Trimethoprim

J01E - Sulfonamides and trimethoprim ATC J01EE01 Small molecule approved 1973 Oral Parenteral Topical Natural product

JFDA label: Septrin D.S Tablets

Mechanism of Action

Inhibitor of Dihydrofolate reductase — Bacterial dihydrofolate reductase inhibitor

Target	Action	Gene / class
Dihydrofolate reductase efficacy	INHIBITOR	folA

Indications

Approved

Cystitis, acute uncomplicated, treatment (tablets, oral solution)
Otitis media, acute (oral solution)

Off-label

Acne vulgaris
Pneumocystis pneumonia in HIV-infected patients (adolescents and adults)
Pneumocystis pneumonia in HIV-infected patients (children)
Urinary tract infection, prophylaxis

Antimicrobial Spectrum

Expected / intrinsic spectrum (EUCAST breakpoints & labels) — not local resistance. Source: EUCAST v16 · curated · openfda-label.

Bacteria

Organism	Activity	MIC
Acinetobacter spp.	Susceptible	0.5 mg/L
Aeromonas spp.	Susceptible	1.0 mg/L
Escherichia coli	Susceptible	2.0 mg/L
Haemophilus influenzae	Susceptible	1.0 mg/L
Haemophilus influenzae	Susceptible	0.5 mg/L
Moraxella catarrhalis	Susceptible	1.0 mg/L
Morganella morganii	Active	—
Pasteurella multocida	Susceptible	0.25 mg/L
Pneumocystis jiroveci	Active	—
Proteus mirabilis	Active	—
Proteus vulgaris	Active	—
Shigella flexneri	Active	—
Shigella sonnei	Active	—
Staphylococcus aureus	Susceptible	2.0 mg/L
Staphylococcus saprophyticus	Susceptible	2.0 mg/L
Staphylococcus spp.	Susceptible	2.0 mg/L
Stenotrophomonas maltophilia	Susceptible	0.001 mg/L
Streptococcus A/B/C/G	Susceptible	0.5 mg/L
Streptococcus pneumoniae	Susceptible	1.0 mg/L
Vibrio spp.	Susceptible	0.25 mg/L
Escherichia coli	Resistant	4.0 mg/L

Class profile

gramStatus	Both
spectrumBreadth	Broad
atypicalCoverage	No
isBactericidal	0
moaCategory	Folate synthesis inhibitor (DHFR inhibition)
pdIndex	Time-dependent
postAntibioticEffect	None
mrsaCoverage	0
resistanceMechanisms	DHFR mutations (dfr genes),Overproduction of DHFR,Efflux pumps

Contraindications

Source: Lexicomp

Hypersensitivity to trimethoprim or any component of the formulation Absolute
megaloblastic anemia due to folate deficiency Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Hepatobiliary disorders (1)

Not Known Increased liver enzymes

Renal and urinary disorders (2)

Not Known Increased blood urea nitrogen · increased serum creatinine

Blood and lymphatic system disorders (5)

Not Known Leukopenia · megaloblastic anemia · methemoglobinemia · neutropenia · thrombocytopenia

Immune system disorders (2)

Not Known Anaphylaxis · hypersensitivity reaction

Metabolism and nutrition disorders (2)

Not Known Hyperkalemia · hyponatremia

Gastrointestinal disorders (4)

Not Known Epigastric distress · glossitis · nausea · vomiting

Skin and subcutaneous tissue disorders (3)

Not Known Maculopapular rash · phototoxicity · pruritus (common)

General disorders and administration site conditions (1)

Not Known Fever

Other (6)

Not Known Aseptic meningitis · cholestatic jaundice · erythema multiforme · exfoliative dermatitis · Stevens-Johnson syndrome · toxic epidermal necrolysis

Dosing

Source: Lexicomp

Cystitis (acute uncomplicated), treatment: Oral: 100 mg every 12 hours for 3 days (Gupta 2011) According to the manufacturer, 200 mg once daily for 10 days may also be used. Acne vulgaris (alternative therapy) (off-label use): Oral: 100 mg 3 times daily or 300 mg twice daily (Amin 2007; Cunliffe 1999). The shortest possible duration should be used to minimize development of bacterial resistance; re-evaluate at 3 to 4 months (AAD [Zaenglein 2016]) Pneumocystis pneumonia (PCP), treatment (off-label use): Oral: 15 mg/kg/day in 3 divided doses in combination with dapsone for 21 days (HHS [adult] 2015) Urinary tract infection (uncomplicated), prophylaxis (off-label use): Oral: 100 mg once daily (Brumfitt 1983; Kasanen 1974; Stamm 1980)

(For additional information see "Trimethoprim: Pediatric drug information") Otitis media, acute: Infants ≥6 months, Children, and Adolescents: Oral: 10 mg/kg/day in divided doses every 12 hours for 10 days Urinary tract infection (uncomplicated), treatment (off-label population): Infants ≥2 months, Children, and Adolescents: Oral: 4 to 6 mg/kg/day in divided doses every 12 hours (Schleiss 2016); Note: Preferred therapy is sulfamethoxazole and trimethoprim combined product (AAP 2011). Pneumocystis pneumonia (PCP), treatment (off-label use): Children and Adolescents: Oral: 15 mg/kg/day in 3 divided doses for 21 days; in combination with dapsone; data in children is limited (HHS [adult] 2015; HHS [pediatric] 2014])

Refer to adult dosing.

