SULFAMETHOX-TMP DS- sulfamethoxazole, trimethoprim tablet

United States - English - NLM (National Library of Medicine)

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Active ingredient:
SULFAMETHOXAZOLE (UNII: JE42381TNV) (SULFAMETHOXAZOLE - UNII:JE42381TNV), TRIMETHOPRIM (UNII: AN164J8Y0X) (TRIMETHOPRIM - UNII:AN164J8Y0X)
Available from:
PharmPak, Inc.
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
To reduce the development of drug-resistant bacteria and maintain the effectiveness of sulfamethoxazole and trimethoprim tablets and other antibacterial drugs, 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. 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 Med
Product summary:
Sulfamethoxazole and Trimethoprim Tablets, USP are supplied as follows: Sulfamethoxazole and Trimethoprim DS (double strength) Tablets USP, 800 mg, are supplied as white, oval, bisected tablets debossed “IP” bisect “272” on one side. They are available as follows: Bottles of 6:                   NDC 54348-625-06 Bottles of 10:                   NDC 54348-625-10 Bottles of 14:                   NDC 54348-625-14 Bottles of 20:                   NDC 54348-625-20 Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. DISPENSE IN TIGHT, LIGHT-RESISTANT CONTAINER.
Authorization status:
Abbreviated New Drug Application
Authorization number:
54348-625-06, 54348-625-10, 54348-625-14, 54348-625-20

SULFAMETHOX-TMP DS- sulfamethoxazole, trimethoprim tablet

PharmPak, Inc.

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Sulfamethoxazole and Trimethoprim Tablets and Double Strength Tablets, USP

Rx only

To reduce the development of drug-resistant bacteria and maintain the effectiveness of

sulfamethoxazole and trimethoprim tablets and other antibacterial drugs, sulfamethoxazole and

trimethoprim tablets should be used only to treat or prevent infections that are proven or strongly

suspected to be caused by bacteria.

DESCRIPTION

Sulfamethoxazole and trimethoprim is a synthetic antibacterial combination product available in DS

(double strength) tablets, each containing 800 mg sulfamethoxazole, USP and 160 mg trimethoprim,

USP; in tablets, each containing 400 mg sulfamethoxazole, USP and 80 mg trimethoprim, USP for oral

administration.

Sulfamethoxazole, USP is N -(5-methyl-3-isoxazolyl) sulfanilamide; the molecular formula is C

S. It is an almost white, odorless, tasteless compound with a molecular weight of 253.28 and

the following structural formula:

Trimethoprim, USP is 2,4-diamino-5-(3,4,5-trimethoxybenzyl) pyrimidine; the molecular formula is C

. It is a white to light yellow, odorless, bitter compound with a molecular weight of 290.3.

It has the following structural formula:

Inactive Ingredients: Magnesium stearate, povidone, pregelatinized starch and sodium starch glycolate.

CLINICAL PHARMACOLOGY

Sulfamethoxazole and trimethoprim 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. Sulfamethoxazole is metabolized in humans to at

least 5 metabolites: the N

-acetyl-, N

-hydroxy-, 5-methylhydroxy-, N

-acetyl-5-methylhydroxy-

sulfamethoxazole metabolites and an N-glucuronide conjugate. The formulation of N

-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 4-

hydroxy derivatives.

The free forms of sulfamethoxazole and trimethoprim 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.

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 mcg/mL. The steady-state mean plasma

levels of free and total sulfamethoxazole were 57.4 mcg/mL and 68 mcg/mL, respectively. These

steady-state levels were achieved after three days of drug administration

. 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

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 N

-acetylated metabolite

. 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.

Geriatric Pharmacokinetics: The pharmacokinetics of sulfamethoxazole 800 mg and trimethoprim 160

mg were studied in 6 geriatric subjects (mean age: 78.6 years) and 6 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

Microbiology

Sulfamethoxazole inhibits bacterial synthesis of dihydrofolic acid by competing with paraaminobenzoic

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 jiroveci

Susceptibility Testing

For specific information regarding susceptibility test interpretive criteria and associated test methods

and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

INDICATIONS AND USAGE

To reduce the development of drug-resistant bacteria and maintain the effectiveness of

sulfamethoxazole and trimethoprim tablets and other antibacterial drugs, 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.

