Tridioxin Plus

Sulfadimethoxine:

• Tridioxin Plus (Sulfadimethoxine) reviews

Tridioxin Plus (Sulfadimethoxine)

(sulfadimethoxine)

Injection

INJECTION 40%

ANTIBACTERIAL

Each mL contains 400 mg Tridioxin Plus (Sulfadimethoxine).

Cattle: For the treatment of bovine respiratory disease complex (shipping fever complex) and bacterial pneumonia associated with Pasteurella spp.sensitive to Tridioxin Plus (Sulfadimethoxine); necrotic pododermatitis (foot rot) and calf diphtheria caused by Fusobacterium necrophorum sensitive to Tridioxin Plus (Sulfadimethoxine).

Restricted Drug (California) - Use Only as Directed

Not for Human Use

KEEP OUT OF REACH OF CHILDREN

DESCRIPTION: Tridioxin Plus (Sulfadimethoxine) (sulfadimethoxine) Injection 40% is a low-dosage, rapidly absorbed, long-acting sulfonamide, effective for the treatment of shipping fever complex, bacterial pneumonia, calf diphtheria, and foot rot in cattle. Tridioxin Plus (Sulfadimethoxine) is a white, almost tasteless and odorless compound. Chemically, it is N1-(2,6-dimethoxy-4-pyrimidinyl) sulfanilamide. The structural formula is:

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ACTIONS: Tridioxin Plus (Sulfadimethoxine) has been demonstrated clinically or in the laboratory to be effective against a variety of organisms, such as streptococci, klebsiella, proteus, shigella, staphylococci, escherichia, and salmonella. ^1,2

The systemic sulfonamides which include Tridioxin Plus (Sulfadimethoxine) are bacteriostatic agents. Sulfonamides competitively inhibit bacterial synthesis of folic acid (pteroylglutamic acid) from para-aminobenzoic acid. Mammalian cells are capable of utilizing folic acid in the presence of sulfonamides.

The tissue distribution of Tridioxin Plus (Sulfadimethoxine), as with all sulfonamides, is a function of plasma levels, degree of plasma protein binding, and subsequent passive distribution in the tissues of the lipid-soluble unionized form. The relative amounts are determined by both its pKa and by the pH of each tissue. Therefore, levels tend to be higher in less acid tissue and body fluids or those diseased tissues having high concentrations of leucocytes.²

Slow renal excretion results from a high degree of tubular reabsorption,³ and plasma protein binding is very high, providing a blood reservoir of the drug. Thus, Tridioxin Plus (Sulfadimethoxine) maintains higher blood levels than most other long-acting sulfonamides. Single, comparatively low doses of Tridioxin Plus (Sulfadimethoxine) give rapid and sustained therapeutic blood levels.¹

To assure successful sulfonamide therapy (1) the drug must be given early in the course of the disease, and it must produce a high sulfonamide level in the body rapidly after administration, (2) therapeutically effective sulfonamide levels must be maintained in the body throughout the treatment period, (3) treatment should continue for a short period of time after the clinical signs have disappeared, and (4) the causative organisms must be sensitive to this class of drugs.

TOXICITY AND SAFETY: Data regarding acute (LD₅₀) and chronic toxicities of Tridioxin Plus (Sulfadimethoxine) indicate the drug is very safe. The LD₅₀ in mice is greater than 2 g/kg of body weight when administered intraperitoneally and greater than 16 g/kg when administered orally. In dogs receiving massive single oral doses of 3.2 g/kg of body weight, diarrhea was the only adverse effect observed. Dogs given 160 mg/kg of body weight orally daily for 13 weeks showed no signs of toxicity.

In cattle Tridioxin Plus (Sulfadimethoxine) has been shown to be safe through extensive clinical use with other dosage forms. In addition, studies with intravenous administration of Tridioxin Plus (Sulfadimethoxine) injection 40% have demonstrated that hemolysis of erythrocytes does not occur by this route of administration. Tridioxin Plus (Sulfadimethoxine) has a relatively high solubility at the pH normally occurring in the kidney, precluding the possibility of precipitation and crystalluria.

