Schedule H

Oral, Intravenous

• Tablet (Immediate-release): 100 mg, 200 mg

• Tablet (Sustained-release): 100 mg, 200 mg, 300 mg, 400 mg

• Oral liquid: 50 mg/5 mL, 80 mg/15 mL

• Injection (as Aminophylline): 250 mg/10 mL (equivalent to theophylline ~200 mg)

INDICATIONS + DOSING — FOR CLINICIAN USE ONLY

Primary Indications (Approved / Standard in India):

1. Chronic Asthma — Add-on Maintenance Therapy (Adults)

Usually reserved for patients not adequately controlled on inhaled corticosteroids ± long-acting beta-agonists

Oral Sustained-Release Theophylline:

Parameter Details

Starting dose 200 mg once daily (preferably at night) OR 100 mg twice daily

Titration Increase by 100–200 mg/day every 3–5 days based on clinical response and serum levels

Usual maintenance dose 200–400 mg/day in 1–2 divided doses

Maximum dose 600 mg/day (only with therapeutic drug monitoring confirmation)

Clinical Notes:

• Target therapeutic serum level: 10–15 mcg/mL (toxic effects increase above 20 mcg/mL)

• Narrow therapeutic index — mandatory TDM for dose optimization

• Sustained-release formulations preferred for maintenance; do not crush or chew

• Third-line add-on as per GINA-adapted Indian practice

1. Chronic Obstructive Pulmonary Disease (COPD) — Maintenance Therapy (Adults)

Parameter Details

Starting dose 200 mg once daily (sustained-release)

Titration Increase gradually every 3–5 days based on response and serum levels

Usual maintenance dose 200–400 mg/day in divided doses

Maximum dose 600 mg/day (with TDM)

Clinical Notes:

• Add-on therapy when symptoms persist despite optimal inhaler therapy

• Provides modest bronchodilation and possible anti-inflammatory effects

• Monitor for cardiac adverse effects in COPD patients with comorbidities

1. Acute Severe Asthma / Acute Exacerbation of COPD — Intravenous Aminophylline (Specialist/ICU Setting)

Parameter Details

Loading dose 5–6 mg/kg IV over 20–30 minutes (maximum 500 mg); OMIT if patient already on oral theophylline

Maintenance infusion 0.5–0.7 mg/kg/hour (adjust based on serum levels and clinical status)

Maximum dose Guided by TDM; do not exceed serum level of 20 mcg/mL

Clinical Notes:

• Reserved for patients not responding to nebulized bronchodilators and corticosteroids

• Administer in ICU or high-dependency unit with continuous cardiac monitoring

• High risk of arrhythmias with rapid IV push — never administer as bolus

• Check baseline theophylline level if patient on chronic oral therapy before loading

Secondary Indications — Adults (Off-label, if any):

1. Central Sleep Apnoea in Congestive Heart Failure

Parameter Details

Dose 200–400 mg oral at bedtime (sustained-release)

Duration Variable; based on specialist assessment

Status OFF-LABEL — Specialist only

Evidence Small RCTs showing reduction in apnoea-hypopnoea index; limited Indian experience

PAEDIATRIC DOSING (Specialist Only)

Primary Indications (Approved / Standard in India):

1. Chronic Asthma — Maintenance Therapy

Oral Sustained-Release Theophylline

Minimum age: ≥1 year (use under specialist supervision for ages 6 months–1 year)

Age/Weight Starting Dose Usual Maintenance Dose Maximum Dose

6 months–1 year 5 mg/kg/day divided BD 10–14 mg/kg/day divided BD 16 mg/kg/day

1–9 years 10 mg/kg/day divided BD 12–16 mg/kg/day divided BD 20 mg/kg/day or 600 mg/day (whichever lower)

9–12 years 10 mg/kg/day divided BD 12–14 mg/kg/day divided BD 20 mg/kg/day or 600 mg/day

12–16 years 200 mg/day 10–13 mg/kg/day divided BD 600 mg/day

Titration: Increase dose every 3–5 days based on clinical response; confirm with serum theophylline levels

Clinical Notes:

• Target serum level: 10–15 mcg/mL

• Viral illnesses reduce theophylline clearance — risk of toxicity; consider temporary dose reduction during febrile illness

• Sustained-release tablets should not be crushed; use oral liquid for younger children

1. Acute Severe Asthma — Intravenous Aminophylline (Specialist/PICU Setting)

Parameter Details

Loading dose 5–6 mg/kg IV over 20–30 minutes (omit if on chronic theophylline therapy)

