Schedule H

Oral

• Tablets: 5 mg

• Fixed-Dose Combinations:

• Linagliptin 2.5 mg + Metformin 500 mg

• Linagliptin 2.5 mg + Metformin 850 mg

• Linagliptin 2.5 mg + Metformin 1000 mg

INDICATIONS + DOSING — FOR CLINICIAN USE ONLY

Primary Indications (Approved / Standard in India)

Type 2 Diabetes Mellitus (Adjunct to Diet and Exercise)

A. Monotherapy (when metformin is contraindicated or not tolerated)

Parameter Details

Starting dose 5 mg once daily

Titration Not required

Usual maintenance dose 5 mg once daily

Maximum dose 5 mg once daily

Clinical Notes:

• May be taken with or without food at any time of day

• Fixed single dose; no dose adjustment needed regardless of timing of meals

• HbA1c reduction typically 0.5–0.7%

• Weight-neutral effect

B. Combination Therapy

Combination Regimen Linagliptin Dose Clinical Notes

Add-on to Metformin 5 mg once daily Well-established combination; FDC available; complementary mechanisms

Add-on to Sulfonylurea 5 mg once daily Increased hypoglycaemia risk; consider reducing sulfonylurea dose

Add-on to SGLT2 inhibitor 5 mg once daily Synergistic effect; low hypoglycaemia risk

Add-on to Thiazolidinedione 5 mg once daily TZD-related weight gain unaffected

Add-on to Insulin (± Metformin) 5 mg once daily May reduce insulin requirement; consider reducing insulin dose to minimize hypoglycaemia

Triple therapy 5 mg once daily Can be used in various triple combinations

Clinical Notes:

• When adding to sulfonylurea or insulin, consider dose reduction of the secretagogue to minimize hypoglycaemia

• No dose adjustment required when combining with other antidiabetic agents

Secondary Indications – Adults Only (Off-label)

Not applicable — No established off-label indications with Indian specialist support.

PAEDIATRIC DOSING (Specialist Only)

Primary Indications

Type 2 Diabetes Mellitus (Children ≥10 years)

10–17 years 5 mg once daily Not required 5 mg once daily

Clinical Notes:

• Use as adjunct to diet and exercise

• May be used as monotherapy or in combination with metformin or insulin

• Paediatric endocrinologist supervision recommended

Safety Monitoring:

• Baseline: HbA1c, fasting plasma glucose, renal function, LFTs

• Follow-up: HbA1c every 3 months; renal and hepatic function every 6 months

• Monitor for symptoms of pancreatitis

• Monitor growth parameters during long-term therapy

Age Restriction: NOT RECOMMENDED below 10 years — safety and efficacy not established.

Secondary Indications – Paediatrics (Off-label)

Not applicable — No established off-label paediatric indications.

Note: Although no dose adjustment is pharmacokinetically required, limited experience exists in severe hepatic impairment.

• Hypersensitivity to linagliptin or any excipient

• History of serious hypersensitivity reaction (angioedema, anaphylaxis) to any DPP-4 inhibitor

• Type 1 diabetes mellitus

• Diabetic ketoacidosis

• History of pancreatitis — discontinue if acute pancreatitis suspected; do not rechallenge

• Concurrent use with sulfonylureas or insulin — increased hypoglycaemia risk; consider dose reduction of secretagogue

• Heart failure (NYHA Class III–IV) — use with caution; cardiovascular safety demonstrated in CARMELINA trial, but limited data in advanced heart failure

• Concomitant use with ACE inhibitors — rare reports of angioedema

• Bullous pemphigoid — rare skin reaction reported with DPP-4 inhibitors class

• Severe hepatic impairment — limited clinical experience

Aspect Details

Overall safety Not recommended; limited human data; animal studies do not indicate direct harmful effects

Preferred alternatives Insulin (first-line); Metformin may be continued under specialist guidance

When it may be used Only if potential benefit clearly outweighs risk and safer alternatives unavailable; specialist supervision mandatory

Monitoring required Maternal glycaemic control (SMBG, HbA1c); fetal growth monitoring

Aspect Details

Compatibility Not recommended; unknown if excreted in human milk

Expected levels in milk Unknown (excreted in animal milk)

Preferred alternatives Insulin (first-line); Metformin (compatible with breastfeeding)

If use unavoidable Monitor infant for signs of hypoglycaemia, adequate feeding, and weight gain

Aspect Recommendation

Starting dose 5 mg once daily (same as adults)

Titration Not required

Dose adjustment for age None required

Additional risks Hypoglycaemia when combined with sulfonylureas or insulin; monitor closely

Advantages Preferred over sulfonylureas due to lower hypoglycaemia risk; no renal dose adjustment needed

Monitoring Periodic renal and hepatic function assessment

Key Point: Linagliptin is particularly suitable for elderly T2DM patients due to weight-neutral effect, low intrinsic hypoglycaemia risk, and no need for renal dose adjustment.

