Canaglu

Each 100 mg tablet contains 100 mg Canaglu (as hemihydrate).

Each 300 mg tablet contains 300 mg Canaglu (as hemihydrate).

Canaglu contains Canagliflozin, an inhibitor of sodium-glucose co-transporter 2 (SGLT2), the transporter responsible for reabsorbing the majority of glucose filtered by the kidney. Canaglu, the active ingredient of Canaglu, 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·½H2O and 453.53, respectively.

Canaglu is practically insoluble in aqueous media from pH 1.1 to 12.9.

Canaglu is supplied as film-coated tablets for oral administration, containing 102 and 306 mg of Canaglu in each tablet strength, corresponding to 100 mg and 300 mg of Canaglu (anhydrous), respectively.

Excipients/Inactive Ingredients: 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).

Monotherapy: Canaglu (Canaglu) is indicated as an adjunct to diet and exercise to improve glycemic control in adult patients with type 2 diabetes mellitus for whom metformin is inappropriate due to contraindications or intolerance.

Combination with Metformin or a Sulfonylurea: Canaglu is indicated in combination with metformin or a sulfonylurea in adult patients with type 2 diabetes mellitus to improve glycemic control when diet and exercise plus monotherapy with one of these agents does not provide adequate glycemic control.

Combination with Metformin and Either a Sulfonylurea or Pioglitazone: Canaglu is indicated in combination with metformin and either a sulfonylurea or pioglitazone in adult patients with type 2 diabetes mellitus to improve glycemic control when diet, exercise, and dual therapy (with metformin plus either a sulfonylurea or pioglitazone) do not provide adequate glycemic control.

Combination with Insulin: Canaglu is indicated as add-on combination therapy with insulin (with or without metformin) in adult patients with type 2 diabetes mellitus as an adjunct to diet and exercise to improve glycemic control when diet and exercise, and therapy with insulin (with or without metformin) do not provide adequate glycemic control.

Canaglu is an oral diabetes medicine that helps control blood sugar levels. Canaglu works by helping the kidneys get rid of glucose from your bloodstream.

Canaglu is used together with diet and exercise to treat type 2 diabetes. Canaglu is not for treating type 1 diabetes.

Canaglu may also be used for purposes not listed in this medication guide.

Recommended

Dosage: The recommended starting dose of Canaglu is 100 mg once daily, taken before the first meal of the day. If a dose is missed, it should be taken as soon as the patient remembers; however, a double dose should not be taken on the same day.

In patients tolerating Canaglu 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.

In patients with volume depletion, correcting this condition prior to initiation of Canaglu is recommended.

A starting dose of 100 mg once daily should be used in patients on loop diuretics and patients ≥75 years of age. In patients with evidence of reduced intravascular volume, correcting this condition prior to initiation of Canaglu is recommended. For those patients who are tolerating Canaglu 100 mg and who need tighter glycemic control, the dose can be increased to Canaglu 300 mg.

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 Canaglu 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.

Canaglu 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 Canaglu therapy and periodically thereafter. Canaglu should be discontinued when eGFR is persistently less than 45 mL/min/1.73 m².

Concomitant Use with UDP-Glucuronosyl Transferase (UGT) Enzyme Inducers: If an inducer of UGTs (e.g., rifampin, phenytoin, phenobarbital, ritonavir) is co-administered with Canaglu, consider increasing the dosage to 300 mg once daily in patients currently tolerating Canaglu 100 mg once daily who have an eGFR of 60 mL/min/1.73 m² or greater and require additional glycemic control.

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.

Children: Safety and effectiveness of Canaglu in pediatric patients under 18 years of age have not been established.

Elderly: Two thousand thirty-four (2034) patients 65 years and older, and 345 patients 75 years and older were exposed to Canaglu in nine clinical studies of Canaglu.

Patients 65 years and older had a higher incidence of adverse reactions related to reduced intravascular volume with Canaglu (such as hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration), particularly with the 300 mg daily dose, compared to younger patients; more prominent increase in the incidence was seen in patients who were 75 years and older. Smaller reductions in HbA1C with Canaglu relative to placebo were seen in older [65 years and older; -0.61% with Canaglu 100 mg and -0.74% with Canaglu 300 mg relative to placebo] compared to younger patients [-0.72% with Canaglu 100 mg and -0.87% with Canaglu 300 mg relative to placebo).

Renal Impairment: The efficacy and safety of Canaglu were evaluated in a study that included patients with moderate renal impairment (eGFR 30 to less than 50 mL/min/1.73 m²). 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); patients treated with Canaglu 300 mg were more likely to experience increases in potassium.

The efficacy and safety of Canaglu have not been established in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m²), with ESRD, or receiving dialysis. Canaglu is not expected to be effective in these patient populations.

Hepatic Impairment: No dosage adjustment is necessary in patients with mild or moderate hepatic impairment. The use of Canaglu has not been studied in patients with severe hepatic impairment and is therefore not recommended.

See also:
What is the most important information I should know about Canaglu?

