Schedule H

Intravenous (IV) Infusion Only

• Concentrate for Infusion: 4 mg/5 mL vial

• Ready-to-Infuse Solution: 5 mg/100 mL bag

INDICATIONS + DOSING — FOR CLINICIAN USE ONLY

Primary Indications (Approved / Standard in India)

1. Hypercalcaemia of Malignancy

Parameter Recommendation

Starting dose 4 mg IV infusion over minimum 15 minutes

Titration Not applicable (single dose therapy)

Usual maintenance dose Single dose; may repeat after minimum 7 days if recurrent or inadequate response

Maximum dose 4 mg per dose; minimum 7-day interval between doses

Clinical Notes:

• Ensure adequate hydration before and during infusion (normal saline preferred)

• Correct severe dehydration before administration

• Check serum calcium at 7 days to assess response

1. Prevention of Skeletal-Related Events in Bone Metastases (Solid Tumours and Multiple Myeloma)

Parameter Recommendation

Starting dose 4 mg IV infusion over minimum 15 minutes

Titration Not applicable

Usual maintenance dose 4 mg IV every 3–4 weeks

Maximum dose 4 mg every 3 weeks

Clinical Notes:

• Continue as long as clinically beneficial

• Administer with daily calcium (500 mg) and vitamin D (400 IU) supplementation

• Assess renal function before each dose; adjust interval if creatinine increases

• Duration of therapy is often lifelong in metastatic disease

1. Postmenopausal Osteoporosis

Parameter Recommendation

Starting dose 5 mg IV infusion over minimum 15 minutes, once yearly

Titration Not applicable

Usual maintenance dose 5 mg IV once yearly

Maximum dose 5 mg per year

Clinical Notes:

• Ensure adequate calcium (1000–1200 mg/day) and vitamin D (800–1000 IU/day) intake

• Correct vitamin D deficiency before administration

• Consider treatment holiday after 3–5 years in patients at lower fracture risk

• Assess renal function before each annual dose

1. Glucocorticoid-Induced Osteoporosis

Parameter Recommendation

Starting dose 5 mg IV infusion over minimum 15 minutes, once yearly

Titration Not applicable

Usual maintenance dose 5 mg IV once yearly

Maximum dose 5 mg per year

Clinical Notes:

• Consider in patients on ≥7.5 mg prednisolone equivalent for ≥3 months (expected)

• Ensure adequate calcium and vitamin D supplementation

• Continue as long as glucocorticoid therapy continues or fracture risk remains elevated

1. Male Osteoporosis

Parameter Recommendation

Starting dose 5 mg IV infusion over minimum 15 minutes, once yearly

Titration Not applicable

Usual maintenance dose 5 mg IV once yearly

Maximum dose 5 mg per year

Clinical Notes:

• Include in management when oral bisphosphonates not tolerated or compliance is concern

• Ensure calcium and vitamin D adequacy

1. Paget's Disease of Bone

Parameter Recommendation

Starting dose 5 mg IV infusion over minimum 15 minutes (single dose)

Titration Not applicable

Usual maintenance dose Single dose; retreatment after 12 months if relapse or suboptimal response

Maximum dose 5 mg; minimum 12-month interval between doses

Clinical Notes:

PAEDIATRIC DOSING (Specialist Only)

Primary Indications (Approved / Standard in India)

NOT APPROVED for routine use in children in India.

• No approved paediatric indications

• Indian regulatory sources (CDSCO) do not list paediatric indications

Secondary Indications – Paediatrics (Off-label, if any)

Osteogenesis Imperfecta — Age ≥1 Year

Parameter Recommendation

Starting dose 0.025–0.05 mg/kg IV infusion over 30–60 minutes

Titration Adjust based on BMD response and fracture frequency

Usual maintenance dose 0.025–0.05 mg/kg IV every 3–6 months

Maximum dose 0.05 mg/kg per dose; typically not exceeding 4 mg absolute

Clinical Notes:

• OFF-LABEL use; Specialist only (Paediatric Endocrinology)

• Evidence: International cohort studies; Indian paediatric endocrinology centre experience

• Pre-treatment assessment: serum calcium, phosphate, 25-OH vitamin D, renal function

• Monitor: growth velocity, biochemical bone markers, radiographic BMD

Safety Monitoring in Paediatric Use:

• Serum calcium at 24–48 hours post-infusion (risk of hypocalcaemia higher in children)

• Renal function before each dose

• Growth and skeletal development monitoring

• Dental health assessment

Not recommended below 1 year of age under any circumstances. Use above 1 year only under paediatric endocrinology specialist supervision in tertiary centres.

