UNIPRIM- trimethoprim and sulfadiazine powder

UNIPRIM by

Drug Labeling and Warnings

UNIPRIM by is a Animal medication manufactured, distributed, or labeled by Neogen Corporation, NANHAI BEISHA PHARMACEUTICAL CO., LTD., Shandong Xinhua Pharmaceutical Co Limited First Plant, Shouguang Fukang Pharmaceutical Co., Ltd.. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

DESCRIPTION

UNIPRIM Powder contains 67 mg trimethoprim and 333 mg sulfadiazine per gram.

UNIPRIM Powder is a combination of trimethoprim and sulfadiazine in the ratio of 1 part to 5 parts by weight, which provides effective antibacterial activity against a wide range of bacterial infections in animals.

Trimethoprim is 2,4 diamino-5-(3, 4, 5-trimethoxybenzyl) pyrimidine.

ACTIONS

Microbiology: Trimethoprim blocks bacterial production of tetrahydrofolic acid from dihydrofolic acid by binding to and reversibly inhibiting the enzyme dihydrofolate reductase.

Sulfadiazine, in common with other sulfonamides, inhibits bacterial synthesis of dihydrofolic acid by competing with para-aminobenzoic acid.

Trimethoprim/sulfadiazine thus imposes a sequential double blockade on bacterial metabolism. This deprives bacteria of nucleic acids and proteins essential for survival and multiplication, and produces a high level of antibacterial activity which is usually bactericidal.

Although both sulfadiazine and trimethoprim are antifolate, neither affects the folate metabolism of animals. The reasons are: animals do not synthesize folic acid and cannot, therefore, be directly affected by sulfadiazine; and although animals must reduce their dietary folic acid to tetrahydrofolic acid, trimethoprim does not affect this reduction because its affinity for dihydrofolate reductase of mammals is significantly less than for the corresponding bacterial enzyme.

Trimethoprim/sulfadiazine is active against a wide spectrum of bacterial pathogens, both gram-negative and gram-positive. The following in vitro data are available, but their clinical significance is unknown. In general, species of the following genera are sensitive to trimethoprim/sulfadiazine:

Very Sensitive	Sensitive	Moderately Sensitive	Not Sensitive
Escherichia	Staphylococcus	Moraxella	Mycobacterium
Streptococcus	Neisseria	Nocardia	Leptospira
Proteus	Klebsiella	Brucella	Pseudomonas
Salmonella	Fusiformis		Erysipelothrix
Pasteurella	Corynebacterium
Shigella	Clostridium
Haemophilus	Bordetella

 As a result of the sequential double blockade of the metabolism of susceptible organisms by trimethoprim and sulfadiazine, the minimum inhibitory concentration (MIC) of trimethoprim/sulfadiazine is markedly less than that of either of the components used separately. Many strains of bacteria that are not susceptible to one of the components are susceptible to trimethoprim/sulfadiazine. A synergistic effect between trimethoprim and sulfadiazine in combination has been shown experimentally both in vitro and in vivo (in dogs).

Trimethoprim/sulfadiazine is bactericidal against susceptible strains and is often effective against sulfonamide-resistant organisms. In vitro sulfadiazine is usually only bacteriostatic.

The precise in vitro MIC of the combination varies with the ratio of the drugs present, but action of trimethoprim/sulfadiazine occurs over a wide range of ratios with an increase in the concentration of one of its components compensating for a decrease in the other. It is usual, however, to determine MICs using a constant ratio of 1 part trimethoprim in 20 parts of the combination.

The following table shows, MICs using the above ratio, of bacteria which were susceptible to both trimethoprim (TMP) and sulfadiazine (SDZ). The organisms are those most commonly involved in conditions for which trimethoprim/sulfadiazine is indicated:

AVERAGE MINIMUM INHIBITORY CONCENTRATION (MIC-mcg/mL)

Bacteria	TMP; Alone	SDZ; Alone	TMP/SDZ; TMP SDZ
Escherichia coli; Proteus species; Staphylococcus aureus; Pasteurella species; Salmonella species; ß Streptococcus	0.31; 1.30; 0.60; 0.06; 0.15; 0.50	26.5; 24.5; 17.6; 20.1; 61.0; 24.5	0.07  1.31; 0.15  2.85; 0.13  2.47; 0.03  0.56; 0.05  0.95; 0.15  2.85

The following table demonstrates the marked effect of the trimethoprim and sulfadiazine combination against sulfadiazine-resistant strains of normally susceptible organisms:

AVERAGE MINIMUM INHIBITORY CONCENTRATION OF SULFADIAZINE-RESISTANT STRAINS (MIC-mcg/mL)

Bacteria	TMP; Alone	SDZ; Alone	TMP/SDZ; TMP  SDZ
Escherichia coli	0.32	>245	0.27  5.0
Proteus species	0.66	>245	0.32  6.2

Susceptibility Testing: In testing susceptibility to trimethoprim/sulfadiazine, it is essential that the medium used does not contain significant amounts of interfering substances which can bypass the metabolic blocking action, e.g., thymidine or thymine.

