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Canagliflozin

PubChem CID
24812758
Structure
Canagliflozin_small.png
Canagliflozin_3D_Structure.png
Molecular Formula
Synonyms
  • Canagliflozin
  • 842133-18-0
  • Invokana
  • Canagliflozin anhydrous
  • TA-7284
Molecular Weight
444.5 g/mol
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Dates
  • Create:
    2008-06-23
  • Modify:
    2025-01-18
Description
Canagliflozin is a C-glycosyl compound that is used (in its hemihydrate form) for treatment of type II diabetes via inhibition of sodium-glucose transport protein subtype 2. It has a role as a hypoglycemic agent and a sodium-glucose transport protein subtype 2 inhibitor. It is a C-glycosyl compound, a member of thiophenes and an organofluorine compound.
Canagliflozin, also known as Invokana, is a sodium-glucose cotransporter 2 (SGLT2) inhibitor used in the management of type 2 diabetes mellitus along with lifestyle changes including diet and exercise. It was initially approved by the FDA in 2013 for the management of diabetes and later approved in 2018 for a second indication of reducing the risk of cardiovascular events in patients diagnosed with type 2 diabetes mellitus,. Canagliflozin is the first oral antidiabetic drug approved for the prevention of cardiovascular events in patients with type 2 diabetes. Cardiovascular disease is the most common cause of death in these patients.
Canagliflozin anhydrous is a Sodium-Glucose Cotransporter 2 Inhibitor. The mechanism of action of canagliflozin anhydrous is as a Sodium-Glucose Transporter 2 Inhibitor, and P-Glycoprotein Inhibitor.

1 Structures

1.1 2D Structure

Chemical Structure Depiction
Canagliflozin.png

1.2 3D Conformer

1.3 Crystal Structures

COD records with this CID as component

2 Names and Identifiers

2.1 Computed Descriptors

2.1.1 IUPAC Name

(2S,3R,4R,5S,6R)-2-[3-[[5-(4-fluorophenyl)thiophen-2-yl]methyl]-4-methylphenyl]-6-(hydroxymethyl)oxane-3,4,5-triol
Computed by Lexichem TK 2.7.0 (PubChem release 2021.10.14)

2.1.2 InChI

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
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.3 InChIKey

XTNGUQKDFGDXSJ-ZXGKGEBGSA-N
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.4 SMILES

CC1=C(C=C(C=C1)[C@H]2[C@@H]([C@H]([C@@H]([C@H](O2)CO)O)O)O)CC3=CC=C(S3)C4=CC=C(C=C4)F
Computed by OEChem 2.3.0 (PubChem release 2024.12.12)

2.2 Molecular Formula

C24H25FO5S
Computed by PubChem 2.2 (PubChem release 2021.10.14)

2.3 Other Identifiers

2.3.1 CAS

2.3.2 European Community (EC) Number

2.3.3 UNII

2.3.4 ChEBI ID

2.3.5 ChEMBL ID

2.3.6 DrugBank ID

2.3.7 DSSTox Substance ID

2.3.8 Metabolomics Workbench ID

2.3.9 NCI Thesaurus Code

2.3.10 Nikkaji Number

2.3.11 Pharos Ligand ID

2.3.12 RXCUI

2.3.13 Wikidata

2.3.14 Wikipedia

2.4 Synonyms

2.4.1 MeSH Entry Terms

  • 1-(Glucopyranosyl)-4-methyl-3-(5-(4-fluorophenyl)-2-thienylmethyl)benzene - T777973
  • canagliflozin
  • Canagliflozin Hemihydrate
  • Canagliflozin, Anhydrous
  • Invokana

2.4.2 Depositor-Supplied Synonyms

3 Chemical and Physical Properties

3.1 Computed Properties

Property Name
Molecular Weight
Property Value
444.5 g/mol
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
XLogP3-AA
Property Value
3.2
Reference
Computed by XLogP3 3.0 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Donor Count
Property Value
4
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Acceptor Count
Property Value
7
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Rotatable Bond Count
Property Value
5
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Exact Mass
Property Value
444.14067323 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Monoisotopic Mass
Property Value
444.14067323 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Topological Polar Surface Area
Property Value
118 Ų
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Heavy Atom Count
Property Value
31
Reference
Computed by PubChem
Property Name
Formal Charge
Property Value
0
Reference
Computed by PubChem
Property Name
Complexity
Property Value
574
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Isotope Atom Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Atom Stereocenter Count
Property Value
5
Reference
Computed by PubChem
Property Name
Undefined Atom Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Undefined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Covalently-Bonded Unit Count
Property Value
1
Reference
Computed by PubChem
Property Name
Compound Is Canonicalized
Property Value
Yes
Reference
Computed by PubChem (release 2021.10.14)

3.2 Experimental Properties

3.2.1 Boiling Point

3.2.2 Melting Point

3.2.3 Solubility

almost insoluble
Practically insoluble in aqueous media from pH 1.1 to pH 12.9 /Canagliflozin hemihydrate/
US Natl Inst Health; DailyMed. Current Medical Information. Available from, as of Oct 13, 2015: https://dailymed.nlm.nih.gov/dailymed/about.cfm

3.2.4 LogP

3.2.5 Dissociation Constants

3.2.6 Other Experimental Properties

log Kow: 1.59; Koc: 5.9 /Canagliflozin hemihydrate (928672-86-0)/
FDA; Environmental Assessment. Canagliflozin/ Metroformin Hydrochloride. Center for Drug Evaluation and Research. Application No. 204353Orig1s000. Available from, as of Oct 14, 2015: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204353Orig1s000EA.pdf

3.3 Chemical Classes

3.3.1 Drugs

Pharmaceuticals -> Listed in ZINC15
S55 | ZINC15PHARMA | Pharmaceuticals from ZINC15 | DOI:10.5281/zenodo.3247749
Pharmaceuticals -> Alimentary tract and metabolism -> Drugs used in diabetes
S92 | FLUOROPHARMA | List of ~340 ATC classified fluoro-pharmaceuticals | DOI:10.5281/zenodo.5979646
Pharmaceuticals -> unsed in Switzerland 2014-2016
S113 | SWISSPHARMA24 | 2024 Swiss Pharmaceutical List with Metabolites | DOI:10.5281/zenodo.10501043
3.3.1.1 Human Drugs
Breast Feeding; Lactation; Milk, Human; Hypoglycemic Agents; Sodium-Glucose Cotransporter 2 Inhibitors; SGLT2 Inhibitors
Human drug -> None (Tentative Approval); Active ingredient (CANAGLIFLOZIN)
Human drug -> Prescription
Human drugs -> Drugs used in diabetes -> Human pharmacotherapeutic group -> EMA Drug Category
Paediatric drug
Oral hypoglycaemic agents

5 Chemical Vendors

6 Drug and Medication Information

6.1 Drug Indication

This drug is used in conjunction with diet and exercise to increase glycemic control in adults diagnosed with type 2 diabetes mellitus. Another indication for canagliflozin is the prevention of major cardiovascular events (myocardial infarction, stroke, or death due to a cardiovascular cause) in patients with type 2 diabetes, as well as hospitalization for heart failure in patients with type 2 diabetes[L5897,. In addition to the above, canagliflozin can be used to lower the risk of end-stage kidney disease and major increases in serum creatinine and cardiovascular death for patients with a combination of type 2 diabetes mellitus, diabetic nephropathy, and albuminuria. It is important to note that this drug is **not** indicated for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis.
Invokana is indicated for the treatment of adults with insufficiently controlled type 2 diabetes mellitus as an adjunct to diet and exercise: as monotherapy when metformin is considered inappropriate due to intolerance or contraindicationsin addition to other medicinal products for the treatment of diabetes. For study results with respect to combination of therapies, effects on glycaemic control, cardiovascular and renal events, and the populations studied, see sections 4. 4, 4. 5 and 5. 1.