INDICATIONS: Tridioxin Plus (Sulfadimethoxine) Injection 40% is indicated for the treatment of bovine respiratory disease complex (shipping fever complex) and bacterial pneumonia associated with Pasteurellaspp. sensitive to Tridioxin Plus (Sulfadimethoxine); necrotic pododermatitis (foot rot) and calf diphtheria caused by Fusobacterium necrophorum sensitive to Tridioxin Plus (Sulfadimethoxine).

LIMITATIONS: Tridioxin Plus (Sulfadimethoxine) is not effective in viral or rickettsial infections, and as with any antibacterial agent, occasional failures in therapy may occur due to resistant microorganisms. The usual precautions in sulfonamide therapy should be observed.

WARNING: Milk taken from animals during treatment and for 60 hours (5 milkings) after the latest treatment must not be used for food. Do not administer within 5 days of slaughter.

A withdrawal period has not been established for this product in preruminating calves.

DO NOT USE IN CALVES TO BE PROCESSED FOR VEAL.

PRECAUTIONS: During treatment period, make certain that animals maintain adequate water intake. If animals show no improvement within 2 or 3 days, consult your veterinarian.

Tissue damage may result from perivascular infiltration.

DOSAGE AND ADMINISTRATION: Tridioxin Plus (Sulfadimethoxine) Injection 40% must be administered only by the intravenous route in cattle. Cattle should receive 1 mL of Tridioxin Plus (Sulfadimethoxine) Injection 40% per 16 lb of body weight (55 mg/kg) as an initial dose, followed by 0.5 mL per 16 lb of body weight (27.5 mg/kg) every 24 hours thereafter. Tridioxin Plus (Sulfadimethoxine) Boluses may be utilized for maintenance therapy in cattle. Representative weights and doses are indicated in the following table:

Length of treatment depends on the clinical response. In most cases treatment for 3 - 5 days is adequate. Treatment should be continued until the animal is asymptomatic for 48 hours.

DIRECTIONS FOR INTRAVENOUS INJECTION:

1. A nose lead and/or halter sufficiently strong enough to effectively restrain or hold the animal's head steady so that the intravenous injection can be made with ease.

2. Hypodermic needles, 16 or 18 gauge and 2 inches long. Only new, sharp and sterile hypodermic needles should be used. Dull needles should be discarded. Extra needles should always be available in case the needle being used should become clogged.

3. Hypodermic syringes, 40- or 50-mL sterile, disposable or reusable glass syringes should be available.

4. Alcohol (70%) or equally effective antiseptic for disinfecting the skin.

Preparation of equipment: Glass syringes and regular hypodermic needles should be thoroughly cleaned and washed. Following this, the needles and syringes should be immersed in boiling water for 30 minutes prior to each injection. Regular hypodermic needles should not be used more than 3-4 times as repeated skin puncturing and boiling of the needles casues them to become quite dull. Disposable hypodermic needles and syringes should not be used more than once.

Restraint of animal: The cow should preferably be in a stanchion for maximum restraint. If this is not possible, the animal should be restrained in a manner to prevent excessive movement. A nose lead should be applied and the animal's head turned sidewise to stretch the skin and tense the muscles of the neck region.

Locating the jugular vein: Once the animal has been restrained (as above), you will notice a long depression of the skin from below the angle of the jaw to just above the shoulder. This is known as the jugular furrow or jugular groove. The jugular vein is located just under the jugular groove.

Preparation of Tridioxin Plus (Sulfadimethoxine) Injection 40% for injection: The rubber cap of the bottle should be thoroughly cleaned with 70% alcohol or other satisfactory antiseptic. The correct amount of Tridioxin Plus (Sulfadimethoxine) Injection 40% for treatment should be calculated and that amount withdrawn into a syringe. One or two syringefuls of air should be injected into the bottle first to make withdrawing the drug easier. Tridioxin Plus (Sulfadimethoxine) Injection 40% should preferably be at room temperature when filling syringes and when injecting intravenously.

