Sulfamethoxazole and Trimethoprim (Page 5 of 7)

8.2 Lactation

Risk Summary

Levels of sulfamethoxazole and trimethoprim injection in breast milk are approximately 2 to 5% of the recommended daily dose for pediatric patients over two months of age. There is no information regarding the effect of sulfamethoxazole and trimethoprim injection on the breastfed infant or the effect on milk production. Because of the potential risk of bilirubin displacement and kernicterus on the breastfed child [see Contraindications (4)] , advise women to avoid breastfeeding during treatment with sulfamethoxazole and trimethoprim injection.

8.4 Pediatric Use

Sulfamethoxazole and trimethoprim injection is contraindicated in pediatric patients younger than two months of age because of the potential risk of bilirubin displacement and kernicterus [see Contraindications (4)].

Serious adverse reactions including fatal reactions and the “gasping syndrome” occurred in premature neonates and low birth weight infants in the neonatal intensive care unit who received benzyl alcohol as a preservative in infusion solutions. In these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 to 1.378 mmol/L). Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm, low-birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol.

When prescribing sulfamethoxazole and trimethoprim injection in pediatric patients consider the combined daily metabolic load of benzyl alcohol from all sources including sulfamethoxazole and trimethoprim injection (Sulfamethoxazole and trimethoprim injection contains 10 mg of benzyl alcohol per mL) and other drugs containing benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known [see Warnings and Precautions (5.7)].

8.5 Geriatric Use

Clinical studies of sulfamethoxazole and trimethoprim injection did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

There may be an increased risk of severe adverse reactions in elderly patients, particularly when complicating conditions exist, e.g., impaired kidney and/or liver function, or concomitant use of other drugs. Severe skin reactions, generalized bone marrow suppression [see Warnings and Precautions (5.10), Adverse Reactions (6.1)], a specific decrease in platelets (with or without purpura), and hyperkalemia are the most frequently reported severe adverse reactions in elderly patients.

In those concurrently receiving certain diuretics, primarily thiazides, an increased incidence of thrombocytopenia with purpura has been reported. Increased digoxin blood levels can occur with concomitant sulfamethoxazole and trimethoprim injection therapy, especially in elderly patients. Serum digoxin levels should be monitored [see Drug Interactions (7)].

Hematologic changes indicative of folic acid deficiency may occur in elderly patients. These effects are reversible by folinic acid therapy. Appropriate dosage adjustments should be made for patients with impaired kidney function and duration of use should be as short as possible to minimize risks of undesired reactions [see Dosage and Administration (2.2)].

The trimethoprim component of sulfamethoxazole and trimethoprim injection may cause hyperkalemia when administered to patients with underlying disorders of potassium metabolism, with renal insufficiency or when given concomitantly with drugs known to induce hyperkalemia, such as angiotensin converting enzyme inhibitors. Close monitoring of serum potassium is warranted in these patients. Discontinuation of sulfamethoxazole and trimethoprim injection treatment is recommended to help lower potassium serum levels.

Pharmacokinetics parameters for sulfamethoxazole were similar for geriatric subjects and younger adult subjects. The mean maximum serum trimethoprim concentration was higher and mean renal clearance of trimethoprim was lower in geriatric subjects compared with younger subjects [see Clinical Pharmacology (12.3)].

10 OVERDOSAGE

Acute

Since there has been no extensive experience in humans with single doses of sulfamethoxazole and trimethoprim injection in excess of 25 mL (400 mg trimethoprim and 2000 mg sulfamethoxazole), the maximum tolerated dose in humans is unknown.

Signs and symptoms of overdosage reported with sulfonamides include anorexia, colic, nausea, vomiting, dizziness, headache, drowsiness and unconsciousness. Pyrexia, hematuria and crystalluria may be noted. Blood dyscrasias and jaundice are potential late manifestations of overdosage.

Signs of acute overdosage with trimethoprim include nausea, vomiting, dizziness, headache, mental depression, confusion and bone marrow depression.

General principles of treatment include the administration of intravenous fluids if urine output is low and renal function is normal. Acidification of the urine will increase renal elimination of trimethoprim. The patient should be monitored with blood counts and appropriate blood chemistries, including electrolytes. If a significant blood dyscrasia or jaundice occurs, specific therapy should be instituted for these complications. Peritoneal dialysis is not effective and hemodialysis is only moderately effective in eliminating trimethoprim and sulfamethoxazole.

Chronic

Use of Sulfamethoxazole and trimethoprim injection at high doses and/or for extended periods of time may cause bone marrow depression manifested as thrombocytopenia, leukopenia and/or megaloblastic anemia. If signs of bone marrow depression occur, the patient should be given leucovorin 5 to 15 mg daily until normal hematopoiesis is restored.

11 DESCRIPTION

Sulfamethoxazole and trimethoprim injection, a sterile solution for intravenous infusion only, is a combination of sulfamethoxazole, a sulfonamide antimicrobial, and trimethoprim, a dihydrofolate reductase inhibitor antibacterial. Each mL contains Sulfamethoxazole, USP 80 mg; trimethoprim, USP 16 mg; benzyl alcohol 10 mg (1.0% v/v and 1.0% w/v) as preservatives; diethanolamine 3 mg (0.3% v/v and 0.3% w/v); ethyl alcohol 100 mg (12.3%v/v and 10.0% w/v); propylene glycol 400 mg (38.6% v/v and 40.0% w/v); sodium metabisulfite 1 mg as an antioxidant; water for injection q.s.; air replaced with nitrogen; pH adjusted with sodium hydroxide and/or hydrochloric acid if necessary.

