Zotrim

Warnings
Precautions

WARNINGS

FATALITIES ASSOCIATED WITH THE ADMINISTRATION OF SULFONAMIDES, ALTHOUGH RARE, HAVE OCCURRED DUE TO SEVERE REACTIONS, INCLUDING STEVENS-JOHNSON SYNDROME, TOXIC EPIDERMAL NECROLYSIS, FULMINANT HEPATIC NECROSIS, AGRANULOCYTOSIS, APLASTIC ANEMIA, AND OTHER BLOOD DYSCRASIAS. SULFONAMIDES, INCLUDING SULFONAMIDE-CONTAINING PRODUCTS SUCH AS TRIMETHOPRIM/ SULFAMETHOXAZOLE, SHOULD BE DISCONTINUED AT THE FIRST APPEARANCE OF SKIN RASH OR ANY SIGN OF ADVERSE REACTION.

In rare instances, a skin rash may be followed by a more severe reaction, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, hepatic necrosis, and serious blood disorders (see

PRECAUTIONS

section).

Clinical signs, such as rash, sore throat, fever, arthralgia, pallor, purpura, or jaundice may be early indications of serious reactions.

Cough, shortness of breath, and pulmonary infiltrates are hypersensitivity reactions of the respiratory tract that have been reported in association with sulfonamide treatment. The sulfonamides should not be used for the treatment of group A beta-hemolytic streptococcal infections. In an established infection, they will not eradicate the streptococcus and, therefore, will not prevent sequelae such as rheumatic fever.

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including trimethoprim/sulfamethoxazole, and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.

Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is one primary cause of "antibiotic-associated colitis."

After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug effective against C. difficile.

PRECAUTIONS

General

Trimethoprim/Sulfamethoxazole: Trimethoprim/sulfamethoxazole should be given with caution to patients with impaired renal or hepatic function, to those with possible folate deficiency (e.g., the elderly, chronic alcoholics, patients receiving anticonvulsant therapy, patients with malabsorption syndrome, and patients in malnutrition states), and to those with severe allergy or bronchial asthma. In glucose-6-phosphate dehydrogenase-deficient individuals, hemolysis may occur. This reaction is frequently dose-related. (See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION sections).

Phenazopyridine Hydrochloride: A yellowish tinge of the skin or sclera may indicate accumulation due to impaired renal excretion and the need to discontinue therapy. The decline in renal function associated with advanced age should be kept in mind.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Sulfamethoxazole/Trimethoprim:

Carcinogenesis: Long-term studies in animals to evaluate carcinogenic potential have not been conducted with sulfamethoxazole/trimethoprim.

Mutagenesis: Bacterial mutagenic studies have not been performed with sulfamethoxazole and trimethoprim in combination. Trimethoprim was demonstrated to be non-mutagenic in the Ames assay.

In studies at two laboratories, no chromosomal damage was detected in cultured Chinese hamster ovary cells at concentrations approximately 500 times human plasma levels; at concentrations approximately 1000 times human plasma levels in these same cells, a low level of chromosomal damage was induced at one of the laboratories. No chromosomal abnormalities were observed in cultured human leukocytes at concentrations of trimethoprim up to 20 times human steady-state plasma levels. No chromosomal effects were detected in peripheral lymphocytes of human subjects receiving 320 mg of trimethoprim in combination with up to 1600 mg of sulfamethoxazole per day for as long as 112 weeks.

Impairment of Fertility: No adverse effects on fertility or general reproductive performance were observed in rats given oral dosages as high as 70 mg/kg/day trimethoprim plus 350 mg/kg/day sulfamethoxazole.

Phenazopyridine Hydrochloride:

Carcinogenesis: Long-term administration of phenazopyridine hydrochloride has induced neoplasia in rats (large intestine) and mice (liver). Although no association between phenazopyridine hydrochloride and human neoplasia has been reported, adequate epidemiological studies along these lines have not been conducted.

Mutagenesis: Adequate mutagenesis studies have not been performed with phenazopyridine hydrochloride.

Impairment of Fertility: There was no evidence of impaired fertility in rats administered doses of phenazopyridine hydrochloride up to 50 mg/kg/day.

