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Alogliptin And Metformin Hydrochloride is a brand name for Alogliptin. The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: 1 INDICATIONS AND USAGE Alogliptin and metformin HCl tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Alogliptin and metformin HCl tablets are a combination of alogliptin, a dipeptidyl-peptidase-4 (DPP-4) inhibitor and metformin hydrochloride…
Verbatim from this product's FDA label. Tap a section to expand.
2 DOSAGE AND ADMINISTRATION Individualize the starting dosage based on the patient's current regimen. 1 ) Given orally twice daily with food. 1 ) Adjust the dosage based on effectiveness and tolerability while not exceeding the maximum recommended daily dosage of 25 mg alogliptin and 2000 mg metformin HCl.
1 ) Prior to initiation, assess renal function with estimated glomerular filtration rate (eGFR). 73 m 2 . Alogliptin and metformin HCl tablets may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures.
1 Recommended Dosage Individualize the starting dosage of alogliptin and metformin HCl tablets based on the patient’s current regimen. Alogliptin and metformin HCl tablets should be taken orally twice daily with food with gradual dose escalation to reduce the gastrointestinal (GI) side effects due to metformin.
Do not split tablets. Adjust the dosage based on effectiveness and tolerability while not exceeding the maximum recommended daily dose of 25 mg alogliptin and 2000 mg metformin hydrochloride (HCl). 2 Recommendations for Use in Renal Impairment Assess renal function prior to initiation of alogliptin and metformin HCl tablets and periodically thereafter.
1) ] . 73 m 2 because these patients require a lower daily dosage of alogliptin than what is available in the fixed combination alogliptin and metformin HCl tablets product. 73 m 2 or greater. 73 m 2 ; in patients with a history of liver disease, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast.
1) ] .
9) ] Most common adverse reactions (incidence ≥4%) are upper respiratory tract infection, nasopharyngitis, diarrhea, hypertension, headache, back pain and urinary tract infection. gov/medwatch . 1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Alogliptin and Metformin HCl Over 2,700 patients with type 2 diabetes mellitus have received alogliptin coadministered with metformin in four large, randomized, double-blind controlled clinical trials. The racial distribution of patients exposed to trial medication was 65% White, 20% Asian, 7% Black or African American, 4% American Indian or Alaska Native, 0% Native Hawaiian/Other Pacific Islander and 4% Multiracial or other racial groups.
The ethnic distribution was 23% Hispanic or Latino and 77% was not Hispanic or Latino. The mean exposure to alogliptin and metformin HCl tablets was 58 weeks, with more than 1,400 subjects treated for more than one year. These included two 26 week placebo-controlled trials, one 52 week active control study and an interim analysis of a 104 week active-controlled trial.
In the alogliptin and metformin HCl tablets arm, the mean duration of diabetes mellitus was approximately six years, the mean body mass index (BMI) was 31 kg/m 2 (56% of patients had a BMI ≥30 kg/m 2 ) and the mean age was 55 years (18% of patients ≥65 years of age).
In a pooled analysis of these four controlled clinical studies, the overall incidence of adverse reactions was 74% in patients treated with alogliptin and metformin HCl tablets compared to 75% treated with placebo. 0% in alogliptin.
Adverse reactions reported in ≥4% of patients treated with alogliptin and metformin HCl tablets and more frequently than in patients who received alogliptin, metformin or placebo are summarized in Table 1. Table 1. 5 mg Metformin Metformin – includes data pooled for patients receiving various doses of metformin Placebo N=2794 N=222 N=1592 N=106 Upper respiratory tract infection 224 (8) 6 (3) 105 (7) 3 (3) Nasopharyngitis 191 (7) 7 (3) 93 (6) 2 (2) Diarrhea 155 (6) 4 (2) 105 (7) 3 (3) Hypertension 154 (6) 5 (2) 96 (6) 6 (6) Headache 149 (5) 11 (5) 74 (5) 3 (3) Back pain 119 (4) 1 (1) 72 (5) 1 (1) Urinary tract infection 116 (4) 4 (2) 59 (4) 2 (2) Alogliptin A total of 14,778 patients with type 2 diabetes mellitus participated in 14 randomized, double-blind, controlled clinical trials of whom 9,052 subjects were treated with alogliptin, 3,469 subjects were treated with placebo and 2,257 were treated with an active comparator.
5 WARNINGS AND PRECAUTIONS Lactic acidosis: See boxed warning. 1 ) Pancreatitis: There have been postmarketing reports of acute pancreatitis. If pancreatitis is suspected, promptly discontinue alogliptin and metformin HCl tablets. 2 ) Heart failure: Consider the risks and benefits of alogliptin and metformin HCl tablets prior to initiating treatment in patients at risk for heart failure.
If heart failure develops, evaluate and manage according to current standards of care and consider discontinuation of alogliptin and metformin HCl tablets. 3 ) Hypersensitivity: There have been postmarketing reports of serious hypersensitivity reactions in patients treated with alogliptin such as anaphylaxis, angioedema and severe cutaneous adverse reactions, including Stevens-Johnson syndrome.
