Canagliflozin: Difference between revisions

{{Short description|Chemical compound}}

{{Use dmy dates|date=August 2021}}

{{cs1 config |name-list-style=vanc |display-authors=6}}

{{Infobox drug

| Verifiedfields = changed

| Watchedfields = changed

| verifiedrevid = 416773181

| image = Canagliflozin structure.svg

| width = 200

| alt =

| caption =

<!-- Clinical data -->

| pronounce = {{IPAc-en|ˌ|k|æ|n|ə|g|l|ᵻ|ˈ|f|l|oʊ|z|ɪ|n}} {{respell|KAN|ə-glif|LOH|zin}}

| tradename = Invokana, Sulisent, Prominad, others

| Drugs.com = {{Drugs.com|monograph|canagliflozin}}

| MedlinePlus = a613033

| DailyMedID = Canagliflozin

| pregnancy_AU = C

| pregnancy_AU_comment = <ref name="Drugs.com pregnancy" />

| pregnancy_category=

| routes_of_administration = [[Oral administration|By mouth]]

| class = [[SGLT2 inhibitor]]

| ATC_prefix = A10

| ATC_suffix = BK02

| ATC_supplemental =

<!-- Legal status -->

| legal_AU = S4

| legal_AU_comment =

| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F -->

| legal_BR_comment =

| legal_CA = Rx-only

| legal_CA_comment =

| legal_DE = <!-- Anlage I, II, III or Unscheduled -->

| legal_DE_comment =

| legal_NZ = <!-- Class A, B, C -->

| legal_NZ_comment =

| legal_UK = POM

| legal_UK_comment =

| legal_US = Rx-only

| legal_US_comment =

| legal_EU = Rx-only

| legal_EU_comment = <ref>{{cite web | title=Invokana EPAR | website=European Medicines Agency | date=15 November 2013 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/invokana | access-date=17 June 2024}}</ref>

| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->

| legal_UN_comment =

| legal_status = Rx-only

<!-- Pharmacokinetic data -->

| bioavailability = 65%

| protein_bound = 99%

| metabolism = [[Liver]] [[glucuronidation]]

| metabolites =

| onset =

| elimination_half-life = 11.8 (10–13) hours

| duration_of_action =

| excretion = 53% faecal and 33% kidney

<!-- Identifiers -->

| CAS_number_Ref = {{cascite|correct|??}}

| CAS_number = 842133-18-0

| CAS_supplemental =

| PubChem = 24812758

| IUPHAR_ligand = 4582

| DrugBank_Ref = {{drugbankcite|changed|drugbank}}

| DrugBank = DB08907

| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}

| ChemSpiderID = 26333259

| UNII_Ref = {{fdacite|changed|FDA}}

| UNII = 6S49DGR869

| KEGG_Ref =

| KEGG = D09592

| ChEBI_Ref = {{ebicite|changed|EBI}}

| ChEBI = 73274

| ChEMBL_Ref = {{ebicite|changed|EBI}}

| ChEMBL = 2103841

| NIAID_ChemDB =

| PDB_ligand =

| synonyms = JNJ-28431754; TA-7284; (1''S'')-1,5-anhydro-1-''C''-(3-{[5-(4-fluorophenyl)thiophen-2-yl]methyl]}-4-methylphenyl)-<small>D</small>-glucitol

<!-- Chemical and physical data -->

| IUPAC_name = (2''S'',3''R'',4''R'',5''S'',6''R'')-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol

| SMILES = Cc1ccc(cc1Cc2ccc(s2)c3ccc(cc3)F)[C@H]4[C@@H]([C@H]([C@@H]([C@H](O4)CO)O)O)O

| StdInChI_Ref = {{stdinchicite|changed|chemspider}}

| StdInChI = 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

| StdInChI_comment =

| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}

| StdInChIKey = XTNGUQKDFGDXSJ-ZXGKGEBGSA-N

| density =

| density_notes =

| melting_point = 98

| melting_high =

| melting_notes =

| boiling_point =

| boiling_notes =

| solubility =

| sol_units =

| specific_rotation =

<!-- Definition and medical uses -->

'''Canagliflozin''', sold under the brand name '''Invokana''' among others, is a medication used to treat [[type 2 diabetes]].<ref name=AHFS2019>{{cite web |title=Canagliflozin Monograph for Professionals |url=https://www.drugs.com/monograph/canagliflozin.html |website=Drugs.com |publisher=American Society of Health-System Pharmacists |access-date=6 April 2019 }}</ref> It is used together with exercise and diet.<ref name=AHFS2019/> It is not recommended in [[type 1 diabetes]].<ref name=AHFS2019/> It is taken [[Oral administration|by mouth]].<ref name=AHFS2019/>

