Schedule H

Oral

• Tablets: 500 mg, 1 g

INDICATIONS + DOSING — FOR CLINICIAN USE ONLY

Primary Indication: Type 2 Diabetes Mellitus (T2DM)

Initiation criteria: After failure of diet and lifestyle modifications alone

Parameter Recommendation

Starting dose 500–1000 mg orally once daily with breakfast

Titration Increase by 250–500 mg every 5–7 days based on glycaemic response

Usual maintenance dose 1–2 g/day in 1–3 divided doses

Maximum dose 3 g/day (in divided doses)

Clinical Notes:

• Shorter half-life compared to other sulfonylureas; lower risk of prolonged hypoglycaemia

• Higher hypoglycaemia risk than newer-generation sulfonylureas (glimepiride, gliclazide)

• Ineffective in patients with absolute insulin deficiency (Type 1 DM, pancreatic diabetes)

• Consider with meals to reduce GI upset and hypoglycaemia risk

Secondary Indications – Adults (Off-label)

Not applicable.

No common off-label indications documented in Indian clinical practice.

PAEDIATRIC DOSING (Specialist Only)

Not recommended below 18 years due to limited safety data and significant hypoglycaemia risk.

Use in adolescents is exceptional and only under paediatric endocrinologist supervision.

Primary Indication: Type 2 Diabetes Mellitus in adolescents (age ≥12 years) — OFF-LABEL

Parameter Recommendation

Starting dose 250 mg once or twice daily

Titration Increase by 250 mg at weekly intervals based on response

Usual maintenance dose 500 mg–1 g/day in divided doses

Maximum dose 1.5 g/day (divided doses)

Safety Monitoring:

• Frequent fasting and pre-meal blood glucose monitoring

• Watch for symptoms of hypoglycaemia (sweating, tremor, confusion, irritability)

• Ensure caregiver education on hypoglycaemia recognition and management

Evidence basis: Limited to small case series; extrapolated from adult data. Metformin remains first-line in paediatric T2DM per ICMR and international guidelines.

Secondary Indications – Paediatrics (Off-label)

Not applicable.

• Type 1 diabetes mellitus

• Diabetic ketoacidosis (DKA) or hyperosmolar hyperglycaemic state

• Known hypersensitivity to tolbutamide or other sulfonylureas

• Severe renal impairment (eGFR <30 mL/min)

• Severe hepatic impairment

• Pregnancy

• Lactation

• Concurrent use with bosentan (risk of hepatotoxicity and reduced drug efficacy)

• Elderly patients (increased susceptibility to hypoglycaemia)

• G6PD deficiency (theoretical haemolysis risk with sulfonamide-related structure)

• Adrenal or pituitary insufficiency

• Malnourished patients or irregular meal patterns

• Chronic alcohol use

• Intercurrent illness, surgery, or reduced oral intake (consider temporary discontinuation)

• Cardiovascular disease (hypoglycaemia symptoms may be masked or mimic cardiac events)

• Patients on multiple antidiabetic agents (additive hypoglycaemia risk)

Parameter Details

Risk Statement Contraindicated in pregnancy

Concern Crosses placenta; may cause neonatal hypoglycaemia, macrosomia

Preferred Alternative Insulin (regular insulin, NPH, or rapid-acting analogues as per obstetric protocol)

If inadvertent exposure Switch promptly to insulin upon pregnancy confirmation

Monitoring Fasting blood glucose, HbA1c, fetal growth scans if exposure occurred

Parameter Details

Compatibility Contraindicated during breastfeeding

Concern Excreted in breast milk; may cause neonatal hypoglycaemia

Preferred Alternative Insulin therapy; metformin may be considered under specialist guidance

Infant Monitoring (if inadvertently used) Monitor feeding pattern, weight gain, excessive drowsiness, jitteriness

Parameter Recommendation

Starting dose 250–500 mg/day

Titration Slower than younger adults; increase every 7–14 days

Special Risks Falls, confusion, unrecognised hypoglycaemia, reduced renal reserve

Monitoring Frequent glucose checks; consider SMBG; caregiver education essential

Clinical Note: Gliclazide MR or low-dose glimepiride are generally preferred over tolbutamide in elderly due to lower hypoglycaemia risk.

