Invokana Special Precautions

Lower Limb Amputation: An approximately 2-fold increased risk of lower limb amputations associated with INVOKANA use was observed in CANVAS and CANVAS-R, two randomized, placebo-controlled trials evaluating patients with type 2 diabetes who had either established cardiovascular disease or were at risk for cardiovascular disease. The risk of lower limb amputations was observed at both the 100 mg and 300 mg once daily dosage regimens. The amputation data for CANVAS and CANVAS-R are shown in Tables 15 and 16, respectively [see Clinical Studies Experience under Adverse Reactions].
Amputations of the toe and midfoot (99 out of 140 patients with amputations receiving INVOKANA in the two trials) were the most frequent; however, amputations involving the leg, below and above the knee, were also observed (41 out of 140 patients with amputations receiving INVOKANA in the two trials). Some patients had multiple amputations, some involving both lower limbs.
Lower limb infections, gangrene, and diabetic foot ulcers were the most common precipitating medical events leading to the need for an amputation. The risk of amputation was highest in patients with a baseline history of prior amputation, peripheral vascular disease, and neuropathy.
Before initiating INVOKANA, consider factors in the patient history that may predispose to the need for amputations, such as a history of prior amputation, peripheral vascular disease, neuropathy and diabetic foot ulcers. Counsel patients about the importance of routine preventative foot care. Monitor patients receiving INVOKANA for signs and symptoms of infection (including osteomyelitis), new pain or tenderness, sores or ulcers involving the lower limbs, and discontinue INVOKANA if these complications occur.
Hypotension: INVOKANA causes intravascular volume contraction. Symptomatic hypotension can occur after initiating INVOKANA [see Clinical Studies Experience under Adverse Reactions] particularly in patients with impaired renal function (eGFR less than 60 mL/min/1.73 m²), elderly patients, patients on either diuretics or medications that interfere with the renin-angiotensin-aldosterone system (e.g., angiotensin-converting enzyme [ACE] inhibitors, angiotensin receptor blockers [ARBs]), or patients with low systolic blood pressure. Before initiating INVOKANA in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy.
Ketoacidosis: Reports of ketoacidosis, a serious life-threatening condition requiring urgent hospitalization have been identified in postmarketing surveillance in patients with type 1 and type 2 diabetes mellitus receiving sodium glucose co-transporter-2 (SGLT2) inhibitors, including INVOKANA. Fatal cases of ketoacidosis have been reported in patients taking INVOKANA. INVOKANA is not indicated for the treatment of patients with type 1 diabetes mellitus [see Indications/Uses].
Patients treated with INVOKANA who present with signs and symptoms consistent with severe metabolic acidosis should beassessed for ketoacidosis regardless of presenting blood glucose levels, as ketoacidosis associated with INVOKANA may be present even if blood glucose levels are less than 250 mg/dL. If ketoacidosisis suspected, INVOKANA should be discontinued, patient should be evaluated, and prompt treatment should be instituted. Treatment of ketoacidosis may require insulin, fluid and carbohydrate replacement.
In many of the postmarketing reports, and particularly in patients with type 1 diabetes, the presence of ketoacidosis was not immediately recognized and institution of treatment was delayed because presenting blood glucose levels were below those typically expected for diabetic ketoacidosis (often less than 250 mg/dL). Signs and symptoms at presentation were consistent with dehydration and severe metabolic acidosis and included nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. In some but not all cases, factors predisposing to ketoacidosis such as insulin dose reduction, acute febrile illness, reduced caloric intake due to illness or surgery, pancreatic disorders suggesting insulin deficiency (e.g., type 1 diabetes, history of pancreatitis or pancreatic surgery), and alcohol abuse were identified.
Before initiating INVOKANA, consider factors in the patient history that may predispose to ketoacidosis including pancreatic insulin deficiency from any cause, caloric restriction, and alcohol abuse. In patients treated with INVOKANA consider monitoring for ketoacidosis and temporarily discontinuing INVOKANA in clinical situations known to predispose to ketoacidosis (e.g., prolonged fasting due to acute illness or surgery).
Acute Kidney Injury: INVOKANA causes intravascular volume contraction [see Hypotension as previously mentioned] and can cause acute kidney injury. There have been postmarketing reports of acute kidney injury, some requiring hospitalization and dialysis, in patients receiving INVOKANA; some reports involved patients younger than 65 years of age.
Before initiating INVOKANA, consider factors that may predispose patients to acute kidney injury including hypovolemia, chronic renal insufficiency, congestive heart failure and concomitant medications (diuretics, ACE inhibitors, ARBs, NSAIDs). Consider temporarily discontinuing INVOKANA in any setting of reduced oral intake (such as acute illness or fasting) or fluid losses (such as gastrointestinal illness or excessive heat exposure); monitor patients for signs and symptoms of acute kidney injury. If acute kidney injury occurs, discontinue INVOKANA promptly and institute treatment.
Initiation of INVOKANA may increase serum creatinine and decrease eGFR. Patients with hypovolemia may be more susceptible to these changes [see Clinical Studies Experience under Adverse Reactions]. Renal function should be evaluated prior to initiation of INVOKANA and monitored periodically thereafter. Dosage adjustment and more frequent renal function monitoring are recommended in patients with an eGFR below 60 mL/min/1.73 m². Use of INVOKANA is not recommended when eGFR is persistently less than 45 mL/min/1.73 m² and is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m² [see Patients with Renal Impairment under Dosage & Administration, Contraindications, and Renal Impairment as follows].