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 tablets in pediatric patients under two years of age. Sulfamethoxazole and

trimethoprim tablets are 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 a

physician deems that sulfamethoxazole and trimethoprim could offer 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 P. jiroveci pneumonia in individuals who are immunosuppressed and considered

to be at an increased risk of developing P. jiroveci pneumonia.

Traveler’s Diarrhea in Adults: For the treatment of traveler’s diarrhea due to susceptible strains of

enterotoxigenic E. coli.

CONTRAINDICATIONS

Sulfamethoxazole and trimethoprim 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.

Sulfamethoxazole and trimethoprim is contraindicated in pediatric patients less than 2 months of age.

Sulfamethoxazole and trimethoprim is also contraindicated in patients with marked hepatic damage or

with severe renal insufficiency when renal function status cannot be monitored.

WARNINGS

Embryofetal Toxicity

Some epidemiologic studies suggest that exposure to sulfamethoxazole/trimethoprim during pregnancy

may be associated with an increased risk of congenital malformations, particularly neural tube defects,

cardiovascular malformations, urinary tract defects, oral clefts, and club foot. If

sulfamethoxazole/trimethoprim is used during pregnancy, or if the patient becomes pregnant while

taking this drug, the patient should be advised of the potential hazards to the fetus.

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

. Co-administration of trimethoprim-

sulfamethoxazole and leucovorin during treatment of Pneumocystis jiroveci pneumonia should be

avoided.

PRECAUTIONS

Development of drug resistant bacteria

Prescribing sulfamethoxazole and trimethoprim tablets in the absence of a proven or strongly suspected

bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases

the risk of the development of drug-resistant bacteria.

Folate deficiency

Sulfamethoxazole and trimethoprim 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 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. These effects are reversible by folinic acid

therapy.

Hemolysis

In glucose-6-phosphate dehydrogenase deficient individuals, hemolysis may occur. This reaction is

frequently dose-related (see CLINICAL PHARMACOLOGY and DOSAGE AND

ADMINISTRATION).

Hypoglycemia

Cases of hypoglycemia in non-diabetic patients treated with sulfamethoxazole and trimethoprim are seen

rarely, usually occurring after a few days of therapy. Patients with renal dysfunction, liver disease,

malnutrition or those receiving high doses of sulfamethoxazole and trimethoprim are particularly at risk.

Phenylalanine metabolism

Trimethoprim has been noted to impair phenylalanine metabolism but this is of no significance in

phenylketonuric patients on appropriate dietary restriction.

Porphyria and Hypothyroidism

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

dysfunction.

Use in the Treatment of and Prophylaxis for Pneumocystis jiroveci Pneumonia in Patients with Acquired

Immunodeficiency Syndrome (AIDS)

AIDS patients may not tolerate or respond to sulfamethoxazole and trimethoprim in the same manner as

non-AIDS patients. The incidence of side effects, particularly rash, fever, leukopenia and elevated

aminotransferase (transaminase) values, with sulfamethoxazole and trimethoprim therapy in AIDS

patients who are being treated for P. jiroveci pneumonia has been reported to be greatly increased

compared with the incidence normally associated with the use of sulfamethoxazole and trimethoprim in

non-AIDS patients. Adverse effects are generally less severe in patients receiving sulfamethoxazole

and trimethoprim for prophylaxis. A history of mild intolerance to sulfamethoxazole and trimethoprim in

AIDS patients does not appear to predict intolerance of subsequent secondary prophylaxis

. However,

if a patient develops skin rash or any sign of adverse reaction, therapy with sulfamethoxazole and

trimethoprim should be reevaluated (see WARNINGS).

Co-administration of sulfamethoxazole and trimethoprim and leucovorin should be avoided with P.

jiroveci pneumonia (see WARNINGS).

Electrolyte Abnormalities

High dosage of trimethoprim, as used in patients with P. jiroveci pneumonia, induces a progressive but

reversible increase of serum potassium concentrations in a substantial number of patients. Even 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 is warranted in these

patients.

Severe and symptomatic hyponatremia can occur in patients receiving sulfamethoxazole and

trimethoprim, particularly for the treatment of P. jiroveci pneumonia. Evaluation for hyponatremia and

appropriate correction is necessary in symptomatic patients to prevent life-threatening complications.

