Linaglip-M 5/1000 ER (4pcs)

Indications

When treatment with both Linagliptin and Metformin is appropriate, Linaglip-M is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Linagliptin and Metformin are not recommended for the treatment of type 1 diabetes or diabetic ketoacidosis and have not been studied in patients with a history of pancreatitis.

Pharmacology

Linaglip-M combines two antihyperglycemic agents with complementary mechanisms of action (Linagliptin, a DPP-4 inhibitor, and Metformin, a member of the biguanide class) to improve glycemic control in patients with type 2 diabetes mellitus.

Linagliptin is a DPP-4 inhibitor, which degrades the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). As a result, Linagliptin raises the concentrations of active incretin hormones, stimulating the release of insulin in a glucose-dependent manner while decreasing glucagon levels in the blood. Both incretin hormones play a role in the physiological control of glucose homeostasis. Throughout the day, incretin hormones are secreted at a low basal level, and levels rise immediately after meals. In the presence of normal and elevated blood glucose levels, GLP-1 and GIP increase insulin biosynthesis and secretion from pancreatic beta cells. Furthermore, GLP-1 inhibits glucagon secretion from pancreatic alpha cells, lowering hepatic glucose output.

Metformin reduces both basal and postprandial plasma glucose levels. It does not stimulate insulin secretion and thus does not cause hypoglycemia or weight gain. Metformin may lower blood glucose levels through four different mechanisms:

- by lowering hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis;

- in muscle, by improving peripheral glucose uptake and utilization by modestly increasing insulin sensitivity;

- by delaying intestinal glucose absorption; 

- by increasing the transport capacity of glucose transporters and stimulating intracellular glycogen synthesis by acting on glycogen synthase (GLUT-1 & GLUT-4)

Dosage and Administration

Starting dose for 2.5/500 & 2.5/850 mg tablets:

• Patients who are not currently taking Metformin should begin treatment with Linaglip-M 2.5/500 tablet twice daily.
• Patients receiving Metformin: If the patient is receiving Metformin 500 mg tablet twice daily, administer Linaglip-M 2.5/500 tablet twice daily. If the patient is already taking Metformin 850 mg twice daily, give him/her Linaglip-M 2.5/850 tablet twice daily.
• Patients who have previously received individual components of Linagliptin and Metformin: It is possible to switch to Linaglip-M, which contains the same doses of each component.

The following is the recommended starting dose for a 5/1000 mg ER tablet:

• In patients who are not currently taking metformin: Begin taking Linaglip-M 5/1000 ER tablet once a day with a meal.
• In patients who have previously been treated with metformin: Begin taking Linaglip-M 5/1000 ER tablet once a day with a meal.
• In patients who have previously received linagliptin and metformin or their combination: Change to Linaglip-M 5/1000 ER tablet once daily with a meal that contains the same doses of each component.

Interaction

Drug Interactions with Metformin

• Cationic Drugs: Cationic drugs that are eliminated by renal tubular secretion (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin) have the potential to interact with Metformin by competing for common renal tubular transport systems. Although such interactions are still theoretical (with the exception of cimetidine), careful patient monitoring and dose adjustment of the Linagliptin & Metformin combination and/or the interfering drug is advised in patients who are taking cationic medications excreted via the proximal renal tubular secretory system.
• Topiramate and other carbonic anhydrase inhibitors (such as zonisamide, acetazolamide, or dichlorphenamide) frequently lower serum bicarbonate and cause the non-anion gap and hyperchloremic metabolic acidosis. Concurrent use of these drugs may result in metabolic acidosis. Use these medications with caution in patients taking Linagliptin and Metformin, as the risk of lactic acidosis may increase.
• Alcohol is known to enhance metformin's effect on lactate metabolism. Warn patients not to drink too much alcohol while taking a combination of Linagliptin and Metformin extended-release tablet.

Drug Interactions with Linagliptin

• P-glycoprotein and CYP3A4 Enzyme Inducers: Rifampin decreased Linagliptin exposure, implying that the efficacy of Linagliptin may be reduced when combined with a strong P-GP inducer or CYP 3A4 inducer. Because Linagliptin & Metformin combination is a fixed-dose combination of Linagliptin and Metformin, it is strongly advised to use alternative treatments (not containing Linagliptin) when concomitant treatment with a strong P-GP or CYP 3A4 inducer is required.

