Schedule H

Oral, Intravenous

• Tablets (Single Strength/SS): Sulfamethoxazole 400 mg + Trimethoprim 80 mg

• Tablets (Double Strength/DS): Sulfamethoxazole 800 mg + Trimethoprim 160 mg

• Oral Suspension: Sulfamethoxazole 200 mg + Trimethoprim 40 mg per 5 mL

• Injection: Sulfamethoxazole 400 mg + Trimethoprim 80 mg per 5 mL ampoule

Note: All dosing in this monograph refers to the Trimethoprim (TMP) component unless otherwise specified. SMX:TMP ratio is fixed at 5:1 in all formulations.

INDICATIONS + DOSING — FOR CLINICIAN USE ONLY

Primary Indications (Approved / Standard in India):

1. Urinary Tract Infections (Uncomplicated and Complicated)

Uncomplicated UTI (Cystitis):

Parameter Dose Clinical Notes

Starting dose 160 mg TMP (1 DS tablet) orally twice daily Take with adequate fluids

Titration Not applicable Fixed dosing

Usual maintenance dose 160 mg TMP twice daily

Maximum dose 320 mg TMP/day (160 mg twice daily)

Duration 3 days (women); 7 days (men)

Complicated UTI / Pyelonephritis:

Parameter Dose Clinical Notes

Starting dose 160 mg TMP orally/IV twice daily IV for severe cases

Titration Not applicable

Usual maintenance dose 160 mg TMP twice daily

Maximum dose 320 mg TMP/day

Duration 10–14 days Step-down to oral when afebrile

1. Acute Exacerbation of Chronic Bronchitis / COPD

Parameter Dose Clinical Notes

Starting dose 160 mg TMP (1 DS tablet) orally twice daily

Titration Not applicable

Usual maintenance dose 160 mg TMP twice daily

Maximum dose 320 mg TMP/day

Duration 5–7 days Based on clinical response

1. Pneumocystis jirovecii Pneumonia (PCP) — Treatment

Parameter Dose Clinical Notes

Starting dose TMP 15–20 mg/kg/day in 3–4 divided doses IV preferred for severe hypoxia (PaO₂ <70 mmHg)

Titration Not applicable

Usual maintenance dose TMP 15 mg/kg/day in 3–4 divided doses Switch to oral when clinically stable

Maximum dose TMP 20 mg/kg/day

Duration 21 days Add corticosteroids if PaO₂ <70 mmHg or A-a gradient >35

Example (70 kg adult): TMP 1050–1400 mg/day = approximately 4–6 DS tablets/day or equivalent IV

1. Pneumocystis jirovecii Pneumonia (PCP) — Prophylaxis

Parameter Dose Clinical Notes

Starting dose 160 mg TMP (1 DS tablet) orally once daily Alternative: 1 DS tablet thrice weekly (Mon/Wed/Fri)

Titration Not applicable

Usual maintenance dose 160 mg TMP once daily or 160 mg TMP thrice weekly

Maximum dose 160 mg TMP daily

Duration Continue until CD4 >200 cells/μL for ≥3 months on ART Per NACO/ICMR guidelines

Indications for PCP prophylaxis:

• HIV with CD4 <200 cells/μL

• HIV with oropharyngeal candidiasis regardless of CD4

• Solid organ transplant recipients

• Haematopoietic stem cell transplant

• Patients on prolonged high-dose corticosteroids

1. Nocardiosis

Parameter Dose Clinical Notes

Starting dose TMP 10–15 mg/kg/day in 2–4 divided doses IV for severe/CNS disease

Titration Not applicable

Usual maintenance dose TMP 10–15 mg/kg/day Oral step-down after clinical improvement

Maximum dose TMP 15 mg/kg/day

Duration 6–12 months (cutaneous); ≥12 months (CNS involvement) Specialist supervision mandatory

1. Acute Bacterial Gastroenteritis (Shigellosis, Traveller's Diarrhoea — where susceptible)

Parameter Dose Clinical Notes

Starting dose 160 mg TMP orally twice daily Only if organism susceptible; increasing resistance limits use

Titration Not applicable

Usual maintenance dose 160 mg TMP twice daily

Maximum dose 320 mg TMP/day

Duration 3–5 days

1. Toxoplasmosis Prophylaxis (HIV patients)

PAEDIATRIC DOSING (Specialist Only)

