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Silver Sulfadiazine (Topical)


VA CLASSIFICATION
Primary: DE101
Secondary: DE102

Commonly used brand name(s): Flamazine; SSD; SSD AF; Silvadene; Thermazene.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antibacterial (topical)—

antifungal (topical){10}
Note: Silver sulfadiazine is a broad-spectrum antibacterial agent having an antibacterial spectrum similar to that of mafenide. {01} {12}



Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Burn wound infections (prophylaxis and treatment)—Silver sulfadiazine is indicated [as a primary agent] {10} in the topical prophylaxis and treatment of burn wound infections caused by Acinetobacter calcoaceticus, Candida albicans (Monilia albicans) , Citrobacter species, Clostridium perfringens, Corynebacterium diphtheriae, Enterobacter species (including E. cloacae), enterococci, Escherichia coli , Klebsiella species, Mima-Herellea species, Morganella morganii (Proteus morganii) , P. mirabilis , P. vulgaris , Providencia rettgeri (Proteus rettgeri) , Pseudomonas aeruginosa , , Serratia species, Staphylococcus aureus , S. epidermidis Xanthomonas (Pseudomonas) maltophilia , and beta-hemolytic streptococci {10} in patients with second- and third-degree burns. {01} {09} {15}

[Skin infections, bacterial, minor (treatment)] or
[Ulcer, dermal (treatment)]—Silver sulfadiazine is used in the topical treatment of minor bacterial skin infections such as those involving skin grafts, incisions and other clean lesions, abrasions, minor cuts and wounds; and dermal ulcer such as leg ulcer. {09}

—Not all species or strains of a particular organism may be susceptible to silver sulfadiazine.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    357.13


Other characteristics
    Sulfonamides have certain chemical similarities to some goitrogens, diuretics (acetazolamide and thiazides), and oral antidiabetic agents {12}

Mechanism of action/Effect:

Bactericidal for many gram-positive and gram-negative organisms. Mechanism of action differs from that of silver nitrate or sodium sulfadiazine. Acts only on the cell membrane and cell wall. {01}


Other actions/effects:

Also active against yeasts and Candida albicans (M. albicans) . {01} {10}

Absorption:

Varies, depending on the percentage of body surface area to which silver sulfadiazine is applied and extent of tissue damage. {01}

Peak serum concentration:

Serum sulfadiazine concentrations may approach therapeutic concentrations (up to 8 to 12 mg per 100 mL) when used in burns over extensive areas of the body. {01}


Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to other sulfonamides, furosemide, thiazide diuretics, sulfonylureas, or carbonic anhydrase inhibitors may be sensitive to this medication also. {01} {03} {09} {12} {13} {14}

Carcinogenicity

Long-term dermal toxicity studies in rats (24 months) and mice (18 months), using 3 to 10% silver sulfadiazine, have shown no evidence of carcinogenicity. {01} {15}

Pregnancy/Reproduction

Pregnancy—
Adequate and well-controlled studies in humans have not been done. However, absorbed sulfonamides may displace bilirubin from protein-binding sites in the fetal plasma, thus increasing the possibility of kernicterus in the neonate. {10}

Studies in rabbits, treated with 3 to 10% silver sulfadiazine cream, have not shown that silver sulfadiazine causes adverse effects on the fetus. {01}

FDA Pregnancy Category B.

Breast-feeding

It is not known whether silver sulfadiazine, applied topically, is distributed into breast milk. {15} However, silver sulfadiazine may be absorbed systemically in variable amounts following topical application {12}. Caution is recommended in nursing women since systemically administered sulfonamides are distributed into breast milk and may cause kernicterus in nursing infants. {15} Also, sulfonamides may cause hemolytic anemia in glucose-6-phosphate dehydrogenase (G6PD)–deficient infants. {01} {03}

Pediatrics

Use is not recommended in premature or newborn infants up to 2 months of age since sulfonamides may cause kernicterus in these neonates. {01} {03}{12} Appropriate studies on the relationship of age to the effects of silver sulfadiazine have not been performed in the pediatric population. However, pediatrics-specific problems that would limit the usefulness of this medication in older infants and children are not expected.