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.

Information for Patients

Patients should be counseled that antibacterial drugs including sulfamethoxazole and trimethoprim

tablets should only be used to treat bacterial infections. They do not treat viral infections (e.g., the

common cold). When sulfamethoxazole and trimethoprim tablets are 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

tablets 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.

Laboratory Tests

Complete blood counts should be done frequently in patients receiving sulfamethoxazole and

trimethoprim; if a significant reduction in the count of any formed blood element is noted,

sulfamethoxazole and trimethoprim should be discontinued. Urinalyses with careful microscopic

examination and renal function tests should be performed during therapy, particularly for those patients

with impaired renal function.

Drug Interactions

Potential for Sulfamethoxazole and Trimethoprim to Affect Other Drugs

Trimethoprim is an inhibitor of CYP2C8 as well as OCT2 transporter. Sulfamethoxazole is an inhibitor

of CYP2C9. Caution is recommended when sulfamethoxazole and trimethoprim is co-administered with

drugs that are substrates of CYP2C8 and 2C9 or OCT2.

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 (a CYP2C9 substrate). 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 (a CYP2C9

substrate). 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 co-administration 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 co-administered with sulfamethoxazole and

trimethoprim.

Sulfamethoxazole and trimethoprim potentiates the effect of oral hypoglycemics that are metabolized by

CYP2C8 (e.g., pioglitazone, repaglinide, and rosiglitazone) or CYP2C9 (e.g., glipizide and glyburide)

or eliminated renally via OCT2 (e.g., metformin). Additional monitoring of blood glucose may be

warranted.

In the literature, a single case of toxic delirium has been reported after concomitant intake of

sulfamethoxazole/trimethoprim and amantadine (an OCT2 substrate). Cases of interactions with other

OCT2 substrates, memantine and metformin, have also been reported.

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

Drug/Laboratory Test Interactions

Sulfamethoxazole and trimethoprim, specifically the trimethoprim component, can interfere with a serum

methotrexate assay as determined by the competitive binding protein technique (CBPA) when a bacterial

dihydrofolate reductase is used as the binding protein. No interference occurs, however, if

methotrexate is measured by a radioimmunoassay (RIA).

The presence of sulfamethoxazole and trimethoprim may also interfere with the Jaffé alkaline picrate

reaction assay for creatinine, resulting in overestimations of about 10% in the range of normal values.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis: Sulfamethoxazole was not carcinogenic when assessed in a 26-week tumorigenic

mouse (Tg-rasH2) study at doses up to 400 mg/kg/day sulfamethoxazole; equivalent to 2.4-fold the

human systemic exposure (at a daily dose of 800 mg sulfamethoxazole b.i.d.).

Mutagenesis: In vitro reverse mutation bacterial tests according to the standard protocol have not been

performed with sulfamethoxazole and trimethoprim in combination. An in vitro chromosomal aberration

test in human lymphocytes with sulfamethoxazole/trimethoprim was negative. In in vitro and in vivo tests

in animal species, sulfamethoxazole/trimethoprim did not damage chromosomes. In vivo micronucleus

assays were positive following oral administration of sulfamethoxazole/trimethoprim. Observations of

leukocytes obtained from patients treated with sulfamethoxazole and trimethoprim revealed no

chromosomal abnormalities.

Sulfamethoxazole alone was positive in an in vitro reverse mutation bacterial assay and in in vitro

micronucleus assays using cultured human lymphocytes.

Trimethoprim alone was negative in in vitro reverse mutation bacterial assays and in in vitro

chromosomal aberration assays with Chinese Hamster ovary or lung cells with or without S9 activation.

In in vitro Comet, micronucleus and chromosomal damage assays using cultured human lymphocytes,

trimethoprim was positive. In mice following oral administration of trimethoprim, no DNA damage in

Comet assays of liver, kidney, lung, spleen, or bone marrow was recorded.

Impairment of Fertility: No adverse effects on fertility or general reproductive performance were

observed in rats given oral dosages as high as 350 mg/kg/day sulfamethoxazole plus 70 mg/kg/day

trimethoprim doses roughly two times the recommended human daily dose on a body surface area basis.