Primary Indications:

1. Urinary Tract Infections, Acute Otitis Media, Shigellosis

Age/Weight Dose (TMP component) Frequency Maximum Daily Dose Duration

2 months, <40 kg 4 mg/kg TMP Every 12 hours 320 mg TMP/day 5–10 days

≥40 kg 160 mg TMP (1 DS tablet) Every 12 hours 320 mg TMP/day 5–10 days

Dosing Summary:

• Starting dose: TMP 4 mg/kg/dose orally twice daily

• Titration: Not applicable

• Usual maintenance dose: TMP 8 mg/kg/day in 2 divided doses

• Maximum dose: 320 mg TMP/day (adult dosing)

1. Pneumocystis jirovecii Pneumonia (PCP) — Treatment

Parameter Dose Comments

Starting dose TMP 15–20 mg/kg/day IV in 3–4 divided doses IV preferred for severe disease

Titration Not applicable

Usual maintenance dose TMP 15–20 mg/kg/day in 3–4 divided doses Switch to oral when stable

Maximum dose TMP 20 mg/kg/day

Duration 21 days Add corticosteroids for hypoxic patients

1. Pneumocystis jirovecii Pneumonia (PCP) — Prophylaxis

Age/Weight Dose (TMP component) Frequency Comments

≥6 weeks, any weight TMP 5 mg/kg (max 160 mg) Once daily OR twice weekly on consecutive days For HIV-exposed/infected infants, transplant recipients

Alternative TMP 2.5 mg/kg Twice daily, 3 days/week

Indications per NACO/IAP:

• HIV-exposed infants from 6 weeks until HIV infection ruled out

• HIV-infected children with CD4 criteria met

• Severe malnutrition with HIV

• Post-transplant per protocol

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

Nocardiosis — OFF-LABEL

Parameter Details

Indication Pulmonary, cutaneous, or disseminated nocardiosis

Dose TMP 10–15 mg/kg/day in 3–4 divided doses

Duration 6–12 months based on site

Specialist only Yes — Paediatric infectious diseases

Evidence basis Extrapolated from adult data; Indian tertiary care practice

Not recommended below 2 months of age except for PCP prophylaxis/treatment under specialist supervision due to risk of kernicterus (bilirubin displacement) and limited safety data.

30 No adjustment required Standard monitoring

15–30 50% of standard dose OR standard dose every 24 hours Monitor creatinine, potassium closely

<15 Avoid unless life-threatening indication; use 25–50% of standard dose with close monitoring TDM if available; frequent electrolytes

Haemodialysis Standard dose; supplement with 50% dose post-dialysis Both components are partially dialyzable

CAPD 50% of standard dose Monitor for accumulation

Key Point: TMP causes reversible increase in serum creatinine (inhibits tubular secretion) without true nephrotoxicity; this should not be confused with renal impairment.

• Known hypersensitivity to sulfonamides, trimethoprim, or any component

• Documented megaloblastic anaemia due to folate deficiency

• Severe hepatic impairment or hepatic failure

• Severe renal impairment (eGFR <15 mL/min) unless no alternative available

• G6PD deficiency — risk of haemolytic anaemia (relative contraindication; avoid if possible)

• Infants <2 months of age (risk of kernicterus) except for PCP under specialist

• Third trimester of pregnancy (near term) — risk of neonatal kernicterus

• Concurrent use with dofetilide (QT prolongation risk)

• Concurrent use with methotrexate in high doses

• Pre-existing renal impairment — increased toxicity risk; dose adjustment required

• Elderly patients — increased risk of hyperkalaemia, hyponatraemia, haematological toxicity

• HIV/AIDS patients — higher incidence of adverse reactions especially rash and cytopenias

• Patients on potassium-sparing diuretics, ACE inhibitors, ARBs — hyperkalaemia risk

• Folate deficiency or chronic alcoholism — increased haematological toxicity risk

• Prolonged or high-dose therapy — monitor for bone marrow suppression

• Patients with asthma or severe allergies — increased hypersensitivity risk

• Risk of crystalluria — ensure adequate hydration (≥1.5 L/day fluids)

