ADVERSE REACTIONS SECTION.


ADVERSE REACTIONS. Several cases of transient leukopenia have been reported in patients receiving silver sulfadiazine therapy.1,2,3 Leukopenia associated with silver sulfadiazine administration is primarily characterized by decreased neutrophil count. Maximal white blood cell depression occurs within two to four days of initiation of therapy. Rebound to normal leukocyte levels follows onset within two to three days. Recovery is not influenced by continuation of silver sulfadiazine therapy. An increased incidence has been seen in patients treated concurrently with cimetidine. Other infrequently occurring events include skin necrosis, erythema multiforme, skin discoloration, burning sensation, rashes, and interstitial nephritis. Reduction in bacterial growth after application of topical antibacterial agents has been reported to permit spontaneous healing of deep partial-thickness burns by preventing conversion of the partial thickness to full thickness by sepsis. However, reduction in bacterial colonization has caused delayed separation, in some cases necessitating escharotomy in order to prevent contracture.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.


Carcinogenesis, Mutagenesis, Impairment of Fertility. Long-term dermal toxicity studies of 24 months duration inrats and 18 months in mice with concentrations of silver sulfadiazine three to ten times the concentration in Thermazene(R) revealed no evidence of carcinogenicity.

CLINICAL PHARMACOLOGY SECTION.


CLINICAL PHARMACOLOGY. Silver sulfadiazine has broad antimicrobial activity. It is bactericidal for many gram-negative and gram-positive bacteria as well as being effective against yeast. Results from in vitro testing are listed below. Sufficient data have been obtained to demonstrate that silver sulfadiazine will inhibit bacteria that are resistant to other antimicrobial agents and that the compound is superior to sulfadiazine. Studies utilizing radioactive micronized silver sulfadiazine, electron microscopy, and biochemical techniques have revealed that the mechanism of action of silver sulfadiazine on bacteria differs from silver nitrate and sodium sulfadiazine. Silver sulfadiazine acts only on the cell membrane and cell wall to produce its bactericidal effect.Results of in Vitro Testing WithSilver Sulfadiazine Cream, USP 1% Concentrationof Silver Sulfadiazine Number of SensitiveStrains Total Number of Strains TestedGenus and Species50 ug/mL100 ug/mLPseudomonas aeruginosa130/130130/130Xanthomonas (Pseudomonas) Maltophilia7/77/7Enterobacter species48/5050/50Enterobacter cloacae24/2424/24Klebsiella species53/5454/54Escherichia coli63/6363/63Serratia species27/2828/28Proteus mirabilis53/5353/53Morganella morganii10/1010/10Providencia rettgeri2/22/2Proteus vulgaris2/22/2Providencia species1/11/1Citrobacter species10/1010/10Acinetobacter calcoaceticus10/11 11/11Stahylococcus aureus100/101101/101Staphylococcus epidermidis51/5151/51-Hemolytic Streptococcus4/44/4Enterococcus species52/5353/53Corynebacterium diphtheriae2/22/2Clostridium perfringens0/22/2Candida albicans43/5050/50Silver sulfadiazine is not carbonic anhydrase inhibitor and may be useful in situations where such agents are contraindicated.

CONTRAINDICATIONS SECTION.


CONTRAINDICATIONS. Thermazene(R) is contraindicated in patients who are hypersensitive to silver sulfadiazine or any of the other ingredients in the preparation. Because sulfonamide therapy is known to increase thepossibility of kernicterus, Thermazene(R) should not be used on pregnant women approaching or at term, on premature infants, or on newborn infants during the first months of life.

DESCRIPTION SECTION.


DESCRIPTION. Thermazene(R) is soft, white, water dispersible cream containing the antimicrobial agent silver sulfadiazine in micronized form for topical application. Each gram of silver sulfadiazine cream contains 10mg of micronized silver sulfadiazine. This active agent has the following structural formula:Silver sulfadiazine cream contains 1% w/w silver sulfadiazine. The vehicle in which the active ingredient is dispersed consists of water, stearyl alcohol, white petrolatum, polyoxyl 40 stearate, propylene glycol, isopropyl myristate, and sorbitan monooleate with 0.3% methylparaben as preservative.. Structural Formula.

DOSAGE & ADMINISTRATION SECTION.


DOSAGE AND ADMINISTRATION. Prompt institution of appropriate regimens for care of the burned patient is of prime importance and includes the control of shock and pain. The burn wounds are then cleansed and debrided, Thermazene(R) is then applied under sterile conditions. The burn areas should be covered with Thermazene(R) at all times. The cream should be applied once to twice daily to thickness of approximately one sixteenth of an inch. Whenever necessary, the cream should be reapplied to any areas from which it has been removed by patient activity. Administration may be accomplished in minimal time because dressings are not required. However, if individual patient requirements make dressings necessary, they may be used. Reapply immediately after hydrotherapy. Treatment with Thermazene(R) should be continued until satisfactory healing has occurred or until the burn site is ready for grafting. The drug should not be withdrawn from the therapeutic regimen while there remains the possibility of infection except if significant adverse reaction occurs.

