Invokana
(Canagliflozin)Dosage & Administration
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Invokana Prescribing Information
Indications and Usage (INVOKANA (canagliflozin) is indicated:
INVOKANA is a sodium-glucose co-transporter 2 (SGLT2) inhibitor indicated:
Limitations of Use:
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 m2. INVOKANA is likely to be ineffective in this setting based upon its mechanism of action. | 12/2024 | ||||||
Dosage and Administration (Recommended Dosage for Glycemic Control in Adults and Pediatric Patients Aged 10 Years and Older
Recommended Dosage for Other Indications in Adults The recommended dosage of INVOKANA is 100 mg orally once daily for the following indications in adults:
Table 1 provides dosage recommendations for adults and pediatric patients aged 10 years and older with renal impairment, based on estimated glomerular filtration rate (eGFR).
| 12/2024 | ||||||
Dosage and Administration (Withhold INVOKANA at least 3 days, if possible, prior to surgery or procedures associated with prolonged fasting. Resume INVOKANA when the patient is clinically stable and has resumed oral intake [see Warnings and Precautions (5.1)and Clinical Pharmacology (12.2)]. | 08/2024 | ||||||
Warnings and Precautions (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. | 08/2024 | ||||||
Warnings and Precautions (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. | 08/2024 |
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.
- Assess renal function before initiating and as clinically indicated. Assess volume status and correct volume depletion before initiating ().
2.1 Prior to Initiation of INVOKANAAssess renal function before initiating INVOKANA and as clinically indicated
[see Dosage and Administration (2.3)and Warnings and Precautions (5.3)].In patients with volume depletion, correct this condition before initiating INVOKANA
[see Warnings and Precautions (5.3)and Use in Specific Populations (8.5, 8.6)]. - The recommended starting dosage in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus is 100 mg orally once daily, taken before the first meal of the day to improve glycemic control. The dosage can be increased to 300 mg once daily in patients tolerating 100 mg once daily who have an eGFR of 60 mL/min/1.73 m
2or greater and require additional glycemic control ().2.2 Recommended Dosage and AdministrationRecommended Dosage for Glycemic Control in Adults and Pediatric Patients Aged 10 Years and Older
- The recommended starting dosage of INVOKANA is 100 mg orally once daily to improve glycemic control, taken before the first meal of the day.
- For additional glycemic control, the dosage of INVOKANA may be increased to the maximum recommended dosage of 300 mg once daily.
Recommended Dosage for Other Indications in Adults
The recommended dosage of INVOKANA is 100 mg orally once daily for the following indications in adults:- 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.
- For all other indications in adults, the recommended dosage of INVOKANA is 100 mg orally once daily ().
2.2 Recommended Dosage and AdministrationRecommended Dosage for Glycemic Control in Adults and Pediatric Patients Aged 10 Years and Older
- The recommended starting dosage of INVOKANA is 100 mg orally once daily to improve glycemic control, taken before the first meal of the day.
- For additional glycemic control, the dosage of INVOKANA may be increased to the maximum recommended dosage of 300 mg once daily.
Recommended Dosage for Other Indications in Adults
The recommended dosage of INVOKANA is 100 mg orally once daily for the following indications in adults:- 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.
- Dosage adjustments for patients with renal impairment may be required ().
2.3 Recommended Dosage in Adults and Pediatric Patients Aged 10 Years and Older with Renal ImpairmentTable 1 provides dosage recommendations for adults and pediatric patients aged 10 years and older with renal impairment, based on estimated glomerular filtration rate (eGFR).Table 1: Recommended Dosage in Adults and Pediatric Patients Aged 10 Years and Older with Renal Impairment Estimated Glomerular Filtration Rate
[eGFR (mL/min/1.73 m2)]Recommended Dosage eGFR 30 to less than 60 The maximum recommended dosage is 100 mg orally once daily. eGFR less than 30 - Initiation is not recommended
- Adult patients taking INVOKANA with albuminuria greater than 300 mg/day may continue INVOKANA 100 mg once daily to reduce the risk of ESKD, doubling of serum creatinine, CV death, and hospitalization for heart failure[see Indications and Usage (1)and Use in Specific Populations (8.6)].
- See full prescribing information for INVOKANA dosage modifications due to drug interactions ().
2.4 Concomitant Use with UDP-Glucuronosyl transferase (UGT) Enzyme InducersWhen co-administering INVOKANA with an inducer of UGT (e.g., rifampin, phenytoin, phenobarbital, ritonavir), increase the dosage of INVOKANA based on renal function
[see Drug Interactions (7)]:- In patients with eGFR 60 mL/min/1.73 m2or greater, increase the dosage to 200 mg orally once daily in patients currently tolerating INVOKANA 100 mg once daily. The maximum recommended dosage of INVOKANA is 300 mg once daily.
