Sulfamethoxazole 40 MG/ML / Trimethoprim 8 MG/ML Oral Suspension
Generic Name: SULFAMETHOXAZOLE AND TRIMETHOPRIM
Brand Name: Sulfamethoxazole and Trimethoprim
- Substance Name(s):
- TRIMETHOPRIM
- SULFAMETHOXAZOLE
WARNINGS
Hypersensitivity and Other Fatal Reactions 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 Sulfamethoxazole/trimethoprim-induced thrombocytopenia may be an immune-mediated disorder.
Severe cases of thrombocytopenia that are fatal or life threatening have been reported.
Thrombocytopenia usually resolves within a week upon discontinuation of sulfamethoxazole/trimethoprim.
Streptococcal Infections and Rheumatic Fever 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 Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including sulfamethoxazole and trimethoprim, 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.
Adjunctive treatment with Leucovorin for Pneumocystis jiroveci pneumonia Treatment failure and excess mortality were observed when trimethoprim-sulfamethoxazole was used concomitantly with leucovorin for the treatment of HIV positive patients with Pneumocystis jiroveci pneumonia in a randomized placebo controlled trial.6 Co-administration of trimethoprim-sulfamethoxazole and leucovorin during treatment of Pneumocystis jiroveci pneumonia should be avoided.
DRUG INTERACTIONS
Drug Interactions In elderly patients concurrently receiving certain diuretics, primarily thiazides, an increased incidence of thrombocytopenia with purpura has been reported.
It has been reported that sulfamethoxazole and trimethoprim may prolong the prothrombin time in patients who are receiving the anticoagulant warfarin.
This interaction should be kept in mind when sulfamethoxazole and trimethoprim is given to patients already on anticoagulant therapy, and the coagulation time should be reassessed.
Sulfamethoxazole and trimethoprim may inhibit the hepatic metabolism of phenytoin.
Sulfamethoxazole and trimethoprim, given at a common clinical dosage, increased the phenytoin half-life by 39% and decreased the phenytoin metabolic clearance rate by 27%.
When administering these drugs concurrently, one should be alert for possible excessive phenytoin effect.
Sulfonamides can also displace methotrexate from plasma protein binding sites and can compete with the renal transport of methotrexate, thus increasing free methotrexate concentrations.
There have been reports of marked but reversible nephrotoxicity with coadministration of sulfamethoxazole and trimethoprim and cyclosporine in renal transplant recipients.
Increased digoxin blood levels can occur with concomitant sulfamethoxazole and trimethoprim therapy, especially in elderly patients.
Serum digoxin levels should be monitored.
Increased sulfamethoxazole blood levels may occur in patients who are also receiving indomethacin.
Occasional reports suggest that patients receiving pyrimethamine as malaria prophylaxis in doses exceeding 25 mg weekly may develop megaloblastic anemia if sulfamethoxazole and trimethoprim is prescribed.
The efficacy of tricyclic antidepressants can decrease when coadministered with sulfamethoxazole and trimethoprim.
Like other sulfonamide-containing drugs, sulfamethoxazole and trimethoprim potentiates the effect of oral hypoglycemics.
In the literature, a single case of toxic delirium has been reported after concomitant intake of sulfamethoxazole/trimethoprim and amantadine.
In the literature, three cases of hyperkalemia in elderly patients have been reported after concomitant intake of sulfamethoxazole/trimethoprim and an angiotensin converting enzyme inhibitor.8,9
OVERDOSAGE
Acute: The amount of a single dose of sulfamethoxazole and trimethoprim that is either associated with symptoms of overdosage or is likely to be life-threatening has not been reported.
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 institution of gastric lavage or emesis, forcing oral fluids, and 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 sulfamethoxazole and trimethoprim.
Chronic: Use of sulfamethoxazole and trimethoprim 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.
DESCRIPTION
Sulfamethoxazole and trimethoprim is a synthetic antibacterial combination product containing 200 mg sulfamethoxazole and 40 mg trimethoprim per 5 mL for oral administration.
Sulfamethoxazole is N 1-(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: 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: alcohol 0.26%, methylparaben 0.1% and sodium benzoate 0.1% (added as preservatives), carboxymethylcellulose sodium, citric acid (anhydrous), glycerin, microcrystalline cellulose, polysorbate 80, purified water, saccharin sodium, and sorbitol.
The light purple, grape flavored suspension contains the following additional inactive ingredients: FD&C Red No.
40, FD&C Blue No.