Geriatrics


No information is available on the relationship of age to the effects of silver sulfadiazine in geriatric patients.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Cimetidine {01}    (concurrent use with cimetidine may increase the incidence of leukopenia )


» Collagenase {01} {05} or
» Papain {01} {04} or
» Sutilains {01} {06}    (concurrent use of proteolytic enzymes with silver sulfadiazine is not recommended since heavy metal salts may inactivate the enzymes)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
Blood dyscrasias    (sulfonamides may cause blood dyscrasias {01} {03})


Glucose-6-phosphate dehydrogenase (G6PD) deficiency    (sulfonamides may cause hemolytic anemia in G6PD-deficient patients {01} {03})


Hepatic function impairment    (sulfonamides are metabolized in the liver and may cause hepatitis; if hepatic function impairment occurs, discontinuation of therapy should be considered {01} {03})


Porphyria    (sulfonamides may precipitate an acute attack of porphyria {03})


Renal function impairment {01} {03}    (if renal function impairment with decreased elimination occurs, discontinuation of therapy should be considered)


Sensitivity to silver sulfadiazine

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Complete blood counts (CBCs)    (may be required prior to and weekly during treatment to detect blood dyscrasias in patients with extensive burns; therapy should be discontinued if a significant decrease in the count of any formed blood elements occurs {01} {03} {10})


Serum sulfadiazine concentrations    (may be required periodically during treatment in patients with extensive burns since serum sulfadiazine concentrations may approach adult therapeutic concentrations {01} {10})


Urinalyses    (may be required prior to and periodically during treatment to detect crystalluria and/or urinary calculi formation in patients on long-term or high-dose therapy and in patients with impaired renal function {01} {03})




Side/Adverse Effects

Note: Hyperosmolality, due to the propylene glycol–containing vehicle, has been reported very rarely in infants during therapy with silver sulfadiazine cream. {01} {10} {11}
If significant absorption occurs, side/adverse effects (e.g., Stevens-Johnson syndrome, Lyell's syndrome, blood dyscrasias, crystalluria) usually seen with systemic sulfonamides may occur with silver sulfadiazine therapy, although few have been reported. {03} {10}
If allergic reactions or hepatic or renal function impairment with decreased elimination occurs, discontinuation of therapy with silver sulfadiazine should be considered. {01}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence rare
    
Erythema multiforme{01} (blistering, peeling, loosening of skin; red skin lesions, often with a purple center)
    
fungal proliferation in and below the eschar{01} (intense itching of burn wounds)
    
increased sensitivity of skin to sunlight {03} {10} —especially in patients with burns on large areas
    
interstitial nephritis{01} (bloody or cloudy urine, greatly decreased frequency of urination or amount of urine)
    
leukopenia{01} (chills; cough; decreased neutrophil count; fever; painful or difficult urination; shortness of breath; sore throat; sores, ulcers, or white spots on lips or in mouth; swollen glands; unusual bleeding or bruising; unusual tiredness or weakness)—transient and may recover without discontinuation of treatment
    
skin necrosis{01} (blue-green to black skin discoloration ; pain, redness, or sloughing of skin)



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Burning feeling {01} {12} on treated area(s)

Incidence less frequent or rare
    
Brownish-gray skin discoloration {01} {07}
    
itching or skin rash {01}





Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Silver Sulfadiazine (Topical)

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to other sulfonamides, furosemide, thiazide diuretics, sulfonylureas, or carbonic anhydrase inhibitors

Pregnancy—Absorbed sulfonamides may increase the possibility of kernicterus in the neonate





Breast-feeding—May cause kernicterus in nursing infants; may cause hemolytic anemia in G6PD-deficient infants





Use in children—Not recommended in premature or newborn infants up to 2 months of age; may cause kernicterus

Other medications, especially cimetidine and proteolytic enzymes such as collagenase, papain, or sutilains

Proper use of this medication

To use
Before applying, cleansing affected area(s); removing necrotic or burned skin and other debris

Wearing a sterile glove to apply the medication; applying a thin layer (approximately 1.5 mm) to affected area(s); keeping affected area(s) covered with the medication at all times

Reapplying silver sulfadiazine that has been removed by patient activity or washed off by bathing, showering, or use of a whirlpool bath

After applying, covering treated area(s) with a dressing or leaving treated area(s) uncovered as desired
» Compliance with full course of therapy; continuing medication until burn has healed or is ready for skin grafting

» Proper dosing
Missed dose: Applying as soon as possible; not applying if almost time for next dose

» Proper storage

Precautions while using this medication
Regular visits to physician to check progress

