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SULFONAMIDES

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Sulfonamide drugs are derivatives of paraaminobenzenesulfonic acid. These agents were the first effective chemotherapeutic agents employed systemically for the prevention and cure of bacterial infections in humans (Gilman et al, 1985).
    B) Refer to "SULFASALAZINE" management for further information.
    C) Refer to "TRIMETHOPRIM-SULFAMETHOXAZOLE" management for further information.

Specific Substances

    A) SULFACYTINE
    1) N-sulfanilyl-1-ethylcytosine
    2) CI-636
    3) CAS 17784-12-2
    SULFADIAZINE
    1) 4-Amino-N-2-pyrimidinylbenzene-sulfonamide
    2) Solfadiazina
    3) Solfapirimidina
    4) Sulfadiazine
    5) Sulfadiazinum
    6) Sulfapyrimidine
    7) Sulphadiaz
    8) CAS 68-35-9
    9) SulfADIAZINE
    SULFAGUANIDINE
    1) 1-Sulphanilylguanidine
    2) N'-Amidinosulphanilamide
    3) Solfaguanidina
    4) Sulfaguanidina
    5) Sulfaguanidinum
    6) Sulfamidinum
    7) Sulginum
    8) Sulphaguanidine
    9) Molecular Formula: C7-H10-N4-O2-S
    10) CAS 57-67-0 (anhydrous sulfaguanidine)
    11) CAS 6190-55-2 (sulfaguanidine monohydrate)
    SULFAMETHIZOLE
    1) 4-Amino-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzene-sulfonamide
    2) Sulfamethylthiadiazole
    3) Sulphamethizole
    4) CAS 144-82-1
    SULFAMETHOXAZOLE
    1) 4-Amino-N-(5-methyl-3-isoxazolyl)benzenesulfonamide
    2) Sulfamethoxazolum
    3) Sulfamethoxizole
    4) Sulfamethylisoxazole
    5) Sulfisomezole
    6) Sulphamethoxazole
    7) CAS 723-46-6
    SULFAPYRIDINE
    1) 4-Amino-N-alpha-pyridinyl-benzenesulfonamide
    2) M&B 693
    3) Sulphapyrid
    4) Sulphapyridine
    5) CAS 144-83-2
    SULFISOXAZOLE
    1) 4-Amino-N-(3,4-dimethyl-5-isoxazolyl)benzenesulfonamide
    2) Sulfafurazole
    3) Sulfafurazolum
    4) Sulphafuraz
    5) Sulphafurazole
    6) CAS 127-69-5
    7) SulfiSOXAZOLE
    SULFACETAMIDE SYNONYMS
    1) Acetosulfaminum
    2) N(1)-acetylsulfanilamide
    3) N-sulfanilylacetamide
    4) p-aminobenzenesulfonoacetamide
    5) Sulphacetam
    6) Sulphacetamide
    7) CAS 144-80-9
    SULFANILAMIDE
    1) 1162 F
    2) p-Aminobenzenesulfonamide
    3) p-Anilinesulfonamide
    4) p-Sulfamidoaniline
    5) Solfammide
    6) Streptocidum
    7) Sulfaminum
    8) Sulfanilamidum
    9) Sulfonamide
    10) Sulphanilam
    11) Sulphanilamide
    12) Sulphonamide
    13) CAS 63-74-1
    MAFENIDE
    1) alpha-Amino-p-toluenesulfonamide
    2) 4-homosulfanilamide
    3) Maphenide
    4) CAS 138-39-6
    SILVER SULFADIAZINE
    1) N(1)-(pyrimidin-2-yl)sulphanilamide (silver salt)
    2) Silver sulphadiazine
    3) CAS 22199-08-2

Available Forms Sources

    A) FORMS
    1) MAFENIDE ACETATE: 85 mg/g cream and a 5% topical solution (reconstituted from 50 grams of mafenide acetate powder and mixed with a 1000 mL of sterile water or 0.9% sodium chloride)
    2) SILVER SULFADIAZINE: 10 mg/g cream
    3) SODIUM SULFACETAMIDE: 10%, 15%, and 30% ophthalmic solutions
    4) SULFACYTINE: 250 mg tablets
    5) SULFADIAZINE: 500 mg tablets
    6) SULFAMETHIZOLE: 500 mg tablets
    7) SULFAMETHOXAZOLE: 500 mg and 1 g tablets, 500 mg/5 mL oral suspension
    8) SULFANILAMIDE: 15% vaginal cream, 1.05 gram vaginal suppository
    9) SULFAPYRIDINE: 500 mg tablets 10% ophthalmic ointment
    10) SULFISOXAZOLE: 500 mg tablets, 500 mg/5 mL syrup and pediatric suspension, 400 mg/5 mL injection, 1 g/5mL long-acting emulsion, 4% ophthalmic solution and ointment
    11) TRIPLE SULFA VAGINAL PREPARATIONS: Vaginal tablet and vaginal cream
    12) TRISULFAPYRIMIDINES: Tablets and suspension