1 and natural and artificial grape flavor.
The pink, cherry flavored suspension contains the following additional inactive ingredients: FD&C Red No.
40, FD&C Yellow No.
6 and artificial cherry flavor.
Chemical Structure_1 Chemical structure _2
HOW SUPPLIED
Sulfamethoxazole and Trimethoprim Oral Suspension, USP is supplied in a purple grape-flavored suspension and in a pink cherry-flavored suspension containing 200 mg sulfamethoxazole and 40 mg trimethoprim per 5 mL (teaspoonful) both packaged in 1 pint (473 mL) bottles.
The grape-flavored suspension is also available in 20 mL unit dose.
Store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature].
Protect from light.
SHAKE WELL BEFORE USING.
Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).
To report SUSPECTED ADVERSE REACTIONS, contact Hi-Tech Pharmacal, Co., Inc.
at 1-800-262-9010 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
Rx only REFERENCES 1.
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.
2.
Kaplan SA, et al.
Pharmacokinetic Profile of Trimethoprim-Sulfamethoxazole in Man.
J Infect Dis.
Nov 1973; 128 (Suppl): S547–S555.
3.
Varoquaux O, et al.
Pharmacokinetics of the trimethoprim-sulfamethoxazole combination in the elderly.
Br J Clin Pharmacol.
1985;20:575–581.
4.
Rudoy RC, Nelson JD, Haltalin KC.
Antimicrobial Agents Chemother.
May 1974;5:439–443.
5.
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.
6.
Safrin S, Lee BL, Sande MA.
Adjunctive folinic acid with trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia in AIDS patients is associated with an increased risk of therapeutic failure and death.
J Infect Dis.
1994 Oct;170(4):912-7.
7.
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.
8.
Marinella Mark A.
1999.
Trimethoprim-induced hyperkalemia: An analysis of reported cases.
Gerontol.
45:209–212.
9.
Margassery, S.
and B.
Bastani.
2002.
Life threatening hyperkalemia and acidosis secondary to trimethoprim-sulfamethoxazole treatment.
J.
Nephrol.
14:410–414.
10.
Brumfitt W, Pursell R.
Trimethoprim/Sulfamethoxazole in the Treatment of Bacteriuria in Women.
J Infect Dis.
Nov 1973; 128 (Suppl):S657–S663.
11.
Masur H.
Prevention and treatment of Pneumocystis pneumonia.
N Engl J Med.
1992; 327: 1853–1880.
12.
Recommendations for prophylaxis against Pneumocystis carinii pneumonia for adults and adolescents infected with human immunodeficiency virus.
MMWR.
1992; 41(RR-4):1–11.
13.
CDC Guidelines for prophylaxis against Pneumocystis carinii pneumonia for children infected with human immunodeficiency virus.
MMWR.
1991; 40(RR-2):1–13.
Manufactured by: Hi-Tech Pharmacal Co., Inc.
Rev.
824:10 07/16 Amityville, New York 11701 Rev.
824:10 07/16
GERIATRIC USE
Geriatric Use Clinical studies of sulfamethoxazole and trimethoprim 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, possible folate deficiency, or concomitant use of other drugs.
Severe skin reactions, generalized bone marrow suppression (see WARNINGS and ADVERSE REACTIONS sections), 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 therapy, especially in elderly patients.
Serum digoxin levels should be monitored.
Hematological 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 section).
The trimethoprim component of sulfamethoxazole and trimethoprim 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 treatment is recommended to help lower potassium serum levels.
Sulfamethoxazole and trimethoprim oral suspension contains 1.741 mg sodium (0.076 mEq) of sodium per 5 mL.
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: Geriatric Pharmacokinetics ).
INDICATIONS AND USAGE
To reduce the development of drug-resistant bacteria and maintain the effectiveness of sulfamethoxazole and trimethoprim oral suspension and other antibacterial drugs, sulfamethoxazole and trimethoprim oral suspension 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.
Urinary Tract Infections: For the treatment of urinary tract infections due to susceptible strains of the following organisms: Escherichia coli, Klebsiella species, Enterobacter species, Morganella morganii, Proteus mirabilis and Proteus vulgaris.
It is recommended that initial episodes of uncomplicated urinary tract infections be treated with a single effective antibacterial agent rather than the combination.
Acute Otitis Media: For the treatment of acute otitis media in pediatric patients due to susceptible strains of Streptococcus pneumoniae or Haemophilus influenzae when in the judgment of the physician sulfamethoxazole and trimethoprim offers some advantage over the use of other antimicrobial agents.