The standard SxT disc is appropriate for testing by the disc diffusion method.

Pharmacology: Following oral administration, trimethoprim/sulfadiazine is rapidly absorbed and widely distributed throughout body tissues. Concentrations of trimethoprim are usually higher in tissues than in blood. The levels of trimethoprim are high in lungs, kidney, and liver, as would be expected from its physical properties.

Serum trimethoprim concentrations in horses following oral administration indicate rapid absorption of the drug; peak concentrations occur in 1.5 hours. The mean serum elimination half-life is 2 to 2.5 hours. Sulfadiazine absorption is slower, requiring 2.5 to 6 hours to reach peak concentrations. The mean serum elimination half-life for sulfadiazine is 4 to 5.5 hours.

Usually, the concentration of an antibacterial in the blood and the in vitro MIC of the infecting organism indicate an appropriate period between doses of a drug. This does not hold entirely for trimethoprim/sulfadiazine because trimethoprim, in contrast to sulfadiazine, localizes in tissues and therefore, its concentration and ratio to sulfadiazine are higher there than in blood.

The following table shows the average concentration of trimethoprim and sulfadiazine, as measured in either serum or plasma, in twenty-four adult horses observed after a single dose of UNIPRIM Powder:

AVERAGE SERUM/PLASMA CONCENTRATION (mcg/mL)

Trimethoprim (5 mg/kg)	Sulfadiazine (25mg/kg)
1hr    3hr    6hr   10hr    24hr	1hr    3hr     6hr     10hr   24hr
0.82  0.69  0.36  0.12   < .025	9.9    18.8   17.3    9.0     1.6

Excretion of trimethoprim/sulfadiazine is chiefly by the kidneys, by both glomerular filtration and tubular secretion. Urine concentrations of both trimethoprim and sulfadiazine are severalfold higher than blood concentrations. Neither trimethoprim nor sulfadiazine interferes with the excretion pattern of the other.

INDICATIONS AND USAGE

Trimethoprim/sulfadiazine is indicated in horses where potent systemic antibacterial action against sensitive organisms is required. Trimethoprim/sulfadiazine is indicated where control of bacterial infections is required during treatment of:

• Acute Strangles: Acute Urogenital Infections
• Respiratory Tract Infections: Wound Infections and Abscesses

Trimethoprim/sulfadiazine is well tolerated by foals.

CONTRAINDICATIONS

Trimethoprim/sulfadiazine should not be used in horses showing marked liver parenchymal damage, blood dyscrasias, or in those with history of sulfonamide sensitivity.

WARNING

Do not use in horses intended for human consumption.

ADVERSE REACTIONS

During clinical trials, one case of anorexia and one case of loose feces following treatment with the drug were reported.

Individual animal hypersensitivity may result in local or generalized reactions, sometimes fatal. Anaphylactoid reactions, although rare, may also occur. Antidote: Epinephrine.

Post Approval Experience: Horses have developed diarrhea during trimethoprim/sulfadiazine treatment, which could be fatal. If fecal consistency changes during trimethoprim/sulfadiazine therapy, discontinue treatment immediately and contact your veterinarian.

PRECAUTION

Water should be readily available to horses receiving sulfonamide therapy.

ANIMAL SAFETY

Toxicity is low. The acute toxicity (LD50) of trimethoprim/sulfadiazine is more than 5 g/kg orally in rats and mice. No significant changes were recorded in rats given doses of 600 mg/kg per day for 90 days.

Horses treated intravenously with trimethoprim/sulfadiazine 48% injection have tolerated up to five times the recommended daily dose for 7 days or on the recommended daily dose for 21 consecutive days without clinical effects or histopathological changes.

Lengthening of clotting time was seen in some of the horses on high or prolonged dosing in one of two trials. The effect, which may have been related to a resolving infection, was not seen in a second similar trial.