Maintenance infusion Age <6 months: 0.5 mg/kg/hour; Age 6 months–1 year: 0.85–1 mg/kg/hour; Age 1–9 years: 1 mg/kg/hour; Age 9–16 years: 0.7–0.8 mg/kg/hour

Maximum dose Guided by TDM; maintain serum levels 10–15 mcg/mL

Clinical Notes:

• Reserved for life-threatening asthma unresponsive to standard therapy

• Continuous cardiac and neurological monitoring mandatory

• Risk of seizures and arrhythmias — especially with rapid infusion or supratherapeutic levels

Secondary Indications — Paediatric Doses (Off-label, if any):

Apnoea of Prematurity

Parameter Details

Dose Loading: 5–6 mg/kg IV/oral; Maintenance: 2–6 mg/kg/day in 2–3 divided doses

Duration Until resolution of apnoea or transition to caffeine citrate

Status OFF-LABEL — Neonatology specialist only

Evidence Historically used; largely replaced by caffeine citrate in most Indian NICUs due to better safety profile

Age Restriction: Not recommended below 6 months of age except under neonatologist or paediatric pulmonologist supervision for specific indications.

Mild-to-moderate impairment No dose adjustment required

• Known hypersensitivity to theophylline, aminophylline, or other xanthine derivatives

• Active peptic ulcer disease (gastric acid secretion increased)

• Uncontrolled seizure disorders

• Acute myocardial infarction (for IV aminophylline)

• Uncontrolled cardiac arrhythmias (especially tachyarrhythmias)

• Severe untreated hyperthyroidism

• Concurrent use of high-dose parenteral epinephrine (arrhythmia risk)

• Elderly patients — reduced drug clearance

• Congestive heart failure — reduced hepatic blood flow decreases clearance; dose reduction required

• Febrile illness (especially viral infections in children) — clearance reduced; toxicity risk increased

• Chronic alcoholism — altered metabolism

• Smoking (tobacco or cannabis) — induces CYP1A2; may require higher doses; counsel on cessation

• Cor pulmonale — increased sensitivity to arrhythmias

• History of seizures (controlled) — lowers seizure threshold

• Concurrent caffeine intake — additive CNS and cardiac effects

• Narrow therapeutic window — mandatory TDM for optimal dosing

Parameter Details

Risk Category No formal Indian classification; generally considered acceptable when indicated

Safety Statement Can be used if benefits outweigh risks; avoid IV form in third trimester if possible

Preferred Alternatives Inhaled corticosteroids and short-acting beta-agonists are first-line for asthma in pregnancy

When It May Be Used Add-on therapy when inhaled medications inadequate; lowest effective dose

Monitoring Serum theophylline levels (clearance increases in pregnancy); fetal heart rate monitoring near term

Parameter Details

Compatibility Compatible with breastfeeding at therapeutic doses

Drug Levels in Milk Low to moderate (approximately 70% of maternal serum concentration)

Preferred Alternatives Inhaled bronchodilators (salbutamol) and inhaled corticosteroids preferred

Monitoring in Infant Irritability, jitteriness, poor feeding, sleep disturbance; consider timing breastfeeding to avoid peak drug levels

Parameter Recommendation

Recommended starting dose 100–200 mg/day (oral sustained-release)

Titration Slower titration every 5–7 days; guided by TDM

Extra Risks Reduced hepatic clearance; increased susceptibility to CNS toxicity (confusion, agitation), cardiac arrhythmias; concurrent cardiac disease common

Monitoring More frequent TDM; baseline and periodic ECG; monitor renal and hepatic function

Interacting Drug Effect & Mechanism Action

Ciprofloxacin, Norfloxacin Strong CYP1A2 inhibition → marked increase in theophylline levels; toxicity risk Avoid combination or reduce theophylline dose by 30–50%; TDM mandatory

Erythromycin, Clarithromycin CYP3A4 inhibition → increased theophylline levels Reduce dose by 25–30%; monitor levels

Cimetidine Inhibits hepatic metabolism → increased theophylline levels Avoid; use ranitidine or proton pump inhibitors instead

Phenytoin, Carbamazepine, Phenobarbital CYP induction → decreased theophylline efficacy Increase theophylline dose; monitor levels and clinical response

Rifampicin Strong CYP induction → markedly reduced theophylline levels May need to double theophylline dose; frequent TDM