To date, there are limited data on the safety of repeated use of sulfamethoxazole and trimethoprim in pediatric patients under two years of age.
Sulfamethoxazole and trimethoprim is not indicated for prophylactic or prolonged administration in otitis media at any age.
Acute Exacerbations of Chronic Bronchitis in Adults: For the treatment of acute exacerbations of chronic bronchitis due to susceptible strains of Streptococcus pneumoniae or Haemophilus influenzae when in the judgment of the physician sulfamethoxazole and trimethoprim offers some advantage over the use of a single antimicrobial agent.
Shigellosis: For the treatment of enteritis caused by susceptible strains of Shigella flexneri and Shigella sonnei when antibacterial therapy is indicated.
Pneumocystis Jiroveci Pneumonia: For the treatment of documented Pneumocystis jiroveci pneumonia and for prophylaxis against Pneumocystis jiroveci pneumonia in individuals who are immunosuppressed and considered to be at an increased risk of developing Pneumocystis jiroveci pneumonia.
Traveler’s Diarrhea In Adults: For the treatment of traveler’s diarrhea due to susceptible strains of enterotoxigenic E.
coli.
PEDIATRIC USE
Pediatric Use Sulfamethoxazole and trimethoprim is contraindicated for infants younger than 2 months of age (see INDICATIONS AND USAGE and CONTRAINDICATIONS sections).
PREGNANCY
Pregnancy Teratogenic Effects: Pregnancy Category C.
In rats, oral doses of 533 mg/kg or 200 mg/kg produced teratologic 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 and 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 sulfamethoxazole and trimethoprim in pregnant women, Brumfitt and Pursell,10 in a retrospective study, reported the outcome of 186 pregnancies during which the mother received either placebo or sulfamethoxazole and trimethoprim.
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 sulfamethoxazole and trimethoprim.
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 sulfamethoxazole and trimethoprim at the time of conception or shortly thereafter.
Because sulfamethoxazole and trimethoprim may interfere with folic acid metabolism, sulfamethoxazole and trimethoprim should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nonteratogenic Effects: See CONTRAINDICATIONS section.
NUSRING MOTHERS
Nursing Mothers See CONTRAINDICATIONS section.
INFORMATION FOR PATIENTS
Information for Patients Patients should be counseled that antibacterial drugs including sulfamethoxazole and trimethoprim oral suspension should only be used to treat bacterial infections.
They do not treat viral infections (e.g., the common cold).
When sulfamethoxazole and trimethoprim oral suspension is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed.
Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by sulfamethoxazole and trimethoprim oral suspension or other antibacterial drugs in the future.
Patients should be instructed to maintain an adequate fluid intake in order to prevent crystalluria and stone formation.
Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued.
Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic.
If this occurs, patients should contact their physician as soon as possible.
DOSAGE AND ADMINISTRATION
Sulfamethoxazole and trimethoprim is contraindicated in pediatric patients less than 2 months of age.
Urinary Tract Infections and Shigellosis in Adults and Pediatric Patients, and Acute Otitis Media in Children: Adults: The usual adult dosage in the treatment of urinary tract infections is four teaspoonfuls (20 mL) sulfamethoxazole and trimethoprim oral suspension every 12 hours for 10 to 14 days.
An identical daily dosage is used for 5 days in the treatment of shigellosis.
Children: The recommended dose for children with urinary tract infections or acute otitis media is 40 mg/kg sulfamethoxazole and 8 mg/kg trimethoprim per 24 hours, given in two divided doses every 12 hours for 10 days.
An identical daily dosage is used for 5 days in the treatment of shigellosis.
The following table is a guideline for the attainment of this dosage: Acute Exacerbations of Chronic Bronchitis in Adults: The usual adult dosage in the treatment of acute exacerbations of chronic bronchitis is four teaspoonfuls (20 mL) sulfamethoxazole and trimethoprim oral suspension every 12 hours for 14 days.
Pneumocystis Jiroveci Pneumonia: Treatment: Adults and Children: The recommended dosage for treatment of patients with documented Pneumocystis jiroveci 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.11 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.
Prophylaxis: Adults: The recommended dosage for prophylaxis in adults is four teaspoonfuls (20 mL) of the oral suspension daily.12 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.13 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 four teaspoonfuls (20 mL) of sulfamethoxazole and trimethoprim oral suspension every 12 hours for 5 days.
Tables Table 2 Table 3