Pregnancy: Teratogenic Effects. Pregnancy Category C

Trimethoprim/Sulfamethoxazole: In rats, oral doses of 533 mg/kg sulfamethoxazole or 200 mg/kg trimethoprim produced teratological effects manifested mainly as cleft palates. The highest dose which did not cause cleft palates in rats was 512 mg/kg sulfamethoxazole or 192 mg/kg trimethoprim when administered separately. In two studies in rats, no teratology was observed when 512 mg/kg of sulfamethoxazole was used in combination with 128 mg/kg of trimethoprim. In one study, however, cleft palates were observed in one litter out of 9 when 355 mg/kg of sulfamethoxazole was used in combination with 88 mg/kg of trimethoprim.

In some rabbit studies, an overall increase in fetal loss (dead, resorbed and malformed conceptuses) was associated with doses of trimethoprim 6 times the human therapeutic dose.

While there are no large, well-controlled studies on the use of trimethoprim and sulfamethoxazole in pregnant women, Brumfitt and Pursells5, in a retrospective study, reported the outcome of 186 pregnancies during which the mother received either placebo or oral trimethoprim and sulfamethoxazole. The incidence of congenital abnormalities was 4.5% (3 of 66) in those who received placebo and 3.3% (4 of 120) in those receiving trimethoprim and sulfamethoxazole. There were no abnormalities in the 10 children whose mothers received the drug during the first trimester. In a separate survey, Brumfitt and Pursell also found no congenital abnormalities in 35 children whose mothers had received oral trimethoprim and sulfamethoxazole at the time of conception or shortly thereafter.

Because trimethoprim and sulfamethoxazole may interfere with folic acid metabolism, trimethoprim/sulfamethoxazole should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Phenazopyridine Hydrochloride: Reproduction studies have been performed in rats at doses up to 50 mg/kg/day and have revealed no harm to the fetus due to phenazopyridine hydrochloride. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nonteratogenic Effects: See CONTRAINDICATIONS section.

Nursing Mothers

No information is available on the appearance of phenazopyridine hydrochloride or its metabolites in human milk. Trimethoprim/sulfamethoxazole is contraindicated in nursing mothers because sulfonamides are excreted in the milk and may cause kernicterus. (See CONTRAINDICATIONS section.)

Pediatric Use

This product is not recommended for pediatric patients (see INDICATIONS AND USAGE and CONTRAINDICATIONS sections).

Geriatric Use

The use of trimethoprim/sulfamethoxazole by elderly patients may increase the risk of severe adverse reactions, particularly when complicating conditions exist, e.g., impaired kidney and/or liver function, or concomitant use of other drugs. Severe skin reactions or generalized bone marrow suppression (see

WARNINGS

and ADVERSE REACTIONS sections) or a specific decrease in platelets (with or without purpura) 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. Appropriate dosage adjustments should be made for patients with impaired kidney function (see DOSAGE AND ADMINISTRATION section).

Information for Patients

Phenazopyridine Hydrochloride produces an orange to red color in the urine and may stain fabric. Patients should be instructed to maintain an adequate fluid intake in order to prevent crystalluria and stone formation. Staining of contact lenses has been reported.

This product contains two tablets: trimethoprim/sulfamethoxazole double strength is a white capsule-shaped scored tablet with beveled edges, plain on one side, scored in half on the other, with "93" embossed on one side of the breakline and "089" embossed on the other side and phenazopyridine hydrochloride is a round, sugar coated, deep maroon tablet imprinted "Z-U10" on one side.

Trimethoprim/sulfamethoxazole double strength tablets should be taken every 12 hours for 10 days. Phenazopyridine Hydrochloride tablets should be taken 3 times a day after meals for no more than 2 days

Laboratory Tests

Appropriate culture and susceptibility studies should be performed before and throughout treatment in patients receiving sulfamethoxazole/trimethoprim. Complete blood counts should be done frequently; if a significant reduction in the count of any formed blood element is noted, trimethoprim/sulfamethoxazole should be discontinued. Urinalysis with careful microscopic examination and renal function tests should be performed during therapy, particularly for those patients with impaired renal function.

Last reviewed on RxList: 1/28/2005
This monograph has been modified to include the generic and brand name in many instances.

Warnings
Precautions
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