<!-- Side effects and mechanism -->

Common side effects include [[vaginal yeast infection]]s, nausea, constipation, and [[urinary tract infection]]s.<ref name=AHFS2019/> Serious side effects may include [[low blood sugar]], [[Fournier's gangrene]], leg [[amputation]], kidney problems, [[high blood potassium]], and [[low blood pressure]].<ref name=AHFS2019/> [[Diabetic ketoacidosis]] may occur despite nearly normal blood sugar levels.<ref name=AHFS2019/> Use in [[pregnancy]] and [[breastfeeding]] is not recommended.<ref name="Drugs.com pregnancy">{{cite web |title=Canagliflozin (Invokana) Use During Pregnancy |url=https://www.drugs.com/pregnancy/canagliflozin.html |website=Drugs.com |access-date=6 April 2019 }}</ref> Canagliflozin is a [[SGLT2 inhibitor|sodium-glucose cotransporter-2 (SGLT2) inhibitor]].<ref name="AHFS2019" /> It works by increasing the amount of glucose lost in the urine.<ref name=AHFS2019/>

<!-- History and culture -->

Canagliflozin was approved for medical use in the United States, in the European Union, and in Australia in 2013.<ref name=AHFS2019/><ref name="FDA approval" /><ref name="Invokana EPAR" /><ref name="Canagliflozin AusPAR">{{cite web | title= Australian Public Assessment Report for Canagliflozin (as hemihydrate) | url=https://www.tga.gov.au/sites/default/files/auspar-canagliflozin-140303.pdf | website=[[Therapeutic Goods Administration]] (TGA) | date=31 March 2014 | access-date=28 August 2020}}</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO22nd">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 22nd list (2021) | year = 2021 | hdl = 10665/345533 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2021.02 | hdl-access=free }}</ref>

==Medical uses==

Canagliflozin is [[Indication (medicine)|indicated]] to be used with diet and exercise to lower blood sugar in adults with type 2 diabetes; to reduce the risk of major heart-related events such as heart attack, stroke, or death in people with type 2 diabetes who have known heart disease; and to reduce the risk of end-stage kidney disease, worsening of kidney function, heart-related death, and being hospitalized for heart failure in certain people with type 2 diabetes and diabetic kidney disease.<ref name="FDA 20200826" />

Canagliflozin is an anti-diabetic medication used to improve blood sugar control in people with type 2 diabetes. It is a third-line medication to [[metformin]].<ref name=BNF76>{{cite book|title=British national formulary : BNF 76|date=2018|publisher=Pharmaceutical Press|isbn=9780857113382|pages=687|edition=76}}</ref> Per the [[British National Formulary]] it is also less preferred than a [[sulfonylurea]] as of 2019, while the [[American Diabetes Association]] and [[European Association for the Study of Diabetes]] consider either a SGLT2 inhibitor or [[GLP-1 receptor agonist]] a reasonable second line medication in those with heart disease.<ref>{{cite journal | vauthors = Davies MJ, D'Alessio DA, Fradkin J, Kernan WN, Mathieu C, Mingrone G, Rossing P, Tsapas A, Wexler DJ, Buse JB | display-authors = 6 | title = Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) | journal = Diabetes Care | volume = 41 | issue = 12 | pages = 2669–2701 | date = December 2018 | pmid = 30291106 | pmc = 6245208 | doi = 10.2337/dci18-0033 | quote = patients with clinical CVD not meeting individualized glycemic targets while treated with metformin (or in whom metformin is contraindicated or not tolerated) should have an SGLT2 inhibitor or GLP-1 receptor agonist with proven benefit for cardiovascular risk reduction added }}</ref>

