CANAGLIFLOZIN

Details

Stereochemistry	ABSOLUTE
Molecular Formula	2C24H25FO5S.H2O
Molecular Weight	907.047
Optical Activity	UNSPECIFIED
Defined Stereocenters	10 / 10
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

O.CC1=CC=C(C=C1CC2=CC=C(S2)C3=CC=C(F)C=C3)[C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O.CC5=CC=C(C=C5CC6=CC=C(S6)C7=CC=C(F)C=C7)[C@@H]8O[C@H](CO)[C@@H](O)[C@H](O)[C@H]8O

InChI

InChIKey=VHOFTEAWFCUTOS-TUGBYPPCSA-N

InChI=1S/2C24H25FO5S.H2O/c2*1-13-2-3-15(24-23(29)22(28)21(27)19(12-26)30-24)10-16(13)11-18-8-9-20(31-18)14-4-6-17(25)7-5-14;/h2*2-10,19,21-24,26-29H,11-12H2,1H3;1H2/t2*19-,21-,22+,23-,24+;/m11./s1

HIDE SMILES / InChI

Molecular Formula	H2O
Molecular Weight	18.0153
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Molecular Formula	C24H25FO5S
Molecular Weight	444.516
Charge	0
Count

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	5 / 5
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description
Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/204042s022lbl.pdf

Canagliflozin (INN, trade name Invokana or Sulisent) is a drug of the gliflozin class. It was developed by Mitsubishi Tanabe Pharma and is marketed under license by Janssen, a division of Johnson & Johnson. Canagliflozin is an antidiabetic drug used to improve glycemic control in people with type 2 diabetes. 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. In extensive clinical trials, canagliflozin produced a consistent dose-dependent reduction in HbA1c of 0.77% to 1.16% when administered as monotherapy, combination with metformin, combination with metformin and a sulfonylurea, combination with metformin and pioglitazone, and in combination with insulin from a baselines of 7.8% to 8.1%, in combination with metformin, or in combination with metformin and a sulfonylurea. When added to metformin, canagliflozin 100 mg was shown to be non-inferior to both sitagliptin 100 mg and glimepiride in reductions on HbA1c at one year, whilst canagliflozin 300 mg successfully demonstrated statistical superiority over both sitagliptin and glimiperide in HbA1c reductions. Secondary efficacy endpoint of superior body weight reduction and blood pressure reduction (versus sitagliptin and glimiperide)) were observed as well. Canagliflozin produces beneficial effects on HDL cholesterol whilst increasing LDL cholesterol to produce no change in total cholesterol.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Sodium/glucose cotransporter 2 25 Target ID: P31639 Gene ID: 6524.0 Gene Symbol: SLC5A2 Target Organism: Homo sapiens (Human) Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/204042s022lbl.pdf	Inhibitor 8297		4.4 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Type 2 diabetes mellitus 259 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/204042s022lbl.pdf	Secondary		Approved 8429	INVOKANA Approved Use Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitation of Use: Not for treatment of type 1 diabetes mellitus or diabetic ketoacidosis Launch Date 2013

C_max

Value	Dose	Co-administered	Analyte	Population
1178 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/26048186	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:		CANAGLIFLOZIN plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

AUC

Value	Dose	Co-administered	Analyte	Population
10521 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/26048186	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:		CANAGLIFLOZIN plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

T_1/2

Value	Dose	Co-administered	Analyte	Population
16 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/26048186	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:		CANAGLIFLOZIN plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

