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  • CLASSES

    Topical Sulfonamides

    DEA CLASS

    Rx

    DESCRIPTION

    Topical sulfonamide antiinfective; wide spectrum of activity against Candida and gram-positive and gram-negative bacteria; used to prevent and treat serious burn and wound infections.

    COMMON BRAND NAMES

    Silvadene, SSD, SSD AF, Thermazene

    HOW SUPPLIED

    Silvadene/Silver/Silver Sulfadiazine/SSD/SSD AF/Thermazene Topical Cream: 1%

    DOSAGE & INDICATIONS

    For the prevention and treatment of burn wound infection due to susceptible organisms in patients with second- and third-degree burns.
    Topical dosage (1% cream)
    Adults, Adolescents and Children

    After cleansing and debridement, apply topically to a thickness of approximately 1.6 mm (1/16th of an inch) twice per day. Reapply the cream whenever necessary to any affected areas where drug removed by activity or hydrotherapy.

    Infants >= 2 months

    Apply topically to a thickness of about 1.6 mm (1/16th of an inch) twice per day.

    Neonates < 2 months

    Use not recommended; sulfonamides may cause kernicterus in neonates.

    MAXIMUM DOSAGE

    Adults

    2 applications/day; additional applications may be necessary if cream is removed by activity.

    Elderly

    2 applications/day; additional applications may be necessary if cream is removed by activity.

    Adolescents

    2 applications/day; additional applications may be necessary if cream is removed by activity.

    Children

    2 applications/day; additional applications may be necessary if cream is removed by activity.

    Infants

    >= 2 months: 2 applications/day; additional applications may be necessary if cream is removed by activity.

    Neonates

    < 2 months: Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Sulfonamides may cause hepatic impairment; use with caution in hepatic disease. Discontinuation of treatment may be needed if hepatic impairment occurs with treatment.

    Renal Impairment

    Sulfadiazine may accumulate with renal impairment. Accumulation will depend on the body surface area involved and the extent of tissue damage.

    ADMINISTRATION

    Topical Administration
    Cream/Ointment/Lotion Formulations

    Silver sulfadiazine is for external use only.
    Do not use if cream has darkened in color.
    Apply to cleansed, debrided, burned areas using a sterile-gloved hand. Apply to a thickness of approx. = 1.6 mm (1/16th of an inch).
    Dressings usually are not required, but may be used.
    Treatment is normally continued until the site is ready for grafting or until satisfactory healing occurs. Unless a significant adverse reaction occurs, do not stop treatment while the threat of infection remains.

    STORAGE

    Silvadene:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    SSD:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    SSD AF:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Thermazene:
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Sulfonamide hypersensitivity

    Silver sulfadiazine is contraindicated in patients with sulfonamide hypersensitivity or sensitivity to any of the components of the commercial product.

    Hepatic disease

    Silver sulfadiazine should be used with caution in patients with hepatic disease or impairment because sulfonamides can cause hepatitis. Discontinuation of therapy may be necessary if hepatic impairment occurs during treatment.

    Renal disease, renal impairment

    Silver sulfadiazine should be used with caution in patients with renal disease or renal impairment; if decreased elimination occurs, discontinuation of therapy may be necessary.

    Hematological disease, leukopenia, thrombocytopenia

    Silver sulfadiazine should be used with caution in patients with leukopenia, thrombocytopenia, or other hematological disease because sulfonamides can cause these and other blood dyscrasias.

    Intramuscular injections

    Intramuscular injections should be administered cautiously to patients receiving silver sulfadiazine. IM injections may cause bleeding, bruising, or hematomas due to platelet effects secondary to silver sulfadiazine therapy.

    G6PD deficiency

    Silver sulfadiazine should be used with caution in patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency because sulfonamides can cause hemolytic anemia in patients with G6PD deficiency.

    Porphyria

    Silver sulfadiazine should be used with caution in patients with porphyria because sulfonamides can precipitate porphyria.

    Children, infants, neonates

    Due to the potential for the development of kernicterus, silver sulfadiazine use is contraindicated in neonates or infants less than 2 months of age. Premature infants may be especially prone to the development of hyperbilirubinemia and/or kernicterus. Sulfonamides compete with bilirubin for binding to plasma albumin. In utero, the fetus can clear free bilirubin by the placental circulation; but after birth, this mechanism for removal of unbound bilirubin is no longer available. Unbound bilirubin can cross the blood-brain barrier, leading to kernicterus. Safe and effective use of silver sulfadiazine in children have not been established.

    Pregnancy

    Silver sulfadiazine is classified in FDA pregnancy category B. According to the manufacturer, it is contraindicated in near-term pregnancy because sulfonamides may promote kernicterus in the newborn by displacing bilirubin from plasma proteins. Sulfonamides can displace bilirubin from protein binding sites and theoretically precipitate kernicterus in newborns. While this adverse reaction has occurred when a sulfonamide was administered directly to the newborn, it has not been demonstrated in a newborn when exposed to the drug in utero. Since silver sulfadiazine is administered topically, it seems even less likely than systemically administered sulfonamides to invoke this adverse reaction. Nevertheless, sulfonamides should be used with caution during near term pregnancy because of the potential risk of causing kernicterus in newborns.

