FDA Label for Bactrim Ds

Description

BACTRIM (sulfamethoxazole and trimethoprim) is a synthetic antibacterial combination product available in DS (double strength) tablets, each containing 800 mg sulfamethoxazole and 160 mg trimethoprim; in tablets, each containing 400 mg sulfamethoxazole and 80 mg trimethoprim for oral administration.

Sulfamethoxazole is N¹-(5-methyl-3-isoxazolyl)sulfanilamide; the molecular formula is C₁₀H₁₁N₃O₃S. It is an almost white, odorless, tasteless compound with a molecular weight of 253.28 and the following structural formula:

Chemical Structure - bactrim 01

Trimethoprim is 2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine; the molecular formula is C₁₄H₁₈N₄O₃. It is a white to light yellow, odorless, bitter compound with a molecular weight of 290.3 and the following structural formula:

Inactive ingredients: Docusate sodium 85%, sodium benzoate 15%, sodium starch glycolate, magnesium stearate and pregelatinized starch.

Clinical Pharmacology

BACTRIM is rapidly absorbed following oral administration. Both sulfamethoxazole and trimethoprim exist in the blood as unbound, protein-bound and metabolized forms; sulfamethoxazole also exists as the conjugated form. The metabolism of sulfamethoxazole occurs predominately by N₄-acetylation, although the glucuronide conjugate has been identified. The principal metabolites of trimethoprim are the 1- and 3-oxides and the 3'- and 4'-hydroxy derivatives. The free forms of sulfamethoxazole and trimethoprim are considered to be the therapeutically active forms. Approximately 70% of sulfamethoxazole and 44% of trimethoprim 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.

Peak blood levels for the individual components occur 1 to 4 hours after oral administration. The mean serum half-lives of sulfamethoxazole and trimethoprim are 10 and 8 to 10 hours, respectively. However, patients with severely impaired renal function exhibit an increase in the half-lives of both components, requiring dosage regimen adjustment (see DOSAGE AND ADMINISTRATION section). Detectable amounts of sulfamethoxazole and trimethoprim are present in the blood 24 hours after drug administration. During administration of 800 mg sulfamethoxazole and 160 mg trimethoprim b.i.d., the mean steady-state plasma concentration of trimethoprim was 1.72 µg/mL. The steady-state mean plasma levels of free and total sulfamethoxazole were 57.4 µg/mL and 68.0 µg/mL, respectively. These steady-state levels were achieved after three days of drug administration.¹ Excretion of sulfamethoxazole and trimethoprim is primarily by the kidneys through both glomerular filtration and tubular secretion. Urine concentrations of both sulfamethoxazole and trimethoprim are considerably higher than are the concentrations in the blood. The average percentage of the dose recovered in urine from 0 to 72 hours after a single oral dose of sulfamethoxazole and trimethoprim is 84.5% for total sulfonamide and 66.8% for free trimethoprim. Thirty percent of the total sulfonamide is excreted as free sulfamethoxazole, with the remaining as N₄-acetylated metabolite.² When administered together as sulfamethoxazole and trimethoprim, neither sulfamethoxazole nor trimethoprim affects the urinary excretion pattern of the other.

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

Microbiology

Sulfamethoxazole inhibits bacterial synthesis of dihydrofolic acid by competing with para-aminobenzoic acid (PABA). Trimethoprim blocks the production of tetrahydrofolic acid from dihydrofolic acid by binding to and reversibly inhibiting the required enzyme, dihydrofolate reductase. Thus, sulfamethoxazole and trimethoprim blocks two consecutive steps in the biosynthesis of nucleic acids and proteins essential to many bacteria.

In vitro studies have shown that bacterial resistance develops more slowly with both sulfamethoxazole and trimethoprim in combination than with either sulfamethoxazole or trimethoprim alone.

Sulfamethoxazole and trimethoprim have been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.

