Schedule H

Subcutaneous injection, Oral

• Semaglutide injection (prefilled pen): 0.25 mg/dose, 0.5 mg/dose, 1 mg/dose

• Semaglutide oral tablets: 3 mg, 7 mg, 14 mg

INDICATIONS + DOSING — FOR CLINICIAN USE ONLY

Primary Indications (Approved / Standard in India)

Type 2 Diabetes Mellitus (T2DM)

Patient selection: As adjunct to diet and exercise in adults with T2DM inadequately controlled on metformin, sulfonylurea, SGLT2 inhibitors, or basal insulin (alone or in combination).

Formulation 1: Subcutaneous Semaglutide (Once Weekly)

Parameter Recommendation

Starting dose 0.25 mg SC once weekly for 4 weeks (dose-escalation phase — not for glycaemic control)

Titration Increase to 0.5 mg once weekly after 4 weeks; if additional glycaemic control required after ≥4 weeks on 0.5 mg, increase to 1 mg once weekly

Usual maintenance dose 0.5–1 mg SC once weekly

Maximum dose 1 mg SC once weekly (2 mg strength not available in India as of 2024)

Administration guidance:

• Administer on same day each week, any time of day, with or without meals

• May change injection day if last dose was given ≥2 days prior

• Inject in abdomen, thigh, or upper arm; rotate injection sites

• If dose missed, administer within 5 days; if >5 days, skip and resume on next scheduled day

Formulation 2: Oral Semaglutide (Once Daily)

Parameter Recommendation

Starting dose 3 mg orally once daily for 30 days (dose-escalation phase)

Titration Increase to 7 mg once daily after 30 days; if additional glycaemic control required after ≥30 days on 7 mg, increase to 14 mg once daily

Usual maintenance dose 7–14 mg orally once daily

Maximum dose 14 mg once daily

Critical administration requirements:

• Take on empty stomach at least 30 minutes before first food, beverage, or other oral medication of the day

• Swallow whole with up to 120 mL (half glass) of plain water only

• Do not crush, chew, or split tablets

• Larger volumes of water or food within 30 minutes significantly reduce absorption

Key Clinical Notes (Both Formulations):

• Not for use in Type 1 diabetes mellitus or diabetic ketoacidosis

• Initial dose-escalation phase is for GI tolerability, not glycaemic efficacy

• Can be used as monotherapy if metformin contraindicated or not tolerated

• Complementary mechanism with metformin, SGLT2 inhibitors, and basal insulin

Secondary Indications — Adults (Off-label)

1. Obesity / Weight Management — OFF-LABEL

Parameter Details

Indication Obesity (BMI ≥30 kg/m²) or overweight (BMI ≥27 kg/m²) with weight-related comorbidities, without T2DM

Dose (SC) Same titration as diabetes: 0.25 mg weekly × 4 weeks → 0.5 mg weekly × 4 weeks → 1 mg weekly

Duration Minimum 12–16 weeks to assess response; continue if ≥5% weight loss achieved

Specialist only Yes — Endocrinology or Obesity Medicine supervision

Evidence basis STEP trial programme (NEJM 2021); demonstrates 10–15% weight loss with 2.4 mg dose (higher dose not available in India); 1 mg provides ~6–8% weight loss

Note: Semaglutide 2.4 mg (Wegovy) approved internationally for obesity is NOT AVAILABLE in India. Off-label use limited to 1 mg maximum, which provides modest weight loss compared to higher doses.

1. Cardiovascular Risk Reduction in T2DM — OFF-LABEL (for CV indication specifically)

Parameter Details

Indication T2DM with established atherosclerotic cardiovascular disease

Dose Standard diabetes dosing (0.5–1 mg SC weekly or 7–14 mg oral daily)

Duration Long-term

Specialist only Cardiologist/Endocrinologist coordination recommended

Evidence basis SUSTAIN-6 trial demonstrated 26% reduction in MACE; CDSCO approval is for T2DM, CV benefit is an added advantage

PAEDIATRIC DOSING (Specialist Only)

Primary Indications (Approved / Standard in India)

Not approved for paediatric use in India.