Checking with physician if no improvement within a few days or weeks (for more serious burns or burns over more extensive areas)

May rarely stain skin brownish gray


Side/adverse effects
Signs of potential side effects, especially erythema multiforme, fungal proliferation in and below the eschar, increased sensitivity of skin to sunlight, interstitial nephritis, leukopenia, and skin necrosis


General Dosing Information
Before application, burn wounds should be cleansed and debrided following control of shock and pain. A sterile glove should be worn to apply the medication. A thin layer (approximately 1.5 mm) of silver sulfadiazine should then be applied to the affected area(s). The burn area(s) should be kept covered with silver sulfadiazine at all times. When necessary, silver sulfadiazine should be reapplied to any area(s) from which it has been removed by patient activity or washed off by bathing, showering, or use of a whirlpool bath. {01} {12}

Dressings, although not required, may be applied if necessary. {01}

Treatment with silver sulfadiazine should be continued until satisfactory healing has occurred or until the burn site is ready for skin grafting. Therapy should not be discontinued while the possibility of infection exists, unless significant toxicity occurs. {01}

Burn patients should be bathed daily, if feasible, to aid in debridement of the burned area(s). Whirlpool baths are particularly helpful, although burn patients may be bathed in bed or in a shower. Following this, silver sulfadiazine should be reapplied. {01}


Topical Dosage Forms

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

SILVER SULFADIAZINE CREAM USP

Usual adult and adolescent dose
Burn wound infections or
[Skin infections, bacterial, minor] or
[Ulcer, dermal]
Topical, to the affected area(s), one or two times a day, applied in a thin layer approximately 1.5 mm thick. {09} {10} {15}

Note: In some other countries, silver sulfadiazine is customarily applied less frequently (e.g., three times a week), in a 3- to 5-mm layer. However, USP medical experts prefer application one or two times a day in a 1.5-mm layer. {09} {10}



Usual pediatric dose
Burn wound infections or
[Skin infections, bacterial, minor] or
[Ulcer, dermal]
Premature and newborn infants up to 2 months of age—Use is not recommended, since sulfonamides may cause kernicterus in these neonates. {01} {03}

Infants and children 2 months of age and over—See Usual adult and adolescent dose. {01} {03} {10}


Strength(s) usually available
U.S.—


1% (Rx) [Silvadene (propylene glycol) (methylparaben 0.3%) ( white petrolatum){01}] [SSD (cetyl alcohol) (propylene glycol) (methylparaben 0.3%)] [SSD AF (propylene glycol ) (methylparaben 0.3%)] [Thermazene (propylene glycol) (methylparaben 0.3%)]{15}{16}

Canada—


1% (Rx) [Flamazine]

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), in a well-closed container, unless otherwise specified by manufacturer. Protect from freezing.

Auxiliary labeling:
   • For external use only.
   • May discolor skin.
   • Continue medicine for full time of treatment.

Additional information:
Silver sulfadiazine cream is available in a water-miscible base containing silver sulfadiazine in micronized form. {01}



Revised: 03/17/2000



References
  1. Product Information: Silvadene®, silver sulfadiazine. Monarch Pharmaceuticals, Bristol, TN. PI revised 3/99, reviewed 3/2000.
  1. Not in use
  1. Sulfonamides (Systemic) monograph, USP DI 1989.
  1. Panafil Ointment package insert (Rystan—US), PDR 1988: 1853-4.
  1. Santyl Ointment package insert (Knoll—US), PDR 1988: 1109-10.
  1. Travase Ointment package insert (Flint—US), PDR 1988: 963.
  1. J Am Acad Derm 1985 Jun; 12: 1112-4.
  1. Not in use
  1. Flamazine package insert (Smith & Nephew—Canada), CPS 1988: 335.
  1. Panel comments, 2/10/89.
  1. JAMA 1985 Mar 15; 253: 1606-9.
  1. Mafenide (Topical) monograph, USP DI 90, revision of 3/9/89.
  1. Flint SSD package insert (Flint—US), PDR 1988: 961-2.
  1. Thermazene package insert (Chesebrough-Ponds—US), Rev 7/86, Rec 7/88.
  1. Silvadene package insert (Marion Merrow Dow—US), PDR 1993: 1400.
  1. SSD and SSD AF 1% Cream package insert (Boots—US), PDR 1993: 721.
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