6.2 Drug Classes

Breast Feeding; Lactation; Milk, Human; Hypoglycemic Agents; Sodium-Glucose Cotransporter 2 Inhibitors; SGLT2 Inhibitors

6.3 FDA Medication Guides

1 of 3
Drug
Active Ingredient
Form;Route
TABLET;ORAL
Company
JANSSEN PHARMS
Date
08/23/2024
2 of 3
Drug
Active Ingredient
Form;Route
TABLET, EXTENDED RELEASE;ORAL
Company
JANSSEN PHARMS
Date
08/23/2024
3 of 3
Drug
Active Ingredient
CANAGLIFLOZIN
Form;Route
TABLET;ORAL
Company
JANSSEN PHARMS
Date
08/23/2024

6.4 WHO Essential Medicines

Drug
Drug Classes
Oral hypoglycaemic agents
Formulation
Indication
Type 2 diabetes mellitus

6.5 FDA Approved Drugs

6.6 FDA Orange Book

6.7 FDA National Drug Code Directory

6.8 Drug Labels

Drug and label
Active ingredient and drug

6.9 Clinical Trials

6.9.1 ClinicalTrials.gov

6.9.2 EU Clinical Trials Register

6.9.3 NIPH Clinical Trials Search of Japan

6.10 EMA Drug Information

1 of 2
Medicine
Category
Human drugs
Therapeutic area
Diabetes Mellitus, Type 2
Active Substance
canagliflozin
INN/Common name
canagliflozin
Pharmacotherapeutic Classes
Drugs used in diabetes
Status
This medicine is authorized for use in the European Union
Company
Janssen-Cilag International NV
Market Date
2013-11-15
2 of 2
Type
Paediatric investigation
Active Substance
Therapeutic Area
Endocrinology-Gynaecology-Fertility-Metabolism
Drug Form
Film-coated tablet
Administration Route
Oral use
Decision Type
PM: decision on the application for modification of an agreed PIP
Decision Date
2022-06-10

6.11 Therapeutic Uses

/CLINICAL TRIALS/ ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. The Web site is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each ClinicalTrials.gov record presents summary information about a study protocol and includes the following: Disease or condition; Intervention (for example, the medical product, behavior, or procedure being studied); Title, description, and design of the study; Requirements for participation (eligibility criteria); Locations where the study is being conducted; Contact information for the study locations; and Links to relevant information on other health Web sites, such as NLM's MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly articles in the field of medicine. Canagliflozin is included in the database.
NIH/NLM; ClinicalTrials.Gov. Available from, as of September 30, 2015: https://clinicaltrials.gov/search/intervention=Canagliflozin
Invokana (canagliflozin) is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. /Included in US product label/
NIH; DailyMed. Current Medication Information for Invokana (Canagliflozin) Tablet, Film Coated (Updated: September 2015). Available from, as of November 20, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b9057d3b-b104-4f09-8a61-c61ef9d4a3f3
EXPL THER The proximal tubule's sodium-glucose linked transporter-2 (SGLT2) accounts for the vast majority of glucose reabsorption by the kidney. Its selective inhibition, accordingly, leads to substantial glycosuria, lowering blood glucose, and facilitating weight loss in individuals with diabetes. During the past year, two SGLT2 inhibitors, canagliflozin and dapagliflozin, have been approved for the treatment of type 2 diabetes. Beyond their anti-hyperglycemic properties, however, this new class of drugs has several other attributes that provide a theoretical basis for kidney protection. Like agents that block the renin-angiotensin system, SGLT2 inhibitors also reduce single-nephron glomerular filtration rate (SNGFR) in the chronically diseased kidney, though by quite different mechanisms. Additional potentially beneficial effects of SGLT2 inhibition include modest reductions in blood pressure and plasma uric acid. Finally, cell culture studies indicate that glucose uptake from the tubular lumen, as well as from the basolateral compartment, can contribute to proximal tubular production of extracellular matrix proteins. Whether such attributes will translate into reducing the progression of chronic kidney disease will require the undertaking of long-term, dedicated studies.
Gilbert RE; Kidney Int 86(4): 693-700 (2014).
EXPL THER Management of hypertension in diabetes is critical for reduction of cardiovascular mortality and morbidity. While blood pressure (BP) control has improved over the past two decades, the control rate is still well below 50% in the general population of patients with type 2 diabetes mellitus (T2DM). A new class of oral glucose-lowering agents has recently been approved; the sodium-glucose co-transporter 2 (SGLT2) inhibitors, which act by eliminating large amounts of glucose in the urine. Two agents, dapagliflozin and canagliflozin, are currently approved in the United States and Europe, and empagliflozin and ipragliflozin have reported Phase 3 trials. In addition to glucose lowering, SGLT2 inhibitors are associated with weight loss and act as osmotic diuretics, resulting in a lowering of BP. While not approved for BP-lowering, they may potentially aid BP goal achievement in people within 7-10 mm Hg of goal.
Oliva RV et al; J Am Soc Hypertens 8(5): 330-9.

6.12 Drug Warnings

Hypersensitivity reactions (e.g., generalized urticaria), some serious, have been reported with canagliflozin treatment. These reactions generally occurred within hours to days of canagliflozin initiation. If a hypersensitivity reaction occurs, the drug should be discontinued, appropriate treatment instituted, and the patient monitored until signs and symptoms resolve.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 3163
Dose-dependent increases in low-density lipoprotein (LDL)-cholesterol can occur during canagliflozin therapy. Serum LDL-cholesterol concentrations should be monitored during treatment with canagliflozin and such lipid elevations treated according to the standard of care.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 3162
When canagliflozin is added to therapy with an insulin secretagogue (e.g., a sulfonylurea) or insulin, the incidence of hypoglycemia is increased compared with sulfonylurea or insulin monotherapy. Therefore, patients receiving canagliflozin may require a reduced dosage of the concomitant insulin secretagogue or insulin to reduce the risk of hypoglycemia.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 3162
Canagliflozin may increase the risk of genital mycotic infections in males (e.g., balanoposthitis, candidal balanitis) and females (e.g., vulvovaginal candidiasis, vulvovaginal mycotic infection, vulvovaginitis). In clinical trials, patients with a history of genital mycotic infections and uncircumcised males were more likely to develop such infections. Patients should be monitored for genital mycotic infections and appropriate treatment should be instituted if these infections occur.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 3162
For more Drug Warnings (Complete) data for Canagliflozin (14 total), please visit the HSDB record page.

7 Pharmacology and Biochemistry

7.1 Pharmacodynamics

This drug increases urinary glucose excretion and decreases the renal threshold for glucose (RTG) in a dose-dependent manner. The renal threshold is defined as the lowest level of blood glucose associated with the appearance of detectable glucose in the urine. The end result of canagliflozin administration is increased urinary excretion of glucose and less renal absorption of glucose, decreasing glucose concentration in the blood and improving glycemic control. **A note on type 2 diabetes and cardiovascular disease** The risk of cardiovascular events in diabetes type 2 is increased due to the damaging effects of diabetes on blood vessels and nerves in the cardiovascular system. In particular, there is a tendency for hyperglycemia to create pro-atherogenic (plaque forming) lesions in blood vessels, leading to various fatal and non-fatal events including stroke and myocardial infarction. Long-term glycemic control has been proven to be effective in the prevention of cardiovascular events such as myocardial infarction and stroke in patients with type 2 diabetes.

7.2 MeSH Pharmacological Classification

Sodium-Glucose Transporter 2 Inhibitors
Compounds that inhibit SODIUM-GLUCOSE TRANSPORTER 2. They lower blood sugar by preventing the reabsorption of glucose by the kidney and are used in the treatment of TYPE 2 DIABETES MELLITUS. (See all compounds classified as Sodium-Glucose Transporter 2 Inhibitors.)

