Linagliptin-Metformin

Linagliptin/Metformin is a combination medication used to treat the symptoms of Type 2 Diabetes Mellitus. 

• Linagliptin/Metformin is available under the following different brand names: Jentadueto, Jentadueto XR

Common side effects of Linagliptin/Metformin include:

• Sore throat,
• Sinus pain,
• Stuffy nose, and
• Diarrhea

Serious side effects of Linagliptin/Metformin include:

• Hives,
• Difficulty breathing,
• Swelling of the face, lips, tongue, or throat,
• Fever,
• Sore throat,
• Burning eyes,
• Skin pain,
• Red or purple skin rash with blistering and peeling,
• Severe pain in the upper stomach spreading to the back,
• Nausea,
• Vomiting,
• Loss of appetite,
• Fast heartbeats,
• Unusual muscle pain,
• Feeling cold,
• Dizziness,
• Lightheadedness,
• Tiredness,
• Weakness,
• Stomach pain,
• Slow or irregular heart rate,
• Itching,
• Blisters,
• Breakdown of the outer layer of skin,
• Severe or ongoing pain in the joints,
• Shortness of breath,
• Swelling in the legs or feet, and
• Rapid weight gain

Rare side effects of Linagliptin/Metformin include:

• None 

Seek medical care or call 911 at once if you have the following serious side effects:

• Severe headache, confusion, slurred speech, arm or leg weakness, trouble walking, loss of coordination, feeling unsteady, very stiff muscles, high fever, profuse sweating, or tremors;
• Serious eye symptoms such as sudden vision loss, blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights;
• Serious heart symptoms include fast, irregular, or pounding heartbeats; fluttering in the chest; shortness of breath; sudden dizziness, lightheadedness, or passing out. 

This is not a complete list of side effects and other serious side effects or health problems that may occur because of the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may report side effects or health problems to FDA at 1-800-FDA-1088.

Adult dosage

Tablet (Jentadueto)

• 2.5 mg/500 mg
• 2.5 mg/850 mg
• 2.5 mg/1000 mg

Extended-release tablet (Jentadueto XR)

• 2.5 mg/1000 mg
• 5 mg/1000 mg

Type 2 Diabetes Mellitus

Adult dosage

• Prompt-release tablets
  • Initial dose (not currently taking metformin): 2.5 mg/500 mg orally two times a day
  • Initial dose (already taking metformin): Base dose on current metformin dose (. g, if taking metformin 1000 mg orally two times a day, initiate with 2.5 mg/1000 mg orally two times a day)
  • Not to exceed 2.5 mg/1,000 mg two times a day
• Extended-release tablets
  • Individualize dose because of both effectiveness and tolerability, while not exceeding the maximum recommended total daily dose of linagliptin/metformin 5 mg/2000 mg
  • Initial dose (not currently taking metformin): 5 mg/1000 mg orally once a day 
  • Initial dose (already taking metformin): 5 mg of linagliptin total daily dose and a similar total daily dose of metformin once a day
  • Switch from prompt-release linagliptin/metformin: 5 mg of linagliptin total daily dose and a similar total daily dose of metformin once a day

Dosage Considerations – Should be Given as Follows: 

• See “Dosages”

If your medical doctor is using this medicine to treat your pain, your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor, health care provider, or pharmacist first.

• Linagliptin/Metformin has severe interactions with no other drugs.
• Linagliptin/Metformin has serious interactions with at least 28 other drugs.
• Linagliptin/Metformin has moderate interactions with at least 252 other drugs.
• Linagliptin/Metformin has moderate interactions with at least 76 other drugs.

This information does not contain all possible interactions or adverse effects. Visit the RxList Drug Interaction Checker for any drug interactions. Therefore, before using this product, tell your doctor or pharmacist about all your products. Keep a list of all your medications with you and share this information with your doctor and pharmacist. Check with your healthcare professional or doctor for additional medical advice, or if you have health questions or concerns.

Contraindications

• Renal impairment (. g, eGFR below 30 ml/min/1.73 m²) which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis
• History of hypersensitivity reaction to linagliptin (. g, urticaria, angioedema, bronchial hyperreactivity) or metformin

Effects of drug abuse

• None

Short-Term Effects

• See “What Are Side Effects Associated with Using Linagliptin/Metformin?”

Long-Term Effects

• See “What Are Side Effects Associated with Using Linagliptin/Metformin?”

