trimethoprim/sulfamethoxazole (Rx)

Frequency Not Defined

Anorexia

Nausea

Vomiting

Vertigo

Seizure

Peripheral neuritis

Erythema multiforme

Hyperkalemia

Rash

Urticaria

Immune hypersensitivity reaction

Stevens-Johnson syndrome

Toxic epidermal necrolysis

Agranulocytosis

Aplastic anemia

Hyponatremia

Disorder of hematopoietic structure

Fulminant hepatic necrosis

Postmarketing Reports

Thrombotic thrombocytopenia purpura

Idiopathic thrombocytopenic purpura

QT prolongation resulting in ventricular tachycardia and torsade de pointes

Embryo-fetal toxicity

Hypersensitivity and other fatal reactions

Thrombocytopenia

Clostridium difficile-associated diarrhea

Sulfite sensitivity

Risk associated with concurrent use of leucovorin for

Pneumocystis jirovecii

Pneumonia

Infusion reactions

Hypoglycemia

Electrolyte abnormalities

Thrombophlebitis

Propylene glycol Toxicity

Metabolic acidosis

Drug reaction with eosinophilia and systemic symptoms (DRESS)

Acute generalized exanthematous pustulosis (AGEP)

Acute febrile neutrophilic dermatosis (AFND)

Circulatory shock

Acute and delayed lung injury

Interstitial lung disease

Acute respiratory failure

Renal failure, interstitial nephritis, BUN and serum creatinine elevation, renal insufficiency, oliguria and anuria, crystalluria, and nephrotoxicity in association with cyclosporine

Contraindications

Known hypersensitivity

Age <2 months

CrCl <15 mL/min when renal function status cannot be monitored

Documented megaloblastic or folate deficiency anemia

Significan hepatic impairment

Contraindicated in pregnant patients at term and in nursing mothers, because sulfonamides, which pass the placenta and are excreted in the milk, may cause kernicterus

History of drug-induced immune thrombocytopenia with use of trimethoprim and/or sulfonamides

Concomitant administration with dofetilide

Cautions

Not for use in areas with resistance rates >10%

Severe and symptomatic hyponatremia can occur in patients receiving sulfamethoxazole/ trimethoprim, particularly for treatment of P. jirovecii pneumonia; evaluation for hyponatremia and appropriate correction is necessary in symptomatic patients to prevent life-threatening complications

If patient treated for Pneumocystis jirovecii develops skin rash, fever, leukopenia, or any other sign of adverse reaction, therapy or re-challenge should be re-evaluated

Circulatory shock with fever, severe hypotension, and confusion requiring intravenous fluid resuscitation and vasopressors has occurred within minutes to hours of re-challenge with trimethoprim-sulfamethoxazole in patients with history of recent (days to weeks) exposure to sulfamethoxazole-trimethoprim

Fatalities associated with the administration of sulfonamides, although rare, have occurred due to severe reactions, including severe cutaneous adverse reactions (SCARs), including Stevens-Johnson Syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP) and acute febrile neutrophilic dermatosis (AFND), fulminant hepatic necrosis, agranulocytosis, aplastic anemia and other blood dyscrasias; clinical signs, such as rash, sore throat, fever, arthralgia, pallor, purpura or jaundice may be early indications of serious reactions; discontinue therapy at first appearance of skin rash or any sign of serious adverse reaction

Acute and delayed lung injury; anaphylaxis and circulatory shock have occurred with administration of sulfamethoxazole and trimethoprim products

Cough, shortness of breath and pulmonary infiltrates potentially representing hypersensitivity reactions of the respiratory tract reported in association with sulfamethoxazole and trimethoprim treatment

Severe pulmonary adverse reactions occurring within days to week of initiation of treatment and resulting in prolonged respiratory failure requiring mechanical ventilation or extracorporeal membrane oxygenation (ECMO), lung transplantation or death also reported in patients and otherwise healthy individuals treated with sulfamethoxazole and trimethoprim products

Caution when used in elderly individuals; risk of bone marrow suppression

PCP prophylaxis with AIDS: Rash, fever, leukopenia, and elevated transaminase values reported; hyperkalemia and hyponatremia also appear to be increased

Severe cases (including fatalities) of immune-mediated thrombocytopenia reported; monitor patients for hematologic toxicity; resolves within a week upon discontinuation of therapy

Sulfonamides should not be used to treat group A beta-hemolytic streptococcal infections; they will not eradicate streptococcus or prevent rheumatic fever

Clostridium difficile-associated diarrhea reported

Coadministration with leucovorin for the treatment of HIV-positive patients with PCP resulted in treatment failure and excess mortality in a randomized, placebo-controlled trial; avoid coadministration

Development of drug-resistant bacteria may occur when prescribed in absence of strongly suspected bacterial infection or prophylactic indication

Prolonged use may result in fungal or bacterial superinfection

Caution with impaired renal or hepatic function, patients with possible folate deficiency (eg, the elderly, chronic alcoholics, patients receiving anticonvulsant therapy, patients with malabsorption syndrome, and patients in malnutrition states), and patients with severe allergies or bronchial asthma