Slight to moderate reductions in hematopoietic activity following high, prolonged dosage in several species have been recorded. This is usually reversible by folinic acid (leucovorin) administration or by stopping the drug. During long-term treatment of horses, periodic platelet counts and white and red blood cell counts are advisable.

TERATOLOGY

The effect of trimethoprim/sulfadiazine on pregnancy has not been determined.  Studies to date show there is no detrimental effect on stallion spermatogenesis with or following the recommended dose of trimethoprim/sulfadiazine.

DOSAGE AND ADMINISTRATION

The recommended dose is 3.75 g UNIPRIM Powder per 110 lbs (50 kg) body weight per day. Administer UNIPRIM Powder orally once a day in a small amount of palatable feed.

Dose Instructions: One 37.5 g packet is sufficient to treat 1100 lbs (500 kg) of body weight. For the 1125 g packets and 12 kg boxes, a level, loose-filled, 67 cc scoop contains 37.5 g, sufficient to treat 1100 lbs (500 kg) of body weight. For the 200 g, 400 g, and 1200 g jars, and 2000 g pail, two level, loose-filled, 32 cc scoops contain 37.5 g, sufficient to treat 1100 lbs (500 kg) of body weight. Since product may settle, gentle agitation during scooping is recommended.

The usual course of treatment is a single, daily dose for 5 to 7 days.

Continue acute infection therapy for 2 or 3 days after clinical signs have subsided.

If no improvement of acute infections is seen in 3 to 5 days, reevaluate the diagnosis.

UNIPRIM Powder may be used alone or in conjunction with intravenous dosing. Following treatment with trimethoprim/sulfadiazine 48% injection, therapy can be maintained using oral Powder.

A complete blood count should be done periodically in patients receiving UNIPRIM Powder for prolonged periods. If significant reduction in the count of any formed blood element is noted, treatment with UNIPRIM Powder should be discontinued.

STORAGE

Store at or below 25°C (77°F)

HOW SUPPLIED

UNIPRIM Powder is available in 37.5 g packets, 1125 g packets, 200 g jars, 400 g jars, 1200 g jars, 2000 g pails and 12 kg boxes. Apple Flavored UNIPRIM Powder is available in 37.5 g packets, 1125 g packets, 200 g jars, 400 g jars, 1200 g jars and 2000 g pails.

CAUTION

Federal (USA) law restricts this drug to use by or on the order of a licensed veterinarian.

SPL UNCLASSIFIED SECTION

ANADA # 200-033, approved by FDA

Lexington, KY 40511 USA

PRINCIPAL DISPLAY PANEL - 400 g Jar

NDC: 59051-3010-3

UNIPRIM®
Powder for Horses

Caution: Federal (USA) law restricts this drug to use by or on the order of a licensed veterinarian.

NEOGENVet

Net Contents: 400 grams

FOR ANIMAL USE ONLY

Each gram contains: 67 mg Trimethoprim, 333 mg Sulfadiazine

Indications: For control of bacterial infections during treatment of acute strangles, respiratory tract infections, acute urogenital infections, wound infections and abscesses.

Recommended Dose: 3.75 g per 110 lbs (50 kg) body weight once daily in a small amount of palatable feed. Two level, loose-filled, 32cc scoops contain 37.5g, sufficient to treat 1100 lbs (500 kg) body weight. Since product contents may settle, gentle agitation during scooping is recommended.

See package insert for additional information.

ANADA # 200-033, Approved by FDA

KEEP OUT OF REACH OF CHILDREN

Store at or below 25°C (77°F)

Warning: Do not use in horses intended for human consumption.

Manufactured by

Neogen Corporation

Lexington, KY 40511 USA

Made in the USA

Item No. UP400

L3438-0915

Rev. 09/15

PRINCIPAL DISPLAY PANEL - 200 g Jar

NDC: 59051-3010-4

UNIPRIM®
Powder for Horses

Caution: Federal (USA) law restricts this drug to use by or on the order of a licensed veterinarian.

NEOGENVet

Net Contents: 200 grams

FOR ANIMAL USE ONLY

Each gram contains: 67 mg Trimethoprim, 333 mg Sulfadiazine

Indications: For control of bacterial infections during treatment of acute strangles, respiratory tract infections, acute urogenital infections, wound infections and abscesses.

Recommended Dose: 3.75 g per 110 lbs (50 kg) body weight once daily in a small amount of palatable feed. Two level, loose-filled, 32cc scoops contain 37.5g, sufficient to treat 1100 lbs (500 kg) body weight. Since product contents may settle, gentle agitation during scooping is recommended.