7.3 FDA Pharmacological Classification

1 of 2
FDA UNII
6S49DGR869
Active Moiety
CANAGLIFLOZIN ANHYDROUS
Pharmacological Classes
Established Pharmacologic Class [EPC] - Sodium-Glucose Cotransporter 2 Inhibitor
Pharmacological Classes
Mechanisms of Action [MoA] - Sodium-Glucose Transporter 2 Inhibitors
Pharmacological Classes
Mechanisms of Action [MoA] - P-Glycoprotein Inhibitors
FDA Pharmacology Summary
Canagliflozin anhydrous is a Sodium-Glucose Cotransporter 2 Inhibitor. The mechanism of action of canagliflozin anhydrous is as a Sodium-Glucose Transporter 2 Inhibitor, and P-Glycoprotein Inhibitor.
2 of 2
Non-Proprietary Name
CANAGLIFLOZIN
Pharmacological Classes
Sodium-Glucose Cotransporter 2 Inhibitor [EPC]; P-Glycoprotein Inhibitors [MoA]; Sodium-Glucose Transporter 2 Inhibitors [MoA]

7.4 ATC Code

A10BK02

A - Alimentary tract and metabolism

A10 - Drugs used in diabetes

A10B - Blood glucose lowering drugs, excl. insulins

A10BK - Sodium-glucose co-transporter 2 (sglt2) inhibitors

A10BK02 - Canagliflozin

7.5 Absorption, Distribution and Excretion

Absorption
**Bioavailability and steady-state** The absolute oral bioavailability of canagliflozin, on average, is approximately 65%. Steady-state concentrations are achieved after 4 to 5 days of daily dose administration between the range of 100mg to 300mg. **Effect of food on absorption** Co-administration of a high-fat meal with canagliflozin exerted no appreciable effect on the pharmacokinetic parameters of canagliflozin. This drug may be administered without regard to food. Despite this, because of the potential of canagliflozin to decrease postprandial plasma glucose excretion due to prolonged intestinal glucose absorption, it is advisable to take this drug before the first meal of the day.
Route of Elimination
After a single oral radiolabeled dose canagliflozin dose to healthy subjects, the following ratios of canagliflozin or metabolites were measured in the feces and urine: **Feces** 41.5% as the unchanged radiolabeled drug 7.0% as a hydroxylated metabolite 3.2% as an O-glucuronide metabolite **Urine** About 33% of the ingested radiolabled dose was measured in the urine, generally in the form of O-glucuronide metabolites. Less than 1% of the dose was found excreted as unchanged drug in urine.
Volume of Distribution
This drug is extensively distributed throughout the body. On average, the volume of distribution of canagliflozin at steady state following a single intravenous dose in healthy patients was measured to be 83.5 L.
Clearance
In healthy subjects, canagliflozin clearance was approximately 192 mL/min after intravenous (IV) administration. The renal clearance of 100 mg and 300 mg doses of canagliflozin was measured to be in the range of 1.30 - 1.55 mL/min.
/MILK/ Canagliflozin is distributed into milk in rats; it is not known whether the drug is distributed into human milk.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 3163
Canagliflozin is an oral antihyperglycemic agent used for the treatment of type 2 diabetes mellitus. It blocks the reabsorption of glucose in the proximal renal tubule by inhibiting the sodium-glucose cotransporter 2. This article describes the in vivo biotransformation and disposition of canagliflozin after a single oral dose of [(14)C]canagliflozin to intact and bile duct-cannulated (BDC) mice and rats and to intact dogs and humans. Fecal excretion was the primary route of elimination of drug-derived radioactivity in both animals and humans. In BDC mice and rats, most radioactivity was excreted in bile. The extent of radioactivity excreted in urine as a percentage of the administered [(14)C]canagliflozin dose was 1.2%-7.6% in animals and approximately 33% in humans. The primary pathways contributing to the metabolic clearance of canagliflozin were oxidation in animals and direct glucuronidation of canagliflozin in humans. Unchanged canagliflozin was the major component in systemic circulation in all species. In human plasma, two pharmacologically inactive O-glucuronide conjugates of canagliflozin, M5 and M7, represented 19% and 14% of total drug-related exposure and were considered major human metabolites. Plasma concentrations of M5 and M7 in mice and rats from repeated dose safety studies were lower than those in humans given canagliflozin at the maximum recommended dose of 300 mg. However, biliary metabolite profiling in rodents indicated that mouse and rat livers had significant exposure to M5 and M7. Pharmacologic inactivity and high water solubility of M5 and M7 support glucuronidation of canagliflozin as a safe detoxification pathway.
Mamidi RN et al. Drug Metab Dispos 42(5): 903-16 (2014).
The mean absolute oral bioavailability of canagliflozin is approximately 65%. Co-administration of a high-fat meal with canagliflozin had no effect on the pharmacokinetics of canagliflozin; therefore, INVOKANA may be taken with or without food. However, based on the potential to reduce postprandial plasma glucose excursions due to delayed intestinal glucose absorption, it is recommended that INVOKANA be taken before the first meal of the day. The mean steady-state volume of distribution of canagliflozin following a single intravenous infusion in healthy subjects was 119 L, suggesting extensive tissue distribution. Canagliflozin is extensively bound to proteins in plasma (99%), mainly to albumin. Protein binding is independent of canagliflozin plasma concentrations. Plasma protein binding is not meaningfully altered in patients with renal or hepatic impairment. Following administration of a single oral [14C] canagliflozin dose to healthy subjects, 41.5%, 7.0%, and 3.2% of the administered radioactive dose was recovered in feces as canagliflozin, a hydroxylated metabolite, and an O-glucuronide metabolite, respectively. Enterohepatic circulation of canagliflozin was negligible. Approximately 33% of the administered radioactive dose was excreted in urine, mainly as O-glucuronide metabolites (30.5%). Less than 1% of the dose was excreted as unchanged canagliflozin in urine. Renal clearance of canagliflozin 100 mg and 300 mg doses ranged from 1.30 to 1.55 mL/min. Mean systemic clearance of canagliflozin was approximately 192 mL/min in healthy subjects following intravenous administration.
NIH; DailyMed. Current Medication Information for Invokana (Canagliflozin) Tablet, Film Coated (Updated: September 2015). Available from, as of November 20, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b9057d3b-b104-4f09-8a61-c61ef9d4a3f3

7.6 Metabolism / Metabolites

Canagliflozin is primarily metabolized by O-glucuronidation. It is mainly glucuronidated by UGT1A9 and UGT2B4 enzymes to two inactive O-glucuronide metabolites. The oxidative metabolism of canagliflozin by hepatic cytochrome enzyme CYP3A4 is negligible (about 7%) in humans.
O-glucuronidation is the major metabolic elimination pathway for canagliflozin, which is mainly glucuronidated by UGT1A9 and UGT2B4 to two inactive O-glucuronide metabolites. CYP3A4-mediated (oxidative) metabolism of canagliflozin is minimal (approximately 7%) in humans.
NIH; DailyMed. Current Medication Information for Invokana (Canagliflozin) Tablet, Film Coated (Updated: September 2015). Available from, as of November 20, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b9057d3b-b104-4f09-8a61-c61ef9d4a3f3

7.7 Biological Half-Life

In a clinical study, the terminal half-life of canagliflozin was 10.6 hours for the 100mg dose and 13.1 hours for the 300 mg dose.

7.8 Mechanism of Action

The sodium-glucose co-transporter2 (SGLT2), is found in the proximal tubules of the kidney, and reabsorbs filtered glucose from the renal tubular lumen. Canagliflozin inhibits the SGLT2 co-transporter. This inhibition leads to lower reabsorption of filtered glucose into the body and decreases the renal threshold for glucose (RTG), leading to increased glucose excretion in the urine.
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 (UGE).
NIH; DailyMed. Current Medication Information for Invokana (Canagliflozin) Tablet, Film Coated (Updated: September 2015). Available from, as of November 20, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b9057d3b-b104-4f09-8a61-c61ef9d4a3f3

8 Use and Manufacturing

8.1 Uses

MEDICATION

8.1.1 Use Classification

Human drugs -> Drugs used in diabetes -> Human pharmacotherapeutic group -> EMA Drug Category
Human Drugs -> EU pediatric investigation plans
Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients

8.2 Formulations / Preparations

Table: Canagliflozin Preparations
Route of Administration
Oral
Dosage Form
Tablet, film-coated
Strength
100 mg (of anhydrous canagliflozin)
Brand or Generic Name (Manufacturer)
Invokana (Janssen)
Route of Administration
Oral
Dosage Form
Tablet, film-coated
Strength
300 mg (of anhydrous canagliflozin)
Brand or Generic Name (Manufacturer)
Invokana (Janssen)
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 3164

