Alogliptin and metformin

What is Alogliptin and metformin?

• Alogliptin and metformin (KAZANO) is a dipeptidyl-peptidase-4 (DPP-4) inhibitor and a biguanide combination product used along with diet and exercise to improve blood sugar (glucose) control in adults with type 2 diabetes.

What are the uses of this medicine?

• This medicine contains 2 prescription diabetes medicines, alogliptin (NESINA) and metformin hydrochloride.
• KAZANO is a prescription medicine used along with diet and exercise to improve blood sugar (glucose) control in adults with type 2 diabetes.

Limitations of Use:

• KAZANO is not for people with type 1 diabetes.
• KAZANO is not for people with diabetic ketoacidosis (increased ketones in blood or urine).

How does this medicine work?

Alogliptin

• Alogliptin (al" oh glip' tin) is an inhibitor of dipeptidyl peptidase-4, which is the major enzyme responsible for the degradation of glucagon-like peptide-1 (GLP-1), an important gastrointestinal hormone (incretin) that increases glucose dependent insulin secretion by the pancreas.
• By prolonging the effect of GLP-1, alogliptin increases insulin levels and lowers blood glucose and helps in glycemic control in patients with type 2 diabetes.

Metformin

• Metformin is a biguanide that improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose.
• Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.
• With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and daylong plasma insulin response may actually decrease.

Who Should Not Use this medicine ?

This medicine cannot be used in patients who:

• have severe kidney problems
• have a condition called metabolic acidosis or have had diabetic ketoacidosis (increased ketones in your blood or urine)
• are going to get an injection of dye or contrast agents for an x-ray procedure, KAZANO may need to be stopped for a short time. Talk to your doctor about when you should stop KAZANO and when you should start KAZANO again
• are allergic to alogliptin (NESINA) or metformin or any of the ingredients in KAZANO or have had a serious allergic (hypersensitivity) reaction to alogliptin or metformin. See the end of this Medication Guide for a complete list of the ingredients in KAZANO

What drug interactions can this medicine cause?

• Concomitant use of carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) drugs with KAZANO may increase the risk of lactic acidosis.
• Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE] inhibitors such as ranolazine, vandetanib, dolutegravir, and cimetidine) could increase systemic exposure to metformin and may increase the risk for lactic acidosis
• Alcohol is known to potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake while receiving KAZANO.
• 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 blocking drugs and isoniazid. When such drugs are administered to a patient receiving KAZANO, the patient should be closely observed for loss of blood glucose control.

Is this medicine FDA approved?

• Initial U.S. Approval: 2013

How should this medicine be used?

Recommended Dosage:

• Healthcare providers should individualize the starting dose of KAZANO based on the patient's current regimen.
• KAZANO should be taken twice daily with food with gradual dose escalation to reduce the gastrointestinal (GI) side effects due to metformin. KAZANO tablets must not be split before swallowing.
• Dosing may be adjusted based on effectiveness and tolerability while not exceeding the maximum recommended daily dose of 25 mg alogliptin and 2000 mg metformin HCl.

Recommendations for Use in Renal Impairment

• KAZANO is contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m2

Administration

• Take KAZANO exactly as your doctor tells you to take it.
• Take KAZANO 2 times each day.
• Take KAZANO with food to lower your chances of having an upset stomach.
• Do not break or cut KAZANO tablets before swallowing.
• Your doctor may need to change your dose of KAZANO to control your blood glucose. Do not change your dose unless told to do so by your doctor.
• If you miss a dose, take it as soon as you remember. If you do not remember until it is time for your next dose, skip the missed dose, and take the next dose at your regular time. Do not take 2 doses of KAZANO at the same time.
• If you take too much KAZANO, call your doctor or go to the nearest hospital emergency room right away.
• If your body is under stress, such as from fever, infection, accident or surgery, the dose of your diabetes medicines may need to be changed. Call your doctor right away.
• Stay on your diet and exercise programs and check your blood sugar as your doctor tells you to.
• Your doctor may do certain blood tests before you start KAZANO and during treatment as needed. Your doctor may ask you to stop taking KAZANO based on the results of your blood tests due to how well your kidneys are working.
• Your doctor will check your diabetes with regular blood tests, including your blood sugar levels and your hemoglobin A1C.