- In patients with eGFR less than 60 mL/min/1.73 m2, increase to a maximum recommended dosage of 200 mg orally once daily in patients currently tolerating INVOKANA 100 mg once daily.
- Withhold INVOKANA at least 3 days, if possible, prior to surgery or procedures associated with prolonged fasting ().
2.5 Temporary Interruption for SurgeryWithhold INVOKANA at least 3 days, if possible, prior to surgery or procedures associated with prolonged fasting. Resume INVOKANA when the patient is clinically stable and has resumed oral intake[see Warnings and Precautions (5.1)and Clinical Pharmacology (12.2)].
- INVOKANA 100 mg tablets are yellow, capsule-shaped, tablets with "CFZ" on one side and "100" on the other side.
- INVOKANA 300 mg tablets are white, capsule-shaped, tablets with "CFZ" on one side and "300" on the other side.
- Pregnancy: Advise females of the potential risk to a fetus especially during the second and third trimesters ().
8.1 PregnancyRisk SummaryBased on juvenile animal data showing adverse renal effects, INVOKANA is not recommended during the second and third trimesters of pregnancy.
Limited data with INVOKANA in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy
[see Clinical Considerations].In juvenile animal studies, adverse renal pelvic and tubule dilatations that were not reversible were observed in rats when canagliflozin was administered during a period of renal development corresponding to the late second and third trimesters of human pregnancy, at an exposure 0.5-times the 300 mg clinical dose, based on AUC.
The estimated background risk of major birth defects is 6–10% in women with pre-gestational diabetes with a HbA1C>7 and has been reported to be as high as 20–25% in women with a HbA1C>10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.
Clinical ConsiderationsDisease-Associated Maternal and/or Embryo/Fetal RiskPoorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.
Animal DataCanagliflozin dosed directly to juvenile rats from postnatal day (PND) 21 until PND 90 at doses of 4, 20, 65, or 100 mg/kg increased kidney weights and dose dependently increased the incidence and severity of renal pelvic and tubular dilatation at all doses tested. Exposure at the lowest dose was greater than or equal to 0.5-times the 300 mg clinical dose, based on AUC. These outcomes occurred with drug exposure during periods of renal development in rats that correspond to the late second and third trimester of human renal development. The renal pelvic dilatations observed in juvenile animals did not fully reverse within a 1-month recovery period.
In embryo-fetal development studies in rats and rabbits, canagliflozin was administered for intervals coinciding with the first trimester period of organogenesis in humans. No developmental toxicities independent of maternal toxicity were observed when canagliflozin was administered at doses up to 100 mg/kg in pregnant rats and 160 mg/kg in pregnant rabbits during embryonic organogenesis or during a study in which maternal rats were dosed from gestation day (GD) 6 through PND 21, yielding exposures up to approximately 19-times the 300 mg clinical dose, based on AUC.
- Lactation: Not recommended when breastfeeding ().
8.2 LactationRisk SummaryThere is no information regarding the presence of INVOKANA in human milk, the effects on the breastfed infant, or the effects on milk production. Canagliflozin is present in the milk of lactating rats
[see Data]. Since human kidney maturation occursin uteroand during the first 2 years of life when lactational exposure may occur, there may be risk to the developing human kidney.Because of the potential for serious adverse reactions in a breastfed infant, advise women that use of INVOKANA is not recommended while breastfeeding.
DataAnimal DataRadiolabeled canagliflozin administered to lactating rats on day 13 post-partum was present at a milk/plasma ratio of 1.40, indicating that canagliflozin and its metabolites are transferred into milk at a concentration comparable to that in plasma. Juvenile rats directly exposed to canagliflozin showed a risk to the developing kidney (renal pelvic and tubular dilatations) during maturation.
- Geriatrics: Higher incidence of adverse reactions related to reduced intravascular volume ().
8.5 Geriatric UseIn 13 clinical trials of INVOKANA, 2,294 patients 65 years and older, and 351 patients 75 years and older were exposed to INVOKANA
[see Clinical Studies (14.1)].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 HbA1Cwith 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). - Renal Impairment: Higher incidence of adverse reactions related to hypotension and renal function ().
8.6 Renal ImpairmentThe efficacy and safety of INVOKANA for glycemic control were evaluated in a trial that included adult patients with moderate renal impairment (eGFR 30 to less than 50 mL/min/1.73 m2)
[see Clinical Studies (14.1)]. These patients had less overall glycemic efficacy, and patients treated with 300 mg per day had increases in serum potassium, which were transient and similar by the end of the trial. Patients with renal impairment using INVOKANA for glycemic control may also be more likely to experience hypotension and may be at higher risk for acute kidney injury[see Warnings and Precautions (5.3)].Efficacy and safety trials with INVOKANA did not enroll adult patients with ESKD on dialysis or patients with an eGFR less than 30 mL/min/1.73 m2
[see Clinical Pharmacology (12.3)]. - Hepatic Impairment: Not recommended in patients with severe hepatic impairment ().