    Breast-feeding

    According to the manufacturer, because of the possibility for serious adverse reactions in nursing infants from sulfonamides, silver sulfadiazine should not be used during breast-feeding. It is not known whether it is excreted in human milk. However, sulfonamides are known to be excreted in human milk, and all sulfonamide derivatives are known to increase the possibility of kernicterus. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    ADVERSE REACTIONS

    Severe

    exfoliative dermatitis / Delayed / 1.0-10.0
    skin necrosis / Early / 1.0-10.0
    erythema multiforme / Delayed / 1.0-10.0
    Stevens-Johnson syndrome / Delayed / 0-1.0
    toxic epidermal necrolysis / Delayed / 0-1.0
    agranulocytosis / Delayed / 0-1.0
    hepatic necrosis / Delayed / 0-1.0
    hemolytic anemia / Delayed / 0-1.0
    aplastic anemia / Delayed / 0-1.0
    interstitial nephritis / Delayed / 0-1.0

    Moderate

    hepatitis / Delayed / 0-1.0
    thrombocytopenia / Delayed / 0-1.0
    superinfection / Delayed / 0-1.0
    leukopenia / Delayed / Incidence not known
    hemolysis / Early / Incidence not known

    Mild

    pruritus / Rapid / 1.0-10.0
    rash / Early / 1.0-10.0
    skin discoloration / Delayed / 1.0-10.0
    photosensitivity / Delayed / Incidence not known

    DRUG INTERACTIONS

    Collagenase: (Severe) Silver sulfadiazine should not be used with the proteolytic enzymes collagenase, papain, or sutilains because heavy metals such as silver inactivate these enzymes.
    Sulfacetamide: (Major) Topical and ophthalmic sulfonamides are incompatible with preparations containing silver. Sulfacetamide sodium should not be applied to the same sites as products containing silver salts, including preparations such as silver nitrate, silver sulfadiazine, or mild silver protein.
    Sulfacetamide; Sulfur: (Major) Topical and ophthalmic sulfonamides are incompatible with preparations containing silver. Sulfacetamide sodium should not be applied to the same sites as products containing silver salts, including preparations such as silver nitrate, silver sulfadiazine, or mild silver protein.

    PREGNANCY AND LACTATION

    Pregnancy

    Silver sulfadiazine is classified in FDA pregnancy category B. According to the manufacturer, it is contraindicated in near-term pregnancy because sulfonamides may promote kernicterus in the newborn by displacing bilirubin from plasma proteins. Sulfonamides can displace bilirubin from protein binding sites and theoretically precipitate kernicterus in newborns. While this adverse reaction has occurred when a sulfonamide was administered directly to the newborn, it has not been demonstrated in a newborn when exposed to the drug in utero. Since silver sulfadiazine is administered topically, it seems even less likely than systemically administered sulfonamides to invoke this adverse reaction. Nevertheless, sulfonamides should be used with caution during near term pregnancy because of the potential risk of causing kernicterus in newborns.

    According to the manufacturer, because of the possibility for serious adverse reactions in nursing infants from sulfonamides, silver sulfadiazine should not be used during breast-feeding. It is not known whether it is excreted in human milk. However, sulfonamides are known to be excreted in human milk, and all sulfonamide derivatives are known to increase the possibility of kernicterus. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Mechanism of Action: The exact mechanism by which silver sulfadiazine exerts its antiinfective activity is unknown. Both free silver and the sulfonamide moiety may exert activity, but the drug does not inhibit folic acid synthesis as other sulfonamides do. Silver sulfadiazine disrupts bacteria by damaging the cell membrane and the cell wall rather than by inhibiting folic acid synthesis.Silver sulfadiazine has a wide spectrum of bactericidal activity against both gram-positive and gram-negative organisms. Organisms that are susceptible to topical silver sulfadiazine include Staphylococcus aureus, S. epidermidis, beta-hemolytic streptococci, Klebsiella, Escherichia coli, Enterobacter (including E. cloacae), Citrobacter, Proteus, Pseudomonas, Morganella morganii, Providencia, Serratia, and Candida albicans.

    PHARMACOKINETICS

    Silver sulfadiazine is administered topically. Once absorbed, sulfadiazine is distributed into most body tissues, and it appears to freely cross cell membranes. Sulfadiazine is metabolized by the liver to an N[23464]-acetyl derivative, glucuronide, and other metabolites, which are then excreted in the urine along with unchanged drug. Within 72 hours, 60—80% of the absorbed drug can be collected in the urine either as metabolites or unchanged drug.

    Topical Route

    Silver sulfadiazine is not absorbed through intact skin. In contact with body fluids, it is converted by sulfhydryl groups and proteins to free sulfadiazine, which can be systemically absorbed, especially when applied to second- or third-degree burns. Systemic concentrations of sulfadiazine are detectable in some patients. Roughly 10% of sulfadiazine can be absorbed, while only 1% of free silver is absorbed. In the treatment of patients with extensive body surface area involvement, serum sulfa concentrations may reach therapeutic levels (8—12 mcg/ml).