Doses

Dose	Population	Adverse events
100 mg 1 times / day steady, oral Recommended Dose: 100 mg, 1 times / day Route: oral Route: steady Dose: 100 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000MedR.pdf Page: 129	unhealthy, adult n = 833 Health Status: unhealthy Condition: type 2 diabetes Age Group: adult Sex: M+F Population Size: 833 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000MedR.pdf Page: 129	Disc. AE: Nausea, Pneumonia... AEs leading to discontinuation/dose reduction: Nausea (0.2%) Pneumonia (0.4%) Vulvovaginal mycotic infection (0.4%) Glomerular filtration rate decreased (0.2%) Weight decreased (0.2%) Pollakiuria (0.1%) Epidermal and dermal conditions (0.6%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000MedR.pdf Page: 129
300 mg 1 times / day steady, oral Recommended Dose: 300 mg, 1 times / day Route: oral Route: steady Dose: 300 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000MedR.pdf Page: 129	unhealthy, adult n = 834 Health Status: unhealthy Condition: type 2 diabetes Age Group: adult Sex: M+F Population Size: 834 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000MedR.pdf Page: 129	Disc. AE: Blood creatinine increased, Blood potassium increased... AEs leading to discontinuation/dose reduction: Blood creatinine increased (0.2%) Blood potassium increased (0.2%) Glomerular filtration rate decreased (0.6%) Weight decreased (0.1%) Pollakiuria (0.2%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000MedR.pdf Page: 129
100 mg 1 times / day steady, oral Recommended Dose: 100 mg, 1 times / day Route: oral Route: steady Dose: 100 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204042s027lbl.pdf Page: 9	unhealthy, mean 56 years n = 425 Health Status: unhealthy Condition: type 2 diabetes Age Group: mean 56 years Sex: F Population Size: 425 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204042s027lbl.pdf Page: 9	Other AEs: Genital infection female, Vulvovaginal pruritus... Other AEs: Genital infection female (10.6%) Vulvovaginal pruritus (1.6%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204042s027lbl.pdf Page: 9
100 mg 1 times / day steady, oral Recommended Dose: 100 mg, 1 times / day Route: oral Route: steady Dose: 100 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204042s027lbl.pdf Page: 9	unhealthy, mean 56 years n = 430 Health Status: unhealthy Condition: type 2 diabetes Age Group: mean 56 years Sex: M Population Size: 430 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204042s027lbl.pdf Page: 9	Other AEs: Genital infection male... Other AEs: Genital infection male (4.2%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204042s027lbl.pdf Page: 9
100 mg 1 times / day steady, oral Recommended Dose: 100 mg, 1 times / day Route: oral Route: steady Dose: 100 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204042s027lbl.pdf Page: 9	unhealthy, mean 56 years n = 834 Health Status: unhealthy Condition: type 2 diabetes Age Group: mean 56 years Sex: M+F Population Size: 834 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204042s027lbl.pdf Page: 9	Other AEs: Urinary tract infections, Urination abnormal NOS... Other AEs: Urinary tract infections (5.9%) Urination abnormal NOS (5.1%) Thirst (2.8%) Constipation (1.8%) Nausea (2.1%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204042s027lbl.pdf Page: 9
300 mg 1 times / day steady, oral Recommended Dose: 300 mg, 1 times / day Route: oral Route: steady Dose: 300 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204042s027lbl.pdf Page: 9	unhealthy, mean 56 years n = 425 Health Status: unhealthy Condition: type 2 diabetes Age Group: mean 56 years Sex: F Population Size: 425 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204042s027lbl.pdf Page: 9	Other AEs: Genital infection female, Vulvovaginal pruritus... Other AEs: Genital infection female (11.6%) Vulvovaginal pruritus (3.2%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204042s027lbl.pdf Page: 9