8.7 Hepatic ImpairmentNo 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)].
INVOKANA is contraindicated in patients with a serious hypersensitivity reaction to INVOKANA, such as anaphylaxis or angioedema
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
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.
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 HbA1Cof 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 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.
| 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 infectionsUrinary tract infections include the following adverse reactions: Urinary tract infection, Cystitis, Kidney infection, and Urosepsis. | 3.8% | 5.9% | 4.4% |
| Increased urinationIncreased urination includes the following adverse reactions: Polyuria, Pollakiuria, Urine output increased, Micturition urgency, and Nocturia. | 0.7% | 5.1% | 4.6% |
| ThirstThirst 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 infectionsFemale 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 infectionsMale 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%).
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
- 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.
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:
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
| 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) |
| 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) |
In the CANVAS trial in adults (mean duration of follow-up of 5.7 years)
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 m2), and age 75 years and older (Table 5)
| Baseline Characteristic | Comparator GroupIncludes placebo and active-comparator groups % | INVOKANA 100 mg % | INVOKANA 300 mg % |
|---|---|---|---|
| Overall population | 1.5% | 2.3% | 3.4% |
| 75 years of age and olderPatients could have more than 1 of the listed risk factors | 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% |
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.
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 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.
In the pool of four placebo-controlled clinical trials in adults, male genital mycotic infections (e.g., candidal balanitis, balanoposthitis) occurred in 0.7%, 4.2%, and 3.8% 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 randomized trials in adults evaluating glycemic control, phimosis was reported in 0.3% of uncircumcised male patients treated with INVOKANA and 0.2% required circumcision to treat the phimosis.
In all glycemic control 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 of glycemic control in adults
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 HCl (26 weeks) | Placebo + Metformin HCl (N=183) | INVOKANA 100 mg + Metformin HCl (N=368) | INVOKANA 300 mg + Metformin HCl (N=367) |
| Overall [N (%)] | 3 (1.6) | 16 (4.3) | 17 (4.6) |
| Severe [N (%)]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) | 0 (0) | 1 (0.3) | 1 (0.3) |
In Combination with Metformin HCl (52 weeks) | Glimepiride + Metformin HCl (N=482) | INVOKANA 100 mg + Metformin HCl (N=483) | INVOKANA 300 mg + Metformin HCl (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 HCl + Sulfonylurea (26 weeks) | Placebo + Metformin HCl + Sulfonylurea (N=156) | INVOKANA 100 mg + Metformin HCl + Sulfonylurea (N=157) | INVOKANA 300 mg + Metformin HCl + 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 HCl + Sulfonylurea (52 weeks) | Sitagliptin + Metformin HCl + Sulfonylurea (N=378) | INVOKANA 300 mg + Metformin HCl + Sulfonylurea (N=377) | |
| Overall [N (%)] | 154 (40.7) | 163 (43.2) | |
| Severe [N (%)] | 13 (3.4) | 15 (4.0) | |
In Combination with Metformin HCl + Pioglitazone (26 weeks) | Placebo + Metformin HCl + Pioglitazone (N=115) | INVOKANA 100 mg + Metformin HCl + Pioglitazone (N=113) | INVOKANA 300 mg + Metformin HCl + 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) |
In the CANVAS trial in adults
Initiation of INVOKANA causes an increase in serum creatinine and decrease in estimated GFR. In adult patients with moderate renal impairment, the increase in serum creatinine generally does not exceed 0.2 mg/dL, occurs within the first 6 weeks of starting therapy, and then stabilizes. Increases that do not fit this pattern should prompt further evaluation to exclude the possibility of acute kidney injury
In a pooled population of adult patients (N=723) in glycemic control trials 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
In CREDENCE, no difference in serum potassium, no increase in adverse events of hyperkalemia, and no increase in absolute (> 6.5 mEq/L) or relative (> upper limit of normal and > 15% increase from baseline) increases in serum potassium were observed in adults treated with INVOKANA 100 mg relative to placebo.
In the pool of four glycemic control placebo-controlled trials in adults, 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.
Dose-related increases in non-HDL-C with INVOKANA were observed in adults. 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.
In the pool of four placebo-controlled trials of glycemic control in adults, 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.
Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry in a clinical trial of 714 older adults (mean age 64 years)
INVOKANA was administered to 84 pediatric patients in a double-blind, placebo-controlled trial of 171 pediatric patients aged 10 to 17 years with a mean exposure to INVOKANA of 48.3 weeks
Additional adverse reactions have been identified during post-approval 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.