If hypersensitivity reactions occur, discontinue alogliptin and metformin HCl tablets, treat promptly and monitor until signs and symptoms resolve. 4 ) Hepatic effects: Postmarketing reports of hepatic failure, sometimes fatal. Causality cannot be excluded.
If liver injury is detected, promptly interrupt alogliptin and metformin HCl tablets and assess patient for probable cause, then treat cause if possible, to resolution or stabilization. Do not restart alogliptin and metformin HCl tablets if liver injury is confirmed and no alternative etiology can be found.
5 ) Vitamin B 12 deficiency: Metformin may lower vitamin B 12 levels. Measure hematologic parameters annually and B 12 at 2 to 3 year intervals and manage any abnormalties. 6 ) Hypoglycemia: Consider lowering the dosage of insulin secretagogue or insulin to reduce the risk of hypoglycemia when initiating Alogliptin and metformin HCl tablets.
7 ) Arthralgia: Severe and disabling arthralgia has been reported in patients taking DPP-4 inhibitors. Consider as a possible cause for severe joint pain and discontinue drug if appropriate. 8 ) Bullous pemphigoid: There have been postmarketing reports of bullous pemphigoid requiring hospitalization in patients taking DPP-4 inhibitors.
1) ]. Acute or chronic metabolic acidosis, including diabetic ketoacidosis with or without coma. 2) ] . 73 m 2 . ( 4 ) Metabolic acidosis, including diabetic ketoacidosis. ( 4 ) History of serious hypersensitivity to alogliptin or metformin or any of the excipients.
( 4 )
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The racial distribution of patients exposed to trial medication was 71% White, 17% Asian, 6% Black or African American, 2% American Indian or Alaska Native, 0% Native Hawaiian/Other Pacific Islander and 5% Multiracial or other racial groups.
The ethnic distribution was 30% Hispanic or Latino and 70% was not Hispanic or Latino. The mean duration of diabetes mellitus was seven years, the mean body mass index (BMI) was 31 kg/m 2 (49% of patients had a BMI ≥30 kg/m 2 ), and the mean age was 58 years (26% of patients ≥65 years of age).
The mean exposure to alogliptin was 49 weeks with 3,348 subjects treated for more than one year. In a pooled analysis of these 14 controlled clinical trials, the overall incidence of adverse reactions was 73% in patients treated with alogliptin 25 mg compared to 75% with placebo and 70% with active comparator.
2% with active comparator. Adverse reactions reported in ≥4% of patients treated with alogliptin 25 mg and more frequently than in patients who received placebo are summarized in Table 2. Table 2. 3% in the metformin HCl 1000 mg treatment groups.
9% in the placebo treatment groups. 5% in the pioglitazone 45 mg with metformin group. 8% in the glipizide with metformin group. Alogliptin Hypoglycemic events were documented based upon a blood glucose value and/or clinical signs and symptoms of hypoglycemia.
6% with placebo. The use of alogliptin as add-on therapy to glyburide or insulin did not increase the incidence of hypoglycemia compared to placebo. 4% with alogliptin compared to 26% with glipizide. 5% in patients receiving placebo. 6% of patients treated with placebo.
Metformin HCl Table 3. 8 Laboratory Abnormalities Alogliptin and Metformin HCl No clinically meaningful differences were observed among treatment groups regarding hematology, serum chemistry or urinalysis results. Metformin HCl In metformin clinical trials of 29 week duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels was observed in approximately 7% of patients.
2 Postmarketing Experience The following adverse reactions have been identified during postmarketing use. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Alogliptin Gastrointestinal Disorders: acute pancreatitis, diarrhea, constipation, nausea, ileus Hepatobiliary Disorders: fulminant hepatic failure Immune System Disorders: hypersensitivity reactions including anaphylaxis Investigations: hepatic enzyme elevations Musculoskeletal and Connective Tissue Disorders: severe and disabling arthralgia, rhabdomyolysis Renal and Urinary Disorders: tubulointerstitial nephritis Skin and Subcutaneous Tissue Disorders: angioedema, rash, urticaria and severe cutaneous adverse reactions including Stevens-Johnson syndrome, bullous pemphigoid Metformin Hepatobiliary Disorders: Cholestatic, hepatocellular, mixed hepatocellular liver injury
Tell patients to report development of blisters or erosions. If bullous pemphigoid is suspected, discontinue alogliptin and metformin HCl tablets. 1 Lactic Acidosis Lactic Acidosis There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases.
These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypothermia, hypotension and resistant bradyarrhythmias have occurred with severe acidosis.
Metformin-associated lactic acidosis was characterized by elevated blood lactate concentrations (greater than 5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate:pyruvate ratio; metformin plasma levels generally greater than 5 mcg/mL.
Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk. If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of alogliptin and metformin HCl tablets.
In alogliptin and metformin HCl tablets-treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin HCl is dialyzable, with a clearance of up to 170 mL/min under good hemodynamic conditions).
Hemodialysis has often resulted in reversal of symptoms and recovery. Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue alogliptin and metformin HCl tablets and report these symptoms to their healthcare provider.
For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below: Renal Impairment The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment.