300 mg 1 times / day steady, oral Recommended Dose: 300 mg, 1 times / day Route: oral Route: steady Dose: 300 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204042s027lbl.pdf Page: 9	unhealthy, mean 56 years n = 842 Health Status: unhealthy Condition: type 2 diabetes Age Group: mean 56 years Sex: F Population Size: 842 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204042s027lbl.pdf Page: 9	Disc. AE: Mycoplasma genitalium infection... AEs leading to discontinuation/dose reduction: Mycoplasma genitalium infection (0.7%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204042s027lbl.pdf Page: 9
300 mg 1 times / day steady, oral Recommended Dose: 300 mg, 1 times / day Route: oral Route: steady Dose: 300 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204042s027lbl.pdf Page: 9	unhealthy, mean 56 years n = 430 Health Status: unhealthy Condition: type 2 diabetes Age Group: mean 56 years Sex: M Population Size: 430 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204042s027lbl.pdf Page: 9	Other AEs: Genital infection male... Other AEs: Genital infection male (3.8%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204042s027lbl.pdf Page: 9
300 mg 1 times / day steady, oral Recommended Dose: 300 mg, 1 times / day Route: oral Route: steady Dose: 300 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204042s027lbl.pdf Page: 9	unhealthy, mean 56 years n = 825 Health Status: unhealthy Condition: type 2 diabetes Age Group: mean 56 years Sex: M Population Size: 825 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204042s027lbl.pdf Page: 9	Disc. AE: Mycoplasma genitalium infection... AEs leading to discontinuation/dose reduction: Mycoplasma genitalium infection (0.5%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204042s027lbl.pdf Page: 9
300 mg 1 times / day steady, oral Recommended Dose: 300 mg, 1 times / day Route: oral Route: steady Dose: 300 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204042s027lbl.pdf Page: 9	unhealthy, mean 56 years n = 1667 Health Status: unhealthy Condition: type 2 diabetes Age Group: mean 56 years Sex: M+F Population Size: 1667 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204042s027lbl.pdf Page: 9	Disc. AE: Hypersensitivity... Other AEs: Limb amputation... AEs leading to discontinuation/dose reduction: Hypersensitivity (2 patients) Other AEs: Limb amputation Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204042s027lbl.pdf Page: 9
300 mg 1 times / day steady, oral Recommended Dose: 300 mg, 1 times / day Route: oral Route: steady Dose: 300 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204042s027lbl.pdf Page: 9	unhealthy, mean 56 years n = 834 Health Status: unhealthy Condition: type 2 diabetes Age Group: mean 56 years Sex: M+F Population Size: 834 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204042s027lbl.pdf Page: 9	Other AEs: Urinary tract infections, Urination abnormal NOS... Other AEs: Urinary tract infections (4.4%) Urination abnormal NOS (4.6%) Thirst (2.4%) Constipation (2.4%) Nausea (2.3%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204042s027lbl.pdf Page: 9
300 mg 1 times / day steady, oral Dose: 300 mg, 1 times / day Route: oral Route: steady Dose: 300 mg, 1 times / day Sources: https://clinicaltrials.gov/ct2/show/NCT01939496	unhealthy n = 56 Health Status: unhealthy Condition: Type 2 Diabetes Mellitus Population Size: 56 Sources: https://clinicaltrials.gov/ct2/show/NCT01939496	Other AEs: Pollakiuria... Other AEs: Pollakiuria (below serious, 3 patients) Sources: https://clinicaltrials.gov/ct2/show/NCT01939496
300 mg 1 times / day steady, oral Dose: 300 mg, 1 times / day Route: oral Route: steady Dose: 300 mg, 1 times / day Sources: https://clinicaltrials.gov/ct2/show/NCT02065791	unhealthy n = 2200 Health Status: unhealthy Condition: Type 2 Diabetes Mellitus Population Size: 2200 Sources: https://clinicaltrials.gov/ct2/show/NCT02065791	Other AEs: Anaemia vitamin B12 deficiency, Disseminated intravascular coagulation... Other AEs: Anaemia vitamin B12 deficiency (serious, 1 patient) Disseminated intravascular coagulation (serious, 1 patient) Anaemia hypochromic (serious, 1 patient) Anaemia iron deficiency (serious, 2 patients) Lymphadenopathy (serious, 1 patient) Pancytopenia (serious, 1 patient) Acute coronary syndrome (serious, 12 patients) Angina pectoris (serious, 21 patient) Arrhythmia (serious, 2 patients) Arteriosclerosis coronary artery (serious, 4 patients) Atrioventricular block first degree (serious, 1 