See package insert for additional information.

ANADA # 200-033, Approved by FDA

KEEP OUT OF REACH OF CHILDREN

Store at or below 25°C (77°F)

Warning: Do not use in horses intended for human consumption.

Manufactured by

Neogen Corporation

Lexington, KY 40511 USA

Made in the USA

Item No. UP200

L3435-0915

Rev. 09/15

PRINCIPAL DISPLAY PANEL - 37.5 g Pouch

NDC: 59051-3010-1

UNIPRIM®
Powder for Horses

Caution: Federal (USA) law restricts this drug to use by or on the order of a licensed veterinarian.

NEOGENVet

Net Contents: 37.5 grams

FOR ANIMAL USE ONLY

Each gram contains: 67 mg Trimethoprim, 333 mg Sulfadiazine

Indications: For control of bacterial infections during treatment of acute strangles, respiratory tract infections, acute urogenital infections, wound infections and abscesses.

Recommended Dose: 3.75 g per 110 lbs (50 kg) body weight once daily in a small amount of palatable feed. Two level, loose-filled, 32cc scoops contain 37.5g, sufficient to treat 1100 lbs (500 kg) body weight. Since product contents may settle, gentle agitation during scooping is recommended.

See package insert for additional information.

ANADA # 200-033, Approved by FDA

KEEP OUT OF REACH OF CHILDREN

Store at or below 25°C (77°F)

Warning: Do not use in horses intended for human consumption.

Manufactured by

Neogen Corporation

Lexington, KY 40511 USA

Made in the USA

Item No. UP375

L3413-0115

Rev. 01/15

PRINCIPAL DISPLAY PANEL - 2000 g Pail

NDC: 59051-3010-6

UNIPRIM®
Powder for Horses

Caution: Federal (USA) law restricts this drug to use by or on the order of a licensed veterinarian.

NEOGENVet

Net Contents: 2000 grams

FOR ANIMAL USE ONLY

Each gram contains: 67 mg Trimethoprim, 333 mg Sulfadiazine

Indications: For control of bacterial infections during treatment of acute strangles, respiratory tract infections, acute urogenital infections, wound infections and abscesses.

Recommended Dose: 3.75 g per 110 lbs (50 kg) body weight once daily in a small amount of palatable feed. Two level, loose-filled, 32cc scoops contain 37.5g, sufficient to treat 1100 lbs (500 kg) body weight. Since product contents may settle, gentle agitation during scooping is recommended.

See package insert for additional information.

ANADA # 200-033, Approved by FDA

KEEP OUT OF REACH OF CHILDREN

Store at or below 25°C (77°F)

Warning: Do not use in horses intended for human consumption.

Manufactured by

Neogen Corporation

Lexington, KY 40511 USA

Made in the USA

Item No. UP2000

L3436-0915

Rev. 09/15

INGREDIENTS AND APPEARANCE

UNIPRIM 
trimethoprim and sulfadiazine powder

Product Information
Product Type	PRESCRIPTION ANIMAL DRUG	Item Code (Source)	NDC: 59051-3010
Route of Administration	ORAL

Active Ingredient/Active Moiety
Ingredient Name	Basis of Strength	Strength
Trimethoprim (UNII: AN164J8Y0X) (Trimethoprim - UNII:AN164J8Y0X)	Trimethoprim	67 mg  in 1 g
Sulfadiazine (UNII: 0N7609K889) (Sulfadiazine - UNII:0N7609K889)	Sulfadiazine	333 mg  in 1 g

Packaging
#	Item Code	Package Description	Marketing Start Date	Marketing End Date
1	NDC: 59051-3010-3	400 g in 1 JAR
2	NDC: 59051-3010-1	37.5 g in 1 PACKET
3	NDC: 59051-3010-4	200 g in 1 JAR
4	NDC: 59051-3010-6	2000 g in 1 PAIL

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANADA	ANADA200033	08/04/2010

Labeler - Neogen Corporation (042125879)

Establishment
Name	Address	ID/FEI	Business Operations
Neogen Corporation		042125879	manufacture, analysis, label

Establishment
Name	Address	ID/FEI	Business Operations
NANHAI BEISHA PHARMACEUTICAL CO., LTD.		527929800	api manufacture

Establishment
Name	Address	ID/FEI	Business Operations
Shandong Xinhua Pharmaceutical Co Limited First Plant		421252895	api manufacture