Fluvoxamine Potent CYP1A2 inhibition → significant theophylline accumulation Avoid combination if possible; reduce theophylline dose substantially

IV Sympathomimetics (salbutamol, adrenaline) Additive cardiac stimulation → arrhythmia risk Use with extreme caution; continuous cardiac monitoring

Interacting Drug Effect Recommendation

Allopurinol (>300 mg/day) May increase theophylline levels Monitor serum theophylline; adjust dose if needed

Oral contraceptives May reduce theophylline clearance slightly Monitor for adverse effects

Beta-blockers (non-selective) May antagonize bronchodilatory effect Avoid non-selective agents; use cardioselective beta-blockers if required

Isoniazid Variable effect on metabolism Monitor theophylline levels during ATT

Ketoconazole, Fluconazole Mild CYP inhibition → slight increase in levels Monitor if hepatic dysfunction present

Propranolol Pharmacodynamic antagonism Prefer cardioselective beta-blockers

Lithium Theophylline may increase lithium excretion Monitor lithium levels

Tobacco/Cannabis smoking CYP1A2 induction → reduced theophylline efficacy Higher doses may be needed; counsel cessation

• Nausea, vomiting, epigastric discomfort

• Headache

• Restlessness, insomnia

• Palpitations, tachycardia

• Tremor

• Increased gastric acid secretion

• Mild diuresis

• Irritability (especially in children)

Adverse Effect Notes

Cardiac arrhythmias Atrial and ventricular tachyarrhythmias; can be fatal; discontinue immediately

Seizures Especially with serum levels >30 mcg/mL or rapid IV administration; may occur without warning; discontinue and treat urgently

Hypotension With rapid IV aminophylline administration

Severe hypokalaemia Can precipitate arrhythmias

Stevens-Johnson Syndrome Rare; immediate discontinuation required

Hepatotoxicity Very rare; discontinue if hepatic derangement

Any signs of toxicity (persistent vomiting, tremors, seizures, arrhythmias) require immediate discontinuation and hospitalisation

After initiation/dose change Serum theophylline level 3–5 days after starting or any dose adjustment (measure trough level for sustained-release)

Long-term Serum theophylline levels every 6–12 months; more frequently if clinical status changes, interacting drugs added, or intercurrent illness

Clinical monitoring Heart rate, blood pressure, symptoms of toxicity (nausea, tremor, palpitations, seizures) at each visit

Therapeutic Range: 10–15 mcg/mL (toxicity increases significantly above 20 mcg/mL)

Plain Theophylline:

• Theo-Asthalin SR (Cipla)

• Theodrip (FDC)

• Unicontin (Glenmark)

• Theobid (Alkem)

• Nuelin (3M Pharmaceuticals)

• Phyllocontin (Napp/Abbott)

Aminophylline Injection:

• Aminophylline Injection IP (various manufacturers)

• Phyllocontin Injection

Fixed-Dose Combinations (FDCs):

• Theo-Asthalin (theophylline + salbutamol)

NLEM Status: Yes — Aminophylline injection and theophylline oral formulations included in NLEM 2022

Government supply: Available through public health facilities

1. Always use TDM — Theophylline has a narrow therapeutic window; serum level monitoring is essential for safe and effective dosing

1. Avoid loading dose if already on oral therapy — Check recent theophylline intake and serum level before IV aminophylline to prevent toxicity

1. Viral illness in children reduces clearance — Temporarily reduce dose or hold theophylline during febrile illnesses to prevent toxicity

1. Smoking cessation affects dosing — Patients who quit smoking will have reduced clearance; decrease theophylline dose by 30–50% and recheck levels

1. Deriphyllin is not pure theophylline — It contains etofylline + theophylline; consider this when calculating doses or interpreting serum levels

1. Reserve for add-on therapy — Inhaled bronchodilators and corticosteroids remain first-line; theophylline is third-line for patients with refractory symptoms

asthma; COPD; bronchodilator; methylxanthine; theophylline; aminophylline; TDM required; paediatric asthma; narrow therapeutic index; NLEM India; IV use caution

RxIndia v1.0 — 10 Jan 2025

• CDSCO approved product information

• Indian Pharmacopoeia

• NLEM India 2022

• API Textbook of Medicine

• ICMR Guidelines for Management of Asthma and COPD

• AIIMS Hospital Formulary

• IAP Guidelines for Management of Childhood Asthma

• Goodman & Gilman's The Pharmacological Basis of Therapeutics (pharmacokinetics reference)

• Harrison's Principles of Internal Medicine