Linagliptin and metformin

Name: Linagliptin and metformin

What should I discuss with my healthcare provider before taking linagliptin and metformin?

You should not use this medicine if you are allergic to metformin (Actoplus Met, Avandamet, Fortamet, Glucophage, Riomet), or:

  • if you have ever had a severe allergic reaction (breathing problems, swelling, severe skin rash) to linagliptin (Tradjenta);

  • if you have severe kidney disease; or

  • if you have diabetic ketoacidosis (call your doctor for treatment).

Some people taking metformin develop a serious condition called lactic acidosis. This may be more likely if you have liver or kidney disease, congestive heart failure, a heart attack or stroke, a severe infection, if you are 65 or older, if you are dehydrated, or if you drink a lot of alcohol. Talk with your doctor about your risk.

To make sure linagliptin and metformin is safe for you, tell your doctor if you have ever had:

  • kidney disease (your kidney function may need to be checked before you take this medicine);

  • liver disease;

  • heart disease;

  • pancreatitis;

  • gallstones;

  • high triglycerides (a type of fat in the blood);

  • alcoholism; or

  • if you are over 80 years old and have not recently had your kidney function checked.

If you need to have surgery or any type of x-ray or CT scan using a dye that is injected into your veins, you will need to temporarily stop taking linagliptin and metformin. Be sure your caregivers know ahead of time that you are using this medication.

Follow your doctor's instructions about using this medicine if you are pregnant or breast-feeding a baby. Blood sugar control is very important during pregnancy, and your dose needs may be different during each trimester of pregnancy. Your dose needs may also be different while you are breast-feeding.

It is not known whether linagliptin and metformin passes into breast milk or if it could affect the nursing baby. Tell your doctor if you are breast-feeding.

This medicine is not approved for use by anyone younger than 18 years old.

Commonly used brand name(s)

In the U.S.

  • Jentadueto
  • Jentadueto XR

Available Dosage Forms:

  • Tablet
  • Tablet, Extended Release

Therapeutic Class: Antidiabetic

Pharmacologic Class: Dipeptidyl Peptidase IV Inhibitor

Chemical Class: Metformin

Uses For linagliptin and metformin

Linagliptin and metformin combination is used to treat high blood sugar levels caused by type 2 diabetes. Linagliptin helps to control blood sugar levels by increasing substances in the body that make the pancreas release more insulin. It also signals the liver to stop producing sugar (glucose) when there is too much sugar in the blood. Metformin reduces the absorption of sugar from the stomach, reduces the release of stored sugar from the liver, and helps your body use sugar better. linagliptin and metformin does not help patients who have insulin-dependent or type 1 diabetes.

linagliptin and metformin is available only with your doctor's prescription.

Precautions While Using linagliptin and metformin

Your doctor will want to check your progress at regular visits, especially during the first few weeks that you take linagliptin and metformin. Blood and urine tests may be needed to check for unwanted effects.

Under certain conditions, too much metformin can cause lactic acidosis. The symptoms of lactic acidosis are severe and quick to appear, and usually occur when other health problems not related to the medicine are present and are very severe, such as a heart attack or kidney failure. Symptoms of lactic acidosis include: abdominal or stomach discomfort, decreased appetite, diarrhea, fast or shallow breathing, a general feeling of discomfort, muscle pain or cramping, and unusual sleepiness, tiredness, or weakness.

If symptoms of lactic acidosis occur, you should get immediate emergency medical help.

Do not let yourself get dehydrated. Be sure to drink extra fluids when you exercise or increase your activity or if you have vomiting or diarrhea.

Pancreatitis may occur while you are using linagliptin and metformin. Check with your doctor right away if you have a sudden and severe stomach pain, chills, constipation, nausea, vomiting, loss of appetite, a fever, or lightheadedness.

Let your doctor or dentist know you are taking linagliptin and metformin. Your doctor may advise you to temporarily stop taking linagliptin and metformin before you have major surgery or diagnostic tests including procedures that use contrast dye.