Manufacturer’s labeling: CrCl >30 mL/minute: No dosage adjustments necessary; use with caution. CrCl 15 to 30 mL/minute: Administer 50% of recommended dose. CrCl Alternate recommendations (Aronoff 2007): CrCl >30 mL/minute: No dosage adjustment necessary. CrCl 10 to 30 mL/minute: 100 mg every 18 hours. CrCl Intermittent Hemodialysis: Moderately dialyzable (20% to 59%). Dose after dialysis Peritoneal dialysis: 100 mg every 24 hours

There are no dosage adjustments provided in the manufacturer’s labeling; use with caution.

Warnings & Precautions

Source: Lexicomp

Hematologic effects

May rarely interfere with hematopoiesis, especially with large doses or long term therapy; monitor patients on long term therapy for signs/symptoms of hematologic disorders.

Hyperkalemia

May cause hyperkalemia; potential risk factors include high dosage (20 mg/kg/day), renal impairment, older age, hypoaldosteronism, and concomitant use of medications causing or exacerbating hyperkalemia (Perazella 2000).

Hypersensitivity

Serious hypersensitivity reactions have been reported (rarely).

Superinfection

Prolonged use may result in fungal or bacterial superinfection, including C. difficile-associated diarrhea (CDAD) and pseudomembranous colitis; CDAD has been observed >2 months postantibiotic treatment. Disease-related concerns:

Hepatic impairment

Use with caution in patients with hepatic impairment.

Renal impairment

Use with caution in patients with renal impairment. Concurrent drug therapy issues:

Drug-drug interactions

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Special populations:

Elderly

Elderly patients may be at risk for hyperkalemia with trimethoprim use and are at an increased risk for severe and potentially life-threatening hyperkalemia when trimethoprim is used concomitantly with medications known to cause or exacerbate hyperkalemia, such as spironolactone, ACE inhibitors, or ARBs (Antoniou 2010; Antoniou 2011; Antoniou 2015).

Patients with potential for folate deficiency

Use with caution in patients with potential folate deficiency (malnourished, chronic anticonvulsant therapy, or elderly). Dosage form specific issues:

Benzyl alcohol and derivatives

Some dosage forms may contain sodium benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol derivative with caution in neonates. See manufacturer’s labeling.

Propylene glycol

Some dosage forms may contain propylene glycol; large amounts are potentially toxic and have been associated hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP ["Inactive" 1997]; Zar 2007). Other warnings/precautions:

Appropriate use

Otitis media: Not indicated for prophylactic or prolonged administration in otitis media at any age.

Pregnancy & Lactation

Pregnancy

FDA category C Teratogenic

Caution

Avoid in T1 if possible (folate antagonist — NTD risk). If unavoidable, supplement folic acid 5 mg/day. Alternative antibiotics preferred in pregnancy

Lactation

Trimethoprim is excreted in breast milk. The manufacturer recommends caution while using trimethoprim in a breast-feeding woman because trimethoprim may interfere with folic acid metabolism. Nondose-related effects could include modification of bowel flora. Also see the sulfamethoxazole/trimethoprim monograph for additional information.

Monitoring

Efficacy	Culture and susceptibility testing; clinical resolution (temperature, WBC, CRP, procalcitonin)
Toxicity	Renal function (dose adjustment in renal impairment); hepatic function for hepatically cleared agents; signs of C. difficile infection (diarrhoea)
Clinical pearl	Culture results guide de-escalation to narrower-spectrum therapy. Review antibiotic appropriateness at 48–72 h (antimicrobial stewardship).
Counseling	Complete the full course. Report persistent diarrhoea, rash, or lack of improvement after 48–72 h.

Chemistry & Properties

Formula	C14H18N4O3
Molecular weight	290.32 g/mol
IUPAC name	5-[(3,4,5-trimethoxyphenyl)methyl]pyrimidine-2,4-diamine
CAS	738-70-5
PubChem CID	5578
InChIKey	`IEDVJHCEMCRBQM-UHFFFAOYSA-N`
logP	1.26 (XLogP 0.9)
Polar surface area	105.51 Å²
H-bond acceptors / donors	7 / 2
Drug-likeness (QED)	0.85
Lipinski violations	0

SMILES

COc1cc(Cc2cnc(N)nc2N)cc(OC)c1OC

Biology & Pharmacokinetics

Pharmacokinetics predicted

Bioavailability	10.0%
Half-life	1.397 h
Volume of distribution	1.003 L/kg
Protein binding	41.4%
BBB penetrant	Yes