8.3 General Manufacturing Information

FDA; Environmental Assessment. Canagliflozin/ Metroformin Hydrochloride. Center for Drug Evaluation and Research. Application No. 204353Orig1s000. Available from, as of Oct 14, 2015: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204353Orig1s000EA.pdf

9 Safety and Hazards

9.1 Hazards Identification

9.1.1 GHS Classification

Pictogram(s)
Corrosive
Irritant
Health Hazard
Environmental Hazard
Signal
Danger
GHS Hazard Statements

H302 (60%): Harmful if swallowed [Warning Acute toxicity, oral]

H318 (20%): Causes serious eye damage [Danger Serious eye damage/eye irritation]

H319 (60%): Causes serious eye irritation [Warning Serious eye damage/eye irritation]

H361 (80%): Suspected of damaging fertility or the unborn child [Warning Reproductive toxicity]

H362 (20%): May cause harm to breast-fed children [Reproductive toxicity, effects on or via lactation]

H411 (80%): Toxic to aquatic life with long lasting effects [Hazardous to the aquatic environment, long-term hazard]

Precautionary Statement Codes

P203, P260, P263, P264, P264+P265, P270, P273, P280, P301+P317, P305+P351+P338, P305+P354+P338, P317, P318, P330, P337+P317, P391, P405, and P501

(The corresponding statement to each P-code can be found at the GHS Classification page.)

ECHA C&L Notifications Summary

Aggregated GHS information provided per 5 reports by companies from 4 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown.

9.1.2 Hazard Classes and Categories

Acute Tox. 4 (60%)

Eye Dam. 1 (20%)

Eye Irrit. 2 (60%)

Repr. 2 (80%)

Lact. (20%)

Aquatic Chronic 2 (80%)

9.2 Fire Fighting

9.2.1 Fire Fighting Procedures

Suitable Extinguishing Media: Use extinguishing measures that are appropriate to local circumstances and the surrounding environment.
Santa Cruz Biotech; Safety Data Sheet for Canagliflozin, Product Identifier: SC-364454, Version 1.0 (Revision Date 12/02/2014). Available from, as of November 16, 2015: https://www.scbt.com/
Protective equipment and precautions for firefighters: Wear self-contained breathing apparatus and protective suit. Wear self contained breathing apparatus for fire fighting if necessary.
Santa Cruz Biotech; Safety Data Sheet for Canagliflozin, Product Identifier: SC-364454, Version 1.0 (Revision Date 12/02/2014). Available from, as of November 16, 2015: https://www.scbt.com/

9.3 Accidental Release Measures

9.3.1 Cleanup Methods

Methods for containment: Prevent further leakage or spillage if safe to do so. Cover powder spill with plastic sheet or tarp to minimize spreading. Dike far ahead of liquid spill for later disposal.
Santa Cruz Biotech; Safety Data Sheet for Canagliflozin, Product Identifier: SC-364454, Version 1.0 (Revision Date 12/02/2014). Available from, as of November 16, 2015: https://www.scbt.com/
Environmental precautions: Prevent further leakage or spillage if safe to do so. Prevent product from entering drains. Do not flush into surface water or sanitary sewer system.
Santa Cruz Biotech; Safety Data Sheet for Canagliflozin, Product Identifier: SC-364454, Version 1.0 (Revision Date 12/02/2014). Available from, as of November 16, 2015: https://www.scbt.com/
Methods for cleaning up: Use personal protective equipment as required. Cover powder spill with plastic sheet or tarp to minimize spreading and keep powder dry. Take up mechanically, placing in appropriate containers for disposal. Avoid creating dust. Clean contaminated surface thoroughly. Soak up with inert absorbent material. Dam up. Pick up and transfer to properly labeled containers. Sweep up and shovel into suitable containers for disposal. After cleaning, flush away traces with water. Take precautionary measures against static discharges.
Santa Cruz Biotech; Safety Data Sheet for Canagliflozin, Product Identifier: SC-364454, Version 1.0 (Revision Date 12/02/2014). Available from, as of November 16, 2015: https://www.scbt.com/

9.3.2 Disposal Methods

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.
Disposal of wastes: Disposal should be in accordance with applicable regional, national and local laws and regulations.
Santa Cruz Biotech; Safety Data Sheet for Canagliflozin, Product Identifier: SC-364454, Version 1.0 (Revision Date 12/02/2014). Available from, as of November 16, 2015: https://www.scbt.com/
Contaminated packaging: Do not reuse container.
Santa Cruz Biotech; Safety Data Sheet for Canagliflozin, Product Identifier: SC-364454, Version 1.0 (Revision Date 12/02/2014). Available from, as of November 16, 2015: https://www.scbt.com/

9.3.3 Preventive Measures

Personal precautions: Use personal protective equipment as required. Keep people away from and upwind of spill/leak. Evacuate personnel to safe areas.
Santa Cruz Biotech; Safety Data Sheet for Canagliflozin, Product Identifier: SC-364454, Version 1.0 (Revision Date 12/02/2014). Available from, as of November 16, 2015: https://www.scbt.com/
SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.
Advice on safe handling: Avoid contact with skin, eyes or clothing. Use personal protective equipment as required. Wash contaminated clothing before reuse. Do not breathe dust/fume/gas/mist/vapors/spray. Do not eat, drink or smoke when using this product. Use with local exhaust ventilation.
Santa Cruz Biotech; Safety Data Sheet for Canagliflozin, Product Identifier: SC-364454, Version 1.0 (Revision Date 12/02/2014). Available from, as of November 16, 2015: https://www.scbt.com/

9.4 Handling and Storage

9.4.1 Storage Conditions

Storage Conditions: Keep container tightly closed in a dry and well-ventilated place. Keep out of the reach of children. Keep containers tightly closed in a cool, well-ventilated place. Keep in properly labeled containers. Store at -20 degrees C.
Santa Cruz Biotech; Safety Data Sheet for Canagliflozin, Product Identifier: SC-364454, Version 1.0 (Revision Date 12/02/2014). Available from, as of November 16, 2015: https://www.scbt.com/

9.5 Exposure Control and Personal Protection

9.5.1 Personal Protective Equipment (PPE)

General Hygiene Considerations: When using do not eat, drink or smoke. Regular cleaning of equipment, work area and clothing is recommended. Avoid contact with skin, eyes or clothing. Wash hands thoroughly after handling. Keep away from food, drink and animal feeding stuffs.
Santa Cruz Biotech; Safety Data Sheet for Canagliflozin, Product Identifier: SC-364454, Version 1.0 (Revision Date 12/02/2014). Available from, as of November 16, 2015: https://www.scbt.com/
Respiratory protection: If exposure limits are exceeded or irritation is experienced, NIOSH/MSHA approved respiratory protection should be worn. Positive-pressure supplied air respirators may be required for high airborne contaminant concentrations. Respiratory protection must be provided in accordance with current local regulations.
Santa Cruz Biotech; Safety Data Sheet for Canagliflozin, Product Identifier: SC-364454, Version 1.0 (Revision Date 12/02/2014). Available from, as of November 16, 2015: https://www.scbt.com/
Skin and Body Protection: Wear protective gloves and protective clothing.
Santa Cruz Biotech; Safety Data Sheet for Canagliflozin, Product Identifier: SC-364454, Version 1.0 (Revision Date 12/02/2014). Available from, as of November 16, 2015: https://www.scbt.com/
Eye/face protection: Tight sealing safety goggles. Face protection shield.
Santa Cruz Biotech; Safety Data Sheet for Canagliflozin, Product Identifier: SC-364454, Version 1.0 (Revision Date 12/02/2014). Available from, as of November 16, 2015: https://www.scbt.com/

9.6 Regulatory Information

9.6.1 FDA Requirements

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including canagliflozin, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Dextroamphetamine sulfate/
DHHS/FDA; Electronic Orange Book-Approved Drug Products with Therapeutic Equivalence Evaluations. Available from, as of September 30, 2015: https://www.fda.gov/cder/ob/