GERIATRIC USE SECTION.


Geriatric Use. Of the total number of subjects in clinical studies of silver sulfadiazine cream, USP 1% seven percent were 65 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

HOW SUPPLIED SECTION.


HOW SUPPLIED. Thermazene(R) white to off-white cream NDC No. Size53097-101-20 20g tube 53097-101-25 25g tube 53097-101-50 50g tube53097-101-85 85g tube 53097-101-05 50g jar53097-101-40 400g jar53097-101-10 1000g jarStore at room temperature. 15-30C (56-86F).Manufactured for:ThePharmaNetwork, LLC180 Summit AvenueMontvale, NJ 07645Manufactured by:Crown Laboratories, Inc.Johnson City, TN 37604Product information: 1-800-272-7901(R)Registered Trademark ofCoviden AG or an affiliate P1852.01.

INDICATIONS & USAGE SECTION.


INDICATIONS AND USAGE. Thermazene(R) is topical antimicrobial drug indicated as an adjunct for the prevention and treatment of wound sepsis in patients with second and third degree burns.

NURSING MOTHERS SECTION.


Nursing Mothers. It is not known whether Thermazene(R) is excreted in human milk. However, sulfonamides are known to be excreted in human milk and all sulfonamides derivatives are known to increase the possibility of kernicterus. Because of the possibility for serious adverse reactions in nursing infants from sulfonamides, decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


PRINCIPAL DISPLAY PANEL 1000g Jar. NDC 53097-101-10 THERMAZENE(R) Silver Sulfadiazine Cream 1% Net Wt. 1000 For Topical Use Only Rx only. Product Label.

PEDIATRIC USE SECTION.


Pediatric Use. Safety and effectiveness in children have not beenestablished. (See CONTRAINDICATIONS).

PRECAUTIONS SECTION.


PRECAUTIONS. General. If hepatic and renal functions become impaired andelimination of the drug decreases accumulation may occur. Discontinuation of Thermazene(R) should be weighed against the therapeutic benefit being achieved. In considering the use of topical proteolytic enzymes inconjunction with Thermazene(R) the possibility should be noted that silver may inactivate such enzymes. Laboratory Tests. In the treatment of burn wounds involving extensive areas ofthe body, the serum sulfa concentrations may approach adult therapeutic levels (8 to 12mg %). Therefore, in these patients it would be advisable to monitor serum sulfa concentrations. Renal function should be carefully monitored and the urine should be checked for sulfa crystals. Absorption of the propylene glycol vehicle has been reportedto affect serum osmolality, which may affect the interpretation of laboratory tests.

PREGNANCY SECTION.


PREGNANCY:TERATOGENIC EFFECTS:. Pregnancy Category B. reproductive study has been performed in rabbits at doses up to three to ten times the concentration of silver sulfadiazine in Thermazene(R) and has revealed no evidence of harm to the fetus due to silver sulfadiazine. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly justified, especially in pregnant women approaching or at term. (See CONTRAINDICATIONS).

REFERENCES SECTION.


REFERENCES. Caffee F, Bingham H. Leukopenia and silver sulfadiazine. Trauma. 1982;22: 586-587.Jarret F, Ellerbe S, Demling R. Acute leukopenia during topical burn therapy with silver sulfadiazine. Amer Surg. 1978;135:818-819.Kiker RG, Carvajal HF, Micak RP, Larson DL. controlled study of the effects of silver sulfadiazine on white blood cell counts in burned children. Trauma. 1977; 17:835-836.. Caffee F, Bingham H. Leukopenia and silver sulfadiazine. Trauma. 1982;22: 586-587.. Jarret F, Ellerbe S, Demling R. Acute leukopenia during topical burn therapy with silver sulfadiazine. Amer Surg. 1978;135:818-819.. Kiker RG, Carvajal HF, Micak RP, Larson DL. controlled study of the effects of silver sulfadiazine on white blood cell counts in burned children. Trauma. 1977; 17:835-836.

SPL UNCLASSIFIED SECTION.


Ascend Title.

WARNINGS SECTION.


WARNINGS. Absorption of silver sulfadiazine varies depending upon thepercent of body surface area and the extent of the tissue damage. Although few have been reported, it is possible that any adverse reaction associated with sulfonamides may occur. Some of the reactions which have been associated with sulfonamides are as follows: blood dyscrasias, including agranulocytosis, aplastic anemia, thrombocytopenia, leukopenia, and hemolytic anemia; dermatologic and allergic reactions, including life-threatening cutaneous reactions [Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and exfoliative dermatitis]; gastrointestinal reactions, hepatitis and hepatocellular necrosis; CNS reactions; and toxic nephrosis. There is potential cross-sensitivity between silver sulfadiazine and other sulfonamides. If allergic reactions attributable to treatment with silver sulfadiazine occur, continuation of therapy must be weighed against the potential hazards of the particular allergic reaction. Fungal proliferation in and below the eschar may occur. However, the incidence of clinically reported fungal superinfection is low. The use of Thermazene(R) in some cases of glucose-6-phosphate dehydrogenase-deficient individuals may be hazardous, as hemolysis may occur.