patient) Cardiac tamponade (serious, 1 patient) Cardio-respiratory arrest (serious, 4 patients) Cor pulmonale (serious, 1 patient) Coronary artery occlusion (serious, 3 patients) Hypertensive heart disease (serious, 2 patients) Myocarditis (serious, 1 patient) Right ventricular failure (serious, 1 patient) Ventricular extrasystoles (serious, 2 patients) Vertigo positional (serious, 1 patient) Goitre (serious, 2 patients) Hypothyroidism (serious, 1 patient) Inappropriate antidiuretic hormone secretion (serious, 1 patient) Thyroid mass (serious, 2 patients) Diabetic retinopathy (serious, 7 patients) Maculopathy (serious, 2 patients) Ischaemic optic neuropathy (serious, 1 patient) Retinal detachment (serious, 3 patients) Uveitis (serious, 1 patient) Vitreous adhesions (serious, 1 patient) Vitreous haemorrhage (serious, 4 patients) Abdominal fat apron (serious, 1 patient) Abdominal incarcerated hernia (serious, 1 patient) Abdominal pain lower (serious, 1 patient) Anal haemorrhage (serious, 1 patient) Colitis (serious, 1 patient) Diarrhoea (serious, 3 patients) Diverticulum (serious, 1 patient) Diverticulum intestinal haemorrhagic (serious, 1 patient) Duodenal ulcer (serious, 2 patients) Duodenitis (serious, 2 patients) Faeces discoloured (serious, 1 patient) Food poisoning (serious, 1 patient) Gastric ulcer (serious, 2 patients) Gastritis (serious, 3 patients) Hernia inguinal (serious, 4 patients) Intestinal obstruction (serious, 7 patients) Intestinal perforation (serious, 1 patient) Leukoplakia oral (serious, 1 patient) Lower gastrointestinal haemorrhage (serious, 1 patient) Melaena (serious, 1 patient) Obstructive pancreatitis (serious, 1 patient) Pancreatitis (serious, 4 patients) Rectal polyp (serious, 1 patient) Small intestinal haemorrhage (serious, 1 patient) Umbilical hernia (serious, 1 patient) Upper gastrointestinal haemorrhage (serious, 4 patients) Cardiac death (serious, 3 patients) Complication associated with device (serious, 1 patient) Critical illness (serious, 1 patient) Death (serious, 7 patients) Gait disturbance (serious, 1 patient) General physical health deterioration (serious, 1 patient) Hernia incarcerated (serious, 1 patient) Non-cardiac chest pain (serious, 8 patients) Pyrexia (serious, 2 patients) Systemic inflammatory response syndrome (serious, 1 patient) Cholangitis acute (serious, 1 patient) Cholangitis sclerosing (serious, 1 patient) Cholecystitis acute (serious, 5 patients) Cholecystitis chronic (serious, 3 patients) Cholelithiasis (serious, 5 patients) Hepatic function abnormal (serious, 1 patient) Abdominal sepsis (serious, 1 patient) Abscess limb (serious, 3 patients) Acute hepatitis B (serious, 1 patient) Arthritis bacterial (serious, 2 patients) Atypical pneumonia (serious, 1 patient) Campylobacter colitis (serious, 1 patient) Clostridium difficile colitis (serious, 2 patients) Clostridium difficile infection (serious, 1 patient) Cystitis (serious, 2 patients) Device related infection (serious, 1 patient) Diabetic gangrene (serious, 5 patients) Diverticulitis (serious, 4 patients) Ear infection (serious, 1 patient) Empyema (serious, 1 patient) Enterobacter infection (serious, 1 patient) Gas gangrene (serious, 1 patient) Gastroenteritis bacterial (serious, 1 patient) Graft infection (serious, 1 patient) Haemophilus infection (serious, 1 patient) Influenza (serious, 3 patients) Laryngitis (serious, 1 patient) Fasciitis necrotising (serious, 2 patients) Onychomycosis (serious, 1 patient) Osteomyelitis acute (serious, 2 patients) Chronic osteomyelitis (serious, 1 patient) Perineal abscess (serious, 1 patient) Pharyngeal abscess (serious, 1 patient) Pneumococcal pneumonia (serious, 1 patient) Pneumonia streptococcal (serious, 1 patient) Pulmonary sepsis (serious, 1 patient) Pyelonephritis acute (serious, 4 patients) Rectal abscess (serious, 1 patient) Respiratory tract infection viral (serious, 1 patient) Scrub typhus (serious, 1 patient) Soft tissue infection (serious, 1 patient) Infection staphylococcal (serious, 1 patient) Subcutaneous abscess (serious, 1 patient) Tonsillitis (serious, 1 patient) Urinary tract infection (serious, 25 patients) Urinary tract infection fungal (serious, 1 patient) Wound infection (serious, 