9.7 Other Safety Information

9.7.1 Toxic Combustion Products

Hazardous combustion products: Hydrogen sulfide. Hydrogen fluoride. Carbon oxides
Santa Cruz Biotech; Safety Data Sheet for Canagliflozin, Product Identifier: SC-364454, Version 1.0 (Revision Date 12/02/2014). Available from, as of November 16, 2015: https://www.scbt.com/

10 Toxicity

10.1 Toxicological Information

10.1.1 Toxicity Summary

IDENTIFICATION AND USE: Canagliflozin, an oral inhibitor of sodium/glucose cotransporter 2 (SGLT2) in the kidneys, leads to glucosuria and provides a unique mechanism to lower blood glucose levels in diabetes. HUMAN EXPOSURE AND TOXICITY: Canagliflozin is used for the treatment of type 2 diabetes. This agent lowers blood glucose mainly by increasing urinary glucose excretion through inhibition of sodium glucose co-transporter 2 (SGLT2) in the kidneys. Data derived from randomized clinical trials lasting up to 52 weeks suggest that canagliflozin is generally well tolerated. The most common adverse effects are genital mycotic infections occurring in 11-15% of women exposed to canagliflozin versus 2-4% of those randomized to glimepiride or sitagliptin. In men, corresponding proportions are 8-9% versus 0.5-1%. Urinary tract infections (UTI) are slightly increased (5-7%) with the use of canagliflozin compared with placebo (4%). The risk of hypoglycemia associated with canagliflozin is marginally higher than placebo, but markedly increases when the drug is used in conjunction of insulin or sulfonylureas (SU), in patients with chronic kidney disease (CKD), and in the elderly. Worsening renal function and hyperkalemia may occur in patients using canagliflozin, particularly in patients with underlying CKD. Mild weight loss (mean 2-4 kg) and lowering of blood pressure represent 2 advantages of canagliflozin owing to its osmotic diuretic effect. However, the latter action may lead to postural hypotension and dizziness in susceptible subjects. Another concerning adverse effect of canagliflozin is an average 8% increase in plasma levels of low-density lipoprotein cholesterol (LDL-C) compared with placebo. Adverse effects such as increased urinary frequency, genital mycotic infections, and urinary tract infections may discourage the use of the drug in the elderly patient. ANIMAL STUDIES: The carcinogenicity potential of canagliflozin was evaluated in a 2-year rat study (10, 30, and 100 mg/kg). Rats showed an increase in pheochromocytomas, renal tubular tumors, and testicular Leydig cell tumors. Leydig cell tumors were associated with increased luteinizing hormone levels and pheochromocytomas were most likely related to glucose malabsorption and altered calcium homeostasis. Renal tubular tumors may also have been linked to glucose malabsorption. Canagliflozin did not increase the incidence of tumors in mice dosed at 10, 30, or 100 mg/kg. In a juvenile toxicity study in which canagliflozin was dosed directly to young rats from postnatal day (PND) 21 until PND 90 at doses of 4, 20, 65, or 100 mg/kg, increased kidney weights and a dose-related increase in the incidence and severity of renal pelvic and renal tubular dilatation were reported at all dose levels. Exposure at the lowest dose tested was greater than or equal to 0.5 times the maximum clinical dose of 300 mg. The renal pelvic dilatations observed in juvenile animals did not fully reverse within the 1-month recovery period. Similar effects on the developing kidney were not seen when canagliflozin was administered to pregnant rats or rabbits during the period of organogenesis or during a study in which maternal rats were dosed from gestation day (GD) 6 through PND 21 and pups were indirectly exposed in utero and throughout lactation. Canagliflozin had no effects on the ability of rats to mate and sire or maintain a litter up to the high dose of 100 mg/kg (approximately 14 times and 18 times the 300 mg clinical dose in males and females, respectively), although there were minor alterations in a number of reproductive parameters (decreased sperm velocity, increased number of abnormal sperm, slightly fewer corpora lutea, fewer implantation sites, and smaller litter sizes) at the highest dosage administered. Canagliflozin was not mutagenic with or without metabolic activation in the Ames assay. Canagliflozin was mutagenic in the in vitro mouse lymphoma assay with but not without metabolic activation. Canagliflozin was not mutagenic or clastogenic in an in vivo oral micronucleus assay in rats and an in vivo oral Comet assay in rats.

10.1.2 Effects During Pregnancy and Lactation

◉ Summary of Use during Lactation

No information is available on the clinical use of canagliflozin during breastfeeding. Canagliflozin is 99% protein bound in plasma, so it is unlikely to pass into breastmilk in clinically important amounts. The manufacturer does not recommend canagliflozin during breastfeeding because of a theoretical risk to the infant's developing kidney. An alternate drug may be preferred, especially while nursing a newborn or preterm infant.

◉ Effects in Breastfed Infants

Relevant published information was not found as of the revision date.

◉ Effects on Lactation and Breastmilk

Relevant published information was not found as of the revision date.

10.1.3 Interactions

Inhibitors of sodium-glucose cotransporters type 2 (SGLT2) reduce hyperglycaemia by decreasing renal glucose threshold and thereby increasing urinary glucose excretion. They are proposed as a novel approach for the management of type 2 diabetes mellitus. They have proven their efficacy in reducing glycated haemoglobin, without inducing hypoglycaemia, as monotherapy or in combination with various other glucose-lowering agents, with the add-on value of promoting some weight loss and lowering arterial blood pressure. As they may be used concomitantly with many other drugs, we review the potential drug-drug interactions (DDIs) regarding the three leaders in the class (dapagliglozin, canagliflozin and empagliflozin). Most of the available studies were performed in healthy volunteers and have assessed the pharmacokinetic interferences with a single administration of the SGLT2 inhibitor. The exposure [assessed by peak plasma concentrations (Cmax) and area under the concentration-time curve (AUC)] to each SGLT2 inhibitor tested was not significantly influenced by the concomitant administration of other glucose-lowering agents or cardiovascular agents commonly used in patients with type 2 diabetes. Reciprocally, these medications did not influence the pharmacokinetic parameters of dapagliflozin, canagliflozin or empagliflozin. Some modest changes were not considered as clinically relevant. However, drugs that could specifically interfere with the metabolic pathways of SGLT2 inhibitors [rifampicin, inhibitors or inducers of uridine diphosphate-glucuronosyltransferase (UGT)] may result in significant changes in the exposure of SGLT2 inhibitors, as shown for dapagliflozin and canagliflozin. Potential DDIs in patients with type 2 diabetes receiving chronic treatment with an SGLT2 inhibitor deserve further attention, especially in individuals treated with several medications or in more fragile patients with hepatic and/or renal impairment.
Scheen; AJ Clin Pharmacokinet 53(4): 295-304 (2014).
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 INVOKANA 300 mg. Patients taking INVOKANA with concomitant digoxin should be monitored appropriately.
NIH; DailyMed. Current Medication Information for Invokana (Canagliflozin) Tablet, Film Coated (Updated: September 2015). Available from, as of November 20, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b9057d3b-b104-4f09-8a61-c61ef9d4a3f3
Concomitant use of canagliflozin with drugs that interfere with the renin-angiotensin-aldosterone system, including angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor antagonists, may increase the incidence of symptomatic hypotension. Prior to initiating canagliflozin in such patients, intravascular volume should be assessed and corrected; patients should be monitored for signs and symptoms of hypotension after initiating therapy. These drugs also may cause hyperkalemia in patients with moderate renal impairment. Serum potassium concentrations should be monitored periodically following initiation of canagliflozin in patients predisposed to hyperkalemia due to drug therapy.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 3166
UGT Enzyme Inducers: Rifampin: Co-administration of canagliflozin with rifampin, a nonselective inducer of several UGT enzymes, including UGT1A9, UGT2B4, decreased canagliflozin area under the curve (AUC) by 51%. This decrease in exposure to canagliflozin may decrease efficacy. If an inducer of these UGTs (e.g., rifampin, phenytoin, phenobarbital, ritonavir) must be co-administered with INVOKANA (canagliflozin), consider increasing the dose to 300 mg once daily if patients are currently tolerating INVOKANA 100 mg once daily, have an eGFR greater than 60 mL/min/1.73 m squared, and require additional glycemic control. Consider other antihyperglycemic therapy in patients with an eGFR of 45 to less than 60 mL/min/1.73 m squared receiving concurrent therapy with a UGT inducer and require additional glycemic control
NIH; DailyMed. Current Medication Information for Invokana (Canagliflozin) Tablet, Film Coated (Updated: September 2015). Available from, as of November 20, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b9057d3b-b104-4f09-8a61-c61ef9d4a3f3
For more Interactions (Complete) data for Canagliflozin (6 total), please visit the HSDB record page.