Canagliflozin decreases [[Glycated hemoglobin|HbA_1c]] levels by 0.77% to 1.16% when given by itself, in combination with [[metformin]], in combination with metformin and a sulfonylurea, in combination with metformin and [[pioglitazone]], or in combination with [[insulin]], from initial HbA_1c levels of 7.8% to 8.1%. When added to metformin, canagliflozin does not appear worse than [[sitagliptin]] or [[glimepiride]] in reducing HbA_1c levels, while canagliflozin maybe better than sitagliptin and glimiperide in decreasing HbA_1c. It is unclear whether or not it has any unique cardiovascular benefits beyond lowering blood sugar.<ref>{{cite journal | vauthors = Heston TF, Olson AH, Randall NR | title = Canagliflozin lowers blood sugar, but does it also lower cardiovascular risk? Maybe not | journal = Annals of Translational Medicine | volume = 5 | issue = 23 | pages = 473 | date = December 2017 | pmid = 29285506 | pmc = 5733311 | doi = 10.21037/atm.2017.09.28 | doi-access = free }}</ref> Although canagliflozin produces beneficial effects on [[HDL cholesterol]], it has also been shown to increase [[LDL cholesterol]] to produce no change in total cholesterol.<ref>{{cite web |url= https://www.accessdata.fda.gov/drugsatfda_docs/NDA/2013/204042Orig1s000SumR.pdf |title=Summary Review |publisher=U.S. [[Food and Drug Administration]] (FDA) |date=29 March 2013 |access-date=9 July 2014}} {{PD-notice}}</ref><ref name="PI">{{cite web | title=Invokana- canagliflozin tablet, film coated | website=[[DailyMed]] | date=21 August 2020 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b9057d3b-b104-4f09-8a61-c61ef9d4a3f3 | access-date=28 August 2020}}</ref>

Evidence shows that apart from positive effects on glycemic levels, canagliflozin also reduces the risk of heart attacks and heart failures.<ref>{{cite journal | vauthors = Usman MS, Siddiqi TJ, Memon MM, Khan MS, Rawasia WF, Talha Ayub M, Sreenivasan J, Golzar Y | display-authors = 6 | title = Sodium-glucose co-transporter 2 inhibitors and cardiovascular outcomes: A systematic review and meta-analysis | journal = European Journal of Preventive Cardiology | volume = 25 | issue = 5 | pages = 495–502 | date = March 2018 | pmid = 29372664 | doi = 10.1177/2047487318755531 | s2cid = 3557967 | doi-access = free }}</ref>

SGLT2 inhibitors, including canagliflozin, reduce the likelihood of hospitalization for congestive heart failure or progression of renal disease in persons with diabetes mellitus type 2 and reduce the likelihood of stroke and heart attack in persons with diabetes mellitus type 2 who have known atherosclerotic vascular disease.<ref>{{cite journal | vauthors = Zelniker TA, Wiviott SD, Raz I, Im K, Goodrich EL, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Furtado RH, Bhatt DL, Leiter LA, McGuire DK, Wilding JP, Sabatine MS | display-authors = 6 | title = SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials | journal = Lancet | volume = 393 | issue = 10166 | pages = 31–39 | date = January 2019 | pmid = 30424892 | doi = 10.1016/S0140-6736(18)32590-X | s2cid = 53277899 }}</ref>

==Contraindications==

Canaglifozin is contraindicated in:

* [[Type 1 diabetes]]

* [[Diabetic ketoacidosis]]<ref>Canagliflozin. Lexi-Drugs. Lexicomp Online [database online]. Hudson, OH: Lexicomp, Inc.&nbsp;http://online.lexi.com .&nbsp;Updated 8 April 2017. Accessed 13 April 2017.</ref>

* Severe [[Kidney failure|renal impairment]] (estimated glomerular filtration rate <30 mL/min/1.73 m²), [[Chronic kidney disease#Stages|end-stage renal disease]]<ref>Canagliflozin. Lexi-Drugs. Lexicomp Online [database online]. Hudson, OH: Lexicomp, Inc.&nbsp;http://online.lexi.com .&nbsp;Updated 31 March 2017. Accessed 5 April 2017.</ref>

