis. Resume INVOKANA when the patient is clinically stable and has resumed oral intake [see Dosage and Administration (2.5) ] . Educate all patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue INVOKANA and seek medical attention immediately if signs and symptoms occur. 5.2 Lower Limb Amputation An increased risk of lower limb amputations associated with INVOKANA use versus placebo was observed in CANVAS (5.9 vs 2.8 events per 1,000 patient-years) and CANVAS-R (7.5 vs 4.2 events per 1,000 patient-years), two randomized, placebo-controlled trials evaluating adult patients with type 2 diabetes mellitus who had either established cardiovascular disease or were at risk for cardiovascular disease. The risk of lower limb amputations was observed at both the 100 mg and 300 mg once daily dosage regimens. The amputation data for CANVAS and CANVAS-R are shown in Tables 3 and 4, respectively [see Adverse Reactions (6.1) ]. Amputations of the toe and midfoot (99 out of 140 patients with amputations receiving INVOKANA in the two trials) were the most frequent; however, amputations involving the leg, below and above the knee, were also observed (41 out of 140 patients with amputations receiving INVOKANA in the two trials). Some patients had multiple amputations, some involving both lower limbs. Lower limb infections, gangrene, and diabetic foot ulcers were the most common precipitating medical events leading to the need for an amputation. The risk of amputation was highest in patients with a baseline history of prior amputation, peripheral vascular disease, and neuropathy. Counsel patients about the importance of routine preventative foot care. Monitor patients receiving INVOKANA for signs and symptoms of infection (including osteomyelitis), new pain or tenderness, sores or ulcers involving the lower limbs, and discontinue INVOKANA if these complications occur. 5.3 Volume Depletion INVOKANA can cause intravascular volume contraction which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine [see Adverse Reactions (6.1) ] . There have been post-marketing reports of acute kidney injury which are likely related to volume depletion, some requiring hospitalizations and dialysis, in patients with type 2 diabetes mellitus receiving SGLT2 inhibitors, including INVOKANA. Patients with impaired renal function (eGFR less than 60 mL/min/1.73 m 2 ), elderly patients, or patients on loop diuretics may be at increased risk for volume depletion or hypotension. Before initiating INVOKANA in patients with one or more of these characteristics, assess and correct volume status. Monitor for signs and symptoms of volume depletion after initiating therapy. 5.4 Urosepsis and Pyelonephritis There have been postmarketing reports of serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization in patients receiving INVOKANA. Treatment with INVOKANA 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) ] . 5.5 Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues Insulin and insulin secretagogues are known to cause hypoglycemia. INVOKANA may increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue [see Adverse Reactions (6.1) ] . The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea (or other concomitantly administered insulin secretagogues) or insulin. Inform patients using these concomitant medications of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia. 5.6 Necrotizing Fasciitis of the Perineum (Fournier's Gangrene) Reports of necrotizing fasciitis of the perineum (Fournier's gangrene), a rare but serious and life-threatening necrotizing infection requiring urgent surgical intervention, have been identified in postmarketing surveillance in patients with diabetes mellitus receiving SGLT2 inhibitors, including INVOKANA. Cases have been reported in both females and males. Serious outcomes have included hospitalization, multiple surgeries, and death. Patients treated with INVOKANA presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise, should be assessed for necrotizing fasciitis. If suspected, start treatment immediately with broad-spectrum antibiotics and, if necessary, surgical debridement. Discontinue INVOKANA, closely monitor blood glucose levels, and provide appropriate alternative therapy for glycemic control. 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, including angioedema and anaphylaxis, have been reported with INVOKANA. 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 , 6.2) ] . 5.9 Bone Fracture An increased risk of bone fracture, occurring as early as 12 weeks after treatment initiation, was observed in adult patients using INVOKANA in the CANVAS trial [see Clinical Studies (14.3) ] . Consider factors that contribute to fracture risk prior to initiating INVOKANA [see Adverse Reactions (6.1) ] .