10.1.4 Antidote and Emergency Treatment

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3rd revised edition, Elsevier Mosby, St. Louis, MO 2007, p. 160
/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3rd revised edition, Elsevier Mosby, St. Louis, MO 2007, p. 160
/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3rd revised edition, Elsevier Mosby, St. Louis, MO 2007, p. 160-1

10.1.5 Human Toxicity Excerpts

/OTHER TOXICITY INFORMATION/ Renal hyperfiltration has been used as a surrogate marker for increased intraglomerular pressure in patients with diabetes mellitus. Previous human investigation examining the pathogenesis of hyperfiltration has focused on the role of neurohormones such as the renin-angiotensin-aldosterone system (RAAS). Unfortunately, RAAS blockade does not completely attenuate hyperfiltration or diabetic kidney injury. More recent work has therefore investigated the contribution of renal tubular factors, including the sodium-glucose cotransporter, to the hyperfiltration state, which is the topic of this review. Novel sodium-glucose cotransporter-2 (SGLT2) inhibitors reduce proximal tubular sodium reabsorption, thereby increasing distal sodium delivery to the macula densa, causing tubuloglomerular feedback, afferent vasoconstriction and decreased hyperfiltration in animals. In humans, SGLT2 inhibition was recently shown to reduce hyperfiltration in normotensive, normoalbuminuric patients with type 1 diabetes. In clinical trials of type 2 diabetes, SGLT2 is associated with significant renal effects, including modest, acute declines in estimated glomerular filtration rate followed by the maintenance of stable renal function, and reduced albuminuria.
Curr Opin Nephrol Hypertens 24(1): 96-103 (2015).
/OTHER TOXICITY INFORMATION/ In type 2 diabetes (T2DM), glycemic control delays the development and slows the progression of complications. Although there are numerous glucose-lowering agents in clinical use, only approximately half of T2DM patients achieve glycaemic control, while undesirable side-effects, such as hypoglycaemia and body weight gain, often impede treatment in those taking these medications. Thus, there is a need for novel agents and treatment options. Sodium-glucose cotransporter-2 inhibitors (SGLT-2-i) have recently been developed for the treatment of T2DM. The available data suggest a good tolerability profile for the three available drugs - canagliflozin, dapagliflozin and empagliflozin - approved by the US Food and Drug Administration (FDA) for the American market as well as in other countries. The most frequently reported adverse events with SGLT-2-i are female genital mycotic infections, urinary tract infections and increased urination. The pharmacodynamic response to SGLT-2-i declines with increasing severity of renal impairment, requiring dosage adjustments or restrictions with moderate-to-severe renal dysfunction. Most patients treated with SGLT-2-i also have a modest reduction in blood pressure and modest effects on serum lipid profiles, some of which are beneficial (increased high-density lipoprotein cholesterol and decreased triglycerides) and others which are not (increased low-density lipoprotein cholesterol, LDL-C). A number of large-scale and longer-term cardiovascular trials are now ongoing. In patients treated with dapagliflozin, a non-significant excess number of breast and bladder cancers has been reported; considered as due to a bias, this is nevertheless being followed in the ongoing trials. No other significant safety issues have been reported so far.
Halimi S et al; Diabetes Metab 40(6 Suppl 1): S28-34 (2014).
/OTHER TOXICITY INFORMATION/ Type 2 diabetes mellitus continues to be a challenging disease to manage successfully. Beyond the first-line option metformin, there are a number of classes of medications from which to select. This article reviews the new sodium-glucose cotransporter 2 inhibitors canagliflozin and dapagliflozin, including their benefits, adverse effects, and potential place in therapy. Upon review, the use of these medications has led to an A1c reduction between -0.37% and -1.16%. These medications also have been shown to reduce A1c when used with insulin. Some adverse effects were noted when using canagliflozin and dapagliflozin, with the most frequent being urinary tract infections and genital mycotic infections.
South Med J 108(2): 82-90 (2015).

10.1.6 Non-Human Toxicity Excerpts

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Canagliflozin is an SGLT2 inhibitor used for the treatment of type 2 diabetes mellitus. Studies were conducted to investigate the mechanism responsible for renal tubular tumors and pheochromocytomas observed at the high dose in a 2-year carcinogenicity study in rats. At the high dose (100 mg/kg) in rats, canagliflozin caused carbohydrate malabsorption evidenced by inhibition of intestinal glucose uptake, decreased intestinal pH and increased urinary calcium excretion. In a 6-month mechanistic study utilization of a glucose-free diet prevented carbohydrate malabsorption and its sequelae, including increased calcium absorption and urinary calcium excretion, and hyperostosis. Cell proliferation in the kidney and adrenal medulla was increased in rats maintained on standard diet and administered canagliflozin (100 mg/kg), and in addition an increase in the renal injury biomarker KIM-1 was observed. Increased cell proliferation is considered as a proximal event in carcinogenesis. Effects on cell proliferation, KIM-1 and calcium excretion were inhibited in rats maintained on the glucose-free diet, indicating they are secondary to carbohydrate malabsorption and are not direct effects of canagliflozin.
Mamidi RN et al; Chem Biol Interact 221: 109-18 (2014).
/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ The carcinogenicity potential of canagliflozin, an inhibitor of SGLT2, was evaluated in a 2-year rat study (10, 30, and 100 mg/kg). Rats showed an increase in pheochromocytomas, renal tubular tumors, and testicular Leydig cell tumors. Systemic exposure multiples at the highest dose relative to the maximum clinical dose were 12- to 21-fold. Pheochromocytomas and renal tubular tumors were noted in both sexes at 100 mg/kg. Leydig cell tumors were observed in males in all dose groups and were associated with increased luteinizing hormone levels. Hyperplasia was increased in the adrenal medulla at 100 mg/kg, but only a limited increase in simple tubular hyperplasia was observed in the kidney of males at 100 mg/kg. Hyperostosis occurred and was accompanied by substantial effects on calcium metabolism, including increased urinary calcium excretion and decreased levels of calcium regulating hormones (1,25-dihydroxyvitamin D and parathyroid hormone). A separate study with radiolabeled calcium confirmed that increased urinary calcium excretion was mediated via increased calcium absorption from the gastrointestinal tract. It was hypothesized that, at high doses, canagliflozin might have inhibited glucose absorption in the intestine via SGLT1 inhibition that resulted in glucose malabsorption, which increased calcium absorption by stimulating colonic glucose fermentation and reducing intestinal pH. Pheochromocytomas and adrenal medullary hyperplasia were attributed to altered calcium homeostasis, which have a known relationship in the rat. In conclusion, Leydig cell tumors were associated with increased luteinizing hormone levels and pheochromocytomas were most likely related to glucose malabsorption and altered calcium homeostasis. Renal tubular tumors may also have been linked to glucose malabsorption.
De Jonghe S et al; Chem Biol Interact 224: 1-12 (2014).
/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, has been developed for the treatment of adults with type 2 diabetes mellitus (T2DM). During the phase 3 program, treatment-related pheochromocytomas, renal tubular tumors, and testicular Leydig cell tumors were reported in the 2-year rat toxicology study. Treatment-related tumors were not seen in the 2-year mouse study.
Ways K et al; Toxicol Pathol 43(1): 48-56 (2015).
/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Carcinogenicity was evaluated in 2-year studies conducted in CD1 mice and Sprague-Dawley rats. Canagliflozin did not increase the incidence of tumors in mice dosed at 10, 30, or 100 mg/kg (less than or equal to 14 times exposure from a 300 mg clinical dose). Testicular Leydig cell tumors, considered secondary to increased luteinizing hormone (LH), increased significantly in male rats at all doses tested (10, 30, and 100 mg/kg). In a 12-week clinical study, LH did not increase in males treated with canagliflozin. Renal tubular adenoma and carcinoma increased significantly in male and female rats dosed at 100 mg/kg, or approximately 12-times exposure from a 300 mg clinical dose. Also, adrenal pheochromocytoma increased significantly in males and numerically in females dosed at 100 mg/kg. Carbohydrate malabsorption associated with high doses of canagliflozin was considered a necessary proximal event in the emergence of renal and adrenal tumors in rats. Clinical studies have not demonstrated carbohydrate malabsorption in humans at canagliflozin doses of up to 2-times the recommended clinical dose of 300 mg.
NIH; DailyMed. Current Medication Information for Invokana (Canagliflozin) Tablet, Film Coated (Updated: September 2015). Available from, as of November 20, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b9057d3b-b104-4f09-8a61-c61ef9d4a3f3
For more Non-Human Toxicity Excerpts (Complete) data for Canagliflozin (8 total), please visit the HSDB record page.