6 patients) Concussion (serious, 1 patient) Facial bones fracture (serious, 1 patient) Femoral neck fracture (serious, 4 patients) Femur fracture (serious, 5 patients) Fibula fracture (serious, 2 patients) Foot fracture (serious, 1 patient) Fracture displacement (serious, 1 patient) Humerus fracture (serious, 4 patients) Joint dislocation (serious, 1 patient) Ligament rupture (serious, 1 patient) Limb injury (serious, 1 patient) Meniscus injury (serious, 1 patient) Muscle strain (serious, 1 patient) Post procedural haemorrhage (serious, 1 patient) Postoperative thrombosis (serious, 1 patient) Postoperative wound complication (serious, 1 patient) Pubis fracture (serious, 2 patients) Road traffic accident (serious, 1 patient) Soft tissue injury (serious, 1 patient) Sternal fracture (serious, 1 patient) Stress fracture (serious, 1 patient) Haemorrhage subdural (serious, 1 patient) Thermal burn (serious, 2 patients) Thoracic vertebral fracture (serious, 1 patient) Tibia fracture (serious, 2 patients) Ulna fracture (serious, 2 patients) Vascular graft occlusion (serious, 2 patients) Aspiration bronchial (serious, 1 patient) Biopsy kidney (serious, 1 patient) Blood creatine phosphokinase increased (serious, 2 patients) Blood urea increased (serious, 1 patient) Glomerular filtration rate decreased (serious, 5 patients) Cachexia (serious, 1 patient) Diabetic ketoacidosis (serious, 9 patients) Fluid retention (serious, 1 patient) Hypoglycaemia (serious, 17 patients) Hypophagia (serious, 1 patient) Lactic acidosis (serious, 1 patient) Obesity (serious, 2 patients) Back pain (serious, 2 patients) Cervical spinal stenosis (serious, 1 patient) Haemarthrosis (serious, 1 patient) Intervertebral disc degeneration (serious, 1 patient) Muscular weakness (serious, 2 patients) Musculoskeletal chest pain (serious, 2 patients) Osteitis (serious, 1 patient) Osteochondrosis (serious, 1 patient) Spinal column stenosis (serious, 1 patient) Osteoarthritis spinal (serious, 4 patients) Symphysiolysis (serious, 1 patient) Acute leukaemia (serious, 1 patient) Adenocarcinoma of colon (serious, 2 patients) B-cell lymphoma (serious, 1 patient) Basal cell carcinoma (serious, 2 patients) Bladder cancer (serious, 5 patients) Brain cancer metastatic (serious, 1 patient) Brain neoplasm (serious, 1 patient) Breast cancer (serious, 3 patients) Cholangiocarcinoma (serious, 2 patients) Colon adenoma (serious, 1 patient) Colon cancer (serious, 6 patients) Endometrial adenocarcinoma (serious, 1 patient) Gastric cancer (serious, 3 patients) Gastric neoplasm (serious, 1 patient) Hepatic neoplasm (serious, 1 patient) Invasive breast carcinoma (serious, 1 patient) Invasive ductal breast carcinoma (serious, 2 patients) Invasive lobular breast carcinoma (serious, 1 patient) Large intestine benign neoplasm (serious, 1 patient) Laryngeal cancer (serious, 1 patient) Lung cancer metastatic (serious, 2 patients) Lung neoplasm (serious, 2 patients) Malignant meningioma (serious, 1 patient) Metastases to bone (serious, 2 patients) Metastatic renal cell carcinoma (serious, 1 patient) Myelodysplastic syndrome (serious, 1 patient) Oesophageal adenocarcinoma (serious, 1 patient) Ovarian endometrioid carcinoma (serious, 1 patient) Pancreatic carcinoma metastatic (serious, 1 patient) Pancreatic neoplasm (serious, 1 patient) Prostate cancer (serious, 8 patients) Prostatic adenoma (serious, 2 patients) Rectal adenoma (serious, 1 patient) Renal oncocytoma (serious, 1 patient) Salivary gland neoplasm (serious, 1 patient) Squamous cell carcinoma of skin (serious, 2 patients) Transitional cell cancer of the renal pelvis and ureter (serious, 2 patients) Transitional cell carcinoma (serious, 3 patients) Brain injury (serious, 1 patient) Brain oedema (serious, 2 patients) Carpal tunnel syndrome (serious, 2 patients) Cauda equina syndrome (serious, 1 patient) Cerebellar haemorrhage (serious, 1 patient) Cerebellar stroke (serious, 1 patient) Chronic inflammatory demyelinating polyradiculoneuropathy (serious, 1 patient) Clonus (serious, 1 patient) Dementia (serious, 2 patients) Diabetic autonomic neuropathy (serious, 1 patient) Diabetic hyperosmolar coma (serious, 1 patient) Embolic cerebral infarction (serious, 1 