* Patients on [[Kidney dialysis|dialysis]]<ref name="PI" />

==Adverse effects==

As with other SGLT2 inhibitors, canagliflozin is associated with increased incidence of urinary tract infections, [[fungal infections]] of the genital area, [[thirst]],<ref name="AustriaCodex">{{cite book|title=Austria-Codex|editor=Haberfeld, H|publisher=Österreichischer Apothekerverlag|location=Vienna|edition=2013/14, supplement 01/14|language=de}}</ref> elevations in LDL cholesterol, increased urination and episodes of [[hypotension|low blood pressure]]. Rarely, use of canagliflozin is associated with [[necrotizing fasciitis]] of the perineum, also called [[Fournier gangrene]].<ref>{{cite web | url=https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-about-rare-occurrences-serious-infection-genital-area-sglt2-inhibitors-diabetes |title = FDA warns about rare occurrences of a serious infection of the genital area with SGLT2 inhibitors for diabetes |publisher = U.S. [[Food and Drug Administration]] (FDA) |date = 29 August 2018}} {{PD-notice}}</ref> There are concerns that it may also increase the risk of [[diabetic ketoacidosis]].<ref>{{cite web | publisher=U.S. [[Food and Drug Administration]] (FDA) | title=SGLT2 inhibitors: Drug Safety Communication - FDA Warns Medicines May Result in a Serious Condition of Too Much Acid in the Blood | url=https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm446994.htm | access-date=19 May 2015 | date=15 May 2015 | archive-date=27 October 2016 | archive-url=https://web.archive.org/web/20161027185104/https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm446994.htm | url-status=dead }} {{PD-notice}}</ref>

Possible cardiovascular problems are an ongoing issue with gliflozin drugs.<ref name=FDA>{{cite web|url=http://www.medscape.com/viewarticle/777503| vauthors = Tucker M | title=FDA Advisory Panel Supports Diabetes Drug Canagliflozin |work=Medscape Family Medicine|date=10 January 2013|access-date=3 August 2015|quote=Safety discussions by the panel circled back repeatedly to the cardiovascular risk data}}</ref> The pre-specified endpoint for cardiovascular safety in the canagliflozin clinical development program was "Major Cardiovascular Events Plus", defined as the occurrence of cardiovascular death, non-fatal myocardial infarctions, non-fatal strokes, or unstable angina leading to hospitalization. This endpoint occurred in more people in the placebo group (20.5%) than in the canagliflozin treated group (18.9%).

Nonetheless, a United States [[Food and Drug Administration]] (FDA) advisory committee expressed concern regarding the cardiovascular safety of canagliflozin. A greater number of cardiovascular events was observed during the first 30 days in study subjects who received canagliflozin (0.45%) compared those who received placebo (0.07%), suggesting an early period of increased cardiovascular risk. In addition, there was an increased risk of stroke in subjects who received canagliflozin. However, none of these effects were statistically significant. Additional cardiovascular safety data from another ongoing study are expected in 2015.<ref name=FDA/>

On 15 May 2015, the FDA issued a warning that certain SGLT2 diabetes drugs, including canagliflozin, may lead to ketoacidosis, a condition where the body produces higher levels of ketone bodies. The FDA is continuing to investigate the issue, and cautions that patients should not stop taking canagliflozin without first talking to their doctor.<ref>{{Cite web|url=https://www.fda.gov/drugs/drugsafety/ucm446845.htm|title=FDA Drug Safety Communication: FDA warns that SGLT2 inhibitors for diabetes may result in a serious condition of too much acid in the blood|website=U.S. [[Food and Drug Administration]] (FDA)|access-date=7 June 2016|date=15 May 2015|archive-date=22 July 2017|archive-url=https://web.archive.org/web/20170722185730/https://www.fda.gov/Drugs/DrugSafety/ucm446845.htm|url-status=dead}} {{PD-notice}}</ref>

On 10 September 2015, the FDA issued a drug safety communication for canagliflozin to address risks for bone fracture and decreased bone density. A label warning for fractures was already included in the ''Adverse Reactions'' section; however, the FDA made the addition to the ''Warnings and Precautions'' section to reflect new information from a placebo study. They advised that health care professionals should consider fracture risk factors before prescribing canagliflozin, and patients should disclose any bone fracture risk factors to their doctors, but that patients should not stop taking the medication without first talking to their doctor.<ref>{{cite web|title=FDA Drug Safety Communication: FDA revises label of diabetes drug canagliflozin (Invokana, Invokamet) to include updates on bone fracture risk and new information on decreased bone mineral density|url=https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-revises-label-diabetes-drug-canagliflozin-invokana-invokamet |website=U.S. [[Food and Drug Administration]] (FDA) |access-date=10 September 2015 | date=10 September 2015}} {{PD-notice}}</ref>