For Oncology Indications (4 mg dose):

Baseline CrCl (mL/min) Recommendation

60 4 mg; no adjustment

50–60 3.5 mg

40–49 3.3 mg

30–39 3.0 mg

<30 Not recommended

For Osteoporosis/Paget's Disease (5 mg dose):

General Notes:

• Evaluate serum creatinine before each dose

• Withhold dose if serum creatinine increases >0.5 mg/dL from baseline or >1.0 mg/dL in patients with baseline creatinine <1.4 mg/dL

• Resume only when creatinine returns to within 10% of baseline

• Ensure adequate hydration; infuse over at least 15 minutes

• Haemodialysis: Not recommended; not significantly dialysed

Note: Zoledronic acid is not hepatically metabolised; excreted unchanged by kidneys.

• Hypocalcaemia (must be corrected before treatment)

• Severe renal impairment (CrCl <30 mL/min for oncology indications; eGFR <35 mL/min for osteoporosis)

• Known hypersensitivity to zoledronic acid, other bisphosphonates, or any excipient

• Pregnancy

• Breastfeeding

• Pre-existing renal impairment — monitor closely; increased risk of acute renal deterioration

• Concurrent nephrotoxic drugs (aminoglycosides, NSAIDs, contrast agents, amphotericin B)

• Dehydration or volume depletion — correct before infusion

• Vitamin D deficiency — correct before administration to reduce hypocalcaemia risk

• Dental disease, poor oral hygiene, or planned invasive dental procedures — risk of osteonecrosis of jaw (ONJ); complete dental work before initiating in oncology patients

• Asthma with aspirin sensitivity — risk of bronchoconstriction

• Previous atypical femoral fracture — assess risk-benefit for continued use

• Concomitant or recent use of other anti-resorptive agents

• Long-term use (>3–5 years) — consider drug holiday due to atypical fracture risk

Parameter Details

Risk Category Contraindicated during pregnancy

Known Risks Animal studies show fetal skeletal abnormalities, hypocalcaemia, dystocia; bisphosphonates accumulate in bone and may be released during pregnancy

Recommendation Do not use during pregnancy

Preferred Alternatives For hypercalcaemia of malignancy: calcitonin (short-term), hydration, loop diuretics; specialist oncology input essential

Women of Childbearing Potential Ensure effective contraception during treatment; counsel regarding long bone half-life (may persist for years after last dose)

Parameter Details

Compatibility Not recommended during breastfeeding

Drug Levels in Milk Unknown; potential for serious adverse effects in infant

Recommendation Avoid use during breastfeeding; if essential, discontinue breastfeeding

Preferred Alternatives Defer treatment until after breastfeeding if clinically appropriate

Parameter Recommendation

Starting dose Same as adult dosing (no age-based reduction)

Titration Not applicable

Special Risks Age-related decline in renal function; higher risk of post-infusion hypocalcaemia (especially if vitamin D deficient); increased susceptibility to dehydration

Monitoring Assess renal function before each dose; ensure adequate hydration; correct vitamin D deficiency before administration

Acute Phase Reaction More pronounced in elderly; consider paracetamol prophylaxis

Interacting Drug Mechanism / Effect Recommendation

Aminoglycosides (gentamicin, amikacin) Additive hypocalcaemic effect; additive nephrotoxicity Avoid concurrent use if possible; if essential, monitor calcium and renal function closely

Loop Diuretics (furosemide, torsemide) Increased risk of hypocalcaemia and electrolyte disturbances Monitor serum calcium and electrolytes; ensure adequate hydration

Nephrotoxic Agents (amphotericin B, cyclosporine, tacrolimus, cisplatin) Additive nephrotoxicity Avoid concurrent use or use with extreme caution; monitor renal function closely

Other Bisphosphonates Additive effects; no benefit from combination Avoid concurrent use

Denosumab Sequential use may increase ONJ and atypical fracture risk Allow adequate washout; specialist guidance

Interacting Drug Mechanism / Effect Recommendation

NSAIDs (ibuprofen, diclofenac, naproxen) Additive nephrotoxicity Use with caution; monitor renal function; ensure hydration

Thiazide Diuretics May affect calcium metabolism Monitor calcium, especially in early post-infusion period

Proton Pump Inhibitors Theoretical concern for reduced bisphosphonate efficacy (not proven for IV) No dose adjustment; clinical significance uncertain for IV route

Calcitonin Additive hypocalcaemic effect Monitor calcium if used concurrently

Acute Phase Reaction (especially first dose):

• Fever (most common)

• Myalgia

• Arthralgia

• Flu-like symptoms

• Headache

• Fatigue

Note: Typically occurs within 24–72 hours of infusion; resolves spontaneously within 2–3 days; less common with subsequent doses.