Pregnancy

While there are no large, well-controlled studies on the use of sulfamethoxazole and trimethoprim in

pregnant women, Brumfitt and Pursell

, 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.

Teratogenic Effects

Pregnancy Category D.

Human Data

While there are no large prospective, well controlled studies in pregnant women and their babies, some

retrospective epidemiologic studies suggest an association between first trimester exposure to

sulfamethoxazole/trimethoprim with an increased risk of congenital malformations, particularly neural

tube defects, cardiovascular abnormalities, urinary tract defects, oral clefts, and club foot. These

studies, however, were limited by the small number of exposed cases and the lack of adjustment for

multiple statistical comparisons and confounders. These studies are further limited by recall, selection,

and information biases, and by limited generalizability of their findings. Lastly, outcome measures

varied between studies, limiting cross-study comparisons. Alternatively, other epidemiologic studies

did not detect statistically significant associations between sulfamethoxazole/trimethoprim exposure and

specific malformations.

Animal Data

In rats, oral doses of either 533 mg/kg sulfamethoxazole or 200 mg/kg trimethoprim produced

teratologic effects manifested mainly as cleft palates. These doses are approximately 5 and 6 times the

recommended human total daily dose on a body surface area basis. 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 some rabbit studies, an overall increase in fetal loss (dead and resorbed conceptuses)

was associated with doses of trimethoprim 6 times the human therapeutic dose based on body surface

area.

Nonteratogenic Effects

See CONTRAINDICATIONS section.

Nursing Mothers: Levels of trimethoprim/sulfamethoxazole in breast milk are approximately 2% to 5%

of the recommended daily dose for infants over 2 months of age. Caution should be exercised when

sulfamethoxazole and trimethoprim is administered to a nursing woman, especially when breastfeeding,

jaundiced, ill, stressed, or premature infants because of the potential risk of bilirubin displacement and

kernicterus.

Pediatric Use: Sulfamethoxazole and trimethoprim is contraindicated for infants younger than 2 months

of age (see INDICATIONS and CONTRAINDICATIONS sections).

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 Tablets contain 1.8 mg sodium (0.08 mEq) of sodium per tablet.

Sulfamethoxazole and Trimethoprim Double Strength Tablets contain 3.6 mg (0.16 mEq) of sodium per

tablet.

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).

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, hyponatremia (see PRECAUTIONS: Electrolyte

Abnormalities).

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

sulfamethoxazole and trimethoprim, mainly in AIDS patients.

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

Miscellaneous: Weakness, fatigue, insomnia.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of trimethoprim-

sulfamethoxazole. Because these reactions were reported voluntarily from a population of uncertain

size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug

exposure:

Thrombotic thrombocytopenia purpura

Idiopathic thrombocytopenic purpura

QT prolongation resulting in ventricular tachycardia and torsade de pointes

To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-

835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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.

DOSAGE AND ADMINISTRATION

Sulfamethoxazole and trimethoprim tablets are 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 1 sulfamethoxazole and

trimethoprim DS (double strength) tablet or 2 sulfamethoxazole and trimethoprim tablets 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:

Children 2 months of age or older:

Weight

Dose – every 12 hours

lb

kg

Tablets

2 or 1 DS tablet

For Patients with Impaired Renal Function

When renal function is impaired, a reduced dosage should be employed using the following table:

Creatinine

Clearance (mL/min)

Recommended

Dosage Regimen

Above 30

Usual standard regimen

15 to 30

½ the usual regimen

Below 15

Use not recommended

Acute Exacerbations of Chronic Bronchitis in Adults

The usual adult dosage in the treatment of acute exacerbations of chronic bronchitis is 1

sulfamethoxazole and trimethoprim double strength tablet, or 2 sulfamethoxazole and trimethoprim

single strength tablets, 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

. The following table is a guideline for the upper limit

of this dosage:

Weight

Dose – every 6 hours

lb

kg

Tablets

2 or 1 DS tablet

3 or 1½ DS tablets

4 or 2 DS tablets

5 or 2½ DS tablets

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 1 sulfamethoxazole and trimethoprim DS (double

strength) tablet daily

Children

For children, the recommended dose is 750 mg/m

/day sulfamethoxazole with 150 mg/m

/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

. The

following table is a guideline for the attainment of this dosage in children:

Body Surface Area

Dose – every 12 hours

(m

)

Tablets

0.26

0.53

1.06

Traveler’s Diarrhea in Adults

For the treatment of traveler’s diarrhea, the usual adult dosage is 1 sulfamethoxazole and trimethoprim

DS (double strength) tablet or 2 sulfamethoxazole and trimethoprim single strength tablets every 12

hours for 5 days.