Aerobic gram-positive microorganisms:

Streptococcus pneumoniae

Aerobic gram-negative microorganisms:

Escherichia coli (including susceptible enterotoxigenic strains implicated in traveler's diarrhea)
Klebsiella species
Enterobacter species
Haemophilus influenzae
Morganella morganii
Proteus mirabilis
Proteus vulgaris
Shigella flexneri
Shigella sonnei

Other Organisms:

Pneumocystis carinii

Quality Control

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard sulfamethoxazole/trimethoprim powder should provide the following range of values:

As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 1.25/23.75 µg sulfamethoxazole/trimethoprim disk

Mueller-Hinton agar should be checked for excessive levels of thymidine or thymine. To determine whether Mueller-Hinton medium has sufficiently low levels of thymidine and thymine, an Enterococcus faecalis (ATCC 29212 or ATCC 33186) may be tested with sulfamethoxazole/trimethoprim disks. A zone of inhibition ≥20 mm that is essentially free of fine colonies indicates a sufficiently low level of thymidine and thymine.

Indications And Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Bactrim (sulfamethoxazole and trimethoprim) tablets and other antibacterial drugs, Bactrim (sulfamethoxazole and trimethoprim) tablets should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to empiric selection of therapy.

Contraindications

BACTRIM is contraindicated in patients with a known hypersensitivity to trimethoprim or sulfonamides, in patients with a history of drug-induced immune thrombocytopenia with use of trimethoprim and/or sulfonamides, and in patients with documented megaloblastic anemia due to folate deficiency. BACTRIM is also contraindicated in pregnant patients and nursing mothers, because sulfonamides pass the placenta and are excreted in the milk and may cause kernicterus. BACTRIM is contraindicated in pediatric patients less than 2 months of age. BACTRIM is also contraindicated in patients with marked hepatic damage or with severe renal insufficiency when renal function status cannot be monitored.

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 SULFAMETHOXAZOLE/TRIMETHOPRIM, 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). 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.

Thrombocytopenia

Thrombocytopenia has been reported with both sulfamethoxazole and trimethoprim usage. A case control study found a 124-fold increased risk of severe thrombocytopenia (platelets <30,000 µL, requiring hospitalization) with sulfamethoxazole and trimethoprim in combination with an incidence of 2 cases per 1000 patient-years of exposure.⁶ The incidence of less severe thrombocytopenia may be higher.

Thrombocytopenia caused by sulfamethoxazole and trimethoprim may be immune-mediated. Drug-induced immune-mediated thrombocytopenia with sulfamethoxazole/trimethoprim is characterized by a drug-dependent antibody that is itself nonreactive, but when soluble drug is present at pharmacologic concentrations, antibody binds tightly to specific platelet membrane glycoproteins, causing platelet destruction.⁷ Serologic testing for drug-specific antibody is commercially available and may be useful for identifying the specific cause of thrombocytopenia in individual cases. Testing is important because a patient with drug-dependent antibodies should not be re-exposed to BACTRIM (see CONTRAINDICATIONS).

Typically, a patient with immune thrombocytopenia will have taken drug for about 1 week or intermittently over a longer period of time (possibly years) before presenting with petechiae or bruising. Systemic symptoms, such as lightheadedness, chills, fever, nausea, and vomiting, often may precede bleeding events. Thrombocytopenia may be severe. Patients should have risk/benefit re-evaluated in order to continue treatment with BACTRIM. If the drug is stopped, symptoms usually resolve within 1 or 2 days and platelet count returns to normal in less than 1 week. If BACTRIM is not stopped, there is a risk of fatal hemorrhage. The onset of thrombocytopenia may be more rapid upon re-exposure.

Sulfamethoxazole has also been shown to occasionally trigger the production of platelet-specific autoantibodies leading to a clinical picture indistinguishable from spontaneous autoimmune thrombocytopenia. In such cases, autoantibodies remain present for up to 9 weeks after sulfamethoxazole has been stopped, corresponding with a marked reduction in platelet counts for the same period.