patient) Encephalopathy (serious, 2 patients) Facial paralysis (serious, 1 patient) Generalised tonic-clonic seizure (serious, 1 patient) Haemorrhagic transformation stroke (serious, 1 patient) Intracranial mass (serious, 1 patient) Ischaemic neuropathy (serious, 1 patient) Lumbosacral radiculopathy (serious, 1 patient) Metabolic encephalopathy (serious, 1 patient) Myelopathy (serious, 1 patient) Paraparesis (serious, 1 patient) Parkinson's disease (serious, 1 patient) Peripheral sensorimotor neuropathy (serious, 1 patient) Polyneuropathy (serious, 1 patient) Seizure (serious, 2 patients) Spinal cord compression (serious, 1 patient) Syncope (serious, 4 patients) Tension headache (serious, 2 patients) Transient ischaemic attack (serious, 10 patients) Vasculitis cerebral (serious, 1 patient) VIth nerve paralysis (serious, 1 patient) Abortion spontaneous (serious, 1 patient) Retained products of conception (serious, 1 patient) Confusional state (serious, 2 patients) Substance-induced psychotic disorder (serious, 1 patient) Suicide attempt (serious, 1 patient) Anuria (serious, 1 patient) Bladder cyst (serious, 1 patient) Calculus urinary (serious, 1 patient) Diabetic nephropathy (serious, 12 patients) Nephrolithiasis (serious, 1 patient) Nephrotic syndrome (serious, 2 patients) Bladder neurogenic (serious, 1 patient) Colic renal (serious, 1 patient) Renal impairment (serious, 10 patients) Renal injury (serious, 1 patient) Renal tubular necrosis (serious, 1 patient) Stress urinary incontinence (serious, 1 patient) Ureterolithiasis (serious, 1 patient) Urinary retention (serious, 2 patients) Adenomyosis (serious, 1 patient) Cervix disorder (serious, 1 patient) Cystocele (serious, 1 patient) Ovarian cyst (serious, 1 patient) Rectocele (serious, 1 patient) Uterine prolapse (serious, 1 patient) Uterovaginal prolapse (serious, 1 patient) Prolapse vaginal (serious, 1 patient) Asthma (serious, 2 patients) Bronchiectasis (serious, 1 patient) Bronchitis chronic (serious, 1 patient) Bronchospasm (serious, 1 patient) Chronic respiratory failure (serious, 1 patient) Cough (serious, 2 patients) Dyspnoea at rest (serious, 1 patient) Hypoxia (serious, 1 patient) Laryngeal haematoma (serious, 1 patient) Pleuritic pain (serious, 1 patient) Pulmonary embolism (serious, 7 patients) Pulmonary fibrosis (serious, 4 patients) Pulmonary infarction (serious, 1 patient) Angioedema (serious, 2 patients) Diabetic foot (serious, 15 patients) Diabetic ulcer (serious, 1 patient) Drug eruption (serious, 1 patient) Erythema (serious, 1 patient) Neuropathic ulcer (serious, 1 patient) Generalised rash (serious, 1 patient) Skin ulcer (serious, 18 patients) Accelerated hypertension (serious, 1 patient) Aortic dissection (serious, 1 patient) Arterial disorder (serious, 1 patient) Arterial insufficiency (serious, 1 patient) Circulatory collapse (serious, 1 patient) Extremity necrosis (serious, 9 patients) Haematoma (serious, 2 patients) Hypotension (serious, 4 patients) Claudication intermittent (serious, 1 patient) Leriche syndrome (serious, 1 patient) Peripheral artery occlusion (serious, 2 patients) Disorder peripheral vascular (serious, 5 patients) Peripheral venous disease (serious, 1 patient) Haemorrhagic shock (serious, 1 patient) Subclavian artery stenosis (serious, 1 patient) Thrombosis (serious, 1 patient) Vascular occlusion (serious, 1 patient) Diabetic retinopathy (below serious, 65 patients) Nausea (below serious, 54 patients) Onychomycosis (below serious, 45 patients) Urinary tract infection (below serious, 202 patients) Pain in extremity (below serious, 56 patients) Headache (below serious, 69 patients) Skin ulcer (below serious, 85 patients) Hypotension (below serious, 57 patients) Sources: https://clinicaltrials.gov/ct2/show/NCT02065791
300 mg 1 times / day steady, oral Dose: 300 mg, 1 times / day Route: oral Route: steady Dose: 300 mg, 1 times / day Sources: https://clinicaltrials.gov/ct2/show/NCT02360774	unhealthy n = 13 Health Status: unhealthy Condition: Type 2 Diabetes Mellitus Population Size: 13 Sources: https://clinicaltrials.gov/ct2/show/NCT02360774	Other AEs: Pneumonia... Other AEs: Pneumonia (serious, 1 patient) Sources: https://clinicaltrials.gov/ct2/show/NCT02360774