Minimum approved age: 18 years (CDSCO)

Secondary Indications — Paediatrics (Off-label)

Type 2 Diabetes Mellitus in Adolescents (Age ≥12 years) — OFF-LABEL

Parameter Details

Minimum age 12 years

Minimum weight ≥45 kg

Formulation Subcutaneous only (oral formulation not studied in paediatrics)

Starting dose 0.25 mg SC once weekly for 4 weeks

Titration Increase to 0.5 mg weekly after 4 weeks; may increase to 1 mg weekly if needed after further 4 weeks

Maximum dose 1 mg SC once weekly

Specialist only Paediatric Endocrinology supervision mandatory

Evidence basis PIONEER TEENS trial; US FDA approved for ≥10 years; not CDSCO-approved in India

Safety monitoring (paediatrics):

• HbA1c every 3 months

• Height and weight at each visit (growth velocity assessment)

• Pubertal staging (Tanner stage) every 6 months

• GI tolerance monitoring

• Signs of pancreatitis

Age restriction: Not recommended below 12 years or body weight <45 kg except under paediatric endocrinology specialist supervision with documented rationale.

Clinical notes:

• Semaglutide is not primarily renally cleared (proteolytic degradation)

• GI adverse effects (nausea, vomiting, diarrhoea) may precipitate dehydration and acute kidney injury

• Monitor renal function in patients with baseline CKD, especially during dose escalation

• Reports of acute kidney injury, typically in setting of GI adverse effects with volume depletion

Note: Semaglutide is metabolised by proteolytic cleavage and not dependent on hepatic CYP enzymes; however, clinical experience in hepatic impairment is limited.

• Personal or family history of medullary thyroid carcinoma (MTC)

• Multiple Endocrine Neoplasia syndrome type 2 (MEN 2)

• Known hypersensitivity to semaglutide or any formulation excipient

• Pregnancy (embryo-fetal toxicity demonstrated in animal studies)

• Type 1 diabetes mellitus

• Diabetic ketoacidosis

• History of serious hypersensitivity reaction to any GLP-1 receptor agonist

• History of pancreatitis — increased risk of recurrence; monitor closely

• Active gallbladder disease or history of cholelithiasis — GLP-1 agonists increase gallstone risk

• Diabetic retinopathy — rapid glycaemic improvement may transiently worsen retinopathy; fundus examination recommended before initiation if retinopathy present

• Gastroparesis or significant GI motility disorders — may exacerbate symptoms

• Risk of volume depletion — monitor hydration, especially during GI adverse effects

• Concurrent sulfonylurea or insulin therapy — increased hypoglycaemia risk; consider dose reduction

• Thyroid nodules — baseline thyroid examination in patients with risk factors

• History of angioedema with other GLP-1 agonists

• Concurrent DPP-4 inhibitor therapy — avoid combination (redundant mechanism, no additional benefit)

Parameter Details

Risk category Contraindicated — embryo-fetal toxicity in animal studies; no adequate human data

Preferred alternatives Insulin therapy (basal-bolus or premixed); metformin may be continued in select cases under specialist guidance

Pre-conception Discontinue semaglutide at least 2 months before planned conception (due to long half-life)

If pregnancy occurs Discontinue immediately; transition to insulin

Monitoring Ensure reliable contraception during therapy

Parameter Details

Compatibility Not recommended — unknown whether excreted in human breast milk

Drug levels in milk Unknown in humans; animal studies suggest presence in milk

Preferred alternatives Insulin (safe during lactation); metformin (low milk transfer, widely used)

Infant monitoring If inadvertent exposure: monitor feeding patterns, GI symptoms, weight gain

Parameter Recommendation

Starting dose Same as adults (0.25 mg SC weekly or 3 mg oral daily)

Titration Consider slower titration (extend each dose level to 6–8 weeks instead of 4 weeks) to improve GI tolerability

Extra risks Increased susceptibility to dehydration from GI adverse effects; higher risk of acute kidney injury; hypoglycaemia risk if combined with sulfonylureas or insulin

Monitoring Renal function at baseline and periodically; hydration status; weight

Note: No dose adjustment required based on age alone; clinical experience in patients >75 years is limited.

Interacting Drug Mechanism / Effect Recommendation

Insulin Additive hypoglycaemia risk Consider reducing insulin dose by 10–20% when initiating semaglutide; monitor closely

Sulfonylureas (glimepiride, gliclazide, glipizide) Additive hypoglycaemia risk Consider reducing sulfonylurea dose by 50% when initiating semaglutide

DPP-4 inhibitors (sitagliptin, vildagliptin) Redundant incretin mechanism Avoid combination — no additional glycaemic benefit; increased cost

Oral levothyroxine Delayed gastric emptying may alter absorption Separate dosing by ≥1 hour; monitor TSH; for oral semaglutide, take levothyroxine at different time of day

Loop diuretics (furosemide) Combined volume depletion risk Monitor hydration and renal function closely

Interacting Drug Effect Management

Metformin Synergistic glucose-lowering; safe and recommended combination No dose adjustment needed

SGLT2 inhibitors (dapagliflozin, empagliflozin) Synergistic effect on glucose and weight Monitor volume status and renal function