The sulfonamides should not be used for treatment of group A β-hemolytic streptococcal infections. In an established infection, they will not eradicate the streptococcus and, therefore, will not prevent sequelae such as rheumatic fever.

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including BACTRIM, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

BACTRIM should be discontinued in case of any signs or symptoms of thrombocytopenia (see WARNINGS).

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

Trimethoprim has been noted to impair phenylalanine metabolism, but this is of no significance in phenylketonuric patients on appropriate dietary restriction.

As with all drugs containing sulfonamides, caution is advisable in patients with porphyria or thyroid dysfunction.

Precautions

Adverse Reactions

The most common adverse effects are gastrointestinal disturbances (nausea, vomiting, anorexia) and allergic skin reactions (such as rash and urticaria). 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 (SEE WARNINGS SECTION).

Hematologic: Agranulocytosis, aplastic anemia, thrombocytopenia, leukopenia, neutropenia, hemolytic anemia, megaloblastic anemia, hypoprothrombinemia, methemoglobinemia, eosinophilia.

Allergic Reactions: Stevens-Johnson syndrome, toxic epidermal necrolysis, anaphylaxis, allergic myocarditis, erythema multiforme, exfoliative dermatitis, angioedema, drug fever, chills, Henoch-Schoenlein purpura, serum sickness-like syndrome, generalized allergic reactions, generalized skin eruptions, photosensitivity, conjunctival and scleral injection, pruritus, urticaria and rash. In addition, periarteritis nodosa and systemic lupus erythematosus have been reported.

Gastrointestinal: Hepatitis (including cholestatic jaundice and hepatic necrosis), elevation of serum transaminase and bilirubin, pseudomembranous enterocolitis, pancreatitis, stomatitis, glossitis, nausea, emesis, abdominal pain, diarrhea, anorexia.

Genitourinary: Renal failure, interstitial nephritis, BUN and serum creatinine elevation, toxic nephrosis with oliguria and anuria, crystalluria and nephrotoxicity in association with cyclosporine.

Metabolic and Nutritional: Hyperkalemia (see PRECAUTIONS: Use in the Treatment of and Prophylaxis for Pneumocystis Carinii Pneumonia in Patients with Acquired Immunodeficiency Syndrome (AIDS).

Neurologic: Aseptic meningitis, convulsions, peripheral neuritis, ataxia, vertigo, tinnitus, headache.

Psychiatric: Hallucinations, depression, apathy, nervousness.

Endocrine: The sulfonamides bear certain chemical similarities to some goitrogens, diuretics (acetazolamide and the thiazides) and oral hypoglycemic agents. Cross-sensitivity may exist with these agents. Diuresis and hypoglycemia have occurred rarely in patients receiving sulfonamides.

Musculoskeletal: Arthralgia and myalgia. Isolated cases of rhabdomyolysis have been reported with BACTRIM, mainly in AIDS patients.

Respiratory: Cough, shortness of breath and pulmonary infiltrates (see WARNINGS).

Miscellaneous: Weakness, fatigue, insomnia.

Dosage And Administration

Not recommended for use in pediatric patients less than 2 months of age.

Acute Exacerbations Of Chronic Bronchitis In Adults:

The usual adult dosage in the treatment of acute exacerbations of chronic bronchitis is 1 BACTRIM DS (double strength) tablet or 2 BACTRIM tablets every 12 hours for 14 days.

Treatment: Adults And Children:

The recommended dosage for treatment of patients with documented Pneumocystis carinii pneumonia is 75 to 100 mg/kg sulfamethoxazole and 15 to 20 mg/kg trimethoprim per 24 hours given in equally divided doses every 6 hours for 14 to 21 days.¹³ The following table is a guideline for the upper limit of this dosage:

For the lower limit dose (75 mg/kg sulfamethoxazole and 15 mg/kg trimethoprim per 24 hours) administer 75% of the dose in the above table.