Possible side effects
labeling: • Diabetic Ketoacidosis in Patients with Type 1 Diabetes and Other Ketoacidosis [see Warnings and Precautions (5.1) ] • Lower Limb Amputation [see Warnings and Precautions (5.2) ] • Volume Depletion [see Warnings and Precautions (5.3) ] • Urosepsis and Pyelonephritis [see Warnings and Precautions (5.4) ] • Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues [see Warnings and Precautions (5.5) ] • Necrotizing Fasciitis of the Perineum (Fournier's gangrene) [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) ] Most common adverse reactions (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. 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. INVOKANA has been evaluated in clinical trials in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus. Additionally, INVOKANA has been studied in clinical trials in adult patients with type 2 diabetes mellitus who also have heart failure or chronic kidney disease. The overall safety profile of INVOKANA was consistent across the studied indications. Clinical Trials in Adult Patients with Type 2 Diabetes Mellitus Pool of Placebo-Controlled Trials for Glycemic Control The data in Table 2 are derived from four 26-week placebo-controlled trials where INVOKANA was used as monotherapy in one trial and as add-on therapy in three trials. These data reflect exposure of 1,667 adult 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 White, 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 HbA 1C 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 m 2 ). Table 2 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 2: Adverse Reactions from Pool of Four 26–Week Placebo-Controlled Trials Reported in ≥ 2% of INVOKANA-Treated Adult Patients The four placebo-controlled trials included one monotherapy trial and three add-on combination trials with metformin HCl, metformin HCl and sulfonylurea, or metformin HCl and pioglitazone. Note: Percentages were weighted by studies. Trial weights were proportional to the harmonic mean of the three treatment sample sizes. Adverse Reaction Placebo N=646 INVOKANA 100 mg N=833 INVOKANA 300 mg N=834 Urinary tract infections Urinary tract infections include the following adverse reactions: Urinary tract infection, Cystitis, Kidney infection, and Urosepsis. 3.8% 5.9% 4.4% Increased urination Increased urination includes the following adverse reactions: Polyuria, Pollakiuria, Urine output increased, Micturition urgency, and Nocturia. 0.7% 5.1% 4.6% Thirst Thirst includes the following adverse reactions: Thirst, Dry mouth, and Polydipsia. 0.1% 2.8% 2.4% Constipation 0.9% 1.8% 2.4% Nausea 1.6% 2.1% 2.3% N=312 N=425 N=430 Female genital mycotic infections Female genital mycotic infections include the following adverse reactions: Vulvovaginal candidiasis, Vulvovaginal mycotic infection, Vulvovaginitis, Vaginal infection, Vulvitis, and Genital infection fungal. 2.8% 10.6% 11.6% Vulvovaginal pruritus 0.0% 1.6% 3.2% N=334 N=408 N=404 Male genital mycotic infections Male genital mycotic infections include the following adverse reactions: Balanitis or Balanoposthitis, Balanitis candida, and Genital infection fungal. 0.7% 4.2% 3.8% 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%). Placebo-Controlled Trial in Diabetic Nephropathy The occurrence of adverse reactions for INVOKANA was evaluated in patients participating in CREDENCE, a trial in adult patients with type 2 diabetes mellitus and diabetic nephropathy with albuminuria > 300 mg/day [see Clinical Studies (14.4) ] . These data reflect exposure of 2,201 adult patients to INVOKANA and a mean duration of exposure to INVOKANA of 137 weeks. • The rate of lower limb amputations associated with the use of INVOKANA 100 mg relative to placebo was 12.3 vs 11.2 events per 1,000 patient-years, respectively, with 2.6 years mean duration of follow-up. • The incidence of hypotension was 2.8% and 1.5% on INVOKANA 100 mg and placebo, respectively. Pool of Placebo- and Active-Controlled Trials for Glycemic Control and Cardiovascular Outcomes in Adult Patients The occurrence of adverse reactions for INVOKANA was evaluated in adult patients participating in placebo- and active-controlled trials and in an integrated analysis of two cardiovascular trials, CANVAS and CANVAS-R. The types and frequency of common adverse reactions observed in the pool of eight clinical trials (which reflect an exposure of 6,177 adult patients to INVOKANA) were consistent with those listed in Table 2. Percentages were weighted by trials. Trial weights were proportional to the harmonic mean of the three treatment sample sizes. In this pool, INVOKANA was also associated with the adverse reactions of fatigue (1.8%, 2.2%, and 2.0% with comparator, INVOKANA 100 mg, and INVOKANA 300 mg, respectively) and loss of strength or energy (i.e., asthenia) (0.6%, 0.7%, and 1.1% with