• Thyroid disease — rare reports of hypothyroidism with prolonged use

Aspect Recommendation

Risk category Teratogenic risk (folate antagonism); avoid in first trimester if possible

First trimester Avoid — associated with increased risk of neural tube defects, cardiovascular malformations

Second trimester May use if clearly indicated and no safer alternative; co-administer folic acid 5 mg/day

Third trimester Avoid near term (last 4–6 weeks) — sulfonamide displaces bilirubin → risk of neonatal kernicterus

Preferred alternatives Nitrofurantoin (UTI, first/second trimester), amoxicillin, cephalexin

When to use PCP treatment/prophylaxis in HIV when no alternative; specialist decision

Monitoring Fetal anomaly scan; neonatal bilirubin if used late in pregnancy

Aspect Recommendation

Compatibility Generally compatible with breastfeeding in healthy term infants

Contraindication in infants Avoid breastfeeding if infant is <2 months, premature, jaundiced, G6PD deficient, or ill

Drug levels in milk Low to moderate (TMP excreted in milk; SMX levels lower)

Preferred alternatives Amoxicillin, cephalexin, nitrofurantoin if safer option needed

Recommendations May breastfeed if infant is healthy and term; monitor infant

Infant monitoring Rash, diarrhoea, jaundice, thrush; discontinue breastfeeding if concerns

Aspect Recommendation

Starting dose Standard dose if renal function normal; adjust per eGFR

Titration Not applicable; fixed dosing

Special considerations Calculate creatinine clearance accurately (serum creatinine alone underestimates renal impairment in elderly)

Extra risks Hyperkalaemia (especially with ACE inhibitors, ARBs, potassium supplements); hyponatraemia; bone marrow suppression; severe skin reactions (SJS/TEN); acute kidney injury

Monitoring Baseline and periodic potassium, sodium, creatinine, CBC; more frequent monitoring in first 2 weeks

Drug Interaction Management

Methotrexate Additive anti-folate toxicity → severe bone marrow suppression, mucositis Avoid concurrent use especially with high-dose MTX; if essential, give folinic acid rescue and monitor closely

Warfarin TMP inhibits CYP2C9 → increased warfarin effect → bleeding risk Reduce warfarin dose by 25–50%; monitor INR frequently (every 2–3 days initially)

Dofetilide Decreased renal clearance of dofetilide → QT prolongation, torsades de pointes Contraindicated combination

ACE inhibitors / ARBs Additive hyperkalaemia (TMP blocks epithelial sodium channels like amiloride) Monitor potassium within first week; avoid if K⁺ already elevated

Potassium-sparing diuretics (spironolactone, amiloride, triamterene) Severe hyperkalaemia risk Avoid combination if possible; if essential, monitor potassium every 2–3 days

Phenytoin TMP inhibits CYP2C9 → increased phenytoin levels and toxicity Monitor phenytoin levels; reduce phenytoin dose if toxicity signs

Digoxin Reduced renal clearance of digoxin Monitor digoxin levels; reduce dose in elderly

Drug Interaction Management

Sulfonylureas (glibenclamide, glimepiride) CYP2C9 inhibition → increased hypoglycaemia risk Monitor blood glucose closely; may need sulfonylurea dose reduction

Rifampicin CYP induction → reduced TMP-SMX levels May need increased TMP-SMX dose; monitor clinical response

Cyclosporine Increased nephrotoxicity; possible decreased cyclosporine levels Monitor renal function and cyclosporine levels

Azathioprine Additive bone marrow suppression Monitor CBC closely

Lamivudine TMP increases lamivudine exposure (inhibits renal secretion) Generally not clinically significant; monitor

Dapsone Additive haematological toxicity; both cause methaemoglobinaemia Avoid if possible; monitor methaemoglobin, CBC

Leucovorin (folinic acid) May reduce antimicrobial efficacy of TMP-SMX Avoid concurrent use unless treating toxicity

Procainamide Increased procainamide levels Monitor for procainamide toxicity

• Nausea, vomiting, anorexia

• Rash (maculopapular, urticarial) — more common in HIV patients (up to 30%)

• Diarrhoea

• Hyperkalaemia

• Reversible increase in serum creatinine (due to tubular secretion inhibition, not nephrotoxicity)