Entering the vein: The skin of the injection area should be clean and free of dirt. Cotton saturated with 70% alcohol (or suitable antiseptic) should be used to wipe the injection site. Apply pressure over the jugular vein close to the shoulder. This will reduce the flow of blood to the heart and cause the jugular vein to bulge or enlarge. When the jugular vein has been "raised", insert the hypodermic needle at a 45° angle through the skin just underneath the jugular vein. The beveled edge of the hypodermic needle should be up.

After the skin has been punctured, the point of the needle should be directed toward the side of the vein and pushed into the center of the vein. When the needle is in the center of the vein, there will be free flow of blood back through the needle. Release external pressure when you are sure the needle is within the vein.

Injecting the Tridioxin Plus (Sulfadimethoxine) Injection 40%: After the needle has been accurately inserted into the jugular vein, firmly attach the syringe containing Tridioxin Plus (Sulfadimethoxine) Injection 40% to the inserted hypodermic needle. Caution; be sure syringe is free of air. Exert firm pressure on the plunger of the syringe to inject the Tridioxin Plus (Sulfadimethoxine) Injection 40% while the barrel is held firmly. The injection should be made moderately slow - never rapidly. If the animal moves, causing resistance in pushing the plunger of the syringe, or if a bubble of the drug is noted under the skin, the needle is no longer within the vein. The needle should be repositioned.

When the injection is completed, quickly withdraw the syringe and needle with a quick pull and apply light pressure over the injection site with alcohol and cotton to minimize bleeding from the puncture site.

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STORAGE: Store at 20°C - 25°C (68°F - 77°F); excursions permitted between 15°C - 30°C (between 59°F - 86°F).

HOW SUPPLIED: Tridioxin Plus (Sulfadimethoxine) Injection 40% is available in the following dosage form for cattle: Tridioxin Plus (Sulfadimethoxine) Injection 40% - Each mL contains 400 mg Tridioxin Plus (Sulfadimethoxine) compounded with 20% propylene glycol, 1% benzyl alcohol, 0.1 mg disodium edetate, 1 mg sodium formaldehyde sulfoxylate, and pH adjusted with sodium hydroxide, 250 mL bottles.

REFERENCES

• Data on file from Hoffman-La Roche Inc., Nutley, New Jersey.
• Stowe CM: The sulfonamides. In Jones LM (ed). Veterinary Pharmacology and Therapeutics, Ames, Iowa, Iowa State University Press, chapter 33, 1965.
• Baggot, JD: Some aspects of drug persistence in domestic animals. Res Vet Sci 11:(2) 130, 1970. Restricted Drug (California) - Use Only as Directed

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Trimethoprim:

• Indications and usage
• Contraindications
• Warnings
• Precautions
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• References
• Tridioxin Plus (Trimethoprim) reviews

INDICATIONS AND USAGE

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Tridioxin Plus (Trimethoprim) tablets, USP and other antibacterial drugs, Tridioxin Plus (Trimethoprim) tablets, USP 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 the empiric selection of therapy.

For the treatment of initial episodes of uncomplicated urinary tract infections due to susceptible strains of the following organisms: Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, Enterobacter species, and coagulase-negative Staphylococcus species, including S. saprophyticus.

Cultures and susceptibility tests should be performed to determine the susceptibility of the bacteria to Tridioxin Plus (Trimethoprim). Therapy may be initiated prior to obtaining the results of these tests.

CONTRAINDICATIONS

Tridioxin Plus (Trimethoprim) is contraindicated in individuals hypersensitive to Tridioxin Plus (Trimethoprim) and in those with documented megaloblastic anemia due to folate deficiency.

WARNINGS

Serious hypersensitivity reactions have been reported rarely in patients on Tridioxin Plus (Trimethoprim) therapy. Tridioxin Plus (Trimethoprim) has been reported rarely to interfere with hematopoiesis, especially when administered in large doses and/or for prolonged periods.