Hematological changes indicative of folic acid deficiency may occur in elderly patients or in patients with preexisting folic acid deficiency or kidney failure; effects are reversible by folinic acid therapy

Hemolysis may occur if administered to patients with G6PD deficiency

Hypoglycemia (rare) reported in nondiabetic patients; patients with renal dysfunction, liver disease, or malnutrition or those receiving high doses at particular risk

Trimethoprim may impair phenylalanine metabolism but may have no significance in phenylketonuric patients on appropriate dietary restriction

Caution with porphyria or thyroid dysfunction; sulfonamides can precipitate porphyria crisis and hypothyroidism; avoid use in patients with porphyria or thyroid dysfunction

Complete blood counts should be done frequently in patients receiving therapy; discontinue therapy if a significant reduction in count of any formed blood element is noted’ perform urinalyses with careful microscopic examination and renal function tests during therapy, particularly for those patients with impaired renal function

When administered at high doses as for the treatment of P. jirovecii pneumonia, monitor for total daily intake of propylene glycol from all sources and for acid-base disturbances; discontinue therapy if propylene glycol toxicity suspected

Treatment failure and excess mortality were observed when trimethoprim-sulfamethoxazole was used concomitantly with leucovorin for treatment of HIV positive patients with Pneumocystis jirovecii pneumonia; co-administration of trimethoprim-sulfamethoxazole and leucovorin during treatment of Pneumocystis jirovecii pneumonia should be avoided

During treatment, adequate fluid intake and urinary output should be ensured to prevent crystalluria; patients who are “slow acetylators” may be more prone to idiosyncratic reactions to sulfonamides

Hyperkalemia

• High dosage of trimethoprim, as used in patients with P. jirovecii pneumonia, induces a progressive but reversible increase of serum potassium concentrations in a substantial number of patients
• Treatment with recommended doses may cause hyperkalemia when trimethoprim is administered to patients with underlying disorders of potassium metabolism, with renal insufficiency, or if drugs known to induce hyperkalemia are given concomitantly; close monitoring of serum potassium recommended

Risk in treatment of Pneumocystis jirovecy pneumonia

• AIDS patients may not tolerate or respond to sulfamethoxazole/ trimethoprim in same manner as non-AIDS patients
• Incidence of adverse reactions, particularly rash, fever, leukopenia and elevated aminotransferase (transaminase) values, with therapy in AIDS patients who are being treated for P. jirovecii pneumonia reported to be increased compared with incidence normally associated with use of drug in non-AIDS patients
• If a patient develops skin rash, fever, leukopenia or any sign of adverse reaction, reevaluate benefit-risk of continuing therapy or re-challenge with drug

Pregnancy

Therapy may cause fetal harm if administered to pregnant woman; some epidemiologic studies suggest that exposure to drug during pregnancy may be associated with increased risk of congenital malformations, particularly neural tube defects, cardiovascular abnormalities, urinary tract defects, oral clefts, and club foot

Urinary tract infection in pregnancy is associated with adverse perinatal outcomes such as preterm birth, low birth weight, and pre-eclampsia, and increased mortality to pregnant woman

P. jirovecii pneumonia in pregnancy is associated with preterm birth and increased morbidity and mortality for the pregnant woman

Use during pregnancy only if potential benefit justifies potential risk to fetus

Lactation

Levels of drug in breast milk are approximately 2 to 5% of recommended daily dose for pediatric patients over two months of age; there is no information regarding effect of therapy on breastfed infant or effect on milk production; because of potential risk of bilirubin displacement and kernicterus on breastfed child, advise women to avoid breastfeeding during therapy

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Blocks 2 consecutive steps in the biosynthesis of nucleic acids and proteins essential to many bacteria

Trimethoprim: Inhibits dihydrofolate reductase, thereby blocking production of tetrahydrofolic acid from dihydrofolic acid

Sulfamethoxazole: Inhibits bacterial synthesis of dihydrofolic acid by competing with para-aminobenzoic acid

Absorption

Time to peak: 1-4 hours

Distribution

Protein bound: TMP (44%); SMX (70%)

Metabolism

Hepatic

Enzymes inhibited: Hepatic CYP2C9

Elimination

Half-life: TMP (8-10 hr); SMX (10 hr)

Excretion: Urine (as unchanged drug)

IV Incompatibilities

Additive: Fluconazole, linezolid, verapamil

Y-site: Cisatracurium (incompatible at 2 mg/mL cisatra; may be compatible at much lower concs), fluconazole, foscarnet (may be compatible at very low TMP/SMX concs), midazolam, vinorelbine

IV Preparation

Do not use NS as diluent

Injection vehicle contains benzyl alcohol and sodium metabisulfite

Stability of parenteral admixture at room temperature (25°C)

• 5 mL/125 mL D5W: 6 hr
• 5 mL/100 mL D5W: 4 hr
• 5 mL/75 mL D5W: 2 hr

IV Administration

Infuse over 60-90 min; give q6hr, 8hr, or 12hr

Must be diluted well

May be given less diluted in a central line

Not for IM

Maintain adequate fluid intake to prevent crystalluria

Storage

Do not refrigerate injection

Less soluble in more alkaline pH

Protect from light