History of a serious hypersensitivity reaction and hypersensitivity to Canaglu or to any of the excipients of Canaglu.

Severe renal impairment (eGFR <30 mL/min/1.73 m²), end stage renal disease or patients on dialysis.

Use Canaglu as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Canaglu comes with an extra patient information sheet called a Medication Guide. Read it carefully. Read it again each time you get Canaglu refilled.
• Take Canaglu by mouth before the first meal of the day, unless your doctor tells you otherwise.
• Check with your doctor to see if you should drink extra fluids while taking Canaglu.
• Take Canaglu on a regular schedule to get the most benefit from it. Taking Canaglu at the same time each day will help you remember to take it.
• Continue to take Canaglu even if you feel well. Do not miss any doses.
• If you miss a dose of Canaglu, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Canaglu.

Canaglu is used with a proper diet and exercise program to control high blood sugar in people with type 2 diabetes. Controlling high blood sugar helps prevent kidney damage, blindness, nerve problems, loss of limbs, and sexual function problems. Proper control of diabetes may also lessen your risk of a heart attack or stroke. Canaglu works by increasing the removal of sugar by your kidneys.

How to use Canaglu

Read the Medication Guide provided by your pharmacist before you start taking Canaglu and each time you get a refill. If you have any questions, ask your doctor or pharmacist.

Take this medication by mouth as directed by your doctor, usually once daily before the first meal of the day. The dosage is based on your medical condition and response to treatment.

Take this medication regularly to get the most benefit from it. To help you remember, take it at the same time each day.

Tell your doctor if your condition does not improve or if it worsens (such as if your blood sugar levels remain high or increase).

See also:
What other drugs will affect Canaglu?

UGT Enzyme Inducers: Rifampin: Co-administration of Canaglu with rifampin, a nonselective inducer of several UGT enzymes, including UGT1A9, UGT2B4, decreased Canaglu area under the curve (AUC) by 51%. This decrease in exposure to Canaglu may decrease efficacy. If an inducer of these UGTs (e.g., rifampin, phenytoin, phenobarbital, ritonavir) must be co-administered with Canaglu, consider increasing the dose to 300 mg once daily if patients are currently tolerating Canaglu 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.

Digoxin: There was an increase in the AUC and mean peak drug concentration (C_max) of digoxin (20% and 36%, respectively) when co-administered with Canaglu 300 mg. Patients taking Canaglu with concomitant digoxin should be monitored appropriately.

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.

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.

Effects of Other Drugs on Canaglu: In clinical studies, the effects of other drugs on Canaglu were assessed. Ciclosporin, hydrochlorothiazide, oral contraceptives (ethinyl estradiol and levonorgestrel), metformin, and probenecid had no clinically relevant effect on the pharmacokinetics of Canaglu.

Effects of Canaglu on Other Drugs: In interaction studies conducted in healthy subjects, Canaglu at steady-state had no clinically relevant effect on the pharmacokinetics of metformin, oral contraceptives (ethinyl estradiol and levonorgestrel), glyburide, simvastatin, paracetamol, hydrochlorothiazide, or warfarin.

Effects on Ability To Drive And Use Machines: Canaglu has no known influence on the ability to drive and use machines. However, patients should be alerted to the risk of hypoglycemia when Canaglu is used as add-on therapy with insulin or an insulin secretagogue, and to the elevated risk of adverse reactions related to reduced intravascular volume, such as postural dizziness.

See also:
What are the possible side effects of Canaglu?

The following important adverse reactions are described as follows and elsewhere in the labeling: Hypotension, impairment in renal function, hyperkalemia, hypoglycemia with concomitant use with insulin and insulin secretagogues, genital mycotic infections, hypersensitivity reactions and increases in low-density lipoprotein (LDL-C).

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 11 is derived from four 26-week placebo-controlled trials. In one trial Canaglu was used as monotherapy and in three trials Canaglu was used as add-on therapy. These data reflect exposure of 1667 patients to Canaglu and a mean duration of exposure to Canaglu of 24 weeks. Patients received Canaglu 100 mg (N=833), Canaglu 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 11 shows common adverse reactions associated with the use of Canaglu. These adverse reactions were not present at baseline, occurred more commonly on Canaglu than on placebo, and occurred in at least 2% of patients treated with either Canaglu 100 mg or Canaglu 300 mg.

Abdominal pain was also more commonly reported in patients taking Canaglu 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 was also evaluated in a larger pool of patients participating in placebo- and active controlled trials.

The data combined eight clinical trials and reflect exposure of 6177 patients to Canaglu. The mean duration of exposure to Canaglu was 38 weeks with 1832 individuals exposed to Canaglu for greater than 50 weeks. Patients received Canaglu 100 mg (N=3092), Canaglu 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 11. In this pool, Canaglu was also associated with the adverse reactions of fatigue [1.7% with comparator, 2.2% with Canaglu 100 mg, and 2.0% with Canaglu 300 mg] and loss of strength or energy (i.e., asthenia) [0.6% with comparator, 0.7% with Canaglu 100 mg, and 1.1% with Canaglu 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, Canaglu 100 mg, and Canaglu 300 mg, respectively.