Interacting Drug Effect Management

Bosentan Hepatotoxicity; reduced sulfonylurea efficacy Contraindicated combination

Rifampicin CYP450 enzyme induction reduces tolbutamide levels; loss of glycaemic control Avoid combination; use alternative antidiabetic if on ATT

High-dose aspirin / NSAIDs Protein binding displacement; enhanced hypoglycaemia Monitor glucose; reduce tolbutamide dose if needed

Warfarin Potentiation of anticoagulant effect Monitor INR closely; adjust warfarin dose

Non-selective beta-blockers Mask sympathetic warning signs of hypoglycaemia Prefer cardioselective beta-blockers; educate patient

Sulfonamide antibiotics Additive hypoglycaemia risk (similar structure) Monitor glucose; short courses with caution

Interacting Drug Effect Management

Isoniazid May impair glycaemic control Monitor glucose during ATT initiation

Thiazide diuretics May increase blood glucose May require tolbutamide dose increase

Fluoroquinolones Unpredictable glycaemic effects (both hypo- and hyperglycaemia reported) Monitor glucose

Alcohol Increased hypoglycaemia risk; disulfiram-like reaction possible Advise limitation of alcohol intake

Pioglitazone Additive hypoglycaemia; fluid retention Monitor; consider dose reduction of either agent

Azole antifungals (fluconazole, ketoconazole) CYP2C9 inhibition; increased tolbutamide levels Monitor glucose; may need dose reduction

• Hypoglycaemia (dose-related; most common)

• Weight gain

• Nausea, epigastric discomfort

• Headache

• Dizziness

• Skin rash

Adverse Effect Clinical Notes

Severe hypoglycaemia May require IV dextrose, hospitalisation; can cause coma, seizures

Agranulocytosis / leukopenia Rare; discontinue if unexplained fever, sore throat, infection

Thrombocytopenia Rare haematological toxicity

Hepatotoxicity Rare; usually reversible on discontinuation

Severe cutaneous reactions Photosensitivity, erythema multiforme (rare)

SIADH Very rare; presents with hyponatraemia

During titration FBG and PPBG weekly; symptom check for hypoglycaemia

Long-term HbA1c every 3 months initially, then every 6 months if stable

As needed LFTs if hepatotoxicity suspected; CBC if haematological symptoms

Patient Education: All patients must be educated on recognition and self-management of hypoglycaemia.

Note: Tolbutamide is an older first-generation sulfonylurea with declining usage. Availability may be limited in certain regions.

• Rastinon (Sanofi) — verify local availability

• Other generic formulations may be available through government supply

Prescribers should verify current local availability before prescribing.

• Not currently under NPPA price control

• May be available at lower cost through government hospitals/PMBJK

1. Shorter half-life advantage: Tolbutamide has the shortest duration of action among sulfonylureas — useful when predictable, short-acting glucose lowering is needed, but requires multiple daily dosing.

1. Not first-line in current practice: Newer sulfonylureas (gliclazide, glimepiride) have largely replaced tolbutamide due to better safety profiles and once-daily dosing.

1. Avoid in elderly with renal impairment: Prefer gliclazide MR which has a better safety margin in this population.

1. Sick day rules: Advise patients to withhold during acute illness, reduced oral intake, or perioperative period to prevent hypoglycaemia.

1. Weight gain counselling: Dietary advice essential; sulfonylureas promote weight gain which may worsen insulin resistance.

1. Cost consideration: May still have role in resource-limited settings where cost is a major constraint and newer agents are unavailable.

tolbutamide; sulfonylurea; first-generation sulfonylurea; type 2 diabetes; hypoglycaemia risk; elderly caution; renal-avoid; hepatic-caution; Schedule H; pregnancy-contraindicated; antidiabetic

RxIndia v1.0 — 10 Jan 2025

• CDSCO approved prescribing information

• Indian Pharmacopoeia (IP)

• NLEM 2022

• API Textbook of Medicine

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

• Harrison's Principles of Internal Medicine

• Goodman & Gilman's The Pharmacological Basis of Therapeutics

• Standard Indian endocrinology clinical practice