Adults:

The recommended dosage for prophylaxis in adults is 1 BACTRIM DS (double strength) tablet daily.¹⁴

Children:

For children, the recommended dose is 750 mg/m²/day sulfamethoxazole with 150 mg/m²/day trimethoprim given orally in equally divided doses twice a day, on 3 consecutive days per week. The total daily dose should not exceed 1600 mg sulfamethoxazole and 320 mg trimethoprim.¹⁵ The following table is a guideline for the attainment of this dosage in children:

Traveler's Diarrhea In Adults:

For the treatment of traveler's diarrhea, the usual adult dosage is 1 BACTRIM DS (double strength) tablet or 2 BACTRIM tablets every 12 hours for 5 days.

How Supplied

BACTRIM™ TABLETS are supplied as follows:

BACTRIM™ DS (double strength) TABLETS (white, oval shaped, scored) containing 160 mg trimethoprim and 800 mg sulfamethoxazole –

bottles of 10 (NDC 54868-0337-3), bottles of 20 (NDC 54868-0337-0), bottles of 30 (NDC 54868-0337-1).  

Imprint on tablets (debossed): (front) BACTRIM DS

References:

• Kremers P, Duvivier J, Heusghem C. Pharmacokinetic Studies of Co-Trimoxazole in Man after Single and Repeated Doses. J Clin Pharmacol. Feb-Mar 1974; 14:112–117.
• Kaplan SA, et al. Pharmacokinetic Profile of Trimethoprim-Sulfamethoxazole in Man. J Infect Dis. Nov 1973; 128 (Suppl): S547–S555.
• Varoquaux O, et al. Pharmacokinetics of the trimethoprim-sulfamethoxazole combination in the elderly. Br J Clin Pharmacol. 1985;20:575–581.
• Rudoy RC, Nelson JD, Haltalin KC. Antimicrobial Agents Chemother. May 1974;5:439–443.
• National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard – Fourth Edition. NCCLS Document M7–A4, Vol.17, No. 2, NCCLS, Wayne, PA, January, 1997.
• Kaufman DW, Kelly JP, Johannes CB, Sandler A, Harmon D, Stolley PD, Shapiro S. Acute thrombocytopenic purpura in relation to the use of drugs. Blood 1993; 82: 2714–18.
• Aster RH, Curtis BR, McFarland JG, Bougie DW. Drug-induced immune thrombocytopenia: pathogenesis, diagnosis, and management. J Thromb Haemost 2009; 7: 911–8.
• Hardy DW, et al. A controlled trial of trimethoprim-sulfamethoxazole or aerosolized pentamidine for secondary prophylaxis of Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome. N Engl J Med. 1992; 327: 1842–1848.
• National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved Standard – Sixth Edition. NCCLS Document M2–A6, Vol.17, No.1, NCCLS, Wayne, PA, January, 1997.
• Marinella Mark A. 1999. Trimethoprim-induced hyperkalemia: An analysis of reported cases. Gerontol. 45:209–212.
• Margassery, S. and B. Bastani. 2002. Life threatening hyperkalemia and acidosis secondary to trimethoprim-sulfamethoxazole treatment. J. Nephrol. 14:410–414.
• Brumfitt W, Pursell R. Trimethoprim/Sulfamethoxazole in the Treatment of Bacteriuria in Women. J Infect Dis. Nov 1973; 128 (Suppl):S657–S663.
• Masur H. Prevention and treatment of Pneumocystis pneumonia. N Engl J Med. 1992; 327: 1853–1880.
• Recommendations for prophylaxis against Pneumocystis carinii pneumonia for adults and adolescents infected with human immunodeficiency virus. MMWR. 1992; 41(RR-4):1­–11.
• CDC Guidelines for prophylaxis against Pneumocystis carinii pneumonia for children infected with human immunodeficiency virus. MMWR. 1991; 40(RR-2):1–13.

Principal Display Panel - 800 Mg/160 Mg Label

Rx only

Bactrim™ DS

sulfamethoxazole and trimethoprim
(double strength) tablets USP

AR
SCIENTIFIC

800 mg/160 mg
DOUBLE STRENGTH