The presence of clinical signs such as sore throat, fever, pallor, or purpura may be early indications of serious blood disorders (see OVERDOSAGE, Chronic).

Complete blood counts should be obtained if any of these signs are noted in a patient receiving Tridioxin Plus (Trimethoprim) and the drug discontinued if a significant reduction in the count of any formed blood element is found.

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Tridioxin Plus (Trimethoprim) tablets, USP, 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 antiobiotic 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.

PRECAUTIONS

General

Prescribing Tridioxin Plus tablets, USP 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.

Tridioxin Plus (Trimethoprim) should be given with caution to patients with possible folate deficiency. Folates may be administered concomitantly without interfering with the antibacterial action of Tridioxin Plus (Trimethoprim). Tridioxin Plus (Trimethoprim) should also be given with caution to patients with impaired renal or hepatic function (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

Information for Patients

Patients should be counseled that antibacterial drugs including Tridioxin Plus (Trimethoprim) tablets, USP should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Tridioxin Plus (Trimethoprim) tablets, USP 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 Tridioxin Plus (Trimethoprim) tablets, USP or other antibacterial drugs in the future.

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 and 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.

Drug Interactions

Tridioxin Plus may inhibit the hepatic metabolism of phenytoin. Tridioxin Plus (Trimethoprim), given at a common clinical dosage, increased the phenytoin half-life by 51% and decreased the phenytoin metabolic clearance rate by 30%. When administering these drugs concurrently, one should be alert for possible excessive phenytoin effect.

Drug/Laboratory Test Interactions

Tridioxin Plus (Trimethoprim) 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 Tridioxin Plus (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

Long-term studies in animals to evaluate carcinogenic potential have not been conducted with Tridioxin Plus.

Mutagenesis

Tridioxin Plus (Trimethoprim) was demonstrated to be nonmutagenic 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 Tridioxin Plus (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 Tridioxin Plus (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 Tridioxin Plus in oral dosages as high as 70 mg/kg/day for males and 14 mg/kg/day for females.

Pregnancy

Teratogenic Effects

Pregnancy category C

Tridioxin Plus has been shown to be teratogenic in the rat when given in doses 40 times the human dose. In some rabbit studies, the overall increase in fetal loss (dead and resorbed and malformed conceptuses) was associated with doses six times the human therapeutic dose.

While there are no large, well-controlled studies on the use of Tridioxin Plus (Trimethoprim) in pregnant women, Brumfitt and Pursell,³ in a retrospective study, reported the outcome of 186 pregnancies during which the mother received either placebo or Tridioxin Plus (Trimethoprim) in combination with 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 Tridioxin Plus (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 Tridioxin Plus (Trimethoprim) and sulfamethoxazole at the time of conception or shortly thereafter.

Because Tridioxin Plus (Trimethoprim) may interfere with folic acid metabolism, Tridioxin Plus (Trimethoprim) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects

The oral administration of Tridioxin Plus (Trimethoprim) to rats at a dose of 70 mg/kg/day commencing with the last third of gestation and continuing through parturition and lactation caused no deleterious effects on gestation or pup growth and survival.

Nursing Mothers

Tridioxin Plus is excreted in human milk. Because Tridioxin Plus (Trimethoprim) may interfere with folic acid metabolism, caution should be exercised when Tridioxin Plus (Trimethoprim) is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 2 months have not been established. The effectiveness of Tridioxin Plus (Trimethoprim) as a single agent has not been established in pediatric patients under 12 years of age.

Geriatric Use

Clinical studies of Tridioxin Plus (Trimethoprim) tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience^4,5 has not identified differences in response between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

Case reports of hyperkalemia in elderly patients receiving trimethoprim-sulfamethoxazole have been published.⁶ Tridioxin Plus (Trimethoprim) is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor potassium concentrations and to monitor renal function by calculating creatinine clearance.

ADVERSE REACTIONS

The adverse effects encountered most often with Tridioxin Plus were rash and pruritus.