Urosepsis and Pyelonephritis: There have been postmarketing reports of serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization in patients receiving SGLT2 inhibitors, including INVOKANA. Treatment with SGLT2 inhibitors increases the risk for urinary tract infections. Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated [see Adverse Reactions].
Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues: Insulin and insulin secretagogues are known to cause hypoglycemia. INVOKANA may increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue [see Clinical Studies Experience under Adverse Reactions]. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with INVOKANA.
Necrotizing Fasciitis of the Perineum (Fournier's Gangrene): Reports of necrotizing fasciitis of the perineum (Fournier's gangrene), a rare but serious and life-threatening necrotizing infection requiring urgent surgical intervention, have been identified in postmarketing surveillance in patients with diabetes mellitus receiving SGLT2 inhibitors, including INVOKANA. Cases have been reported in both females and males. Serious outcomes have included hospitalization, multiple surgeries, and death.
Patients treated with INVOKANA presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise, should be assessed for necrotizing fasciitis. If suspected, start treatment immediately with broad-spectrum antibiotics and, if necessary, surgical debridement. Discontinue INVOKANA, closely monitor blood glucose levels, and provide appropriate alternative therapy for glycemic control.
Genital Mycotic Infections: INVOKANA increases the risk of genital mycotic infections. Patients with a history of genital mycotic infections and uncircumcised males were more likely to develop genital mycotic infections [see Clinical Studies Experience under Adverse Reactions]. Monitor and treat appropriately.
Hypersensitivity Reactions: Hypersensitivity reactions, including angioedema and anaphylaxis, have been reported with INVOKANA. These reactions generally occurred within hours to days after initiating INVOKANA. If hypersensitivity reactions occur, discontinue use of INVOKANA; treat and monitor until signs and symptoms resolve [see Contraindications and Clinical Studies Experience and Postmarketing Experience under Adverse Reactions].
Bone Fracture: An increased risk of bone fracture, occurring as early as 12 weeks after treatment initiation, was observed in patients using INVOKANA in the CANVAS trial [see Pharmacology: Pharmacodynamics: Clinical Studies: Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus and Atherosclerotic Cardiovascular Disease under Actions]. Consider factors that contribute to fracture risk prior to initiating INVOKANA [see Clinical Studies Experience under Adverse Reactions].
Increases in Low-Density Lipoprotein (LDL-C): Dose-related increases in LDL-C occur with INVOKANA [see Clinical Studies Experience under Adverse Reactions]. Monitor LDL-C and treat if appropriate after initiating INVOKANA.
Renal Impairment: The efficacy and safety of INVOKANA were evaluated in a trial that included patients with moderate renal impairment (eGFR 30 to less than 50 mL/min/1.73 m²) [see Pharmacology: Pharmacodynamics: Clinical Studies: Glycemic Control Trials in Adults with Type 2 Diabetes Mellitus under Actions]. These patients had less overall glycemic efficacy and had a higher occurrence of adverse reactions related to reduced intravascular volume, renal-related adverse reactions, and decreases in eGFR compared to patients with mild renal impairment or normal renal function (eGFR greater than or equal to 60 mL/min/1.73 m²). Dose-related, transient mean increases in serum potassium were observed early after initiation of INVOKANA (i.e., within 3 weeks) in this trial. Increases in serum potassium of greater than 5.4 mEq/L and 15% above baseline occurred in 16.1%, 12.4%, and 27.0% of patients treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Severe elevations (greater than or equal to 6.5 mEq/L) occurred in 1.1%, 2.2%, and 2.2% of patients treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively [see Patients with Renal Impairment under Dosage & Administration, Hypotension and Acute Kidney Injury as previously mentioned, and Clinical Studies Experience under Adverse Reactions].
The efficacy and safety of INVOKANA have not been established in patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m²), with ESRD, or receiving dialysis. INVOKANA is not expected to be effective in these patient populations [see Contraindications and Pharmacology: Pharmacokinetics under Actions].
Hepatic Impairment: No dosage adjustment is necessary in patients with mild or moderate hepatic impairment. The use of INVOKANA has not been studied in patients with severe hepatic impairment and is therefore not recommended [see Pharmacology: Pharmacokinetics under Actions].
Use in Children: Safety and effectiveness of INVOKANA in pediatric patients under 18 years of age have not been established.
Use in Elderly: In 13 clinical trials of INVOKANA, 2,294 patients 65 years and older, and 351 patients 75 years and older were exposed to INVOKANA [see Pharmacology: Pharmacodynamics: Clinical Studies: Glycemic Control Trials in Adults with Type 2 Diabetes Mellitus under Actions].
Patients 65 years and older had a higher incidence of adverse reactions related to reduced intravascular volume with INVOKANA (such as hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration), particularly with the 300 mg daily dose, compared to younger patients; a more prominent increase in the incidence was seen in patients who were 75 years and older [see Prior to Initiation of INVOKANA under Dosage & Administration and Clinical Studies Experience under Adverse Reactions]. Smaller reductions in HbA_1C with INVOKANA relative to placebo were seen in older (65 years and older; -0.61% with INVOKANA 100 mg and -0.74% with INVOKANA 300 mg relative to placebo) compared to younger patients (-0.72% with INVOKANA 100 mg and -0.87% with INVOKANA 300 mg relative to placebo).