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) WITH THERAPEUTIC USE
    1) Adverse reactions to sulfonamides can involve nearly every organ system; many effects appear to be hypersensitivity reactions, and are dose related. Although there is a difference as to the frequency of toxic effects between the short-acting and long-acting, there is also considerable overlap. DERMATOLOGIC: Various dermatological reactions, including rash, pruritus, erythema nodosum, and quite severe and often fatal erythema multiforme of the Stevens-Johnson type have been reported. Lyell's Syndromes are usually associated with the use of a long-acting sulfonamides. GASTROINTESTINAL: Nausea and vomiting are common. HYPERSENSITIVITY REACTION: Transient myopia, conjunctivitis, hepatic injury, and keratitis may occur in association with a hypersensitivity reaction. NEUROLOGIC: Headache, depression, and hallucinations have been reported with therapy.
    B) WITH POISONING/EXPOSURE
    1) Data limited. Effects may be an extension of adverse events reported with sulfonamides. Methemoglbinemia has been reported after overdose.
    2) Refer to "SULFASALAZINE" management for further information.
    3) Refer to "TRIMETHOPRIM-SULFAMETHOXAZOLE" management for further information.
    0.2.4) HEENT
    A) Transient myopia, conjunctivitis, and keratitis may occur in association with hypersensitivity reaction.
    0.2.7) NEUROLOGIC
    A) Headache, depression, and hallucinations have been reported with therapeutic use of sulfonamides. Tremor occurred in one patient following a fixed-dose combination of trimethoprim/sulfamethoxazole.
    0.2.8) GASTROINTESTINAL
    A) Nausea and vomiting are likely to occur.
    0.2.9) HEPATIC
    A) Hypersensitivity reactions to sulfonamide antibiotics may produce hepatic injury.
    0.2.10) GENITOURINARY
    A) Adverse effects increase in renal failure without dose reduction.
    0.2.12) FLUID-ELECTROLYTE
    A) Hyperkalemia has been reported following therapeutic use of trimethoprim/sulfamethoxazole.
    0.2.13) HEMATOLOGIC
    A) Hematologic effects are uncommon, but several have been reported. These include acute hemolytic anemia, agranulocytosis, thrombocytopenia, aplastic anemia, and methemoglobinemia.
    0.2.14) DERMATOLOGIC
    A) Various dermatological reactions, including rash, pruritus, erythema nodosum, and quite severe and often fatal erythema multiforme of the Stevens-Johnson type have been reported.
    1) The Stevens-Johnson and Lyell's Syndromes are usually associated with the use of a long-acting sulfonamide, although other sulfonamides have been reported to cause these reactions.
    2) This serious reaction has been reported even with the use of ophthalmic preparations. Rashes and fever appear ten days after initiation of therapy and reoccur immediately upon additional courses of the therapy.
    0.2.17) METABOLISM
    A) Administration to premature infants leads to kernicterus. Longer acting sulfonamides may displace other drugs and metabolites from their protein binding sights. Hypoglycemia may occur in patients with chronic renal failure.
    0.2.20) REPRODUCTIVE
    A) Mafenide acetate, sulfADIAZINE, and sodium sulfacetamide are classified as FDA pregnancy category C. Silver sulfADIAZINE is classified as FDA pregnancy category B. At the time of this review, there are no adequate and well-controlled studies of mafenide acetate, sodium sulfacetamide, sulfADIAZINE, or silver sulfADIAZINE use in pregnant women. In animal studies, there was evidence of increased cleft palate and bony abnormalities with high oral doses of sulfonamides. Sulfonamides compete with bilirubin for binding to plasma albumin, which may result in kernicterus in the newborn.
    B) It is not known whether mafenide acetate, sodium sulfacetamide, or silver sulfADIAZINE are excreted in breast milk. However, other sulfonamides, including sulfADIAZINE, are excreted in breast milk. SulfADIAZINE is contraindicated as it may increase the risk of kernicterus.
    C) NOTE: For information on other sulfonamides, please refer to individual documents.