HOW SUPPLIED

Sulfamethoxazole and Trimethoprim Tablets, USP are supplied as follows:

Sulfamethoxazole and Trimethoprim DS (double strength) Tablets USP, 800 mg, are supplied as white,

oval, bisected tablets debossed “IP” bisect “272” on one side.

They are available as follows:

Bottles of 6: NDC 54348-625-06

Bottles of 10: NDC 54348-625-10

Bottles of 14: NDC 54348-625-14

Bottles of 20: NDC 54348-625-20

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

DISPENSE IN TIGHT, LIGHT-RESISTANT CONTAINER.

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. 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

5. Hardy DW, et al. A controlled trial of trimethoprim-sulfamethoxazole or aerosolized pentamidine

for secondary prophylaxis of Pneumocystis cariniipneumonia in patients with the acquired

immunodeficiency syndrome. N Engl J Med. 1992; 327:1842-1848.

6. Marinella, Mark A. 1999. Trimethoprim-induced hyperkalemia: An analysis of reported cases.

Gerontol. 45:209-212.

7. Margassery, S. and B. Bastani. 2002. Life threatening hyperkalemia and acidosis secondary to

2

trimethoprim-sulfamethoxazole treatment. J. Nephrol. 14:410-414.

8. Brumfitt W, Pursell R. Trimethoprim/Sulfamethoxazole in the Treatment of Bacteriuria in Women. J

Infect Dis. Nov 1973; 128 (Suppl):S657-S663.

9. Masur H. Prevention and treatment of Pneumocystis pneumonia. N Engl J Med. 1992; 327:1853-1880.

10. Recommendations for prophylaxis against Pneumocystis cariniipneumonia for adults and adolescents

infected with human immunodeficiency virus. MMWR. 1992; 41(RR-4):1-11.

11. CDC Guidelines for prophylaxis against Pneumocystis cariniipneumonia for children infected with

human immunodeficiency virus. MMWR. 1991; 40(RR-2):1-13.

Distributed by:

Amneal Pharmaceuticals LLC

Bridgewater, NJ 08807

Rev. 04-2019-01

Package Labeling: (54348-625-06)

Package Labeling: (54348-625-10)

Package Labeling: (54348-625-14)

Package Labeling: (54348-625-20)

SULFAMETHOX-TMP DS

sulfamethoxazole, trimethoprim tablet

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:54348 -6 25(NDC:53746 -272)

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

SULFAMETHO XAZO LE (UNII: JE4238 1TNV) (SULFAMETHOXAZOLE - UNII:JE4238 1TNV)

SULFAMETHOXAZOLE

8 0 0 mg

TRIMETHO PRIM (UNII: AN16 4J8 Y0 X) (TRIMETHOPRIM - UNII:AN16 4J8 Y0 X)

TRIMETHOPRIM

16 0 mg

Inactive Ingredients

Ingredient Name

Stre ng th

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

PO VIDO NE (UNII: FZ9 8 9 GH9 4E)

STARCH, CO RN (UNII: O8 232NY3SJ)

SO DIUM STARCH GLYCO LATE TYPE A PO TATO (UNII: 58 56 J3G2A2)

Product Characteristics

Color

white

S core

2 pieces

S hap e

OVAL

S iz e

19 mm

Flavor

Imprint Code

IP;272

Contains

PharmPak, Inc.

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:54348 -6 25-0 6

1 in 1 BOX

0 7/11/20 19

1

6 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

2

NDC:54348 -6 25-10

1 in 1 BOX

0 7/11/20 19

2

10 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

3

NDC:54348 -6 25-14

1 in 1 BOX

0 7/11/20 19

3

14 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

4

NDC:54348 -6 25-20

1 in 1 BOX

0 7/11/20 19

4

20 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 76 8 9 9

0 7/11/20 19

Labeler -

PharmPak, Inc. (175493840)

Revised: 8/2019

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