What are the dosage forms and brand names of this medicine?

This medicine is available in fallowing doasage form: As Tablets: 12.5 mg alogliptin and 500 mg metformin HCl, 12.5 mg alogliptin and 1000 mg metformin HCl.

This medicine is available in fallowing brand namesː

• KAZANO

What side effects can this medication cause?

The most common side effects of this medicine include:

• cold-like symptoms (upper respiratory tract infection)
• increase in blood pressure
• urinary tract infection
• stuffy or runny nose and sore throat
• headache
• diarrhea
• back pain

KAZANO can cause serious side effects, including:

• Lactic Acidosis
• Inflammation of the pancreas (pancreatitis)
• Heart failure
• Allergic (hypersensitivity) reactions
• Liver problems
• Low blood sugar (hypoglycemia)
• Joint pain
• Skin reaction

What special precautions should I follow?

• Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. Educate patients and their families about the symptoms of lactic acidosis and if these symptoms occur instruct them to discontinue KAZANO and report these symptoms to their healthcare provider.
• The postmarketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. KAZANO is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2. Before initiating KAZANO, obtain an eGFR.
• Acute pancreatitis has been reported in the postmarketing setting and in randomized clinical trials. If pancreatitis is suspected, promptly discontinue KAZANO.
• Consider the risks and benefits of KAZANO 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 KAZANO.
• 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. In such cases, promptly discontinue KAZANO, assess for other potential causes, institute appropriate monitoring and treatment and initiate alternative treatment for diabetes.
• Postmarketing reports of hepatic failure, sometimes fatal. Causality cannot be excluded. If liver injury is detected, promptly interrupt KAZANO and assess patient for probable cause, then treat cause if possible, to resolution or stabilization. Do not restart KAZANO if liver injury is confirmed and no alternative etiology can be found.
• Metformin may lower vitamin B12 levels. Monitor hematologic parameters annually.
• When used with an insulin secretagogue (e.g., sulfonylurea) or with insulin, a lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia.
• 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
• There have been postmarketing reports of bullous pemphigoid requiring hospitalization in patients taking DPP-4 inhibitors. Tell patients to report development of blisters or erosions. If bullous pemphigoid is suspected, discontinue KAZANO.
• There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with KAZANO or any other antidiabetic drug.

What to do in case of emergency/overdose?

Alogliptin

• No serious adverse reactions have been reported.

Management of overdosage:

• In the event of an overdose, it is reasonable to institute the necessary clinical monitoring and supportive therapy as dictated by the patient's clinical status.
• Alogliptin is minimally dialyzable; over a three-hour hemodialysis session, approximately 7% of the drug was removed. Therefore, hemodialysis is unlikely to be beneficial in an overdose situation. It is not known if alogliptin is dialyzable by peritoneal dialysis.

Metformin Hydrochloride Symptoms of overdosage may include:

• Hypoglycemia
• Lactic acidosis

Management of overdosage:

• Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions.
• Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin overdosage is suspected.

Can this medicine be used in pregnancy?

• Limited available data with KAZANO or alogliptin in pregnant women are not sufficient to inform a drug-associated risk for major birth defects and miscarriage.

Can this medicine be used in children?

• Safety and effectiveness of KAZANO in pediatric patients have not been established.

What are the active and inactive ingredients in this medicine?

• Active ingredients: alogliptin and metformin hydrochloride
• Inactive ingredients: mannitol, microcrystalline cellulose, povidone, crospovidone and magnesium stearate; the tablets are film-coated with hypromellose 2910, talc, titanium dioxide and ferric oxide yellow.

Who manufactures and distributes this medicine?

• Distributed by Takeda Pharmaceuticals America, Inc. Lexington

What should I know about storage and disposal of this medication?

• Store KAZANO at room temperature between 68°F to 77°F (20°C to 25°C).
• Keep the container of KAZANO tightly closed.
• Keep KAZANO and all medicines out of the reach of children.

• Dailymed label info on Alogliptin and metformin
• FDA Alogliptin and metformin

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