It is very important to carefully follow any instructions from your health care team about:

  • Alcohol—Drinking alcohol may cause severe low blood sugar. Discuss this with your health care team.
  • Other medicines—Do not take other medicines unless they have been discussed with your doctor. This especially includes nonprescription medicines such as aspirin, and medicines for appetite control, asthma, colds, cough, hay fever, or sinus problems.
  • Counseling—Other family members need to learn how to prevent side effects or help with side effects if they occur. Also, patients with diabetes may need special counseling about diabetes medicine dosing changes that might occur with lifestyle changes, such as changes in exercise or diet. Furthermore, counseling on contraception and pregnancy may be needed, because of the problems that can occur in patients with diabetes during pregnancy.
  • Travel—Keep a recent prescription and your medical history with you. Be prepared for an emergency as you would normally. Make allowances for changing time zones and keep your meal times as close as possible to your usual meal times.
  • In case of emergency—There may be a time when you need emergency help for a problem caused by your diabetes. You need to be prepared for these emergencies. It is a good idea to wear a medical identification (ID) bracelet or neck chain at all times. Also, carry an ID card in your wallet or purse that says you have diabetes and that lists all of your medicines.

linagliptin and metformin may cause hypoglycemia (low blood sugar). This is more common when linagliptin and metformin is taken together with certain medicines. Low blood sugar must be treated before it causes you to pass out (unconsciousness). People feel different symptoms of low blood sugar. It is important that you learn which symptoms you usually have so you can treat it quickly. Talk to your doctor about the best way to treat low blood sugar.

Hyperglycemia (high blood sugar) may occur if you do not take enough or skip a dose of your medicine, overeat or do not follow your meal plan, have a fever or infection, or do not exercise as much as usual. High blood sugar can be very serious and must be treated right away. It is important that you learn which symptoms you have in order to treat it quickly. Talk to your doctor about the best way to treat high blood sugar.

linagliptin and metformin may cause severe and disabling joint pain. Call your doctor right away if you have severe joint pain while using linagliptin and metformin.

linagliptin and metformin may cause bullous pemphigoid. Tell your doctor right away if you have large, hard skin blisters while you are using linagliptin and metformin.

Dosing Geriatric

Refer to adult dosing. The initial and maintenance dosing should be conservative, due to the potential for decreased renal function (monitor).

Dosing Renal Impairment

eGFR >45 mL/minute/1.73 m2: No dosage adjustment necessary.

eGFR 30 to 45 mL/minute/1.73 m2: Use is not recommended for initiation of therapy; if eGFR falls to <45 mL/minute/1.73 m2 during therapy, consider benefits/risks of continuing therapy.

eGFR <30 mL/minute/1.73 m2: Use is contraindicated.

Monitoring Parameters

HbA1c (at least twice yearly in patients who have stable glycemic control and are meeting treatment goals; quarterly in patients not meeting treatment goals or with therapy change [ADA 2017a]); serum glucose; hematologic parameters (eg, hemoglobin/hematocrit, red blood cell indices) annually; hepatic function, renal function (prior to initiation of therapy then at least annually or more frequently if necessary); vitamin B12 (periodically with long-term treatment) and folate (if megaloblastic anemia is suspected), signs/symptoms of pancreatitis

Pregnancy Considerations

Metformin crosses the placenta (ADA 2017c). Refer to individual agents.

For Healthcare Professionals

Applies to linagliptin / metformin: oral tablet, oral tablet extended release

General

The most commonly reported adverse events included nasopharyngitis and diarrhea.[Ref]

Metabolic

Linagliptin-Metformin:
Frequency not reported: Hypoglycemia

Linagliptin:
Common (1% to 10%): Hypertriglyceridemia, hyperlipidemia, weight increased

Metformin:
Very rare (less than 0.01%): Lactic acidosis, vitamin B12 deficiency[Ref]

Hypoglycemia was more commonly reported in patients receiving the combination linagliptin / metformin plus a sulfonylurea compared with those receiving metformin plus a sulfonylurea (22.9% vs 14.8%; n=792).[Ref]

Gastrointestinal

Gastrointestinal events such as nausea, vomiting, diarrhea, decreased appetite, and abdominal pain occur most frequently during initiation of therapy and resolve spontaneously in most cases.
During clinical trials, pancreatitis was reported in 15.2 cases per 10,000 patient year exposure in patients receiving linagliptin compared with 3.7 cases per 10,000 patient year exposure in those receiving active comparator (sulfonylurea). Following completion of clinical trials, 3 additional cases of pancreatitis were reported among those receiving linagliptin. Postmarketing reports of acute pancreatitis, including fatalities, have been received.[Ref]

