Linagliptin and metformin hydrochloride 2.5 mg; 1000 mg Tablet, Film Coated, 180-count
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This medicine belongs to the Dipeptidyl Peptidase 4 Inhibitor class.
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🩺 Clinical
Linagliptin is used along with diet and exercise and sometimes with other medications to lower blood sugar levels in patients with type 2 diabetes (condition in which blood sugar is too high because the body does not produce or use insulin normally). Linagliptin is in a class of medications called dipeptidyl peptidase-4 (DPP-4) inhibitors. It works by increasing the amounts of certain natural substances that lower blood sugar when it is high. Linagliptin is not used to treat type 1 diabetes (condition in which the body does not produce insulin and, therefore, cannot control the amount of sugar...
Read the full MedlinePlus article ↗- It's combining two different medicines in one tablet to tackle high blood sugar in two ways. The linagliptin part helps your body release more insulin after meals and tells your li...
- What exactly is this medicine doing for my diabetes?
- Lactic acidosis is rare, but it's serious enough that the FDA put a prominent warning on this medicine. Your risk is low if your kidneys are working well, you don't drink heavily,...
- I've heard metformin can cause a serious problem with lactic acid. Should I be worried?
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| Price system | Per each | Per package |
|---|---|---|
| Retail pharmacies payNADAC · weekly | Not in the retail survey — common for institutional, discontinued, or low-volume packs. | |
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🔁 Therapeutic equivalents
| Product | Labeler | Pack | NADAC/unit | TE | Status | Price vs. this |
|---|---|---|---|---|---|---|
| Jentadueto 2.5 mg/1; 1000 mg 00597-0148-18 | Boehringer | 180 tablets | $8.440 | AB | Availability likely | — |
| Linagliptin and metformin hydrochloride 2.5 mg/1; 1000 mgthis 72205-0409-02 | Novadoz | 180 tablets | — | AB | FDA listed | — |
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This product is an FDA-approved generic. Other versions of the same drug are listed under Therapeutic equivalents, least expensive first.
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📦 Packaging — all sizes for this product
| Package NDC | Description | Marketing start | Status |
|---|---|---|---|
| 72205-0409-01 | 60 TABLET, FILM COATED in 1 BOTTLE (72205-409-01) | 2025-11-04 | Active |
| 72205-0409-02 You're viewing this | 180 TABLET, FILM COATED in 1 BOTTLE (72205-409-02) | 2025-11-04 | Active |
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| NDC identity (package / product / labeler codes) | ✓ Available |
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| Marketing category & status | ✓ Available |
| Active ingredient / dosage form / route | ✓ Available |
| FDA label (SPL via DailyMed) | ✓ Available |
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| Inactive ingredients (structured) | — Not published for this NDC The labeler did not submit a structured excipient list, or no SPL is available. |
| NADAC pharmacy acquisition price (CMS) | — Not published for this NDC CMS publishes NADAC only for NDCs reported in its retail-pharmacy survey. |
| Orange Book / therapeutic-equivalence data | ✓ Available |
| HCPCS J-code billing crosswalk | — Not published for this NDC Most self-administered / retail products have no J-code — that is normal. |
| Medicaid utilization (CMS SDUD) | — Not published for this NDC CMS reports utilization only for NDCs with Medicaid claims above its privacy threshold. |
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📄 Full prescribing information FDA SPL
🚨 Boxed Warning ▾
WARNING: 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 was characterized by elevated blood lactate levels (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL [see Warnings and Precautions (5.1) ].
Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (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 these high risk groups are provided in the full prescribing information [see Dosage and Administration (2.2) , Contraindications (4) , Warnings and Precautions (5.1) , Drug Interactions (7) , and Use in Specific Populations (8.6 , 8.7 )].
If metformin-associated lactic acidosis is suspected, immediately discontinue linagliptin and metformin hydrochloride and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended [see Warnings and Precautions (5.1) ]. WARNING: LACTIC ACIDOSIS See full prescribing information for complete boxed warning.
Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. Symptoms included malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Laboratory abnormalities included elevated blood lactate levels, anion gap acidosis, increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL.
( 5.1 ) Risk factors include renal impairment, concomitant use of certain drugs, age ≥65 years old, radiological studies with contrast, surgery and other procedures, hypoxic states, excessive alcohol intake, and hepatic impairment. Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the Full Prescribing Information. ( 5.1 ) If lactic acidosis is suspected, discontinue linagliptin and metformin hydrochloride and institute general supportive measures in a hospital setting.
Prompt hemodialysis is recommended. ( 5.1 )
🎯 Indications and Usage ▾
1 INDICATIONS AND USAGE Linagliptin and metformin hydrochloride tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitations of Use Linagliptin and metformin hydrochloride tablets are not recommended in patients with type 1 diabetes mellitus. Linagliptin and metformin hydrochloride tablets have not been studied in patients with a history of pancreatitis.