On 4 December 2015, the FDA issued another safety communication for SGLT2 inhibitors, indicating that it would require new warnings to be added to the canagliflozin label about elevated blood acid levels and urinary tract infections.<ref>{{cite web|title=SGLT2 Inhibitors: Drug Safety Communication - Labels to Include Warnings About Too Much Acid in the Blood and Serious Urinary Tract Infections|url=https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm475553.htm|website=U.S. [[Food and Drug Administration]] (FDA)|access-date=11 March 2016|date=4 December 2015|archive-date=16 March 2016|archive-url=https://web.archive.org/web/20160316082405/http://www.fda.gov/safety/medwatch/safetyinformation/safetyalertsforhumanmedicalproducts/ucm475553.htm|url-status=dead}} {{PD-notice}}</ref>

In June 2016, the FDA strengthened the warning about the risk of acute kidney injury for the type 2 diabetes medicines canagliflozin (Invokana, Invokamet) and dapagliflozin (Farxiga, Xigduo XR).<ref>{{cite web | title=FDA Drug Safety Communication: FDA strengthens kidney warnings for diabetes medicines canagliflozin (Invokana, Invokamet) and dapagliflozin (Farxiga, Xigduo XR) | website=U.S. [[Food and Drug Administration]] (FDA) | date=14 June 2016 | url=https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-strengthens-kidney-warnings-diabetes-medicines-canagliflozin | access-date=28 August 2020}} {{PD-notice}}</ref>

A 29 June 2016, report on the ongoing cardiovascular outcomes trial for canagliflozin (CANVAS) revealed interim findings of new safety concerns including heightened risk of bone fracture that was found to increase with the duration of treatment.<ref>{{cite web| vauthors = Schroeder C |title=New Report Warns of Increasing SGLT2 & Invokana Risks|url=https://www.drugnews.net/news/sglt2-growth-increased-invokana-risk-side-effects/|website=DrugNews|publisher=Pro Media One|access-date=8 August 2016}}</ref>

In May 2016, the FDA announced they were going to investigate a safety issue related to clinical trials that found an increase in leg and foot amputations, mostly affecting the toes, in people treated with the diabetes medicine canagliflozin (Invokana, Invokamet).<ref>{{cite web | title=FDA Drug Safety Communication: Interim clinical trial results find increased risk of leg and foot amputations, mostly affecting the toes, with the diabetes medicine canagliflozin (Invokana, Invokamet); FDA to investigate | website=U.S. [[Food and Drug Administration]] (FDA) | date=18 May 2016 | url=https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-interim-clinical-trial-results-find-increased-risk-leg-and-foot | access-date=28 August 2020}} {{PD-notice}}</ref> In May 2017, the FDA concluded that canagliflozin causes an increased risk of leg and foot amputations.<ref name="Fox Business">{{Cite news|url=http://www.foxbusiness.com/features/2017/05/16/press-release-fda-confirms-increased-risk-leg-and-foot-amputations-with-diabetes-medicine-canagliflozin.html|title=Press Release: FDA Confirms Increased Risk of Leg and Foot Amputations With Diabetes Medicine Canagliflozin|date=16 May 2017|work=Fox Business|access-date=16 May 2017}}</ref> The FDA began requiring a [[boxed warning]] to be added to the canagliflozin drug labels to describe this risk.<ref name="FDA.gov">{{cite web|url=https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-confirms-increased-risk-leg-and-foot-amputations-diabetes-medicine|title=FDA Drug Safety Communication: FDA confirms increased risk of leg and foot amputations with the diabetes medicine canagliflozin (Invokana, Invokamet, Invokamet XR)|date=16 May 2017|work=U.S. [[Food and Drug Administration]] (FDA)|access-date=16 May 2017}} {{PD-notice}}</ref> In August 2020, the FDA removed the requirement for the boxed warning.<ref name="FDA 20200826">{{cite web | title=FDA removes Boxed Warning for type 2 diabetes medicine canagliflozin | website=U.S. [[Food and Drug Administration]] (FDA) | date=26 August 2020 | url=https://www.fda.gov/drugs/drug-safety-and-availability/fda-removes-boxed-warning-about-risk-leg-and-foot-amputations-diabetes-medicine-canagliflozin | access-date=28 August 2020}} {{PD-notice}}</ref>

