CANAGLIFLOZIN ANHYDROUS

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C24H25FO5S
Molecular Weight	444.516
Optical Activity	UNSPECIFIED
Defined Stereocenters	5 / 5
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

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

InChI

InChIKey=XTNGUQKDFGDXSJ-ZXGKGEBGSA-N

InChI=1S/C24H25FO5S/c1-13-2-3-15(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/h2-10,19,21-24,26-29H,11-12H2,1H3/t19-,21-,22+,23-,24+/m1/s1

HIDE SMILES / InChI

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 8504		4.4 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Type 2 diabetes mellitus 262 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/204042s022lbl.pdf	Secondary		Approved 8583	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	unhealthy, adult Health Status: unhealthy Age Group: adult Sex: M+F Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000MedR.pdf	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
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	unhealthy, adult Health Status: unhealthy Age Group: adult Sex: M+F Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000MedR.pdf	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
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	unhealthy, mean 56 years Health Status: unhealthy Age Group: mean 56 years Sex: F Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204042s027lbl.pdf	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
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	unhealthy, mean 56 years Health Status: unhealthy Age Group: mean 56 years Sex: M Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204042s027lbl.pdf	Other AEs: Genital infection male... Other AEs: Genital infection male (4.2%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204042s027lbl.pdf
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	unhealthy, mean 56 years Health Status: unhealthy Age Group: mean 56 years Sex: M+F Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204042s027lbl.pdf	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
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	unhealthy, mean 56 years Health Status: unhealthy Age Group: mean 56 years Sex: F Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204042s027lbl.pdf	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
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	unhealthy, mean 56 years Health Status: unhealthy Age Group: mean 56 years Sex: F Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204042s027lbl.pdf	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
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	unhealthy, mean 56 years Health Status: unhealthy Age Group: mean 56 years Sex: M Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204042s027lbl.pdf	Other AEs: Genital infection male... Other AEs: Genital infection male (3.8%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204042s027lbl.pdf
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	unhealthy, mean 56 years Health Status: unhealthy Age Group: mean 56 years Sex: M Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204042s027lbl.pdf	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
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	unhealthy, mean 56 years Health Status: unhealthy Age Group: mean 56 years Sex: M+F Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204042s027lbl.pdf	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
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	unhealthy, mean 56 years Health Status: unhealthy Age Group: mean 56 years Sex: M+F Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204042s027lbl.pdf	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
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 Health Status: unhealthy 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 Health Status: unhealthy 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 Health Status: unhealthy 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 2252 inducer 1087	inhibitor 2438 inducer 440	inhibitor 2507	inhibitor 2217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP2B6 926 CYP1A2 2153 CYP2A6 879 CYP2C19 2057 CYP2C8 1057 CYP2E1 1060 P-gp 1741 MRP2 499 OAT1 725 OAT3 747 OCT1 620 OCT2 779 NTCP 39 OATP1B1 1079	UGT2B4 278 UGT1A9 423 P-gp 2052 MRP2 252	CYP1A2 832 CYP2B6 669 CYP2C19 329

Drug as perpetrator

Target	Modality	Activity	Metabolite	Clinical evidence
OATP1B1 1095	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000ClinPharmR.pdf#page=70 Page: 70.0	inconclusive
CYP2E1 1146	inhibitor 4027 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 2141	inhibitor 4027 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 2546	inhibitor 4027 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 2333	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000ClinPharmR.pdf#page=69 Page: 69.0	no
CYP1A2 2333	inhibitor 4027 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 911	inhibitor 4027 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 1160	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000ClinPharmR.pdf#page=69 Page: 69.0	no
CYP2C19 2141	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000ClinPharmR.pdf#page=69 Page: 69.0	no
CYP2C9 2497	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000ClinPharmR.pdf#page=69 Page: 69.0	no
CYP3A4 2633	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000ClinPharmR.pdf#page=69 Page: 69.0	no
OAT1 730	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000ClinPharmR.pdf#page=70 Page: 70.0	no
OAT3 749	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000ClinPharmR.pdf#page=70 Page: 70.0	no
OCT1 656	inhibitor 4027 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 782	inhibitor 4027 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 40	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000ClinPharmR.pdf#page=70 Page: 70.0	slight
P-gp 1932	inhibitor 4027 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 2633	inhibitor 4027 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 2497	inhibitor 4027 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 1117	inhibitor 4027 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 1160	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000ClinPharmR.pdf#page=68 Page: 68.0	yes [IC50 16 uM]
MRP2 625	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000ClinPharmR.pdf#page=70 Page: 70.0	yes [IC50 21.5 uM]
NTCP 40	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000ClinPharmR.pdf#page=70 Page: 70.0	yes [Inhibition 100 uM]	M7 3
OAT3 749	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000ClinPharmR.pdf#page=70 Page: 70.0	yes [Inhibition 100 uM]	M7 3
OATP1B1 1095	inhibitor 4027 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 252	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000ClinPharmR.pdf#page=70 Page: 70.0	yes
P-gp 2052	substrate 4014 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 278	substrate 4014 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 423	substrate 4014 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 2263	inhibitor 2237 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000PharmR.pdf#page=75 Page: 75.0

PubMed

Title	Date	PubMed
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.

Name

Type

Language

CANAGLIFLOZIN ANHYDROUS

Common Name

English

JNJ-28431754

Preferred Name

English

Canagliflozin [WHO-DD]

Common Name

English

canagliflozin [INN]

Common Name

English

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

Common Name

English

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

Common Name

English

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

Common Name

English

TA-7284

Code

English

CANAGLIFLOZIN [MI]

Common Name

English

Classification Tree Code System Code

NDF-RT

N0000187059