It is unknown whether patients with a history of pancreatitis are at an increased risk for the development of pancreatitis while using linagliptin and metformin hydrochloride tablets [see Warnings and Precautions (5.2 )]. Linagliptin and metformin hydrochloride tablets are a combination of linagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor and metformin hydrochloride (HCl), a biguanide, indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus ( 1 ) Limitations of Use • Not recommended in patients with type 1 diabetes mellitus ( 1 ) • Has not been studied in patients with a history of pancreatitis ( 1 )
⏱️ Dosage and Administration ▾
2 DOSAGE AND ADMINISTRATION • Individualize the starting dosage of linagliptin and metformin hydrochloride tablets based on the patient's current regimen ( 2.1 ) • The maximum recommended dosage is 2.5 mg linagliptin/1,000 mg metformin HCl twice daily ( 2.1 ) • Take orally twice daily with meals, with gradual dosage escalation to reduce the gastrointestinal effects due to metformin ( 2.1 ) • Prior to initiation, assess renal function with estimated glomerular filtration rate (eGFR) ( 2.2 ) o Do not use in patients with eGFR below 30 mL/min/1.73 m 2 o Initiation is not recommended in patients with eGFR between 30 to 45 mL/min/1.73 m 2 o Assess risk/benefit of continuing if eGFR falls below 45 mL/min/1.73 m 2 o Discontinue if eGFR falls below 30 mL/min/1.73 m 2 • Linagliptin and metformin hydrochloride tablets may need to be discontinued at time of, or prior to, iodinated contrast imaging procedures ( 2.3 )
2.1Recommended Dosage and Administration The dosage of linagliptin and metformin hydrochloride tablets should be individualized on the basis of both effectiveness and tolerability, while not exceeding the maximum recommended dosage of 2.5 mg linagliptin/1,000 mg metformin hydrochloride (HCl), taken orally twice daily. Linagliptin and metformin hydrochloride tablets should be given twice daily with meals. Dosage escalation should be gradual to reduce the gastrointestinal (GI) side effects associated with metformin use.
Recommended starting dosage: • In patients currently not treated with metformin HCl, initiate treatment with 2.5 mg linagliptin/500 mg metformin HCl twice daily. • In patients already treated with metformin HCl, start with 2.5 mg linagliptin and the current dosage of metformin HCl taken at each of the two daily meals (e.g., a patient on metformin HCl 1,000 mg twice daily would be started on 2.5 mg linagliptin/1,000 mg metformin HCl twice daily with meals). • Patients already treated with linagliptin and metformin HCl individual components may be switched to linagliptin and metformin hydrochloride tablets containing the same dosages of each component.
2.2Recommended Dosing in Renal Impairment Assess renal function prior to initiation of linagliptin and metformin hydrochloride tablets and periodically thereafter. Linagliptin and metformin hydrochloride tablets are contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m 2 . Initiation of linagliptin and metformin hydrochloride tablets in patients with an eGFR between 30 to 45 mL/min/1.73 m 2 is not recommended.
In patients taking linagliptin and metformin hydrochloride tablets whose eGFR later falls below 45 mL/min/1.73 m 2 , assess benefit /risk of continuing therapy. Discontinue linagliptin and metformin hydrochloride tablets if the patient's eGFR later falls below 30 mL/min/1.73 m 2 [ see Contraindications (4) and Warnings and Precautions (5.1)] .
2.3Discontinuation for Iodinated Contrast Imaging Procedures Discontinue linagliptin and metformin hydrochloride tablets at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/ 1.73 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. Re-evaluate eGFR 48 hours after the imaging procedure; restart linagliptin and metformin hydrochloride tablets if renal function is stable [ see Warnings and Precautions (5.1 ) ].
💊 Dosage Forms and Strengths ▾
3 DOSAGE FORMS AND STRENGTHS Linagliptin and metformin hydrochloride tablets are a combination of linagliptin and metformin hydrochloride available as: 2.5 mg linagliptin/500 mg metformin hydrochloride tablets are yellow, oval, biconvex film-coated tablets debossed with "500" on one side and "LM" on the other side 2.5 mg linagliptin/850 mg metformin hydrochloride tablets are orange, oval, biconvex film-coated tablets debossed with "850" on one side and "LM" on the other side 2.5 mg linagliptin/1,000 mg metformin hydrochloride tablets are pink, oval, biconvex film-coated tablets debossed with "1,000" on one side and "LM" on the other side Tablets: 2.5 mg linagliptin/500 mg metformin hydrochloride ( 3 ) 2.5 mg linagliptin/850 mg metformin hydrochloride ( 3 ) 2.5 mg linagliptin/1,000 mg metformin hydrochloride ( 3 )
⛔ Contraindications ▾
4 CONTRAINDICATIONS Linagliptin and metformin hydrochloride are contraindicated in patients with: • severe renal impairment (eGFR below 30 mL/min/1.73 m 2 ) [see Warnings and Precautions (5.1 )] . • acute or chronic metabolic acidosis, including diabetic ketoacidosis [see Warnings and Precautions (5.1 )]. • hypersensitivity to linagliptin, metformin, or any of the excipients in linagliptin and metformin hydrochloride, reactions such as anaphylaxis, angioedema, exfoliative skin conditions, urticaria, or bronchial hyperreactivity have occurred with linagliptin [see Warnings and Precautions (5.4 ) and Adverse Reactions (6.1 )] .
Severe renal impairment (eGFR below 30 mL/min/1.73 m 2 ) ( 4 ) Metabolic acidosis, including diabetic ketoacidosis ( 4 ) Hypersensitivity to linagliptin, metformin, or any of the excipients in linagliptin and metformin hydrochloride ( 4 )
⚠️ Warnings and Cautions ▾
5 WARNINGS AND PRECAUTIONS Lactic acidosis: See boxed warning ( 5.1 ) Pancreatitis: There have been reports of acute pancreatitis, including fatal pancreatitis. If pancreatitis is suspected, promptly discontinue linagliptin and metformin hydrochloride. ( 5.2 ) Hypoglycemia: Consider lowering the dosage of insulin secretagogue or insulin to reduce the risk of hypoglycemia when initiating linagliptin and metformin hydrochloride ( 5.3 ) Hypersensitivity reactions: Serious hypersensitivity reactions (e.g., anaphylaxis, angioedema, and exfoliative skin conditions) have occurred with linagliptin and metformin hydrochloride.
If hypersensitivity reactions occur discontinue linagliptin and metformin hydrochloride, treat promptly, and monitor until signs and symptoms resolve. ( 5.4 ) Vitamin B 12 deficiency: Metformin may lower vitamin B 12 levels. Measure hematologic parameters annually and vitamin B 12 at 2 to 3 year intervals and manage any abnormalities.
( 5.5 ) Arthralgia: Severe and disabling arthralgia has been reported in patients taking linagliptin. Consider as a possible cause for severe joint pain and discontinue drug if appropriate. ( 5.6 ) Bullous pemphigoid : There have been reports of bullous pemphigoid requiring hospitalization.
Tell patients to report development of blisters or erosions. If bullous pemphigoid is suspected, discontinue linagliptin and metformin hydrochloride. ( 5.7 ) Heart failure: Heart failure has been observed with two other members of the DPP-4 inhibitor class.
Consider risks and benefits of linagliptin and metformin hydrochloride in patients who have known risk factors for heart failure. Monitor for signs and symptoms. ( 5.8 )
5.1Lactic Acidosis Metformin 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 (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate: pyruvate ratio; metformin plasma levels generally >5 mcg/mL.
Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase 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 linagliptin and metformin hydrochloride. In linagliptin and metformin hydrochloride-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 linagliptin and metformin hydrochloride 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. Clinical recommendations based upon the patient’s renal function include [see Dosage and Administration (2.2 ) and Clinical Pharmacology (12.3 )] : • Before ini…
🤒 Adverse Reactions ▾
6 ADVERSE REACTIONS The following serious adverse reactions are described below or elsewhere in the prescribing information: • Lactic Acidosis [see Warnings and Precautions (5.1 )] • Pancreatitis [see Warnings and Precautions (5.2 )] • Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see Warnings and Precautions (5.3 )] • Hypersensitivity Reactions [see Warnings and Precautions (5.4 )] • Vitamin B 12 Deficiency [see Warnings and Precautions (5.5 )] • Severe and Disabling Arthralgia [see Warnings and Precautions (5.6 )] • Bullous Pemphigoid [see Warnings and Precautions (5.7 )] • Heart Failure [see Warnings and Precautions (5.8 )] Most common adverse reactions (incidence ≥5% and more often than placebo) were nasopharyngitis and diarrhea ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Novadoz Pharmaceuticals LLC at 1-855-668-2369 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1Clinical 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. Linagliptin/Metformin The safety of concomitantly administered linagliptin (daily dosage 5 mg) and metformin (mean daily dosage of approximately 1,800 mg) has been evaluated in 2,816 patients with type 2 diabetes mellitus treated for ≥12 weeks in clinical trials.
Three placebo-controlled trials with linagliptin + metformin were conducted: 2 studies were 24 weeks in duration, 1 trial was 12 weeks in duration. In the 3 placebo-controlled clinical studies, adverse reactions which occurred in ≥5% of patients receiving linagliptin + metformin (n=875) and were more common than in patients given placebo+ metformin (n=539) included nasopharyngitis (5.7% vs 4.3%). In a 24-week factorial design trial, adverse reactions reported in ≥5% of patients receiving linagliptin + metformin and were more common than in patients given placebo are shown in Table 1.
Table 1 Adverse Reactions Reported in ≥5% of Patients Treated with Linagliptin + Metformin and Greater than with Placebo in a 24-week Factorial-Design Trial Adverse Reactions Placebo (%) n =72 Li n a g li pt in M o n o th er a py (%) n =142 M e tf or m i n M o n o th er a py (%) n =291 C o m b i n a t io n of Li n a g li pt i n with Metformin(%) n =286 Nasopharyngitis 1.4 5.6 2.7
6.3Diarrhea 2.8 3.5 3.8
6.3Other adverse reactions reported in clinical studies with treatment of linagliptin + metformin were hypersensitivity (e.g., urticaria, angioedema, or bronchial hyperreactivity), cough, decreased appetite, nausea, vomiting, pruritus, and pancreatitis. Linagliptin Adverse reactions reported in ≥2% of patients treated with linagliptin 5 mg and more commonly than in patients treated with placebo included: nasopharyngitis (7% vs 6.1%), diarrhea (3.3% vs 3%), and cough (2.1% vs 1.4%). Rates for other adverse reactions for linagliptin 5 mg vs placebo when linagliptin was used in combination with specific anti-diabetic agents were: urinary tract infection (3.1% vs 0%) and hypertriglyceridemia (2.4% vs 0%) when linagliptin was used as add-on to sulfonylurea; hyperlipidemia (2.7% vs 0.8%) and weight increased (2.3% vs 0.8%) when linagliptin was used as add-on to pioglitazone; and constipation (2.1% vs 1%) when linagliptin was used as add-on to basal insulin therapy.
Other adverse reactions reported in clinical studies with treatment of linagliptin monotherapy were hypersensitivity (e.g., urticaria, angioedema, localized skin exfoliation, or bronchial hyperreactivity) and myalgia. In the clinical trial program, pancreatitis was reported in 15.2 cases per 10,000 patient year exposure while being treated with linagliptin compared with 3.7 cases per 10,000 patient year exposure while being treated with comparator (placebo and active comparator, sulfonylurea). Three additional cases of pancreatitis were re…
🔄 Drug Interactions ▾
7 DRUG INTERACTIONS Table 2 describes clinically relevant interactions with linagliptin and metformin hydrochloride. Table 2 Clinically Relevant Interactions with linagliptin and metformin hydrochloride Carbonic Anhydrase Inhibitors Clinical Impact Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with linagliptin and metformin hydrochloride may increase the risk of lactic acidosis.
Intervention Consider more frequent monitoring of these patients. Drugs that Reduce Metformin Clearance Clinical Impact 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 [see Clinical Pharmacology (12.3 )].
Intervention Consider the benefits and risks of concomitant use. Alcohol Clinical Impact Alcohol is known to potentiate the effect of metformin on lactate metabolism. Intervention Warn patients against excessive alcohol intake while receiving linagliptin and metformin hydrochloride.
Insulin or Insulin Secretagogues Clinical Impact The risk of hypoglycemia is increased when linagliptin and metformin hydrochloride is used in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin. Intervention Coadministration of linagliptin and metformin hydrochloride with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower dosages of the insulin secretagogue or insulin to reduce the risk of hypoglycemia. Drugs Affecting Glycemic Control Clinical Impact 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. Intervention When such drugs are administered to a patient receiving linagliptin and metformin hydrochloride, the patient should be closely observed to maintain adequate glycemic control. When such drugs are withdrawn from a patient receiving linagliptin and metformin hydrochloride, the patient should be observed closely for hypoglycemia.
Inducers of P-glycoprotein or CYP3A4 Enzymes Clinical Impact Rifampin decreased linagliptin exposure, suggesting that the efficacy of linagliptin may be reduced when administered in combination with a strong P-gp or CYP3A4 inducer. Intervention Use of alternative treatments is strongly recommended when linagliptin is to be administered with a strong P-gp or CYP3A4 inducer. Carbonic Anhydrase Inhibitors: May increase risk of lactic acidosis.
Consider more frequent monitoring. ( 7 ) Drugs that Reduce Metformin Clearance: May increase risk of lactic acidosis. Consider benefits and risks of concomitant use.
(7 ) Alcohol: Can potentiate the effect of metformin on lactate metabolism. Warn patients against excessive alcohol intake. ( 7 ) Strong P-glycoprotein/CYP3A4 Inducer: Efficacy may be reduced when administered in combination (e.g., rifampin).
Use of alternative treatments is strongly recommended. ( 7 )
👥 Use in Specific Populations ▾
8 USE IN SPECIFIC POPULATIONS Females and Males of Reproductive Potential: Advise premenopausal females of the potential for an unintended pregnancy ( 8.3 ) Geriatric Use: Assess renal function more frequently ( 8.5 ) Hepatic Impairment: Avoid use in patients with hepatic impairment ( 8.7 )
8.1Pregnancy Risk Summary The limited data with linagliptin and metformin hydrochloride and linagliptin use in pregnant women are not sufficient to inform a linagliptin and metformin hydrochloride-associated or linagliptin-associated risk for major birth defects and miscarriage. Published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defector miscarriage risk [see Data]. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations].
In animal reproduction studies, no adverse developmental effects were observed when the combination of linagliptin and metformin was administered to pregnant rats during the period of organogenesis at doses similar to the maximum recommended clinical dose, based on exposure [see Data]. The estimated background risk of major birth defects is 6% to10% in women with pre-gestational diabetes with a HbA1c>7 and has been reported to be as high as 20% to 25% in women with HbA1c>10. The estimated background risk of miscarriage for the indicated population is unknown.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.
Data Human Data Published data from postmarketing studies have not reported a clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin was used during pregnancy. However, these studies cannot definitely establish the absence of any metformin-associated risk because of methodological limitations, including small sample size and inconsistent comparator groups. Animal Data Linagliptin and metformin, the components of linagliptin and metformin hydrochloride, were coadministered to pregnant Wistar Han rats during the period of organogenesis.
No adverse developmental outcome was observed at doses similar to the maximum recommended clinical dose, based on exposure. At higher doses associated with maternal toxicity, the metformin component of the combination was associated with an increased incidence of fetal rib and scapula malformations at ≥9-times a 2,000 mg clinical dose, based on exposure. Linagliptin No adverse developmental outcome was observed when linagliptin was administered to pregnant Wistar Han rats and Himalayan rabbits during the period of organogenesis at doses up to 240 mg/kg/day and 150 mg/kg/day, respectively.
These doses represent approximately 943-times (rats) and 1,943-times (rabbits) the 5 mg maximum clinical dose, based on exposure. No adverse functional, behavioral, or reproductive outcome was observed in offspring following administration of linagliptin to Wistar Han rats from gestation day 6 to lactation day 21 at a dose 49-times the maximum recommended human dose, based on exposure. Linagliptin crosses the placenta into the fetus following oral dosing in pregnant rats and rabbits.
Metformin HCl Metformin HCl did not cause adverse developmental effects when administered to pregnant Sprague Dawley rats and rabbits at doses up to 600 mg/kg/day during the period of organogenesis. This represents an exposure of approximately 2- and 6-times a clinical dose of 2,000 mg, based on body surface area (mg/m…
🤰 Pregnancy ▾
8.1Pregnancy Risk Summary The limited data with linagliptin and metformin hydrochloride and linagliptin use in pregnant women are not sufficient to inform a linagliptin and metformin hydrochloride-associated or linagliptin-associated risk for major birth defects and miscarriage. Published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defector miscarriage risk [see Data]. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations].
In animal reproduction studies, no adverse developmental effects were observed when the combination of linagliptin and metformin was administered to pregnant rats during the period of organogenesis at doses similar to the maximum recommended clinical dose, based on exposure [see Data]. The estimated background risk of major birth defects is 6% to10% in women with pre-gestational diabetes with a HbA1c>7 and has been reported to be as high as 20% to 25% in women with HbA1c>10. The estimated background risk of miscarriage for the indicated population is unknown.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.
Data Human Data Published data from postmarketing studies have not reported a clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin was used during pregnancy. However, these studies cannot definitely establish the absence of any metformin-associated risk because of methodological limitations, including small sample size and inconsistent comparator groups. Animal Data Linagliptin and metformin, the components of linagliptin and metformin hydrochloride, were coadministered to pregnant Wistar Han rats during the period of organogenesis.
No adverse developmental outcome was observed at doses similar to the maximum recommended clinical dose, based on exposure. At higher doses associated with maternal toxicity, the metformin component of the combination was associated with an increased incidence of fetal rib and scapula malformations at ≥9-times a 2,000 mg clinical dose, based on exposure. Linagliptin No adverse developmental outcome was observed when linagliptin was administered to pregnant Wistar Han rats and Himalayan rabbits during the period of organogenesis at doses up to 240 mg/kg/day and 150 mg/kg/day, respectively.
These doses represent approximately 943-times (rats) and 1,943-times (rabbits) the 5 mg maximum clinical dose, based on exposure. No adverse functional, behavioral, or reproductive outcome was observed in offspring following administration of linagliptin to Wistar Han rats from gestation day 6 to lactation day 21 at a dose 49-times the maximum recommended human dose, based on exposure. Linagliptin crosses the placenta into the fetus following oral dosing in pregnant rats and rabbits.
Metformin HCl Metformin HCl did not cause adverse developmental effects when administered to pregnant Sprague Dawley rats and rabbits at doses up to 600 mg/kg/day during the period of organogenesis. This represents an exposure of approximately 2- and 6-times a clinical dose of 2,000 mg, based on body surface area (mg/m 2 ) for rats and rabbits, respectively.
🧒 Pediatric Use ▾
8.4Pediatric Use Safety and effectiveness of linagliptin and metformin hydrochloride have not been established in pediatric patients. "Pediatric information describing a clinical study in which efficacy was not demonstrated is approved for Boehringer Ingelheim Pharmaceuticals, Inc.’s Jentadueto® (Linagliptin; Metformin hydrochloride) Tablets. However, due to Boehringer Ingelheim Pharmaceuticals, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information."
🧓 Geriatric Use ▾
8.5Geriatric Use Linagliptin is minimally excreted by the kidney; however, metformin is substantially excreted by the kidney [see Warnings and Precautions (5.1 ) and Clinical Pharmacology (12.3) ] . Linagliptin In linagliptin studies, 1,085 linagliptin-treated patients were 65 years of age and older and 131 patients were 75 years of age and older. In these linagliptin studies, no overall differences in safety or effectiveness of linagliptin were observed between geriatric patients and younger adult patients.
Metformin Controlled clinical studies of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of lactic acidosis. Assess renal function more frequently in elderly patients [see Contraindications (4 ), Warnings and Precautions (5.1 ), and Clinical Pharmacology (12.3 )] .
🆘 Overdosage ▾
10 OVERDOSAGE In the event of an overdose with linagliptin and metformin hydrochloride, consider contacting the Poison Help line (1-800-222-1222) or medical toxicologist for additional overdosage management recommendations. Overdose of metformin HCl has occurred, including ingestion of amounts greater than 50 grams. Lactic acidosis has been reported in approximately 32% of metformin overdose cases [see Warnings and Precautions (5.1 )].
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. Removal of linagliptin by hemodialysis or peritoneal dialysis is unlikely.
🧬 Clinical Pharmacology ▾
12 CLINICAL PHARMACOLOGY
12.1Mechanism of Action Linagliptin and Metformin Hydrochloride Linagliptin and metformin hydrochloride contains: linagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, and metformin, a biguanide. Linagliptin Linagliptin is an inhibitor of DPP-4, an enzyme that degrades the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Thus, linagliptin increases the concentrations of active incretin hormones, stimulating the release of insulin in a glucose-dependent manner and decreasing the levels of glucagon in the circulation.
Both incretin hormones are involved in the physiological regulation of glucose homeostasis. Incretin hormones are secreted at a low basal level throughout the day and levels rise immediately after meal intake. GLP-1 and GIP increase insulin biosynthesis and secretion from pancreatic beta cells in the presence of normal and elevated blood glucose levels.
Furthermore, GLP-1 also reduces glucagon secretion from pancreatic alpha cells, resulting in a reduction in hepatic glucose output. Metformin HCl Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes mellitus, 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 day-long plasma insulin response may decrease.
12.2Pharmacodynamics Linagliptin Linagliptin binds to DPP-4 in a reversible manner and increases the concentrations of incretin hormones. Linagliptin glucose-dependently increases insulin secretion and lowers glucagon secretion, thus resulting in a better regulation of the glucose homeostasis. Linagliptin binds selectively to DPP-4 and selectively inhibits DPP-4, but not DPP-8 or DPP-9 activity in vitro at concentrations approximating therapeutic exposures.
Cardiac Electrophysiology In a randomized, placebo-controlled, active-comparator, 4-way crossover study, 36 healthy subjects were administered a single oral dose of linagliptin 5 mg, linagliptin 100 mg (20 times the recommended dose), moxifloxacin, and placebo. No increase in QTc was observed with either the recommended dose of 5 mg or the 100 mg dose. At the 100 mg dose, peak linagliptin plasma concentrations were approximately 38-fold higher than the peak concentrations following a 5 mg dose.
12.3Pharmacokinetics Linagliptin and Metformin Hydrochloride Administration of linagliptin 2.5 mg/metformin HCl 1,000 mg fixed-dose combination with food resulted in no change in overall exposure of linagliptin. There was no change in metformin AUC; however, mean peak serum concentration of metformin was decreased by 18% when administered with food. A delayed time-to-peak serum concentrations by 2 hours was observed for metformin under fed conditions.
These changes are not likely to be clinically significant. Absorption Linagliptin The absolute bioavailability of linagliptin is approximately 30%. Following oral administration, plasma concentrations of linagliptin decline in at least a biphasic manner with a long terminal half-life (>100 hours), related to the saturable binding of linagliptin to DPP-4.
However, the prolonged elimination does not contribute to the accumulation of the drug. The effective half-life for accumulation of linagliptin, as determined from oral administration of multiple doses of linagliptin 5 mg, is approximately 12 hours. After once-daily dosing, steady-state plasma concentrations of linagliptin 5 mg are reached by the third dose, and C max and AUC increased by a factor of 1.3 at steady-state compared with the first dose.
Plasma AUC of linagliptin increased in a less than dose-proportional manner in the dose range of 1 to 10 mg. The pharmacokinetics of linagliptin is similar in healthy s…
🧬 Mechanism of Action ▾
12.1Mechanism of Action Linagliptin and Metformin Hydrochloride Linagliptin and metformin hydrochloride contains: linagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, and metformin, a biguanide. Linagliptin Linagliptin is an inhibitor of DPP-4, an enzyme that degrades the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Thus, linagliptin increases the concentrations of active incretin hormones, stimulating the release of insulin in a glucose-dependent manner and decreasing the levels of glucagon in the circulation.
Both incretin hormones are involved in the physiological regulation of glucose homeostasis. Incretin hormones are secreted at a low basal level throughout the day and levels rise immediately after meal intake. GLP-1 and GIP increase insulin biosynthesis and secretion from pancreatic beta cells in the presence of normal and elevated blood glucose levels.
Furthermore, GLP-1 also reduces glucagon secretion from pancreatic alpha cells, resulting in a reduction in hepatic glucose output. Metformin HCl Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes mellitus, 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 day-long plasma insulin response may decrease.
📦 How Supplied / Storage and Handling ▾
16 HOW SUPPLIED/STORAGE AND HANDLING Linagliptin and metformin hydrochloride tablets 2.5 mg/500 mg are yellow, oval, biconvex film-coated tablets debossed with “500” on one side and “LM” on the other side, and are supplied as follows: Bottles of 60 (NDC 72205-407-01) Bottles of 180 (NDC 72205-407-02) Linagliptin and metformin hydrochloride tablets 2.5 mg/850 mg are orange, oval, biconvex film-coated tablets debossed with “850” on one side and “LM” on the other side, and are supplied as follows: Bottles of 60 (NDC 72205-408-01) Bottles of 180 (NDC 72205-408-02) Linagliptin and metformin hydrochloride tablets 2.5 mg/1,000 mg are pink, oval, biconvex film-coated tablets debossed with “1000” on one side and “LM” on the other side, and are supplied as follows: Bottles of 60 (NDC 72205-409-01) Bottles of 180 (NDC 72205-409-02) Storage Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].
Protect from exposure to high humidity.
📋 Description ▾
11 DESCRIPTION Linagliptin and metformin hydrochloride tablets for oral use contain: linagliptin and metformin hydrochloride. Linagliptin Linagliptin is an inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme. The chemical name of linagliptin is 1H-Purine-2,6-dione, 8-[(3R)-3-amino-1-piperidinyl]-7-(2-butyn-1-yl)-3,7-dihydro-3-methyl-1-[(4-methyl-2-quinazolinyl)methyl]- The molecular formula is C 25 H 28 N 8 O 2 and the molecular weight is 472.54 g/mol.
The structural formula is: Linagliptin is a white to yellowish, not or only slightly hygroscopic solid substance. It is very slightly soluble in water (0.9 mg/mL). Linagliptin is soluble in methanol (ca.
60 mg/mL), sparingly soluble in ethanol (ca. 10 mg/mL), very slightly soluble in isopropanol (<1 mg/mL), and very slightly soluble in acetone (ca.1 mg/mL). Metformin Hydrochloride Metformin hydrochloride (N,N-dimethylimidodicarbonimidic diamide hydrochloride) is a biguanide.
Metformin hydrochloride is a white to off-white crystalline compound with a molecular formula of C 4 H 11 N 5 •HCl and a molecular weight of 165.63 g/mol. Metformin hydrochloride is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin is 12.4.
The pH of a 1% aqueous solution of metformin hydrochloride is 6.68. The structural formula is: Linagliptin and Metformin Hydrochloride Tablets Linagliptin and metformin hydrochloride tablets are available for oral administration as tablets containing: • 2.5 mg linagliptin and 500 mg metformin hydrochloride (equivalent to 389.93 mg of metformin) • 2.5 mg linagliptin and 850 mg metformin hydrochloride (equivalent 662.88 mg of metformin) • 2.5 mg linagliptin and 1,000 mg metformin hydrochloride (equivalent to 779.86 mg of metformin) Each film-coated tablet of linagliptin and metformin hydrochloride tablets contains the following inactive ingredients: colloidal silicon dioxide, copovidone, corn starch, hypromellose, magnesium stearate, meglumine, povidone, propylene glycol, titanium dioxide, talc, yellow iron oxide (2.5 mg/500 mg; 2.5 mg/850 mg) and/or red iron oxide (2.5 mg/850 mg; 2.5 mg/1,000 mg). lina-met-tabs-structure1 lina-met-tabs-structure2
💬 Information for Patients ▾
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide) Lactic Acidosis Inform patients of the risks of lactic acidosis due to metformin, its symptoms, and conditions that predispose to its development. Advise patients to discontinue linagliptin and metformin hydrochloride immediately and to notify their healthcare provider promptly if unexplained hyperventilation, malaise, myalgia, unusual somnolence, or other nonspecific symptoms occur. Counsel patients against excessive alcohol intake and inform patients about importance of regular testing of renal function while receiving linagliptin and metformin hydrochloride.
Instruct patients to inform their healthcare provider that they are taking linagliptin and metformin hydrochloride prior to any surgical or radiological procedure, as temporary discontinuation may be required until renal function has been confirmed to be normal [see Warnings and Precautions (5.1 )]. Pancreatitis Inform patients that acute pancreatitis has been reported during use of linagliptin. Inform patients that persistent severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting, is the hallmark symptom of acute pancreatitis.
Instruct patients to discontinue linagliptin and metformin hydrochloride promptly and contact their healthcare provider if persistent severe abdominal pain occurs [see Warnings and Precautions (5.2 )]. Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues Inform patients that the risk of hypoglycemia is increased when linagliptin and metformin hydrochloride is used in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin [see Warnings and Precautions (5.3 )]. Hypersensitivity Reactions Inform patients that serious allergic reactions, such as anaphylaxis, angioedema, and exfoliative skin conditions, have been reported during postmarketing use of linagliptin (one of the components of linagliptin and metformin hydrochloride).
If symptoms of allergic reactions (such as rash, skin flaking or peeling, urticaria, swelling of the skin, or swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing) occur, patients must stop taking linagliptin and metformin hydrochloride and seek medical advice promptly [see Warnings and Precautions (5.4 )] . Vitamin B 12 Deficiency Inform patients about the importance of regular hematological parameters while receiving linagliptin and metformin hydrochloride [see Warnings and Precautions (5.5 )].
Severe and Disabling Arthralgia Inform patients that severe and disabling joint pain may occur with this class of drugs. The time to onset of symptoms can range from one day to years. Instruct patients to seek medical advice if severe joint pain occurs [see Warnings and Precautions (5.6 )].
Bullous Pemphigoid Inform patients that bullous pemphigoid has been reported during use of linagliptin. Instruct patients to seek medical advice if blisters or erosions occur [see Warnings and Precautions (5.7 )] . Heart Failure Inform patients of the signs and symptoms of heart failure.
Before initiating linagliptin and metformin hydrochloride, patients should be asked about a history of heart failure or other risk factors for heart failure including moderate to severe renal impairment. Instruct patients to contact their healthcare provider as soon as possible if they experience symptoms of heart failure, including increasing shortness of breath, rapid increase in weight or swelling of the feet [see Warnings and Precautions (5.8 )]. Patients of Reproductive Potential Inform patients that treatment with metformin may result in ovulation in some premenopausal anovulatory patients, which may lead to unintended pregnancy [see Use in Specific Populations (8.3) ].
Missed Dose Instruct patients to take linagliptin and metformin hydrochloride only as prescribed. If a dose is missed, it should be taken as soon as…
💬 Medication Guide ▾
MEDICATION GUIDE Linagliptin and metformin hydrochloride Tablets (LIN-a-GLIP-tin and met-FOR-min HYE-droe-KLOR-ide) for oral use What is the most important information I should know about linagliptin and metformin hydrochloride tablets? Linagliptin and metformin hydrochloride tablets can cause serious side effects, including: 1. Lactic acidosis.
Metformin hydrochloride (HCl), one of the medicines in linagliptin and metformin hydrochloride tablets, can cause a rare but serious condition called lactic acidosis (a build-up of lactic acid in the blood) that can cause death. Lactic acidosis is a medical emergency and must be treated in a hospital. Stop taking linagliptin and metformin hydrochloride tablets and call your healthcare provider right away or go to the nearest hospital emergency room if you get any of the following symptoms of lactic acidosis: • feel very weak and tired • have unusual sleepiness or sleep longer than usual • have unusual (not normal) muscle pain • feel cold, especially in your arms and legs • have trouble breathing • feel dizzy or lightheaded • have unexplained stomach or intestinal problems with nausea and vomiting, or diarrhea • have a slow or irregular heartbeat You have a higher chance of getting lactic acidosis with linagliptin and metformin hydrochloride tablets if you: • have severe kidney problems. • have liver problems. • drink a lot of alcohol (very often or short-term “binge” drinking). • get dehydrated (lose a large amount of body fluids).
This can happen if you are sick with a fever, vomiting, or diarrhea. Dehydration can also happen when you sweat a lot with activity or exercise and do not drink enough fluids. • have certain x-ray tests with injectable dyes or contrast agents. • have surgery or other procedures for which you need to restrict the amount of food and liquid you eat and drink. • have congestive heart failure. • have a heart attack, severe infection, or stroke. • are 65 years of age or older. Tell your healthcare provider if you have any of the problems in the list above.
Tell your healthcare provider that you are taking linagliptin and metformin hydrochloride before you have surgery or x-ray tests. Your healthcare provider may decide to stop your linagliptin and metformin hydrochloride tablets for a while if you have surgery or certain x-ray tests. Linagliptin and metformin hydrochloride tablets can have other serious side effects.
See “What are the possible side effects of linagliptin and metformin hydrochloride tablets?” 2. Inflammation of the pancreas (pancreatitis) which may be severe and lead to death. Certain medical problems make you more likely to get pancreatitis.
Before you start taking linagliptin and metformin hydrochloride tablets, tell your healthcare provider if you have ever had: • inflammation of your pancreas (pancreatitis) • stones in your gallbladder (gallstones) • a history of alcoholism • high blood triglyceride levels Stop taking linagliptin and metformin hydrochloride tablets and call your healthcare provider right away if you have pain in your stomach area (abdomen) that is severe and will not go away. The pain may be felt going from your abdomen to your back.
The pain may happen with or without vomiting. These may be symptoms of pancreatitis. What are linagliptin and metformin hydrochloride tablets?
Linagliptin and metformin hydrochloride tablets are a prescription medicine that contains 2 diabetes medicines, linagliptin and metformin HCl. Linagliptin and metformin hydrochloride tablets can be used along with diet and exercise to lower blood sugar in adults with type 2 diabetes mellitus. Linagliptin and metformin hydrochloride tablets are not for people with type 1 diabetes mellitus.
If you have had pancreatitis in the past, it is not known if you have a higher chance of getting pancreatitis while you take linagliptin and metformin hydrochloride tablets. It is not known if linagliptin and metformin hydrochloride tablets are safe and effective in childre…