Insulin Secretagogues or Insulin

• To reduce the risk of hypoglycemia, coadministration of Linagliptin & Metformin extended-release tablets with an insulin secretagogue (e.g., sulfonylurea) or insulin may necessitate lower doses of the insulin secretagogue or insulin.

Drugs Affecting Glycemic Control

• Certain medications can cause hyperglycemia and lead to a loss of glycemic control. Thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel-blocking drugs, and isoniazid are examples of these medications. When such medications are given to a patient who is taking a combination of Linagliptin and Metformin extended-release tablets, the patient should be closely monitored to ensure adequate glycemic control. When such medications are removed from a patient who is taking a combination of Linagliptin and Metformin extended-release tablets, the patient should be closely monitored for hypoglycemia.

Contraindications

This combination of Linagliptin and Metformin is not recommended for patients who have a renal impairment (e.g., serum creatinine >1.5 mg/dL for men, >1.4 mg/dL for women, or abnormal creatinine clearance), which can be caused by conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia. This combination is also not recommended if you have acute or chronic metabolic acidosis, such as diabetic ketoacidosis. Insulin should be used to treat diabetic ketoacidosis in the event of a previous history of hypersensitivities to Linagliptin, such as anaphylaxis, angioedema, exfoliative skin conditions, urticaria, or bronchial hyperreactivity. It is also not recommended if you are allergic to Metformin.

Side effects

The most common side effects of this combination of Linagliptin & Metformin are weakness or tiredness, unusual muscle pain, breathing in trouble, nausea, vomiting, diarrhea, dizziness. Adverse reactions reported in >5% of patients treated with Linagliptin & Metformin combination and more commonly than in patients treated with placebo are nasopharyngitis and diarrhea. Hypoglycemia was more commonly reported in patients treated with the combination of Linagliptin & Metformin and SU compared with those treated with the combination of SU and Metformin.

Pregnancy & Lactation

Pregnancy: Linagliptin & Metformin combination is pregnancy Category B. Linagliptin & Metformin combination tablets should be used during pregnancy only if clearly needed. But the limited data on the combination of Linagliptin & Metformin combination extended-release tablet use in pregnant women are not sufficient to inform a Linagliptin & Metformin extended-release combination - associated or Linagliptin-associated risk for major birth defects and miscarriage.

Nursing mothers: There is no information regarding the presence of both Linagliptin & Metformin combination and Linagliptin & Metformin combination extended-release tablet or Linagliptin in human milk, the effects on the breastfed infant, or the effects on milk production.

Precautions & Warnings

• Lactic acidosis: Avoid excessive alcohol consumption. The combination of linagliptin and metformin is not recommended in hepatic or hypoxic states, and it is also contraindicated in renal impairment. Check renal function before starting and at least once a year after that.
• Hypoglycemia: When used in conjunction with an insulin secretagogue (e.g., sulfonylurea (SU)) or insulin, consider lowering the insulin secretagogue or insulin dose to reduce the risk of hypoglycemia. There have been postmarketing reports of severe hypersensitivity reactions, including anaphylaxis, angioedema, and exfoliative skin conditions, in patients treated with Linagliptin (one of the components of the Linagliptin & Metformin combination). In such cases, discontinue the Linagliptin/Metformin combination immediately, assess for other potential causes, institute appropriate monitoring and treatment, and begin alternative diabetes treatment.
• Metformin has been linked to vitamin B12 deficiency. Hematologic parameters should be checked on an annual basis.
• Arthralgia: Severe and disabling arthralgia has been reported in DPP-4 inhibitor patients. Consider it as a possible cause of severe joint pain and, if necessary, discontinue the medication.
• Macrovascular outcomes: There is no conclusive evidence that the combination of Linagliptin and Metformin, or any other antidiabetic drug, reduces macrovascular risk.
• If pancreatitis is suspected, discontinue the Linagliptin/Metformin combination immediately.

Storage Conditions

Store at 25°C and dry place, protect from light. Keep out of the reach of children.