comparator, INVOKANA 100 mg, and INVOKANA 300 mg, respectively). In the pool of eight clinical trials, the incidence rate of pancreatitis (acute or chronic) was 0.1%, 0.2%, and 0.1% receiving 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 adult 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: Lower Limb Amputation An increased risk of lower limb amputations associated with INVOKANA use versus placebo was observed in CANVAS (5.9 vs 2.8 events per 1,000 patient-years) and CANVAS-R (7.5 vs 4.2 events per 1,000 patient-years), two randomized, placebo-controlled trials evaluating adult patients with type 2 diabetes who had either established cardiovascular disease or were at risk for cardiovascular disease. Patients in CANVAS and CANVAS-R were followed for an average of 5.7 and 2.1 years, respectively [see Clinical Studies (14.3) ] . The amputation data for CANVAS and CANVAS-R are shown in Tables 3 and 4, respectively . Table 3: Amputations in the CANVAS Trial in Adults with Type 2 Diabetes Mellitus and Atherosclerotic Cardiovascular Disease Placebo N=1,441 INVOKANA 100 mg N=1,445 INVOKANA 300 mg N=1,441 INVOKANA (Pooled) N=2,886 Note: Incidence is based on the number of patients with at least one amputation, and not the total number of amputation events. A patient's follow-up is calculated from Day 1 to the first amputation event date. Some patients had more than one amputation. Patients with an amputation, n (%) 22 (1.5) 50 (3.5) 45 (3.1) 95 (3.3) Total amputations 33 83 79 162 Amputation incidence rate (per 1,000 patient-years) 2.8 6.2 5.5 5.9 Hazard Ratio (95% CI) -- 2.24 (1.36, 3.69) 2.01 (1.20, 3.34) 2.12 (1.34, 3.38) Table 4: Amputations in the CANVAS-R Trial in Adults with Type 2 Diabetes Mellitus and Atherosclerotic Cardiovascular Disease Placebo N=2,903 INVOKANA 100 mg (with up-titration to 300 mg) N=2,904 Note: Incidence is based on the number of patients with at least one amputation, and not the total number of amputation events. A patient's follow-up is calculated from Day 1 to the first amputation event date. Some patients had more than one amputation. Patients with an amputation, n (%) 25 (0.9) 45 (1.5) Total amputations 36 59 Amputation incidence rate (per 1,000 patient-years) 4.2 7.5 Hazard Ratio (95% CI) -- 1.80 (1.10, 2.93) Renal Cell Carcinoma In the CANVAS trial in adults (mean duration of follow-up of 5.7 years) [see Clinical Studies (14.3) ] , the incidence of renal cell carcinoma was 0.15% (2/1,331) and 0.29% (8/2,716) for placebo and INVOKANA, respectively, excluding patients with less than 6 months of follow-up, less than 90 days of treatment, or a history of renal cell carcinoma. A causal relationship to INVOKANA could not be established due to the limited number of cases. Volume Depletion-Related Adverse Reactions INVOKANA results in an osmotic diuresis, which may lead to reductions in intravascular volume. In clinical trials for glycemic control, 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 adult patients on the 300 mg dose. The three factors associated with the largest increase in volume depletion-related adverse reactions in these trials were the use of loop diuretics, moderate renal impairment (eGFR 30 to less than 60 mL/min/1.73 m 2 ), and age 75 years and older (Table 5) [see Use in Specific Populations (8.5 and 8.6) ] . Table 5: Proportion of Adult Patients with at Least One Volume Depletion-Related Adverse Reaction (Pooled Results from 8 Clinical Trials for Glycemic Control) Baseline Characteristic Comparator Group Includes placebo and active-comparator groups % INVOKANA 100 mg % INVOKANA 300 mg % Overall population 1.5% 2.3% 3.4% 75 years of age and older Patients could have more than 1 of the listed risk factors 2.6% 4.9% 8.7% eGFR less than 60 mL/min/1.73 m 2 2.5% 4.7% 8.1% Use of loop diuretic 4.7% 3.2% 8.8% Falls In a pool of nine clinical trials in adults 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. Genital Mycotic Infections In the pool of four placebo-controlled clinical trials in adults for glycemic control, female genital mycotic infections (e.g., vulvovaginal mycotic infection, vulvovaginal candidiasis, and vulvovaginitis) occurred in 2.8%, 10.6%, and 11.6% of females treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Patients with a history of genital…
Storage
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. Bottles of approximately 2070 film-coated tablets, NDC 55154-1425-8 300 mg tablets are white, capsule-shaped, film-coated tablets with "CFZ" on one side and "300" on the other side. Bottles of approximately 720 film-coated tablets, NDC 55154-1426-8 Storage and Handling Keep out of reach of children. Store at 20 °C to 25 °C (68 °F to 77 °F); excursions permitted between 15 °C to 30 °C (59 °F to 86 °F) [see USP Controlled Room Temperature] .
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