The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. 3) ]: Before initiating alogliptin and metformin HCl tablets, obtain an eGFR.
73 m 2 [see Contraindications (4) ] . 73 m 2 because these patients require a lower dosage of alogliptin than what is available in the fixed combination alogliptin and metformin HCl tablets product. Obtain an eGFR at least annually in all patients taking alogliptin and metformin HCl tablets.
, the elderly), renal function should be assessed more frequently. Drug Interactions The concomitant use of alogliptin and metformin HCl tablets with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance or increase metformin accumulation [see Drug Interactions (7) ].
Therefore, consider more frequent monitoring of patients. Age 65 or Greater The risk of metformin-associated lactic acidosis increases with the patient's age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients.
5) ]. Radiological Studies with Contrast Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. 73 m 2 ; in patients with a history of hepatic impairment, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast.
Re-evaluate eGFR 48 hours after the imaging procedure, and restart alogliptin and metformin HCl tablets if renal function is stable. Surgery and Other Procedures Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension and renal impairment.
Alogliptin and metformin HCl tablets should be temporarily discontinued while patients have restricted food and fluid intake. Hypoxic States Several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia).
Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur, discontinue alogliptin and metformin HCl tablets.
Excessive Alcohol Intake Alcohol potentiates the effect of metformin on lactate metabolism and this may increase the risk of metformin-associated lactic acidosis. Warn patients against excessive alcohol intake while receiving alogliptin and metformin HCl tablets.
Hepatic Impairment Patients with hepatic impairment have developed with cases of metformin-associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of alogliptin and metformin HCl tablets in patients with clinical or laboratory evidence of hepatic disease.
2 Pancreatitis Acute pancreatitis has been reported in the postmarketing setting and in randomized clinical trials. 1%) patients treated with active comparators or placebo. 3%) patients treated with placebo. It is unknown whether patients with a history of pancreatitis are at increased risk for pancreatitis while using alogliptin and metformin HCl tablets .
After initiation of alogliptin and metformin HCl tablets, patients should be observed for signs and symptoms of pancreatitis. If pancreatitis is suspected, alogliptin should promptly be discontinued and appropriate management should be initiated.
3%) of patients treated with placebo were hospitalized for congestive heart failure. Consider the risks and benefits of alogliptin and metformin HCl tablets prior to initiating treatment in patients at risk for heart failure, such as those with a prior history of heart failure and a history of renal impairment, and observe these patients for signs and symptoms of heart failure during therapy.
Patients should be advised of the characteristic symptoms of heart failure and should be instructed to immediately report such symptoms. If heart failure develops, evaluate and manage according to current standards of care and consider discontinuation of alogliptin and metformin HCl tablets.
2) ] . These reactions include anaphylaxis, angioedema and severe cutaneous adverse reactions, including Stevens-Johnson syndrome. If a serious hypersensitivity reaction is suspected, discontinue alogliptin and metformin HCl tablets, assess for other potential causes for the event and institute alternative treatment for diabetes mellitus.
Use caution in patients with a history of angioedema with another dipeptidyl peptidase-4 (DPP-4) inhibitor because it is unknown whether such patients will be predisposed to angioedema with alogliptin and metformin HCl tablets. 2) ].
7% of patients treated with active comparators or placebo. 8% of patients treated with placebo. Measure liver tests promptly in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice.
In this clinical context, if the patient is found to have clinically significant liver enzyme elevations and if abnormal liver tests persist or worsen, alogliptin and metformin HCl tablets should be interrupted and investigation done to establish the probable cause.
Alogliptin and metformin HCl tablets should not be restarted in these patients without another explanation for the liver test abnormalities. 6 Vitamin B 12 Levels In metformin clinical trials of 29 week duration, a decrease to subnormal levels of previously normal serum vitamin B 12 levels was observed in approximately 7% of patients.
Such decrease, possibly due to interference with B 12 absorption from the B 12 -intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin or vitamin B 12 supplementation.
Certain individuals (those with inadequate vitamin B 12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B 12 levels. 1) ] . 7 Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues Insulin and insulin secretagogues, such as sulfonylureas, are known to cause hypoglycemia.
Therefore, a lower dosage of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with alogliptin and metformin HCl tablets. 8 Severe and Disabling Arthralgia There have been postmarketing reports of severe and disabling arthralgia in patients taking DPP-4 inhibitors.
The time to onset of symptoms following initiation of drug therapy varied from one day to years. Patients experienced relief of symptoms upon discontinuation of the medication. A subset of patients experienced a recurrence of symptoms when restarting the same drug or a different DPP-4 inhibitor.
Consider DPP-4 inhibitors as a possible cause for severe joint pain and discontinue drug if appropriate. 9 Bullous Pemphigoid Postmarketing cases of bullous pemphigoid requiring hospitalization have been reported with DPP-4 inhibitor use.
In reported cases, patients typically recovered with topical or systemic immunosuppressive treatment and discontinuation of DPP-4 inhibitor. Tell patients to report development of blisters or erosions while receiving alogliptin and metformin HCl tablets.
If bullous pemphigoid is suspected, alogliptin and metformin HCl tablets should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.