Laboratory Monitoring

    A) The hepatotoxicity and nephrotoxicity of these pharmaceuticals may alter lab tests of liver function and kidney function. These systems as well as the hematopoietic should be monitored.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) Treatment is symptomatic and supportive. There is no specific antidote for sulfonamide intoxication.
    B) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
    C) HYPERSENSITIVITY REACTION
    1) The drug should be immediately discontinued and the patient observed for the possibility of anaphylactic shock. In this situation the normal treatment for anaphylaxis is carried out with the establishment of an open airway, epinephrine, and diphenhydramine.
    D) HYPOTENSION: Infuse 10 to 20 mL/kg isotonic fluid. If hypotension persists, administer dopamine (5 to 20 mcg/kg/min) or norepinephrine (ADULT: begin infusion at 0.5 to 1 mcg/min; CHILD: begin infusion at 0.1 mcg/kg/min); titrate to desired response.
    E) DIURESIS: If kidney function is normal, consider administration of D5/0.45 NaCl with a diuretic such as furosemide 1 mg/kg to a maximum of 40 mg/dose to obtain a urine flow of 3 to 6 mL/kg/hr.
    F) For anuria or agranulocytosis, dialysis and/or isolation should be considered. Obtain a baseline CBC, hepatic and renal function test.
    G) CHRONIC THERAPY: Discontinue the use of the drug; provide symptomatic and supportive care.
    H) SEIZURES: Administer a benzodiazepine; DIAZEPAM (ADULT: 5 to 10 mg IV initially; repeat every 5 to 20 minutes as needed. CHILD: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed) or LORAZEPAM (ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist. CHILD: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue).
    1) Consider phenobarbital or propofol if seizures recur after diazepam 30 mg (adults) or 10 mg (children greater than 5 years).
    2) Monitor for hypotension, dysrhythmias, respiratory depression, and need for endotracheal intubation. Evaluate for hypoglycemia, electrolyte disturbances, and hypoxia.
    I) METHEMOGLOBINEMIA: Determine the methemoglobin concentration and evaluate the patient for clinical effects of methemoglobinemia (ie, dyspnea, headache, fatigue, CNS depression, tachycardia, metabolic acidosis). Treat patients with symptomatic methemoglobinemia with methylene blue (this usually occurs at methemoglobin concentrations above 20% to 30%, but may occur at lower methemoglobin concentrations in patients with anemia, or underlying pulmonary or cardiovascular disorders). Administer oxygen while preparing for methylene blue therapy.
    J) METHYLENE BLUE: INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules and 10 mg/1 mL (1% solution) vials. Additional doses may sometimes be required. Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection. NEONATES: DOSE: 0.3 to 1 mg/kg.
    K) Concomitant use of methylene blue with serotonergic drugs, including serotonin reuptake inhibitors (SRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), norepinephrine-dopamine reuptake inhibitors (NDRIs), triptans, and ergot alkaloids may increase the risk of potentially fatal serotonin syndrome.

Range Of Toxicity

    A) Since many of the adverse effects appear to be hypersensitivity reactions, there is no specific toxic dose. The incidence of the adverse effects appears to increase with increased sulfonamide dosage.

Clinical Effects

Summary Of Exposure

    A) WITH THERAPEUTIC USE
    1) Adverse reactions to sulfonamides can involve nearly every organ system; many effects appear to be hypersensitivity reactions, and are dose related. Although there is a difference as to the frequency of toxic effects between the short-acting and long-acting, there is also considerable overlap. DERMATOLOGIC: Various dermatological reactions, including rash, pruritus, erythema nodosum, and quite severe and often fatal erythema multiforme of the Stevens-Johnson type have been reported. Lyell's Syndromes are usually associated with the use of a long-acting sulfonamides. GASTROINTESTINAL: Nausea and vomiting are common. HYPERSENSITIVITY REACTION: Transient myopia, conjunctivitis, hepatic injury, and keratitis may occur in association with a hypersensitivity reaction. NEUROLOGIC: Headache, depression, and hallucinations have been reported with therapy.
    B) WITH POISONING/EXPOSURE
    1) Data limited. Effects may be an extension of adverse events reported with sulfonamides. Methemoglbinemia has been reported after overdose.
    2) Refer to "SULFASALAZINE" management for further information.
    3) Refer to "TRIMETHOPRIM-SULFAMETHOXAZOLE" management for further information.

Vital Signs

    3.3.3) TEMPERATURE
    A) FEVER may be associated with sensitivity reactions related to sulfonamide therapy (Weinstein et al, 1960).

Heent

    3.4.1) SUMMARY
    A) Transient myopia, conjunctivitis, and keratitis may occur in association with hypersensitivity reaction.
    3.4.3) EYES
    A) TRANSIENT MYOPIA has been reported as a result of a hypersensitivity reaction (Bovino & Marcus, 1982; Grant, 1986).
    B) CONJUNCTIVITIS and keratitis associated with skin reactions have been noted (Grant, 1986).
    C) OPTIC NEURITIS - Disturbances of the optic nerve and retina are uncommon but have been associated with use of sulfonamides (Grant, 1986).
    D) DEPTH PERCEPTION - Temporary impairment of depth perception has been associated with the use of sulfonamide antibiotics (Grant, 1986).