Interacting Drug Effect Recommendation

Rifampicin Strong CYP3A4 and P-glycoprotein inducer; significantly reduces linagliptin exposure (~40% reduction in AUC) Avoid combination if possible; if essential, monitor glycaemic control closely and consider alternative DPP-4 inhibitor or antidiabetic class

Carbamazepine, Phenytoin, Phenobarbital CYP3A4 inducers; may reduce linagliptin levels Monitor glycaemic response; consider alternative antidiabetic if inadequate control

Interacting Drug Effect Recommendation

Sulfonylureas (glimepiride, gliclazide) Additive hypoglycaemic effect Consider reducing sulfonylurea dose when adding linagliptin

Insulin Additive hypoglycaemic effect Consider reducing insulin dose; monitor blood glucose closely

ACE inhibitors (enalapril, ramipril) Rare increased risk of angioedema Monitor for facial/lip swelling; counsel patient to report symptoms immediately

Ritonavir Strong CYP3A4 inhibitor; may increase linagliptin levels Likely clinically insignificant due to saturable protein binding; no dose adjustment needed

Digoxin Minimal interaction reported Standard monitoring; no dose adjustment needed

Warfarin No significant interaction Standard INR monitoring sufficient

• Nasopharyngitis

• Upper respiratory tract infection

• Headache

• Cough

• Arthralgia

• Back pain

• Hypoglycaemia (when combined with sulfonylureas or insulin)

Adverse Effect Action Required

Acute pancreatitis Discontinue immediately; supportive management; do not rechallenge with any DPP-4 inhibitor

Angioedema Rare; discontinue and provide emergency management; avoid all DPP-4 inhibitors subsequently

Bullous pemphigoid Rare skin condition; discontinue and refer to dermatology

Severe hypersensitivity reactions (anaphylaxis, urticaria) Discontinue immediately; emergency management

Hepatic enzyme elevation Monitor if symptomatic (fatigue, jaundice, dark urine); discontinue if significant elevation

Phase Parameters Frequency

Baseline HbA1c, fasting plasma glucose, serum creatinine, LFTs Before initiation

After initiation HbA1c At 3 months

Stable long-term therapy HbA1c Every 3–6 months

Stable long-term therapy Renal function, LFTs Annually

If combined with sulfonylurea/insulin Blood glucose (SMBG) Regularly; adjust doses to avoid hypoglycaemia

As needed Lipase/amylase If abdominal pain suggestive of pancreatitis

Special populations Renal function in CKD patients Every 6 months

Single-ingredient formulations:

• Trajenta (Boehringer Ingelheim)

• Ondero (USV)

• Glyxita (Zydus)

• Trigreat (Sun Pharma)

• Linaone (Micro Labs)

• Linares (Glenmark)

Fixed-Dose Combinations (with Metformin):

• Trajenta Duo (Boehringer Ingelheim)

• Ondero Met (USV)

• Glyxita M (Zydus)

• Multiple generic FDCs available

Note: Linagliptin is NOT included in NLEM 2022; not under NPPA price control. Available in private sector and some Jan Aushadhi outlets.

1. Unique renal advantage: Linagliptin is the only DPP-4 inhibitor that requires no dose adjustment in any degree of renal impairment, including ESRD on dialysis. Preferred choice in diabetic nephropathy patients.

1. Cardiovascular safety: CARMELINA and CAROLINA trials demonstrated cardiovascular safety without increased heart failure risk, unlike some other DPP-4 inhibitors (saxagliptin).

1. Fixed single dose: 5 mg once daily regardless of renal function, hepatic function, age, or combination therapy — simplifies prescribing in complex patients.

1. Rifampicin interaction: Significant reduction in linagliptin levels when co-administered with rifampicin (common in Indian TB practice). Consider alternative antidiabetic class or close glycaemic monitoring.

1. Nomenclature caution: Do not confuse "linagliptin" (DPP-4 inhibitor, oral) with "liraglutide" (GLP-1 receptor agonist, injectable) — medication error risk.

1. Modest efficacy: HbA1c reduction typically 0.5–0.7%; not suitable as sole agent for patients requiring aggressive glycaemic control. Best used in combination therapy.

Type 2 diabetes; DPP-4 inhibitor; gliptin; renal-safe; no-dose-adjustment; CKD-friendly; elderly-safe; weight-neutral; once-daily; CARMELINA

RxIndia v1.0 — 25 Jan 2025

• CDSCO Approved Package Inserts

• Indian Pharmacopoeia (latest edition)

• National List of Essential Medicines (NLEM) 2022 — Linagliptin not listed

• API Textbook of Medicine (11th edition)

• ICMR Guidelines for Management of Type 2 Diabetes (2023)

• AIIMS Pharmacology Handbook

• Goodman & Gilman's The Pharmacological Basis of Therapeutics

• Product inserts from Boehringer Ingelheim and USV Pvt Ltd

• CARMELINA and CAROLINA trials (cardiovascular safety data)