Warfarin Variable INR changes reported; delayed vitamin K absorption possible Monitor INR more frequently when initiating or changing semaglutide dose

Paracetamol Delayed absorption (reduced Cmax, prolonged Tmax) Usually not clinically significant; no dose adjustment

Oral contraceptives Potentially delayed absorption Clinical significance uncertain; monitor contraceptive efficacy

Oral antibiotics (ciprofloxacin, amoxicillin) Potentially delayed absorption Monitor clinical response

PPIs / H2 blockers May affect oral semaglutide absorption (pH-dependent) Consider separating doses; clinical significance unclear

• Nausea (20–40% — most common, typically dose-related and transient)

• Vomiting

• Diarrhoea

• Constipation

• Abdominal pain/discomfort

• Decreased appetite

• Dyspepsia

• Flatulence

• Gastroesophageal reflux

• Fatigue

• Headache

• Dizziness

• Injection site reactions (SC formulation)

Adverse Effect Clinical Action

Acute pancreatitis Discontinue immediately; do not rechallenge; supportive care

Diabetic retinopathy complications More common with rapid HbA1c reduction in pre-existing retinopathy; ophthalmology referral

Acute cholecystitis / Cholelithiasis Evaluate with imaging; surgical consultation if indicated

Severe hypoglycaemia More likely with concurrent insulin/SU; treat appropriately; adjust concomitant therapy

Acute kidney injury Usually secondary to dehydration from GI symptoms; discontinue if severe; rehydrate

Anaphylaxis / Angioedema Discontinue permanently; emergency management

Thyroid C-cell tumours Theoretical risk from rodent studies; clinical relevance in humans uncertain; monitor in at-risk patients

During dose escalation GI tolerance weekly; hypoglycaemia symptoms (if on insulin/SU); weight; renal function at 4–8 weeks if at-risk

Long-term HbA1c every 3 months until stable, then every 6 months; weight at each visit; renal function every 6–12 months; fundus examination annually (if pre-existing retinopathy); signs/symptoms of pancreatitis (persistent severe abdominal pain); thyroid nodules (clinical exam annually if at-risk)

• OZEMPIC (Novo Nordisk) — subcutaneous injection prefilled pen (0.25 mg, 0.5 mg, 1 mg)

• RYBELSUS (Novo Nordisk) — oral tablets (3 mg, 7 mg, 14 mg)

Note: No fixed-dose combinations available. Wegovy (semaglutide 2.4 mg for obesity) is NOT AVAILABLE in India.

Notes:

• Not included in NLEM 2022

• Not price-controlled by NPPA

• Limited government hospital availability

• High cost may be a significant barrier to adherence

1. GI tolerability improves with slow titration — do not skip the dose-escalation phase; extending titration intervals (6–8 weeks instead of 4 weeks) significantly reduces nausea and dropout rates.

1. Oral formulation requires strict adherence to administration instructions — taking with food, larger water volumes, or other medications within 30 minutes dramatically reduces bioavailability; patient counselling is essential.

1. Weight loss is an advantage, not just a side effect — semaglutide is preferred over insulin or sulfonylureas in obese T2DM patients where weight reduction is a treatment goal.

1. Pre-emptive sulfonylurea/insulin dose reduction prevents hypoglycaemia — reduce SU by ~50% and insulin by 10–20% when initiating semaglutide.

1. Avoid combining with DPP-4 inhibitors — overlapping incretin mechanism provides no additional glycaemic benefit; discontinue DPP-4 inhibitor when starting semaglutide.

1. Screen for retinopathy before initiation — rapid HbA1c improvement can transiently worsen diabetic retinopathy; ensure baseline fundus examination in patients with known retinopathy.

semaglutide; GLP-1 agonist; type 2 diabetes; weight loss; incretin mimetic; oral GLP-1; subcutaneous injection; cardiovascular benefit; renal-safe; pregnancy-contraindicated; not NLEM

RxIndia v0.9 — 11 Jun 2025

• CDSCO approved product information (Ozempic, Rybelsus — India)

• Indian Pharmacopoeia / National Formulary of India

• API Textbook of Medicine, 11th edition — Diabetes chapter

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

• RSSDI Clinical Practice Recommendations for Management of Type 2 Diabetes

• AIIMS Endocrinology Department Formulary

• Harrison's Principles of Internal Medicine (pharmacology reference)

• Goodman & Gilman's The Pharmacological Basis of Therapeutics

• SUSTAIN trial programme (for CV outcomes data)

• STEP trial programme (for off-label obesity data — NEJM 2021)

• PIONEER TEENS trial (for off-label paediatric data)