10.1.7 Populations at Special Risk

Contraindicated in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 sq m), end stage renal disease (ESRD), or patients on dialysis.
NIH; DailyMed. Current Medication Information for Invokana (Canagliflozin) Tablet, Film Coated (Updated: September 2015). Available from, as of November 20, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b9057d3b-b104-4f09-8a61-c61ef9d4a3f3

10.1.8 Protein Binding

Canagliflozin is mainly bound to albumin. The plasma protein binding of this drug is 99%.

10.2 Ecological Information

10.2.1 Environmental Fate / Exposure Summary

Canagliflozin's production administration as a medication may result in its release to the environment through various waste streams. If released to air, an estimated vapor pressure of 1.1X10-18 mm Hg at 25 °C indicates canagliflozin will exist solely in the particulate phase in the atmosphere. Particulate-phase canagliflozin will be removed from the atmosphere by wet and dry deposition. Canagliflozin does not contain chromophores that absorb at wavelengths >290 nm and, therefore, is not expected to be susceptible to direct photolysis by sunlight. If released to soil, canagliflozin is expected to be immobile based upon an estimated Koc of 6.9X10+4. Volatilization from moist soil surfaces is not expected to be an important fate process based upon an estimated Henry's Law constant of 1.0X10-16 atm-cu m/mole. Canagliflozin is not expected to volatilize from dry soil surfaces based upon its vapor pressure. Biodegradation data in soil or water were not available. If released into water, canagliflozin is expected to adsorb to suspended solids and sediment based upon the estimated Koc. Volatilization from water surfaces is not expected to be an important fate process based upon this compound's estimated Henry's Law constant. An estimated BCF of 120 suggests the potential for bioconcentration in aquatic organisms is high. Hydrolysis is not expected to be an important environmental fate process since this compound lacks functional groups that hydrolyze under environmental conditions (pH 5 to 9). Occupational exposure to canagliflozin may occur through inhalation and dermal contact with this compound at workplaces where canagliflozin is produced or used. Exposure to canagliflozin among the general population may be limited to those administered the drug. (SRC)

10.2.2 Artificial Pollution Sources

Canagliflozin's production and administration as a medication(1) may result in its release to the environment through various waste streams(SRC).
(1) FDA; Environmental Assessment. Canagliflozin/Metroformin Hydrochloride. Center for Drug Evaluation and Research. Application No. 204353Orig1s000. Available from, as of Oct 14, 2015: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204353Orig1s000EA.pdf

10.2.3 Environmental Fate

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 6.9X10+4(SRC), determined from a structure estimation method(2), indicates that canagliflozin is expected to be immobile in soil(SRC). Volatilization of canagliflozin from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.0X10-16 atm-cu m/mole(SRC), using a fragment constant estimation method(3). Canagliflozin is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.1X10-18 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Biodegradation data in soil were not available(SRC, 2015).
(1) Swann RL et al; Res Rev 85: 17-28 (1983)
(2) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Oct 14, 2015: https://www.epa.gov/oppt/exposure/pubs/episuitedl.htm
(3) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991)
AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 6.9X10+4(SRC), determined from a structure estimation method(2), indicates that canagliflozin is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 1.0X10-16 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 120(SRC), from an estimated log Kow of 4.05(2) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is high(SRC). Biodegradation data in water were not available(SRC, 2015).
(1) Swann RL et al; Res Rev 85: 17-28 (1983)
(2) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Oct 14, 2015: https://www.epa.gov/oppt/exposure/pubs/episuitedl.htm
(3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990)
(4) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991)
(5) Franke C et al; Chemosphere 29: 1501-14 (1994)
ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), canagliflozin, which has an estimated vapor pressure of 1.1X10-18 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase canagliflozin may be removed from the air by wet and dry deposition(SRC). Canagliflozin does not contain chromophores that absorb at wavelengths >290 nm(3) and, therefore, is not expected to be susceptible to direct photolysis by sunlight(SRC).
(1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988)
(2) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of ct 14, 2015: https://www.epa.gov/oppt/exposure/pubs/episuitedl.htm
(3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 8-12 (1990)

10.2.4 Environmental Abiotic Degradation

Canagliflozin is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(1). Canagliflozin does not contain chromophores that absorb at wavelengths >290 nm(1) and, therefore, is not expected to be susceptible to direct photolysis by sunlight(SRC).
(1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 7-4, 7-5, 8-12 (1990)

10.2.5 Environmental Bioconcentration

An estimated BCF of 120 was calculated in fish for canagliflozin(SRC), using an estimated log Kow of 4.05(1) and a regression-derived equation(1). According to a classification scheme(2), this BCF suggests the potential for bioconcentration in aquatic organisms is high(SRC).
(1) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Oct 14, 2015: https://www.epa.gov/oppt/exposure/pubs/episuitedl.htm/
(2) Franke C et al; Chemosphere 29: 1501-14 (1994)

10.2.6 Soil Adsorption / Mobility

Using a structure estimation method based on molecular connectivity indices(1), the Koc of canagliflozin can be estimated to be 6.9X10+4(SRC). According to a classification scheme(2), this estimated Koc value suggests that canagliflozin is expected to be immobile in soil.
(1) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Oct 14, 2015: https://www.epa.gov/oppt/exposure/pubs/episuitedl.htm
(2) Swann RL et al; Res Rev 85: 17-28 (1983)

10.2.7 Volatilization from Water / Soil

The Henry's Law constant for canagliflozin is estimated as 1.0X10-16 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that canagliflozin is expected to be essentially nonvolatile from water surfaces(2). Canagliflozin is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.1X10-18 mm Hg(SRC), determined from a fragment constant method(3).
(1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991)
(2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990)
(3) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Oct 14, 2015: https://www.epa.gov/oppt/exposure/pubs/episuitedl.htm

10.2.8 Probable Routes of Human Exposure

Occupational exposure to canagliflozin may occur through inhalation and dermal contact with this compound at workplaces where canagliflozin is produced or used. Use data indicate that the general population may be exposed to canagliflozin via administration of this drug in treating Type II diabetes. (SRC)

11 Associated Disorders and Diseases

12 Literature

12.1 Consolidated References

12.2 NLM Curated PubMed Citations

12.3 Springer Nature References

12.4 Thieme References

12.5 Chemical Co-Occurrences in Literature

12.6 Chemical-Gene Co-Occurrences in Literature

12.7 Chemical-Disease Co-Occurrences in Literature

13 Patents

13.1 Depositor-Supplied Patent Identifiers

13.2 WIPO PATENTSCOPE

13.3 FDA Orange Book Patents

13.4 Chemical Co-Occurrences in Patents

13.5 Chemical-Disease Co-Occurrences in Patents

13.6 Chemical-Gene Co-Occurrences in Patents

14 Interactions and Pathways

14.1 Protein Bound 3D Structures

14.1.1 Ligands from Protein Bound 3D Structures

PDBe Ligand Code
PDBe Structure Code
PDBe Conformer

14.2 Chemical-Target Interactions

14.3 Drug-Drug Interactions

14.4 Drug-Food Interactions

  • Avoid alcohol. Excess alcohol intake may promote ketoacidosis.
  • Drink plenty of fluids.
  • Take before a meal. It is recommended to take this drug before the first meal of the day.