To lessen the risk of developing ketoacidosis (a serious condition in which the body produces high levels of blood acids called ketones) after surgery, the FDA approved changes to the prescribing information for SGLT2 inhibitor diabetes medicines to recommend they be stopped temporarily before scheduled surgery. Canagliflozin, dapagliflozin, and empagliflozin should each be stopped at least three days before, and ertugliflozin should be stopped at least four days before scheduled surgery.<ref name="FDA drug safety 20200319">{{cite web | title=FDA revises labels of SGLT2 inhibitors for diabetes to include warning | website=U.S. [[Food and Drug Administration]] (FDA) | date=19 March 2020 | url=https://www.fda.gov/drugs/drug-safety-and-availability/fda-revises-labels-sglt2-inhibitors-diabetes-include-warnings-about-too-much-acid-blood-and-serious | access-date=6 June 2020}} {{PD-notice}}</ref>

Symptoms of ketoacidosis include nausea, vomiting, abdominal pain, tiredness, and trouble breathing.<ref name="FDA drug safety 20200319" />

== Interactions ==

The drug may increase the risk of [[dehydration]] in combination with [[diuretic]] drugs.<ref>{{cite journal | vauthors = Yamout H, Perkovic V, Davies M, Woo V, de Zeeuw D, Mayer C, Vijapurkar U, Kline I, Usiskin K, Meininger G, Bakris G | display-authors = 6 | title = Efficacy and safety of canagliflozin in patients with type 2 diabetes and stage 3 nephropathy | journal = American Journal of Nephrology | volume = 40 | issue = 1 | pages = 64–74 | date = August 2014 | pmid = 25059406 | doi = 10.1159/000364909 | doi-access = free }}</ref>

Because it increases renal excretion of glucose, treatment with canagliflozin prevents renal reabsorption of [[1,5-Anhydroglucitol|1,5-anhydroglucitol]], leading to artifactual decreases in serum 1,5-anhydroglucitol. Therefore, canagliflozin can interfere with the use of serum 1,5-anhydroglucitol (assay trade name, GlycoMark) as a measure of postprandial glucose levels.<ref name=Balis2014>{{cite journal | vauthors = Balis DA, Tong C, Meininger G | title = Effect of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, on measurement of serum 1,5-anhydroglucitol | journal = Journal of Diabetes | volume = 6 | issue = 4 | pages = 378–380 | date = July 2014 | pmid = 24330128 | doi = 10.1111/1753-0407.12116 | s2cid = 36348840 | doi-access = free }}</ref>

Dosing adjustment is also required for concomitant therapy with [[UDP glucuronosyltransferase 1 family, polypeptide A1|UDP-glucuronosyl transferase]] (UGT) inducers such as [[Rifampicin|rifampin]], [[phenytoin]], or [[phenobarbital]], [[ritonavir]].<ref name="AHFS2019" />

==Pharmacology==

===Mechanism of action===

Canagliflozin is an [[Enzyme inhibitor|inhibitor]] of subtype 2 sodium-glucose transport proteins ([[SGLT2]]), which is responsible for at least 90% of [[renal glucose reabsorption]] (the remaining 10% is done by [[SGLT1]] inhibition<ref>{{cite journal | vauthors = Sokolov V, Yakovleva T, Chu L, Tang W, Greasley PJ, Johansson S, Peskov K, Helmlinger G, Boulton DW, Penland RC | display-authors = 6 | title = Differentiating the Sodium-Glucose Cotransporter 1 Inhibition Capacity of Canagliflozin vs. Dapagliflozin and Empagliflozin Using Quantitative Systems Pharmacology Modeling | journal = CPT: Pharmacometrics & Systems Pharmacology | volume = 9 | issue = 4 | pages = 222–229 | date = April 2020 | pmid = 32064793 | pmc = 7180004 | doi = 10.1002/psp4.12498 }}</ref><ref>{{cite journal | vauthors = Koufakis T, Mustafa OG, Tsimihodimos V, Ajjan RA, Kotsa K | title = Insights Into the Results of Sotagliflozin Cardiovascular Outcome Trials: Is Dual Inhibition the Cherry on the Cake of Cardiorenal Protection? | journal = Drugs | volume = 81 | issue = 12 | pages = 1365–1371 | date = August 2021 | pmid = 34232488 | pmc = 8261816 | doi = 10.1007/s40265-021-01559-1 }}</ref>). Blocking this transporter causes up to 119 grams of blood glucose per day to be eliminated through the urine,<ref name="prous.com">{{cite web|url=http://www.prous.com/molecules/default.asp?ID=165|title=Integrity - Clarivate}}</ref> corresponding to 476 [[kilocalories]]. Additional water is eliminated by [[osmotic diuresis]], resulting in a lowering of blood pressure.