Other Common Effects:

• Nausea / Vomiting

• Transient hypocalcaemia

• Hypophosphataemia

• Bone pain (transient)

• Injection site reactions

Adverse Effect Clinical Action

Acute Renal Failure / Renal Deterioration Check creatinine before each dose; withhold if significant increase; ensure adequate hydration; avoid in severe renal impairment

Osteonecrosis of the Jaw (ONJ) Higher risk with oncology doses, poor dental hygiene, invasive dental procedures; dental assessment before oncology use; discontinue if ONJ develops

Atypical Femoral Fractures Associated with long-term use (>3–5 years); consider drug holiday; investigate prodromal thigh/groin pain

Severe Hypocalcaemia / Hypocalcaemic Tetany Medical emergency; IV calcium gluconate; more common in vitamin D deficient or hypoparathyroid patients

Anaphylaxis / Severe Allergic Reactions (rare) Observe during and after first infusion; discontinue permanently if occurs

Ocular Inflammation (uveitis, scleritis, episcleritis) Ophthalmology referral; may require discontinuation

Severe Bone, Joint, or Muscle Pain May occur days to months after starting; consider discontinuation if severe

24–72 Hours Post-Infusion Serum calcium (especially in vitamin D deficient patients, elderly, or those at high risk of hypocalcaemia)

1–2 Weeks Post-Infusion Serum creatinine and calcium

Long-term (Oncology) Renal function before every dose; serum calcium periodically; annual dental review; monitor for jaw symptoms

Long-term (Osteoporosis) Renal function before annual dose; BMD every 2–3 years; dental health; assess for atypical fracture symptoms (thigh/groin pain)

• Zometa (Novartis) — Originator

• Zoledros (Dr. Reddy's)

• Zoldonat (Natco)

• Zoledronic Acid (Intas)

• Zornic (Cipla)

• Zobone (Sun Pharma)

• Xobone (Hetero)

• Zolfrac (Glenmark)

Note: Multiple generics available; verify exact strength and formulation (4 mg vs 5 mg). FDCs not applicable.

• Included in NLEM 2022 for certain indications (oncology, osteoporosis)

• May be available at subsidised rates in government oncology and endocrinology centres

• Significant price variation between generics and originator

• Always correct hypocalcaemia and vitamin D deficiency before infusion — post-infusion hypocalcaemia can be severe, especially in vitamin D deficient patients

• Acute phase reaction (fever, myalgia, flu-like symptoms) is common after first dose — prophylactic paracetamol (1 g before and 1 g 6–8 hours after infusion) reduces severity; reassure patients this is self-limiting

• Annual IV dosing for osteoporosis offers significant adherence advantage over weekly or monthly oral bisphosphonates — excellent choice for patients with GI intolerance or poor compliance

• Dental assessment is mandatory before starting in oncology patients — complete invasive dental work before initiation; avoid dental extractions during therapy; risk of ONJ higher with oncology doses

• Do not confuse the two formulations: 4 mg is for oncology indications (every 3–4 weeks), 5 mg is for osteoporosis/Paget's (once yearly) — prescribing errors between formulations have occurred

• Consider drug holiday after 3–5 years of osteoporosis treatment in patients at lower fracture risk — atypical femoral fractures are associated with prolonged use

Zoledronic Acid; bisphosphonate; osteoporosis; hypercalcaemia of malignancy; bone metastases; Paget's disease; skeletal-related events; osteonecrosis of jaw; renal-caution; IV infusion; NLEM India; Schedule H

RxIndia v1.0 — 05 May 2025

• CDSCO approved product information

• Indian Pharmacopoeia (IP)

• National Formulary of India (NFI)

• National List of Essential Medicines (NLEM) 2022

• API Textbook of Medicine — Endocrinology and Oncology chapters

• AIIMS Endocrinology and Oncology Treatment Protocols

• ICMR Cancer Management Guidelines

• Goodman & Gilman's: The Pharmacological Basis of Therapeutics

• Harrison's Principles of Internal Medicine

• Indian Menopause Society Guidelines for Osteoporosis

• Indian paediatric endocrinology practice (for off-label Osteogenesis Imperfecta indication)