In the pool of eight clinical trials with a longer mean duration of exposure to Canaglu (68 weeks), the incidence rate of bone fracture was 14.2, 18.7, and 17.6 per 1000 patient years of exposure to comparator, Canaglu 100 mg, and Canaglu 300 mg, respectively. Upper extremity fractures occurred more commonly on Canaglu than comparator.

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, Canaglu 100 mg, and Canaglu 300 mg respectively. Five patients experienced serious adverse reactions of hypersensitivity with Canaglu, which included 4 patients with urticaria and 1 patient with a diffuse rash and urticaria occurring within hours of exposure to Canaglu. Among these patients, 2 patients discontinued Canaglu. One patient with urticaria had recurrence when Canaglu 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, Canaglu 100 mg, and Canaglu 300 mg, respectively.

Other adverse reactions occurring more frequently on Canaglu than on comparator were: Volume Depletion-Related Adverse Reactions: Canaglu results in an osmotic diuresis, which may lead to reductions in intravascular volume. In clinical studies, treatment with Canaglu 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 12).

Impairment in Renal Function: Canaglu is associated with a dose-dependent increase in serum creatinine and a concomitant fall in estimated GFR (Table 13). Patients with moderate renal impairment at baseline had larger mean changes.

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 Canaglu 100 mg, and 4.1% with Canaglu 300 mg. At the end of treatment, 0.5% with placebo, 0.7% with Canaglu 100 mg, and 1.4% with Canaglu 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), 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 Canaglu 100 mg, and 22.5% with Canaglu 300 mg. At the end of treatment, 4.6% with placebo, 3.4% with Canaglu 100 mg, and 3.4% with Canaglu 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 Canaglu was 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 Canaglu 100 mg, and 9.3% with Canaglu 300 mg. Discontinuations due to renal-related adverse events occurred in 1.0% with placebo, 1.2% with Canaglu 100 mg, and 1.6% with Canaglu 300 mg.

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, Canaglu 100 mg, and Canaglu 300 mg, respectively. Patients with a history of genital mycotic infections were more likely to develop genital mycotic infections on Canaglu. Female patients who developed genital mycotic infections on Canaglu were more likely to experience recurrence and require treatment with oral or topical antifungal agents and anti-microbial agents.

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, Canaglu 100 mg, and Canaglu 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 Canaglu were more likely to experience recurrent infections [22% on Canaglu versus none on placebo], and require treatment with oral or topical antifungal agents and anti-microbial agents than patients on comparators. In the pooled analysis of 8 controlled trials, phimosis was reported in 0.3% of uncircumcised male patients treated with Canaglu and 0.2% required circumcision to treat the phimosis.

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, episodes of hypoglycemia occurred at a higher rate when Canaglu was co-administered with insulin or sulfonylureas.

Laboratory Tests: Increases in Serum Potassium: Dose-related, transient mean increases in serum potassium were observed early after initiation of Canaglu (i.e., within 3 weeks) in a trial of patients with moderate renal impairment. 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, Canaglu 100 mg, and Canaglu 300 mg, respectively. More severe elevations (i.e., equal or greater than 6.5 mEq/L) occurred in 1.1%, 2.2%, and 2.2% of patients treated with placebo, Canaglu 100 mg, and Canaglu 300 mg, respectively. In patients with moderate renal impairment, increases in potassium were more commonly seen in those with elevated potassium at baseline and in those using medications that reduce potassium excretion, such as potassium-sparing diuretics, angiotensin-converting-enzyme inhibitors, and angiotensin-receptor blockers.

Increases in Serum Magnesium: Dose-related increases in serum magnesium were observed early after initiation of Canaglu (within 6 weeks) and remained elevated throughout treatment. In the pool of four placebo-controlled trials, the mean change in serum magnesium levels was 8.1% and 9.3% with Canaglu 100 mg and Canaglu 300 mg, respectively, compared to -0.6% with placebo. In a trial of patients with moderate renal impairment, serum magnesium levels increased by 0.2%, 9.2%, and 14.8% with placebo, Canaglu 100 mg, and Canaglu 300 mg, respectively.

Increases in Serum Phosphate: Dose-related increases in serum phosphate levels were observed with Canaglu. In the pool of four placebo controlled trials, the mean change in serum phosphate levels were 3.6% and 5.1% with Canaglu 100 mg and Canaglu 300 mg, respectively, compared to 1.5% with placebo. In a trial of patients with moderate renal impairment, the mean serum phosphate levels increased by 1.2%, 5.0%, and 9.3% with placebo, Canaglu 100 mg, and Canaglu 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 Canaglu 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 Canaglu 100 mg and Canaglu 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 Canaglu 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 Canaglu 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 Canaglu 100 mg, and 0.51 g/dL (3.8%) with Canaglu 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, Canaglu 100 mg, and Canaglu 300 mg, respectively, had hemoglobin above the upper limit of normal.