Linagliptin-Metformin:
Common (1% to 10%): Decreased appetite, diarrhea, nausea, vomiting
Uncommon (0.1% to 1%): Increased blood amylase
Postmarketing reports: Mouth ulceration

Linagliptin:
Common (1% to 10%): Constipation, diarrhea
Frequency not reported: Pancreatitis

Metformin:
Very common (10% or more): Diarrhea, nausea, vomiting, abdominal pain, decreased appetite
Common (1% to 10%): Constipation
Frequency not reported: Flatulence, indigestion[Ref]

Hypersensitivity

Linagliptin-Metformin:
Rare (less than 0.1%): Drug hypersensitivity

Linagliptin
Postmarketing reports: Serious hypersensitivity reactions[Ref]

Serious hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions have been reported postmarketing in patients treated with linagliptin. These reactions have occurred within the first 3 months, with some occurring after the first dose.[Ref]

Respiratory

Linagliptin-Metformin
Common (1% to 10%): Nasopharyngitis (6.3%),
Uncommon (0.1% to 1%): Cough

Linagliptin
Common (1% to 10%): Nasopharyngitis, cough

Metformin
Common (1% to 10%): Nasopharyngitis[Ref]

Dermatologic

Postmarketing reports of bullous pemphigoid requiring hospitalization have been reported with dipeptidyl peptidase-4 (DPP-4) inhibitors use. These case typically recovered with topical or systemic immunosuppressive treatment and discontinuation of DPP-4 inhibitor.[Ref]

Linagliptin-Metformin:
Uncommon (0.1% to 1%): Pruritus
Postmarketing reports: Angioedema, urticaria, rash

Metformin:
Very rare (less than 0.01%): Skin reactions such as erythema, pruritus, and urticaria

Dipeptidyl peptidase-4 inhibitors:
Postmarketing reports: Bullous pemphigoid[Ref]

Hematologic

Metformin
Very rare (less than 0.01%): Megaloblastic anemia[Ref]

Hepatic

Metformin:
Very rare (less than 0.01%): Hepatitis, liver function test abnormalities[Ref]

Musculoskeletal

Linagliptin:
Frequency not reported: Myalgia, arthralgia[Ref]

Between October 2006 and December 2013, thirty-three cases of severe arthralgia have been reported to the FDA Adverse Event Reporting System Database. Each case involved the use of 1 or more dipeptidyl peptidase-4 (DPP-4) inhibitor. In all cases, substantial reduction in prior activity level was reported, 10 patients were hospitalized due to disabling joint pain. In 22 cases, symptoms appeared within 1 month of starting therapy, in 23 cases symptoms resolved less than 1 month after discontinuation. A positive rechallenge was reported in 8 cases, with 6 cases involving use of a different DPP-4 inhibitor. Sitagliptin had the greatest number of cases reported (n=28) followed by saxagliptin (n=5), linagliptin (n=2), alogliptin (n=1), and vildagliptin (n=2).[Ref]

Nervous system

Metformin:
Common (1% to 10%): Taste disturbance[Ref]

Genitourinary

Linagliptin:
Common (1% to 10%): Urinary tract infection,[Ref]

Psychiatric

Linagliptin:
Common (1% to 10%): Headache

Metformin:
Common (1% to 10%): Headache[Ref]

Some side effects of linagliptin / metformin may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Precautions

US BOXED WARNING: Risk of lactic acidosis
-Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis is characterized by elevated blood lactate levels (greater than 5 mmol/L), anion gap, acidosis (without evidence of ketonuria or ketonemia) and increased lactate/pyruvate ratio; and metformin plasma levels generally greater than 5 mcg/mL.
-Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., cationic drugs such as topiramate), age 65 years or greater, radiological study with contrast, surgery, and other procedures, hypoxic state (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment.
-Steps to reduce the risk of and manage metformin-associated lactic acidosis in high risk groups are provided in the full prescribing information.
-If metformin-associated lactic acidosis is suspected, immediately discontinue therapy and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.

Safety and efficacy have not been established in patients younger than 18 years.

Consult WARNINGS section for additional precautions.

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