15 Biological Test Results

15.1 BioAssay Results

16 Classification

16.1 MeSH Tree

16.2 NCI Thesaurus Tree

16.3 ChEBI Ontology

16.4 WHO ATC Classification System

16.5 FDA Pharm Classes

16.6 ChemIDplus

16.7 IUPHAR / BPS Guide to PHARMACOLOGY Target Classification

16.8 ChEMBL Target Tree

16.9 UN GHS Classification

16.10 NORMAN Suspect List Exchange Classification

16.11 EPA DSSTox Classification

16.12 PFAS and Fluorinated Organic Compounds in PubChem

16.13 MolGenie Organic Chemistry Ontology

17 Information Sources

  1. CAS Common Chemistry
    LICENSE
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    https://creativecommons.org/licenses/by-nc/4.0/
  2. ChemIDplus
    ChemIDplus Chemical Information Classification
    https://pubchem.ncbi.nlm.nih.gov/source/ChemIDplus
  3. DrugBank
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    Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode)
    https://www.drugbank.ca/legal/terms_of_use
  4. EPA DSSTox
    CompTox Chemicals Dashboard Chemical Lists
    https://comptox.epa.gov/dashboard/chemical-lists/
  5. European Chemicals Agency (ECHA)
    LICENSE
    Use of the information, documents and data from the ECHA website is subject to the terms and conditions of this Legal Notice, and subject to other binding limitations provided for under applicable law, the information, documents and data made available on the ECHA website may be reproduced, distributed and/or used, totally or in part, for non-commercial purposes provided that ECHA is acknowledged as the source: "Source: European Chemicals Agency, http://echa.europa.eu/". Such acknowledgement must be included in each copy of the material. ECHA permits and encourages organisations and individuals to create links to the ECHA website under the following cumulative conditions: Links can only be made to webpages that provide a link to the Legal Notice page.
    https://echa.europa.eu/web/guest/legal-notice
    (2S,3R,4R,5S,6R)-2-(3-{[5-(4-fluorophenyl)thiophen-2-yl]methyl}-4-methylphenyl)-6-(hydroxymethyl)oxane-3,4,5-triol
    https://echa.europa.eu/substance-information/-/substanceinfo/100.223.671
    (2S,3R,4R,5S,6R)-2-(3-{[5-(4-fluorophenyl)thiophen-2-yl]methyl}-4-methylphenyl)-6-(hydroxymethyl)oxane-3,4,5-triol (EC: 695-192-1)
    https://echa.europa.eu/information-on-chemicals/cl-inventory-database/-/discli/details/229660
  6. FDA Global Substance Registration System (GSRS)
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    https://www.fda.gov/about-fda/about-website/website-policies#linking
  7. Hazardous Substances Data Bank (HSDB)
  8. ChEBI
  9. FDA Pharm Classes
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    https://www.fda.gov/about-fda/about-website/website-policies#linking
  10. NCI Thesaurus (NCIt)
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    https://www.cancer.gov/policies/copyright-reuse
  11. Open Targets
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    https://platform-docs.opentargets.org/licence
  12. ChEMBL
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    http://www.ebi.ac.uk/Information/termsofuse.html
  13. ClinicalTrials.gov
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    https://clinicaltrials.gov/ct2/about-site/terms-conditions#Use
  14. Comparative Toxicogenomics Database (CTD)
    LICENSE
    It is to be used only for research and educational purposes. Any reproduction or use for commercial purpose is prohibited without the prior express written permission of NC State University.
    http://ctdbase.org/about/legal.jsp
  15. IUPHAR/BPS Guide to PHARMACOLOGY
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    The Guide to PHARMACOLOGY database is licensed under the Open Data Commons Open Database License (ODbL) https://opendatacommons.org/licenses/odbl/. Its contents are licensed under a Creative Commons Attribution-ShareAlike 4.0 International License (http://creativecommons.org/licenses/by-sa/4.0/)
    https://www.guidetopharmacology.org/about.jsp#license
    Guide to Pharmacology Target Classification
    https://www.guidetopharmacology.org/targets.jsp
  16. Therapeutic Target Database (TTD)
  17. Crystallography Open Database (COD)
    LICENSE
    All data in the COD and the database itself are dedicated to the public domain and licensed under the CC0 License. Users of the data should acknowledge the original authors of the structural data.
    https://creativecommons.org/publicdomain/zero/1.0/
  18. DailyMed
  19. European Medicines Agency (EMA)
    LICENSE
    Information on the European Medicines Agency's (EMA) website is subject to a disclaimer and copyright and limited reproduction notices.
    https://www.ema.europa.eu/en/about-us/legal-notice
  20. Drugs and Lactation Database (LactMed)
  21. Drugs@FDA
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    https://www.fda.gov/about-fda/about-website/website-policies#linking
  22. WHO Model Lists of Essential Medicines
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    https://www.who.int/about/policies/publishing/copyright
  23. EU Clinical Trials Register
  24. FDA Orange Book
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    https://www.fda.gov/about-fda/about-website/website-policies#linking
  25. WHO Anatomical Therapeutic Chemical (ATC) Classification
    LICENSE
    Use of all or parts of the material requires reference to the WHO Collaborating Centre for Drug Statistics Methodology. Copying and distribution for commercial purposes is not allowed. Changing or manipulating the material is not allowed.
    https://www.whocc.no/copyright_disclaimer/
  26. FDA Medication Guides
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    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  27. National Drug Code (NDC) Directory
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  28. Japan Chemical Substance Dictionary (Nikkaji)
  29. Metabolomics Workbench
  30. NIPH Clinical Trials Search of Japan
  31. NLM RxNorm Terminology
    LICENSE
    The RxNorm Terminology is created by the National Library of Medicine (NLM) and is in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from NLM. Credit to the U.S. National Library of Medicine as the source is appreciated but not required. The full RxNorm dataset requires a free license.
    https://www.nlm.nih.gov/research/umls/rxnorm/docs/termsofservice.html
  32. NORMAN Suspect List Exchange
    LICENSE
    Data: CC-BY 4.0; Code (hosted by ECI, LCSB): Artistic-2.0
    https://creativecommons.org/licenses/by/4.0/
    CANAGLIFLOZIN
    NORMAN Suspect List Exchange Classification
    https://www.norman-network.com/nds/SLE/
  33. Pharos
    LICENSE
    Data accessed from Pharos and TCRD is publicly available from the primary sources listed above. Please respect their individual licenses regarding proper use and redistribution.
    https://pharos.nih.gov/about
  34. Protein Data Bank in Europe (PDBe)
  35. RCSB Protein Data Bank (RCSB PDB)
    LICENSE
    Data files contained in the PDB archive (ftp://ftp.wwpdb.org) are free of all copyright restrictions and made fully and freely available for both non-commercial and commercial use. Users of the data should attribute the original authors of that structural data.
    https://www.rcsb.org/pages/policies
  36. Springer Nature
  37. Thieme Chemistry
    LICENSE
    The Thieme Chemistry contribution within PubChem is provided under a CC-BY-NC-ND 4.0 license, unless otherwise stated.
    https://creativecommons.org/licenses/by-nc-nd/4.0/
  38. Wikidata
  39. Wikipedia
  40. Medical Subject Headings (MeSH)
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    https://www.nlm.nih.gov/copyright.html
    Sodium-Glucose Transporter 2 Inhibitors
    https://www.ncbi.nlm.nih.gov/mesh/2027927
  41. PubChem
  42. GHS Classification (UNECE)
  43. MolGenie
    MolGenie Organic Chemistry Ontology
    https://github.com/MolGenie/ontology/
  44. PATENTSCOPE (WIPO)
  45. NCBI
CONTENTS