强生Invokamet（坎格列净/二甲双胍固定剂量复方药物）新药获FDA批准
强生旗下杨森制药公司于8月8日宣布，美国食品药品监督管理局（FDA）正式批准旗下新药Invokamet（坎格列净/二甲双胍固定剂量复方药物）用于2型糖尿病)成人患者的治疗。
坎格列净（商品名Invokana，杨森制药）是首个获批的钠葡萄糖协同转运蛋白2（SGLT2）抑制剂，于2013年3月获得美国FDA的批准用于2型糖尿病治疗。而二甲双胍则是2型糖尿病的常用药。
此次FDA对Invokamet的批准基于杨森公司发布的III期临床试验数据。该III期临床试验共有4732人参与，数据表明，相较二甲双胍和其他单药治疗，INVOKAMET能大幅度降低患者体内的HbA1c水平，INVOKAMET与相应剂量坎格列净+二甲双胍联合治疗方案具有等效性。
FDA批准Invokamet作为一种辅助药物，结合运动和饮食，用于改善2型糖尿病成人患者的血糖控制，主要用于（1）服用坎格列净或二甲双胍单药不能充分控制血糖水平的患者；（2）已经在接受坎格列净+二甲双胍两种药物联合治疗的患者。Invokamet不适用于1型糖尿病和糖尿病酮症酸中毒的治疗。
在美国，Invokamet是首个SGLT2抑制剂和二甲双胍固定剂量复方产品。此前，Invokamet已于2014年4月获欧盟批准上市。
Invokamet同时还附带黑框警告，即二甲双胍累积有可能会出现乳酸酸中毒，可致死。患者如果有严重肾功能或属于血液透析治疗阶段，也禁止服用该药物。
Canagliflozin 50 mg and metformin hydrochloride 500 mg
Canagliflozin 50 mg and metformin hydrochloride 1,000 mg
Canagliflozin 150 mg and metformin hydrochloride 500 mg
Canagliflozin 150 mg and metformin hydrochloride 1,000 mg
Invokamet (canagliflozin and metformin hydrochloride) Tablets (坎格列净/二甲双胍复方片)
IMPORTANT SAFETY INFORMATION
WARNING: LACTIC ACIDOSIS
Lactic acidosis is a rare but serious complication that can occur due to metformin accumulation. The risk increases with conditions such as renal impairment, sepsis, dehydration, excess alcohol intake, hepatic impairment, and acute congestive heart failure.
The onset is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress.
Laboratory abnormalities include low pH, increased anion gap, and elevated blood lactate.
If lactic acidosis is suspected, INVOKAMET™ should be discontinued and the patient hospitalized immediately.
CONTRAINDICATIONS
•Renal impairment (ie, serum creatinine levels ≥1.5 mg/dL for males or ≥1.4 mg/dL for females, or eGFR is less than 45 mL/min/1.73 m2), which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia; end stage renal disease (ESRD) or patients on dialysis
•Acute or chronic metabolic acidosis, including diabetic ketoacidosis
•History of a serious hypersensitivity reaction to canagliflozin or metformin
WARNINGS and PRECAUTIONS
•Lactic Acidosis: Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with INVOKAMET™. When lactic acidosis occurs, it is fatal in approximately 50% of cases. The reported incidence of lactic acidosis in patients receiving metformin is approximately 0.03 cases/1000 patient-years (with approximately 0.015 fatal cases/1000 patient-years). Reported cases have occurred primarily in diabetic patients with significant renal insufficiency, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications.
Patients with congestive heart failure requiring pharmacologic management, particularly when accompanied by hypoperfusion and hypoxemia due to unstable or acute failure, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal dysfunction and the patient's age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking metformin. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. INVOKAMET™ treatment should not be initiated in any patient unless measurement of creatinine clearance demonstrates that renal function is not reduced. In addition, INVOKAMET™ should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis.
Because impaired hepatic function has been associated with some cases of lactic acidosis, INVOKAMET™ should generally be avoided in patients with clinical or laboratory evidence of hepatic impairment. Patients should be cautioned against excessive alcohol intake when taking metformin, since alcohol potentiates the effects of metformin on lactate metabolism.
In addition, INVOKAMET™ should be temporarily discontinued prior to any intravascular radiocontrast study, withheld for 48 hours subsequent to the procedure, and reinstituted only after renal function has been confirmed to be normal. For any surgical procedure necessitating restricted intake of food or fluids, INVOKAMET™ should be temporarily discontinued and not be initiated until the patient's oral intake has resumed and renal function has been eva luated as normal.
Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria or ketonemia). Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with lactic acidosis who is taking INVOKAMET™, the drug should be discontinued immediately and general supportive measures promptly instituted. Metformin is dialyzable (clearance of up to 170 mL/min under good hemodynamic conditions), and prompt hemodialysis is recommended to remove the accumulated metformin and correct the metabolic acidosis. Such management often results in prompt reversal of symptoms and recovery.
•Hypotension: Canagliflozin causes intravascular volume contraction. Symptomatic hypotension can occur after initiating INVOKAMET™, particularly in patients with an eGFR <60 mL/min/1.73 m2, elderly patients, patients on either diuretics or medications that interfere with the renin-angiotensin-aldosterone system, or patients with low systolic blood pressure. Before initiating INVOKAMET™ in patients with ≥1 of these characteristics who were not already on canagliflozin, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy.
•Impairment in Renal Function: Canagliflozin increases serum creatinine and decreases eGFR. Patients with hypovolemia may be more susceptible to these changes. Renal function abnormalities can occur after initiating INVOKAMET™.
Before initiation of INVOKAMET™ therapy and at least annually thereafter, assess and verify normal renal function. In patients in whom development of renal impairment is anticipated (eg, elderly patients), assess renal function more frequently and discontinue INVOKAMET™ if evidence of renal impairment is present (ie, serum creatinine levels ≥1.5 mg/dL for males or ≥1.4 mg/dL for females, or eGFR is <45 mL/min/1.73 m2).
Use of Concomitant Medications That May Affect Renal Function or Metformin Disposition
Monitor and adjust dose of INVOKAMET™ or concomitant drug in patients taking medication(s) that may affect renal function, result in a significant hemodynamic change, or interfere with the disposition of metformin.
•Hyperkalemia: Canagliflozin can lead to hyperkalemia. Patients with moderate renal impairment who are taking medications that interfere with potassium excretion, such as potassium-sparing diuretics, or medications that interfere with the renin-angiotensin-aldosterone system are more likely to develop hyperkalemia.
Monitor serum potassium levels periodically after initiating INVOKAMET™ in patients with impaired renal function and in patients predisposed to hyperkalemia due to medications or other medical conditions.
•Impaired Hepatic Function: Metformin use in patients with impaired hepatic function has been associated with some cases of lactic acidosis. Therefore, INVOKAMET™ is not recommended in patients with clinical or laboratory evidence of hepatic impairment.
•Use With Medications Known to Cause Hypoglycemia
Canagliflozin
Canagliflozin can increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue. A lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with INVOKAMET™.
Metformin
Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or when used concomitantly with other glucose-lowering agents (such as sulfonylureas or insulin) or ethanol. Elderly, debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication, are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly and in people who are taking beta-adrenergic blocking drugs. Monitor for a need to lower the dose of INVOKAMET™ to minimize the risk of hypoglycemia in these patients.
•Genital Mycotic Infections: Canagliflozin increases risk of genital mycotic infections. Patients with a history of these infections and uncircumcised males were more likely to develop these infections. Monitor and treat appropriately.
•Hypersensitivity Reactions: Hypersensitivity reactions (eg, generalized urticaria), some serious, were reported with canagliflozin; these reactions generally occurred within hours to days after initiation. If reactions occur, discontinue INVOKAMET™; treat per standard of care and monitor until signs and symptoms resolve.
•Vitamin B12 Levels: In clinical trials of metformin, a decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of metformin-treated patients. The decrease in vitamin B12 levels appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. Measure hematologic parameters on an annual basis in patients on INVOKAMET™ and investigate and treat if abnormalities occur. Patients with inadequate vitamin B12 or calcium intake or absorption may be predisposed to develop subnormal vitamin B12 levels.
•Alcohol Intake: Alcohol is known to potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake while receiving INVOKAMET™.
•Hypoxic States: Cardiovascular collapse (shock) from whatever cause (eg, acute congestive heart failure, acute myocardial infarction, or other conditions characterized by hypoxemia) have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur, promptly discontinue INVOKAMET™.
•Increases in Low-Density Lipoprotein (LDL-C): Dose-related increases in LDL-C can occur with canagliflozin. Monitor LDL-C and treat per standard of care after initiating INVOKAMET™.
•Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with canagliflozin or metformin or any other antidiabetic drug.
DRUG INTERACTIONS
•Drug Interactions With Metformin
Cationic Drugs
Cationic drugs (eg, amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. Although such interactions remain theoretical (except with cimetidine), careful patient monitoring and dose adjustment of INVOKAMET™ and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system.
Carbonic Anhydrase Inhibitors
Topiramate or other carbonic anhydrase inhibitors (eg, zonisamide, acetazolamide, or dichlorphenamide) frequently decrease serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs may induce metabolic acidosis. Use these drugs with caution in patients treated with metformin, as the risk of lactic acidosis may increase.
Drugs Affecting Glycemic Control
Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid. When such drugs are administered to a patient receiving INVOKAMET™, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving INVOKAMET™, the patient should be observed closely for hypoglycemia.
•Drug Interactions With Canagliflozin
UGT Enzyme Inducers
Rifampin: Rifampin lowered canagliflozin exposure, which may reduce the efficacy of INVOKAMET™. If an inducer of UGT enzymes must be coadministered with INVOKAMET™, consider increasing the dose to canagliflozin 150 mg twice daily if patients are currently tolerating INVOKAMET™ with 50 mg canagliflozin twice daily, have an eGFR ≥60 mL/min/1.73 m2, and require additional glycemic control.
Digoxin
Canagliflozin increased digoxin exposure. Digoxin, as a cationic drug, also has the potential to compete with metformin for common renal tubular transport systems. Monitor patients taking INVOKAMET™ with concomitant digoxin for a need to adjust dose of either drug.
•Drug/Laboratory Test Interference
Positive Urine Glucose Test
Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors as SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose test results. Use alternative methods to monitor glycemic control.
Interference With 1,5-Anhydroglucitol (1,5-AG) Assay
Monitoring glycemic control with 1,5-AG assay is not recommended as measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control.
USE IN SPECIFIC POPULATIONS
•Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women with INVOKAMET™ or its individual components. During pregnancy, consider appropriate alternative therapies, especially during the second and third trimesters.
•Nursing Mothers: No studies in lactating animals have been conducted with the combined components of INVOKAMET™. Because of the potential for serious adverse reactions in nursing infants, discontinue INVOKAMET™.
•Pediatric Use: Safety and effectiveness of INVOKAMET™ in patients <18 years of age have not been established.
•Geriatric Use: Because renal function abnormalities can occur after initiating canagliflozin, metformin is substantially excreted by the kidney, and aging can be associated with reduced renal function, frequently monitor renal function after initiating INVOKAMET™ in elderly patients and adjust dose based on renal function.
Canagliflozin
2034 patients ≥65 years and 345 patients ≥75 years were exposed to canagliflozin in 9 clinical studies. Patients ≥65 years had a higher incidence of adverse reactions related to reduced intravascular volume (eg, hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration), particularly with the 300-mg dose, compared to younger patients; more prominent increase in the incidence was seen in patients who were ≥75 years. Smaller reductions in HbA1c relative to placebo were seen in patients ≥65 years (-0.61% with canagliflozin 100 mg and -0.74% with canagliflozin 300 mg) compared to younger patients (-0.72% with canagliflozin 100 mg and -0.87% with canagliflozin 300 mg).
Metformin
Controlled clinical studies of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and younger patients. The initial and maintenance dosing of metformin should be conservative in patients with advanced age due to the potential for decreased renal function in this population. Any dose adjustment should be based on a careful assessment of renal function.
•Renal Impairment: No dose adjustment of INVOKAMET™ is needed in patients with mild renal impairment or normal renal function (eGFR ≥60 mL/min/1.73 m2). INVOKAMET™ should not be used in patients with severe renal impairment (eGFR <30 mL/min/1.73 m2), with end-stage renal disease, or receiving dialysis.
OVERDOSAGE
•In the event of an overdose with INVOKAMET™, contact the Poison Control Center. Employ the usual supportive measures (eg, remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive treatment) as needed.
Canagliflozin
There were no reports of overdose during the clinical development program of canagliflozin.
Metformin
Overdose of metformin hydrochloride has occurred, including ingestion of amounts >50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin hydrochloride has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases.
ADVERSE REACTIONS
•The most common (≥5%) adverse reactions with canagliflozin were female genital mycotic infections, urinary tract infections, and increased urination.
•The most common adverse reactions due to initiation of metformin are diarrhea, nausea/vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache.