Linagliptin
JFDA label: Diabeten
Mechanism of Action
Inhibitor of Dipeptidyl peptidase 4 — Dipeptidyl peptidase IV inhibitor
| Target | Action | Gene / class |
|---|---|---|
| Dipeptidyl peptidase 4 efficacy | INHIBITOR | DPP4 |
Indications
Approved
- Diabetes mellitus, type 2
Class profile
| mechanismClass | DPP-4 inhibitor (no renal dose adjustment needed) |
|---|---|
| insulinSecretagogue | 0 |
| weightEffect | Neutral |
| hypoglycemiaRisk | None |
| renalContraindicated | 0 |
| cardioProtective | 0 |
| renalProtective | 0 |
| source | ADA-EASD2023/Maruthur2016 |
Contraindications
Source: Lexicomp
- Additional contraindications: Use in type 1 diabetes mellitus or diabetic ketoacidosis Absolute
- Hypersensitivity (eg, anaphylaxis, angioedema, exfoliative skin conditions, urticaria, or bronchial hyperreactivity) to linagliptin or any component of the formulation Absolute
Adverse Reactions
Metabolism and nutrition disorders (2)
Common Hypoglycemia · increased uric acid
Gastrointestinal disorders (1)
Common Increased serum lipase
Skin and subcutaneous tissue disorders (1)
Not Known Urticaria
Musculoskeletal and connective tissue disorders (1)
Not Known Myalgia
Respiratory, thoracic and mediastinal disorders (3)
Common cough · Nasopharyngitis
Not Known Asthma
Dosing
Source: Lexicomp
Warnings & Precautions
Source: Lexicomp
Arthralgia
Severe and disabling arthralgia has been reported with DPP-4 inhibitor use; onset may occur within one day to years after treatment initiation and may resolve with discontinuation of therapy. Some patients may experience a recurrence of symptoms if DPP-4 inhibitor therapy resumed.
Bullous pemphigoid
DPP-4 inhibitor use has been associated with development of bullous pemphigoid; cases have typically resolved with topical or systemic immunosuppressive therapy and discontinuation of DPP-4 inhibitor therapy. Advise patients to report development of blisters or erosions. Discontinue therapy if bullous pemphigoid is suspected and consider referral to a dermatologist.
Hypersensitivity reactions
Rare hypersensitivity reactions (including anaphylaxis, angioedema, and exfoliative skin conditions) have been reported in patients treated with linagliptin; events have generally been noted within the first 3 months of therapy and may occur with the initial dose. Discontinue if signs/symptoms of hypersensitivity reactions occur. Use with caution if patient has experienced angioedema with other DPP-4 inhibitor use.
Pancreatitis
Cases of acute pancreatitis, including fatalities, have been reported with use. Monitor for signs/symptoms of pancreatitis; discontinue use immediately if pancreatitis is suspected and initiate appropriate management. Use with caution in patients with a history of pancreatitis as it is not known if this population is at greater risk. Disease-related concerns:
Heart failure
In cardiovascular outcome trials of patients with type 2 diabetes and atherosclerotic cardiovascular disease, treatment with other DPP-4 inhibitors has been associated with heart failure. Use caution in patients at risk for heart failure (eg, history of heart failure or renal impairment) and monitor for signs and symptoms of heart failure during therapy; consider discontinuation if heart failure develops. Concurrent drug therapy issues:
Drug-drug interactions
Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Other warnings/precautions:
Appropriate use
Not indicated for use in patients with type 1 diabetes mellitus (insulin dependent, IDDM) or with diabetic ketoacidosis (DKA).
Patient education
Diabetes self-management education (DSME) is essential to maximize the effectiveness of therapy.
Pregnancy & Lactation
Pregnancy
In women with diabetes, maternal hyperglycemia can be associated with congenital malformations as well as adverse effects in the fetus, neonate, and the mother (ACOG 2005; ADA 2018c; Metzger 2007). To prevent adverse outcomes prior to conception and throughout pregnancy, maternal blood glucose and HbA1c should be kept as close to target goals as possible but without causing significant hypoglycemia (ADA 2018c; Blumer 2013). Agents other than linagliptin are currently recommended to treat diabetes in pregnant women (ADA 2018c).
Lactation
It is not known if linagliptin is present in breast milk. According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother.
LactMed: monitor the infant.
Monitoring
| Efficacy | HbA1c every 3 months initially, then every 6–12 months when stable; fasting and post-prandial blood glucose; patient-reported hypoglycaemia episodes |
|---|---|
| Toxicity | Hypoglycaemia symptoms; eGFR for renally-cleared agents; weight; blood pressure |
| Clinical pearl | Individualise HbA1c targets based on patient age, comorbidities, and hypoglycaemia risk. Targets of < 7% are appropriate for most patients but < 8% may be safer in frail elderly. |
| Counseling | Monitor blood glucose regularly. Know how to recognise and treat hypoglycaemia. Keep carbohydrate snacks available. |
Chemistry & Properties
| Formula | C25H28N8O2 |
|---|---|
| Molecular weight | 472.55 g/mol |
| IUPAC name | 8-[(3R)-3-aminopiperidin-1-yl]-7-but-2-ynyl-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]purine-2,6-dione |
| CAS | 668270-12-0 |
| PubChem CID | 10096344 |
| InChIKey | LTXREWYXXSTFRX-QGZVFWFLSA-N |
| logP | 1.15 (XLogP 1.9) |
| Polar surface area | 116.86 Ų |
| H-bond acceptors / donors | 10 / 1 |
| Drug-likeness (QED) | 0.44 |
| Lipinski violations | 0 |
SMILES
CC#CCn1c(N2CCC[C@@H](N)C2)nc2c1c(=O)n(Cc1nc(C)c3ccccc3n1)c(=O)n2CBiology & Pharmacokinetics
Pharmacokinetics predicted
| Bioavailability | 70.0% |
|---|---|
| Half-life | 1.202 h |
| Volume of distribution | 12.152 L/kg |
| Protein binding | 82.4% |
| BBB penetrant | No |
Enzyme interactions
| Enzyme | Role | Detail |
|---|---|---|
| CYP1A2 | Inhibitor | — |
| CYP1A2 | Substrate | — |
| CYP2C19 | Substrate | — |
| CYP3A4 | Inhibitor | — |
| CYP3A4 | Substrate | — |
Receptor binding (top 1)
| Target | Action | Affinity |
|---|---|---|
| dipeptidyl peptidase 4 (DPP4) | Inhibitor | pKi 9.0 |
Transporters
BCRP (Inhibitor)BCRP (Inhibitor)BSEP (Inhibitor)MDR1 (Inhibitor)MRP1 (Inhibitor)MRP2 (Inhibitor)OAT1 (Inhibitor)OAT3 (Inhibitor)OAT4 (Inhibitor)OATP1B1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OATP1B3 (Inhibitor)OATP2 (Inhibitor)OATP2B1 (Inhibitor)OCT(unspecified) (Inhibitor)OCT1 (Inhibitor)OCT2 (Inhibitor)OCTN1 (Inhibitor)OCTN2 (Inhibitor)P-gp (Inhibitor)Transporter(unspecified) (Inhibitor)BCRP (Substrate)MDR1 (Substrate)MRP2 (Substrate)OAT3 (Substrate)OAT4 (Substrate)OATP1B3 (Substrate)OATP2 (Substrate)OATP2B1 (Substrate)OCT(unspecified) (Substrate)OCT2 (Substrate)OCTN1 (Substrate)OCTN2 (Substrate)P-gp (Substrate)
Drug–drug interactions (100+, DDInter)
| Interacting drug | Severity | Management |
|---|---|---|
| Bexarotene | major | |
| Gatifloxacin | major | |
| Abametapir (topical) | moderate | |
| Acetazolamide | moderate | |
| Acetohexamide | moderate | |
| Alimemazine | moderate | |
| Aloe Vera Leaf | moderate | |
| Alpelisib | moderate | |
| Aminoglutethimide | moderate | |
| Amobarbital | moderate | |
| Amprenavir | moderate | |
| Apalutamide | moderate | |
| Aripiprazole | moderate | |
| Armodafinil | moderate | |
| Asenapine | moderate | |
| Asparaginase Erwinia chrysanthemi | moderate | |
| Asparaginase Escherichia coli | moderate | |
| Atazanavir | moderate | |
| Benazepril | moderate | |
| Bendroflumethiazide | moderate | |
| Benzphetamine | moderate | |
| Benzthiazide | moderate | |
| Betamethasone | moderate | |
| Bortezomib | moderate | |
| Bosentan | moderate | |
| Brentuximab vedotin | moderate | |
| Brexpiprazole | moderate | |
| Brigatinib | moderate | |
| Bumetanide | moderate | |
| Butabarbital | moderate | |
| Butalbital | moderate | |
| Calaspargase pegol | moderate | |
| Captopril | moderate | |
| Carbamazepine | moderate | |
| Cariprazine | moderate | |
| Cenobamate | moderate | |
| Ceritinib | moderate | |
| Chlorothiazide | moderate | |
| Chlorpromazine | moderate | |
| Chlorpropamide | moderate |
Showing 40 of 100+.
Registered Products (23)
| Brand | Form / strength | Pack | Agent | Citizen (JOD) |
|---|---|---|---|---|
| LINESTA | Tablet 5 mg | 10 tab | Omicron Pharma | 10.470 |
| Olinpa | Tablet 5 mg | 30 tab | Sana Pharmaceutical Industry Co. | 18.490 |
| Diabeten | Tablet 5 mg | 30 tab | UNITED PHARM.MFG.CO.LTD(UPM)/JORDAN | 19.040 |
| Lynxelin | Tablet 5 mg | 30 tab | The Arab Pharmaceutical Manufactruing Co. | 21.140 |
| Diabeten M | Tablet 500 mg, 2.5 mg | 60 tab | United Pharmaceutical | 22.270 |
| Diabeten M | Tablet 850 mg, 2.5 mg | 60 tab | United Pharmaceutical | 22.270 |
| Diabeten M | Tablet 1000 mg, 2.5 mg | 60 tab | United Pharmaceutical | 22.270 |
| Leena | Tablet 5 mg | 30 tab pack varies | Pharma International Company/ Jordan | 22.460 |
| Nulina | Tablet 5 mg | 30 tab | Dar Al Dawa Development and Investment | 23.780 |
| Trajenta | Tablet 5 mg | 30 tab | THE ARAB DRUG STORE P.S.C | 26.420 |
| Leena-Met | Tablet Metformin Hcl 850 mg, Linagliptin 2.5 mg | 60 tab | / Pharma International Company/Jordan / General | 26.940 |
| Leena-Met | Tablet Metformin Hcl 1000 mg, Linagliptin 2.5 mg | 60 tab | / Pharma International Company/Jordan / General | 26.940 |
| Embalix 10mg/ 5mg film coated tablet | Film-Coated Tablet Linagliptin 5 mg, Empagliflozin 10 mg | 30 tab | Hikma Pharmaceuticals | 37.800 |
| Embalix 25mg/ 5mg film coated tablet | Film-Coated Tablet Linagliptin 5 mg, Empagliflozin 25 mg | 30 tab | Hikma Pharmaceuticals | 37.800 |
| Jentadueto 2.5mg/1000mg | Tablet 1000 mg, 2.5 mg | 60 tab | THE ARAB DRUG STORE P.S.C | 37.960 |
| Jentadueto 2.5mg/850mg | Tablet 850 mg, 2.5 mg | 60 tab | THE ARAB DRUG STORE P.S.C | 37.960 |
| Glenpa | Tablet 5 mg, 10 mg | 30 tab | Dar Al Dawa Development and Investment Co Ltd/Jordan | 42.530 |
| Glenpa | Tablet 5 mg, 25 mg | 30 tab | Dar Al Dawa Development and Investment Co Ltd/Jordan | 42.530 |
| GlipAct | Tablet 5 mg, 25 mg | 30 tab | Jordan river Pharmaceutical industries | 42.530 |
| GlipAct | Tablet 5 mg, 10 mg | 30 tab | Jordan river Pharmaceutical industries | 42.530 |
| Glyxambi | Tablet 5 mg, 25 mg | 30 tab | THE ARAB DRUG STORE P.S.C | 50.290 |
| Glyxambi | Tablet 5 mg, 10 mg | 30 tab | THE ARAB DRUG STORE P.S.C | 50.290 |
| Leena | Tablet 5 mg | 500 tab pack varies | Pharma International Company/ Jordan | 325.570 |