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Suitable Extinguishing Media: Use extinguishing measures that are appropriate to local circumstances and the surrounding environment.

Protective equipment and precautions for firefighters: Wear self-contained breathing apparatus and protective suit. Wear self contained breathing apparatus for fire fighting if necessary.

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.

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.

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.

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.

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.

Contaminated packaging: Do not reuse container.

Personal precautions: Use personal protective equipment as required. Keep people away from and upwind of spill/leak. Evacuate personnel to safe areas.

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.

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.

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.

Skin and Body Protection: Wear protective gloves and protective clothing.

Eye/face protection: Tight sealing safety goggles. Face protection shield.

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.

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.

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.

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

For more Interactions (Complete) data for Canagliflozin (6 total), please visit the HSDB record page.

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).

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).

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).

In 2017, the FDA gave canagliflozin a box warning, highlighting the increased risk of leg and foot amputations. As of August 2020, the FDA has removed this box warning associated with canagliflozin and any other medications that include canagliflozin as part of combination therapy.；Common Adverse Drug Reactions of Canagliflozin ；* Genital yeast infections in both men and women；* Urinary tract infections；* Increased urination；* Dehydration；* Orthostatic hypotension；* Increased cholesterol levels (LDL-C)；Drug-Drug Interactions；* UDP-glucuronosyltransferase (UGT) enzyme inducers: If patients are currently tolerating a 100 mg daily dose of canagliflozin and have an eGFR ≥60 mL/min/1.73 m2, consider increasing the dosage of canagliflozin to 300 mg daily if coadministered with UGT enzyme inducers. UGT enzyme inducers, such as rifampin, phenytoin, phenobarbital, or ritonavir, all work on UGT enzymes such as UGT1A9 and UGT2B4. When coadministered with canagliflozin, medications that induce UGT enzymes decrease the efficacy of canagliflozin. Alternative antihyperglycemic therapy should be considered in patients with an eGFR 2.；* Digoxin: An increase in digoxin's peak drug concentration occurs when used concurrently with canagliflozin 300 mg daily dosing. Patients treated with canagliflozin with concomitant digoxin should be monitored and have the dose adjusted for digoxin accordingly.；* Diuretics: Canagliflozin results in osmotic diuresis, leading to reduced intravascular volume. Loop diuretics, hydrochlorothiazide, and thiazide-like diuretics are associated with the most significant increase in volume depletion-related adverse reactions. Concomitant use of canagliflozin with diuretics can increase the risk of dehydration and hypotension, and the dosing of diuretics should be adjusted accordingly.；* CYP3A4 inducers: Medications that induce the CYP3A4 enzyme, such as rifampin, can decrease drug concentrations of canagliflozin. Dose adjustments of canagliflozin may be necessary when coadministered with CYP3A4 inducers.；* CYP3A4 inhibitors: Medications that inhibit the CYP3A4 enzyme, such as ketoconazole, can increase drug concentrations of canagliflozin in the body. This can potentially lead to an increased risk for adverse events associated with canagliflozin.

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, a

Signs and Symptoms of Overdose；Canagliflozin overdose and toxicity can increase the risk of hypoglycemia when administered with other diabetic medications. If a patient has severe hypoglycemia, they should self-administer an emergency glucagon kit. Additional symptoms of overdose include severe dehydration, electrolyte imbalances, and constant low blood pressure.；Management of Overdose；If an overdose is suspected, it is crucial to seek immediate medical attention and contact emergency services such as the poison control center. Overdose treatment typically consists of supportive care to reverse electrolyte imbalances with fluid replacement and additional supportive measures to manage symptoms. If clinicians deem it necessary to remove unabsorbed drug components of canagliflozin, a 4-hour hemodialysis session can remove canagliflozin to negligible levels. Healthcare teams should implement clinical monitoring based on the patient's health status. As canagliflozin is highly protein plasma bound, it is not expected to be dialyzable through peritoneal dialysis.

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.

/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.

/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.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Canagliflozin

vLess-DILI-concern

0

No match

DOI:10.1016/j.drudis.2016.02.015

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).

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).

/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.

/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.

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/