Enzyme interactions

Enzyme	Role	Detail
CYP2C8	Inhibitor	—
CYP2C9	Substrate	—
CYP3A4	Substrate	—

Transporters

BCRP (Inhibitor)BCRP (Inhibitor)BSEP (Inhibitor)BSEP (Inhibitor)MATE1 (Inhibitor)MATE2 (Inhibitor)MDR1 (Inhibitor)MRP1 (Inhibitor)MRP2 (Inhibitor)MRP3 (Inhibitor)MRP4 (Inhibitor)OATP1B1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OATP1B3 (Inhibitor)OATP2B1 (Inhibitor)OCT1 (Inhibitor)OCT2 (Inhibitor)OCT3 (Inhibitor)OCTN2 (Inhibitor)P-gp (Inhibitor)MATE2 (Substrate)MDR1 (Substrate)P-gp (Substrate)

Drug–drug interactions (41, DDInter)

Interacting drug	Severity	Management
Leucovorin	major
Levoleucovorin	major
Methotrexate	major
Potassium Iodide	major
Potassium acetate	major
Potassium bicarbonate	major
Potassium chloride	major
Potassium citrate	major
Potassium gluconate	major
Potassium perchlorate	major
Azathioprine	moderate
Balsalazide	moderate
Binimetinib	moderate
Cyclosporine	moderate
Dapsone	moderate
Dicoumarol	moderate
Enzalutamide	moderate
Ethanol	moderate
Folic acid	moderate
Glucarpidase	moderate
Lumacaftor	moderate
Lusutrombopag	moderate
Mercaptopurine	moderate
Metformin	moderate
Montelukast	moderate
Paclitaxel	moderate
Paclitaxel (protein-bound)	moderate
Picosulfuric acid	moderate
Pioglitazone	moderate
Porfimer sodium	moderate
Pralatrexate	moderate
Pyrimethamine	moderate
Repaglinide	moderate
Rosiglitazone	moderate
Sapropterin	moderate
Selexipag	moderate
Tacrolimus	moderate
Treprostinil	moderate
Warfarin	moderate
Atovaquone	minor

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Registered Products (17)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Balkatrin Suspension	Suspension 40 mg/5 ml, 200 mg/5 ml	60 ml pack varies	The Arab Pharmaceutical Manufacturing PSC/Salt	0.690
Trimol Susp.	Suspension 40 mg/5 ml, 200 mg/5 ml	100 ml	Professional Drug Store	0.830
TRIMIDAR M SUSP.	Suspension 40 mg/5 ml, 200 mg/5 ml	100 ml	Dar Al Dawa Development and Investment Co Ltd/Jordan	1.120
Tiromax Suspension	Suspension 40 mg/5 ml, 200 mg/5 ml	100 ml	Hikma Pharmaceuticals Co.Ltd/Jordan	1.120
Balkatrin Suspension	Suspension 40 mg/5 ml, 200 mg/5 ml	100 ml pack varies	The Arab Pharmaceutical Manufacturing PSC/Salt	1.150
TRIMIDAR M FORTE TAB.	Tablet 160 mg, 800 mg	10 tab pack varies	Dar Al Dawa Development and Investment Co Ltd/Jordan	1.220
Balkatrin Tablets	Tablet 80 mg, 400 mg	20 tab pack varies	The Arab Pharmaceutical Manufacturing PSC/Salt	1.310
Nortrime tablet	Tablet 80 mg, 400 mg	20 tab	THE JORDANIAN PHARMACEUTICAL MANUFACTURING COMPANY/JORDAN	1.350
TRIMIDAR M TAB.	Tablet 80 mg, 400 mg	20 tab pack varies	Dar Al Dawa Development and Investment Co Ltd/Jordan	1.350
Septrin Paed. Susp.	Suspension 40 mg/5 ml, 200 mg/5 ml	100 ml	Suleiman Tannous & Sons Co. Ltd	1.980
TRIMIDAR M FORTE TAB.	Tablet 160 mg, 800 mg	16 tab pack varies	Dar Al Dawa Development and Investment Co Ltd/Jordan	2.240
Septrin D.S Tablets	Tablet 160 mg, 800 mg	10 tab	Suleiman Tannous & Sons Co. Ltd	2.390
Septrin Tablets	Tablet 80 mg, 400 mg	20 tab	Suleiman Tannous & Sons Co. Ltd	2.410
TRIMIDAR M TAB.	Tablet 80 mg, 400 mg	500 tab pack varies	Dar Al Dawa Development and Investment Co Ltd/Jordan	20.500
TRIMIDAR M FORTE TAB.	Tablet 160 mg, 800 mg	504 tab pack varies	Dar Al Dawa Development and Investment Co Ltd/Jordan	52.260
Balkatrin Tablets	Tablet 80 mg, 400 mg	1000 tab pack varies	The Arab Pharmaceutical Manufacturing PSC/Salt	55.680
Septrin for Inf. Amp.	Ampoule 80 mg, 400 mg	5 ml	Suleiman Tannous & Sons Co. Ltd	—