Trimethoprim is 2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine. It is a white to light yellow, odorless, bitter compound with a molecular weight of 290.3 and the following structural formula:

molecular structure -- trimethoprim

C14 H18 N4 O3 M.W. 290.3

Sulfamethoxazole is N1 -(5-methyl-3-isoxazolyl) sulfanilamide. It is an almost white, odorless, tasteless compound with a molecular weight of 253.28 and the following structural formula:

molecular structure -- sulfamethoxazole
(click image for full-size original)

C10 H11 N3 O3 S M.W. 253.28

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Sulfamethoxazole and trimethoprim injection is an antimicrobial drug [see Microbiology (12.4)].

12.3 Pharmacokinetics

Following a 1-hour intravenous infusion of a single dose of 160 mg trimethoprim and 800 mg sulfamethoxazole to 11 patients whose weight ranged from 105 lbs to 165 lbs (mean, 143 lbs), the peak plasma concentrations of trimethoprim and sulfamethoxazole were 3.4 ± 0.3 μg/mL and 46.3 ± 2.7 μg/mL, respectively. Following repeated intravenous administration of the same dose at 8-hour intervals, the mean plasma concentrations just prior to and immediately after each infusion at steady state were 5.6 ± 0.6 μg/mL and 8.8 ± 0.9 μg/mL for trimethoprim and 70.6 ± 7.3 μg/mL and 105.6 ± 10.9 μg/mL for sulfamethoxazole. The mean plasma half-life was 11.3 ± 0.7 hours for trimethoprim and 12.8 ± 1.8 hours for sulfamethoxazole. All of these 11 patients had normal renal function, and their ages ranged from 17 to 78 years (median, 60 years).11

Pharmacokinetic studies in children and adults suggest an age-dependent half-life of trimethoprim, as indicated in Table 5.12

Table 5: Half-life of Trimethoprim (TMP) in Pediatric Patients and Adults

Age (years) No. of Patients Mean TMP Half-life (hours)
<1 2 7.67
1-10 9 5.49
10-20 5 8.19
20-63 6 12.82

Patients with severely impaired renal function exhibit an increase in the half-lives of both components, requiring dosage regimen adjustment [see Dosage and Administration (2.2)].

Distribution

Both trimethoprim and sulfamethoxazole exist in the blood as unbound, protein-bound and metabolized forms; sulfamethoxazole also exists as the conjugated form.

Approximately 44% of trimethoprim and 70% of sulfamethoxazole are bound to plasma proteins. The presence of 10 mg percent sulfamethoxazole in plasma decreases the protein binding of trimethoprim by an insignificant degree; trimethoprim does not influence the protein binding of sulfamethoxazole.

Both trimethoprim and sulfamethoxazole distribute to sputum and vaginal fluid; trimethoprim also distributes to bronchial secretions, and both pass the placental barrier and are excreted in breast milk.

Elimination

Metabolism

Sulfamethoxazole is metabolized in humans to at least 5 metabolites: the N4 -acetyl-, N4-hydroxy-, 5methylhydroxy-, N4 -acetyl-5-methylhydroxy- sulfamethoxazole metabolites, and an N-glucuronide conjugate. The formation of N4 -hydroxy metabolite is mediated via CYP2C9.

Trimethoprim is metabolized in vitro to 11 different metabolites, of which, five are glutathione adducts and six are oxidative metabolites, including the major metabolites, 1- and 3-oxides and the 3- and 4hydroxy derivatives.

The free forms of trimethoprim and sulfamethoxazole are considered to be the therapeutically active forms. In vitro studies suggest that trimethoprim is a substrate of P-glycoprotein, OCT1 and OCT2, and that sulfamethoxazole is not a substrate of P-glycoprotein.

Excretion

Excretion of trimethoprim and sulfamethoxazole is primarily by the kidneys through both glomerular filtration and tubular secretion. Urine concentrations of both trimethoprim and sulfamethoxazole are considerably higher than are the concentrations in the blood. The percent of dose excreted in urine over a 12-hour period following the intravenous administration of the first dose of 240 mg of trimethoprim and 1200 mg of sulfamethoxazole on day 1 ranged from 17% to 42.4% as free trimethoprim; 7% to 12.7% as free sulfamethoxazole; and 36.7% to 56% as total (free plus the N4-acetylated metabolite) sulfamethoxazole. When administered together as Sulfamethoxazole and trimethoprim injection, neither trimethoprim nor sulfamethoxazole affects the urinary excretion pattern of the other.

Specific Populations

Geriatric Patients: The pharmacokinetics of sulfamethoxazole 800 mg and trimethoprim 160 mg were studied in six geriatric subjects (mean age: 78.6 years) and six young healthy subjects (mean age: 29.3 years) using a non-US approved formulation. Pharmacokinetic values for sulfamethoxazole in geriatric subjects were similar to those observed in young adult subjects. The mean renal clearance of trimethoprim was significantly lower in geriatric subjects compared with young adult subjects (19 mL/h/kg vs. 55 mL/h/kg). However, after normalizing by body weight, the apparent total body clearance of trimethoprim was on average 19% lower in geriatric subjects compared with young adult subjects.

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