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 1587 inducer 781	inhibitor 1767 inducer 389	inhibitor 1852	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP2B6 810 CYP1A2 1524 CYP2A6 707 CYP2C19 1478 CYP2C8 911 CYP2E1 882 P-gp 1461 MRP2 383 OAT1 599 OAT3 642 OCT1 512 OCT2 647 NTCP 34 OATP1B1 788	UGT2B4 249 UGT1A9 380 P-gp 1537 MRP2 205	CYP1A2 701 CYP2B6 547 CYP2C19 293

Drug as perpetrator

Target	Modality	Activity	Metabolite	Clinical evidence
OATP1B1 803	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000ClinPharmR.pdf#page=70 Page: 70.0	inconclusive
CYP2E1 970	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000ClinPharmR.pdf#page=69; label: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000Lbl.pdf#page=19 Page: 69.0	no [IC50 18 uM]
CYP2C19 1553	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000ClinPharmR.pdf#page=69; label: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000Lbl.pdf#page=19 Page: 69.0	no [IC50 39 uM]
CYP2D6 1891	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000ClinPharmR.pdf#page=69; label: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000Lbl.pdf#page=19 Page: 69.0	no [IC50 65 uM]
CYP1A2 1692	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000ClinPharmR.pdf#page=69 Page: 69.0	no
CYP1A2 1692	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000ClinPharmR.pdf#page=68; label: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000Lbl.pdf#page=19 Page: 68.0	no
CYP2A6 739	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000ClinPharmR.pdf#page=68; label: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000Lbl.pdf#page=19 Page: 68.0	no
CYP2B6 1001	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000ClinPharmR.pdf#page=69 Page: 69.0	no
CYP2C19 1553	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000ClinPharmR.pdf#page=69 Page: 69.0	no
CYP2C9 1819	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000ClinPharmR.pdf#page=69 Page: 69.0	no
CYP3A4 1925	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000ClinPharmR.pdf#page=69 Page: 69.0	no
OAT1 603	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000ClinPharmR.pdf#page=70 Page: 70.0	no
OAT3 644	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000ClinPharmR.pdf#page=70 Page: 70.0	no
OCT1 543	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000ClinPharmR.pdf#page=70 Page: 70,72	no		no (co-administration study) Comment: no effect when administered with metformin Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000ClinPharmR.pdf#page=70 Page: 70,72
OCT2 648	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000ClinPharmR.pdf#page=70 Page: 70,72	no		no (co-administration study) Comment: no effect when administered with metformin Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000ClinPharmR.pdf#page=70 Page: 70,72
NTCP 35	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000ClinPharmR.pdf#page=70 Page: 70.0	slight
P-gp 1650	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000ClinPharmR.pdf#page=70 Page: 70,73	weak [IC50 19.3 uM]		weak (co-administration study) Comment: The AUC0-24 and Cmax values of digoxin were approximately 20% and 36% higher, respectively, when digoxin was co-administered with canagliflozin Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000ClinPharmR.pdf#page=70 Page: 70,73
CYP3A4 1925	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000ClinPharmR.pdf#page=68 Page: 68,69	weak [IC50 27 uM]		weak (co-administration study) Comment: IC50 value obtained when drug is adminstered with testosterone; had not effect on midazolam metabolism (IC50 > 100); Cmax of both oral contraceptive components (ethinyl estradiol and levonorgestrel) was increased (~20%) in presence of canagliflozin; the increase in Cmax for simvastatin and simvastatin acid was 9% and 18%, respectively, while the increase in AUC was 12% and 26%, respectively; Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000ClinPharmR.pdf#page=68 Page: 68,69
CYP2C9 1819	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000ClinPharmR.pdf#page=69; label: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000Lbl.pdf#page=19 Page: 69.0	weak [IC50 55 uM]		no (co-administration study) Comment: no effect when administered with warfarin and glyburide Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000ClinPharmR.pdf#page=69; label: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000Lbl.pdf#page=19 Page: 69.0
CYP2C8 965	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000ClinPharmR.pdf#page=69; label: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000Lbl.pdf#page=19 Page: 69.0	weak [IC50 75 uM]
CYP2B6 1001	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000ClinPharmR.pdf#page=68 Page: 68.0	yes [IC50 16 uM]
MRP2 475	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000ClinPharmR.pdf#page=70 Page: 70.0	yes [IC50 21.5 uM]
NTCP 35	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000ClinPharmR.pdf#page=70 Page: 70.0	yes [Inhibition 100 uM]	M7 3
OAT3 644	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000ClinPharmR.pdf#page=70 Page: 70.0	yes [Inhibition 100 uM]	M7 3
OATP1B1 803	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000ClinPharmR.pdf#page=70 Page: 70.0	yes [Inhibition 100 uM]	M7 3