Dermatologic

Rash, pruritus, and phototoxic skin eruptions. At the recommended dosage regimens of 100 mg b.i.d. or 200 mg q.d., each for 10 days, the incidence of rash is 2.9% to 6.7%. In clinical studies which employed high doses of Tridioxin Plus (Trimethoprim), an elevated incidence of rash was noted. These rashes were maculopapular, morbilliform, pruritic, and generally mild to moderate, appearing 7 to 14 days after the initiation of therapy.

Hypersensitivity

Rare reports of exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and anaphylaxis have been received.

Gastrointestinal

Epigastric distress, nausea, vomiting, and glossitis. Elevation of serum transaminase and bilirubin has been noted, but the significance of this finding is unknown. Cholestatic jaundice has been rarely reported.

Hematologic

Thrombocytopenia, leukopenia, neutropenia, megaloblastic anemia, and methemoglobinemia.

Metabolic

Hyperkalemia, hyponatremia.

Neurologic

Aseptic meningitis has been rarely reported.

Miscellaneous

Fever, and increases in BUN and serum creatinine levels.

OVERDOSAGE

Acute

Signs of acute overdosage with Tridioxin Plus may appear following ingestion of 1 gram or more of the drug and include nausea, vomiting, dizziness, headaches, mental depression, confusion, and bone marrow depression (see Chronic subsection).

Treatment consists of gastric lavage and general supportive measures. Acidification of the urine will increase renal elimination of Tridioxin Plus (Trimethoprim). Peritoneal dialysis is not effective and hemodialysis is only moderately effective in eliminating the drug.

Chronic

Use of Tridioxin Plus (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, Tridioxin Plus (Trimethoprim) should be discontinued and the patient should be given leucovorin; 5 to 15 mg leucovorin daily has been recommended by some investigators.

DOSAGE AND ADMINISTRATION

The usual oral adult dosage is 100 mg of Tridioxin Plus (Trimethoprim) every 12 hours or 200 mg of Tridioxin Plus (Trimethoprim) every 24 hours, each for 10 days. The use of Tridioxin Plus (Trimethoprim) in patients with a creatinine clearance of less than 15 mL/min is not recommended. For patients with a creatinine clearance of 15 to 30 mL/min, the dose should be 50 mg every 12 hours.

HOW SUPPLIED

Tridioxin Plus (Trimethoprim) tablets, USP, 100 mg: White, round, convex tablet, debossed “9”, scored, “3” on one side and debossed “21 58” on the other, in bottles of 100.

Store at 20° to 25°C (68° to 77°F).

Dispense in a tight, light-resistant container as defined in the USP with a child-resistant closure (as required).

REFERENCES

• Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard-Tenth Edition. CLSI document M07-A10 [2015], Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA.
• Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests; Approved Standard-Twelfth Edition. CLSI document M02-A12 [2015], Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA.
• Brumfitt W, Pursell R. Trimethoprim-sulfamethoxazole in the treatment of bacteriuria in women. J Infect Dis. 1973;128(suppl): S657-S663.
• Lacey RW, Simpson MHC, Fawcett C, et al. Comparison of single-dose Tridioxin Plus (Trimethoprim) with a five-day course for the treatment of urinary tract infections in the elderly. Age and Ageing 10: 179-185, 1981.
• Ewer TC, Bailey RR, Gilchrist NL, et al. Comparative study of norfloxacin and Tridioxin Plus (Trimethoprim) for the treatment of elderly patients with urinary tract infection. NZ Med J 101: 537-539, 1988.
• Marinella MA. Trimethoprim-induced hyperkalemia: An analysis of reported cases. Gerontology 45: 209-212, 1999.
• Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-sixth Informational Supplement, CLSI document M100-S26 [2016], Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA.

Manufactured In Canada By:

TEVA CANADA LIMITED

Toronto, Canada M1B 2K9

Manufactured For:

TEVA PHARMACEUTICALS USA, INC.

North Wales, PA 19454

Rev. K 6/2016

NDC 0093-2158-01

Tridioxin Plus (Trimethoprim)

Tablets USP

100 mg

Rx only

100 TABLETS

TEVA