• Headache

• Photosensitivity

• Elevated liver transaminases (usually mild)

Adverse Effect Clinical Notes

Stevens-Johnson Syndrome (SJS) / Toxic Epidermal Necrolysis (TEN) Higher risk in HIV, slow acetylators; discontinue immediately if mucocutaneous lesions develop; hospitalization required

Agranulocytosis / Aplastic anaemia Rare; discontinue immediately; haematology consultation required

Thrombocytopenia May be immune-mediated; discontinue and monitor

Megaloblastic anaemia Due to folate antagonism; more common in malnourished or alcoholic patients

Haemolytic anaemia Especially in G6PD deficiency; discontinue immediately

Hepatotoxicity / Cholestatic jaundice Monitor LFTs; discontinue if significant elevation

Severe hyperkalaemia Can be life-threatening; particularly in elderly, renal impairment, concurrent ACE-I/ARB use

Aseptic meningitis Rare; consider if CNS symptoms develop

Acute kidney injury Usually reversible; due to crystalluria or interstitial nephritis

Hypersensitivity pneumonitis Rare; presents as cough, dyspnoea, infiltrates

Action: Discontinue co-trimoxazole immediately if severe rash, mucosal involvement, significant cytopenias, or hepatotoxicity occurs.

During short-course therapy (<14 days) Clinical monitoring; electrolytes if on ACE-I/ARB/diuretics

High-dose therapy (PCP treatment) CBC, electrolytes, creatinine, LFTs every 3–5 days

Prolonged therapy (prophylaxis, nocardiosis) CBC monthly for first 3 months, then every 3 months; LFTs, creatinine, potassium every 1–3 months

HIV patients More frequent monitoring (weekly CBC for first month) due to higher ADR rates

Note: Rise in serum creatinine by 10–20% is expected with TMP (competitive inhibition of creatinine secretion) and does not indicate true nephrotoxicity.

• Septran (GSK) — widely recognized brand

• Bactrim (Roche)

• Oriprim (Mankind)

• Cotrimoxazole (Cipla)

• Trizole (FDC)

• Cotrim DS (Various)

• Sepmax (Alkem)

• Cotrimox (Sun Pharma)

• Multiple generic manufacturers

• Listed in NLEM 2022

• Under NPPA/DPCO price control

• Available through government supply (free) at public health facilities; essential for HIV programs (NACO)

1. Dose by TMP component — all dosing calculations should be based on the trimethoprim component; SMX follows automatically due to fixed 5:1 ratio.

1. Creatinine rise is expected — TMP inhibits tubular secretion of creatinine, causing reversible increase in serum creatinine (10–20%) without true renal injury; do not confuse with nephrotoxicity.

1. Hyperkalaemia vigilance — TMP acts like a potassium-sparing diuretic (blocks ENaC channels); monitor potassium especially in elderly, diabetics, and those on ACE-I/ARB/spironolactone.

1. HIV patients have higher ADR rates — rash occurs in up to 30% of HIV patients; consider desensitization protocols if reaction is mild and drug is essential for PCP prophylaxis.

1. Hydration prevents crystalluria — ensure adequate fluid intake (≥1.5 L/day) especially with high-dose therapy to prevent sulfonamide crystalluria.

1. Not near term in pregnancy — sulfonamides displace bilirubin and can cause neonatal kernicterus; avoid in last 4–6 weeks of pregnancy if possible.

1. First-line for Stenotrophomonas — S. maltophilia is intrinsically carbapenem-resistant; TMP-SMX is the drug of choice; confirm susceptibility on culture.

co-trimoxazole; TMP-SMX; sulfonamide; trimethoprim; PCP prophylaxis; HIV; UTI; opportunistic infection; hyperkalaemia; NLEM India; Schedule H; pregnancy-avoid

RxIndia v1.0 — 04 May 2025

• CDSCO approved prescribing information

• Indian Pharmacopoeia

• NLEM 2022

• API Textbook of Medicine

• NACO Guidelines for Prevention and Management of Opportunistic Infections in HIV/AIDS

• ICMR Guidelines on Antimicrobial Use

• IAP Guidelines on Antimicrobial Use in Children

• AIIMS Paediatric HIV Protocols

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

• Harrison's Principles of Internal Medicine (supportive)