Drug as victim

Target	Modality	Activity	Clinical evidence
MRP2 205	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000ClinPharmR.pdf#page=70 Page: 70.0	yes
P-gp 1537	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000ClinPharmR.pdf#page=70 Page: 70,72	yes	yes (co-administration study) Comment: efflux was inhibited up to 95% by verapamil (P-gp inhibitor); with cyclosporine increased the AUC of canagliflozin by 23% with no change in Cmax; Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000ClinPharmR.pdf#page=70 Page: 70,72
UGT2B4 249	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000ClinPharmR.pdf#page=68 Page: 68,73,88	yes	yes (co-administration study) Comment: probenecid increased the plasma canagliflozin Cmax and AUCtau by 13% and 21%, respectively; mean plasma Cmax and AUCinf values for canagliflozin were approximately 30% and 52% lower, respectively, when administered with rifampin (inducer) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000ClinPharmR.pdf#page=68 Page: 68,73,88
UGT1A9 380	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000ClinPharmR.pdf#page=68 Page: 68,73,88	yes	yes (pharmacogenomic study) Comment: probenecid increased the plasma canagliflozin Cmax and AUCtau by 13% and 21%, respectively; mean plasma Cmax and AUCinf values for canagliflozin were approximately 30% and 52% lower, respectively, when administered with rifampin (inducer); carriers of the UGT1A9*3 allele exhibit higher plasma canagliflozin trough concentrations on average Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000ClinPharmR.pdf#page=68 Page: 68,73,88

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000PharmR.pdf#page=75 Page: 75.0

PubMed

Title	Date	PubMed
Discovery of novel N-β-D-xylosylindole derivatives as sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors for the management of hyperglycemia in diabetes.	2011 Jan 13	21128592
Effect of canagliflozin on renal threshold for glucose, glycemia, and body weight in normal and diabetic animal models.	2012	22355316
Canagliflozin , an inhibitor of sodium-glucose cotransporter 2, for the treatment of type 2 diabetes mellitus.	2013 Jun	23590413
Carcinogenicity in rats of the SGLT2 inhibitor canagliflozin.	2014 Dec 5	25289773
Carbohydrate malabsorption mechanism for tumor formation in rats treated with the SGLT2 inhibitor canagliflozin.	2014 Sep 25	25130857

Patents

Sample Use Guides

In Vivo Use Guide

The recommended starting dose is 100 mg once daily, taken before the first meal of the day. Dose 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^2 or greater and require additional glycemic control

Route of Administration: Oral

In Vitro Use Guide

For sodium-dependent glucose uptake in Chinese Hamster Ovary (CHO) cells expressing SGLT1 and SGLT2 co-transporters parental CHO-K (CHOK) cells expressing human or mouse SGLT1 and SGLT2 were seeded into 96-well plates, washed one time with 0.15 ml assay buffer at 37°C. After the assay buffer was removed 0.3–300 nM canagliflozin was added, followed by 10 minutes of incubation.

Substance Class	Chemical Created by `admin` on `Fri Dec 15 16:07:11 GMT 2023` Edited by `admin` on `Fri Dec 15 16:07:11 GMT 2023`
Record UNII	0SAC974Z85
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

CANAGLIFLOZIN

Official Name

English

INVOKAMET COMPONENT CANAGLIFLOZIN

Brand Name

English

Canagliflozin hemihydrate [WHO-DD]

Common Name

English

CANAGLIFLOZIN [VANDF]

Common Name

English

CANAGLIFLOZIN HYDRATE

Common Name

English

CANAGLIFLOZIN HEMIHYDRATE

Common Name

English

INVOKANA

Brand Name

English

(1S)-1,5-ANHYDRO-1-C-(3-((5-(4-FLUOROPHENYL)THIOPHEN-2-YL)METHYL)-4-METHYLPHENYL)-D- GLUCITOL HEMIHYDRATE

Common Name

English

(1S)-1,5-ANHYDRO-1-(3-((5-(4-FLUOROPHENYL)-2-THIENYL)METHYL)-4-METHYLPHENYL)-D-GLUCITOL HEMIHYDRATE

Common Name

English

D-GLUCITOL, 1,5-ANHYDRO-1-C-(3-((5-(4-FLUOROPHENYL)-2-THIENYL)METHYL)-4-METHYLPHENYL)-, HYDRATE (2:1), (1S)-

Common Name

English

CANAGLIFLOZIN HEMIHYDRATE [MI]

Common Name

English

CANAGLIFLOZIN [ORANGE BOOK]

Common Name

English

JNJ-28431754-AAA

Code

English

CANAGLIFLOZIN [USAN]

Common Name

English

CANAGLIFLOZIN COMPONENT OF INVOKAMET

Brand Name

English

JNJ-24831754-ZAE

Code

English

CANAGLIFLOZIN HYDRATE [JAN]

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C98083