Cautions

• Diabetic ketoacidosis should be treated with insulin
• Monitor hepatic and renal function; risk of metformin accumulation and lactic acidosis increases with renal impairment; hepatic impairment limits the ability to clear lactate
• Avoid excessive alcohol intake; alcohol is known to potentiate the effect of metformin on lactate metabolism
• Use of concomitant medications that may affect renal function or metformin disposition
• Use in combination with an insulin secretagogue (.g, sulfonylurea) was associated with a higher rate of hypoglycemia compared with a placebo in a clinical trial; therefore, a lower dose of insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia when used in combination with this drug
• Cardiovascular collapse (shock) from whatever cause (. g, acute congestive heart failure, acute myocardial infarction, and other conditions characterized by hypoxemia) has been associated with lactic acidosis and may also cause prerenal azotemia; discontinue drug promptly
• Severe and disabling arthralgia reported in patients taking DPP-4 inhibitors; consider as a possible cause for severe joint pain and discontinue drug if appropriate
• No conclusive evidence of macrovascular risk reduction was reported with antidiabetic drugs
• Serious hypersensitivity reactions were reported including anaphylaxis, angioedema, and exfoliative skin conditions; discontinue therapy promptly, assess for other potential causes, institute appropriate monitoring and treatment, and initiate alternative treatment for diabetes
• Heart failure has been observed with two other members of the DPP-4 inhibitor class; consider risks and benefits of empagliflozin in patients with risk factors for heart failure; monitor for signs and symptoms; if heart failure develops, manage accordingly to the standard of care, and consider interrupting treatment; advise patients of the characteristic symptoms of heart failure and to immediately report such symptoms
• Bullous pemphigoid reported with DPP-4 inhibitor use, which required hospitalization; in reported cases, patients recovered with topical or systemic immunosuppressive treatment and discontinuation of DPP-4 inhibitor; patients should report development blisters/erosions; discontinue DPP-4 therapy and consult a dermatologist if bullous pemphigoid suspected
• Vitamin B12 deficiency
  • May lead to decreased levels of vitamin B12 without clinical manifestations (occurred in approximately 7% of patients)
  • Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels
  • Measure hematologic parameters on an annual basis and vitamin B12 at 2 to 3-year intervals in patients on this drug and manage any abnormalities
• Iodinated contrast imaging procedures
  • Discontinue metformin at the time of or before an iodinated contrast imaging procedure in patients with an eGFR between 30-60 mL/minute/1.73 m²; in patients with a history of liver disease, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast
  • Reevaluate eGFR 48 hr after the imaging procedure; restart metformin if renal function is stable
• Pancreatitis
  • Post-marketing reports of acute pancreatitis, including fatal pancreatitis; monitor for signs and symptoms of pancreatitis, and discontinue if suspected
  • Unknown if patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using linagliptin
• Lactic acidosis
  • 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 therapy
  • In treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin is dialyzable, with 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 therapy and report these symptoms to their healthcare provider
  • Withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension, and renal impairment; therapy should be temporarily discontinued while patients have restricted food and fluid intake
  • Several of the post-marketing 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 therapy
  • 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 this drug
  • Patients with hepatic impairment have developed cases of metformin-associated lactic acidosis; this may be due to impaired lactate clearance resulting in higher lactate blood levels; therefore, avoid the use of this drug in patients with clinical or laboratory evidence of hepatic disease
  • The post-marketing 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
• Clinical recommendations for renal impairment
• Before initiating therapy, obtain an estimated glomerular filtration rate (eGFR)
  • Therapy is contraindicated in patients with an eGFR below 30 mL/min/1.73 m2
  • Initiation of therapy is not recommended in patients with eGFR between 30 – 45 mL/min/1.73 m2
  • Obtain an eGFR at least annually in all patients receiving therapy; in patients at increased risk for the development of renal impairment (. g, the elderly), renal function should be assessed more frequently
  • In patients receiving therapy whose eGFR later falls below 45 mL/min/1.73 m2 assess the benefits and risks of continuing therapy
• Drug interaction overview
  • Concomitant use of this drug with specific drugs may increase the risk of metformin-associated lactic acidosis, including drugs that impair renal function, result in significant hemodynamic change, interfere with acid-base balance, or increase metformin accumulation; therefore, consider more frequent monitoring of patients
  • Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and occurrence of lactic acidosis; stop this drug at the time of, or before, an iodinated contrast imaging procedure in patients with an eGFR between 30 and60 mL/min/1.73 m2; 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 imaging procedure, and restart therapy if renal function is stable

Pregnancy and Lactation

• Limited data on pregnant women are not sufficient to inform associated risk for major birth defects and miscarriage with the product; published studies with metformin use during pregnancy have not reported a clear association between metformin and major birth defect or miscarriage risk; there are risks to mother and fetus associated with poorly controlled diabetes in pregnancy
• Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, and delivery complications; poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia-related morbidity
• Lactation
  • There is no information regarding the presence of the product in human milk, its effects on the breastfed infant, or its effects on milk production; however, linagliptin is present in rat milk; limited studies report that metformin is present in human milk; there is insufficient information to determine effects of metformin on the breastfed infant and no available information on effects of metformin on milk production; therefore, developmental and health benefits of breastfeeding should be considered along with mother’s clinical need for therapy and any potential adverse effects on the breastfed child from therapy or underlying maternal condition