This mechanism is associated with a low risk of [[hypoglycaemia]] (too low blood glucose) compared to other types of anti-diabetic drugs such as [[sulfonylurea]] derivatives and insulin.<ref name="Klement">{{cite journal| vauthors = Klement A |date=20 January 2014|title=Tubuläre Senkung des Blutzuckers bei Diabetes mellitus: Invokana|journal=Österreichische Apothekerzeitung|issue=2/2014|page=20f|language=de}}</ref>

===Pharmacokinetics===

When taken [[Oral administration|by mouth]], canagliflozin reaches highest [[blood plasma]] concentrations after one to two hours and has an absolute [[bioavailability]] of 65%, independently of food intake. When in the bloodstream, 99% of the substance are bound to plasma proteins, mainly [[albumin]]. It is metabolized mainly by O-[[glucuronidation]] via the enzymes [[UGT1A9]] and [[UGT2B4]], and by [[hydroxylation]] to a lesser extent. The terminal half life is 10.6 hours for a 100&nbsp;mg dose and 13.1 hours for a 300&nbsp;mg dose, with 43% being excreted in the faeces (mostly in unchanged form) and 33% in the urine (mostly as glucuronide).<ref>[[Drugs.com]]: Canagliflozin {{drugs.com|monograph|canagliflozin}}.</ref>

==History==

It was developed by [[Mitsubishi Tanabe Pharma]] and is marketed under license by [[Janssen Pharmaceutica|Janssen]], a division of [[Johnson & Johnson]].<ref name=JNJ>{{cite web|url=http://www.investor.jnj.com/releasedetail.cfm?releaseid=710584|title=First Results from Phase 3 CANVAS Trial Show Canagliflozin as Add-on Therapy to Insulin Lowered Blood Sugar Levels in Patients with Type 2 Diabetes at an Elevated Risk for Cardiovascular Disease|access-date=21 February 2013|archive-url=https://web.archive.org/web/20130313045912/http://www.investor.jnj.com/releaseDetail.cfm?releaseid=710584|archive-date=13 March 2013|url-status=dead}}</ref>

On 4 July 2011, the [[European Medicines Agency]] (EMA) approved a paediatric investigation plan and granted both a deferral and a waiver for canagliflozin (EMEA-001030-PIP01-10) in accordance with EC Regulation No.1901/2006 of the European Parliament and of the council.<ref>{{cite web|url=http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/pips/EMEA-001030-PIP01-10/pip_000744.jsp&mid=WC0b01ac058001d129|title=EMEA-001030-PIP01-10|publisher=EMA European Medicines Agency|access-date=6 May 2013|archive-date=20 December 2013|archive-url=https://web.archive.org/web/20131220190026/http://www.ema.europa.eu/ema/index.jsp?curl=pages%2Fmedicines%2Fpips%2FEMEA-001030-PIP01-10%2Fpip_000744.jsp&mid=WC0b01ac058001d129|url-status=dead}}</ref> It was approved for medical use in the European Union in November 2013.<ref name="Invokana EPAR">{{cite web | title=Invokana EPAR | website=[[European Medicines Agency]] (EMA) | date=29 November 2013 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/invokana | access-date=29 August 2020}}</ref>

Canagliflozin was approved by the FDA on 29 March 2013, and became the first [[SGLT2 inhibitor]] in the United States.<ref name="FDA approval">{{cite web | title=Drug Approval Package: Invokana (canagliflozin) Tablets NDA #204042 | website=U.S. [[Food and Drug Administration]] (FDA) | date=24 December 1999 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000TOC.cfm | access-date=28 August 2020 }}</ref><ref>{{cite news|url=https://www.reuters.com/article/johnsonjohnson-diabetes-idUSL3N0CL1FV20130329|title=U.S. FDA approves Johnson & Johnson diabetes drug, canagliflozin|quote=U.S. health regulators have approved a new diabetes drug from Johnson & Johnson, making it the first in its class to be approved in the United States.|date=29 March 2013|publisher=Reuters|access-date=30 June 2017|archive-date=24 September 2015|archive-url=https://web.archive.org/web/20150924180346/http://www.reuters.com/article/2013/03/29/johnsonjohnson-diabetes-idUSL3N0CL1FV20130329|url-status=live}}</ref>

Canagliflozin was approved for medical use in Australia in September 2013.<ref name="Canagliflozin AusPAR" />

== See also ==

*[[Canagliflozin/metformin]]

== References ==

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