Neurologic

    3.7.1) SUMMARY
    A) Headache, depression, and hallucinations have been reported with therapeutic use of sulfonamides. Tremor occurred in one patient following a fixed-dose combination of trimethoprim/sulfamethoxazole.
    3.7.2) CLINICAL EFFECTS
    A) HALLUCINATIONS
    1) SUBJECTIVE COMPLAINTS - Headache, depression, and hallucinations have been experienced by patients receiving therapeutic doses of sulfonamides (Frisch, 1973).
    B) TREMOR
    1) CASE REPORT - Bilateral, high frequency, postural tremors were reported in an AIDS patient following therapeutic use of trimethoprim/sulfamethoxazole (Van Gerpen, 1997). Despite the patient's underlying disease, symptoms resolved within 3 days of drug cessation leading the author to conclude that the symptoms were drug induced.

Gastrointestinal

    3.8.1) SUMMARY
    A) Nausea and vomiting are likely to occur.
    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) Nausea and vomiting are frequently reported adverse effects of therapeutic doses of sulfonamides (Frisch, 1973).
    B) DIARRHEA
    1) Diarrhea is an uncommon adverse effect of sulfonamide therapy (Frisch, 1973).
    C) INFLAMMATORY DISEASE OF MUCOUS MEMBRANE
    1) Glossitis and stomatitis have been reported with therapeutic doses of sulfonamides and is thought to be an immunologic response (Frisch, 1973).

Hepatic

    3.9.1) SUMMARY
    A) Hypersensitivity reactions to sulfonamide antibiotics may produce hepatic injury.
    3.9.2) CLINICAL EFFECTS
    A) TOXIC HEPATITIS
    1) Hepatocellular, cholestatic, or mixed types of hepatitis have been reported with therapeutic doses of sulfonamides (Berg & Daniel, 1987).
    2) Hepatic injury from sulfonamide antibiotics is rare and may be a hypersensitivity reaction (Berg & Daniel, 1987; Stevenson et al, 1978).

Genitourinary

    3.10.1) SUMMARY
    A) Adverse effects increase in renal failure without dose reduction.
    3.10.2) CLINICAL EFFECTS
    A) RENAL FAILURE SYNDROME
    1) CASE REPORT - Oliguria is reported in a 3-year-old following sulfADIAZINE 450 mg/24 hours for 48 hours (Craft et al, 1977).
    2) CASE REPORT - Renal insufficiency and obstruction of the Foley catheter was reported in a 70-year-old man with urinary retention who ingested 8 grams of sulfamethoxazole and 1.6 grams of trimethoprim (Goff, 1989).
    B) BLOOD IN URINE
    1) CASE REPORT - SulfADIAZINE crystals in the urine and hematuria is reported in a 3-year-old who received sulfADIAZINE 450 mg/kg/24 hours for 48 hours (Craft et al, 1977).
    C) CRYSTALLURIA
    1) Crystalluria is not as much of a problem as it once was due to the introduction of more soluble sulfonamides (Ball, 1986).
    D) CRUSH SYNDROME
    1) CASE REPORT - Acute tubular necrosis (confirmed by biopsy), bone marrow and liver involvement, and scrotal skin infarction were seen in a 78-year-old man within 48 hours of beginning a regimen of co-trimoxazole (dose not given) and flucloxacillin (500 mg every 8 hours) (Rudra et al, 1989).

Hematologic

    3.13.1) SUMMARY
    A) Hematologic effects are uncommon, but several have been reported. These include acute hemolytic anemia, agranulocytosis, thrombocytopenia, aplastic anemia, and methemoglobinemia.
    3.13.2) CLINICAL EFFECTS
    A) DISORDER OF HEMATOPOIETIC STRUCTURE
    1) Hematologic effects are uncommon, but may be manifested as acute hemolytic anemia (Heimpel & Raghavachar, 1987), agranulocytosis (Frisch, 1973), thrombocytopenia (Frisch, 1973; Rudra et al, 1989) (occasionally with hemorrhage), and aplastic anemia (Frisch, 1973) Weinstein et al, 1960).
    B) HEMOLYTIC ANEMIA
    1) Hemolytic anemia in glucose-6-phosphate deficient patients is the most common hematological effect (Heimpel & Raghavachar, 1987). Hemolytic anemia is reported after several days of sulfasoxazole (2 g daily) in patients with hemoglobin Hasharon (Adams et al, 1977).
    C) LEUKOPENIA
    1) Granulocytopenia is not related to the dose or blood level of the drug and usually develops only after 10 days of therapy.
    2) CASE REPORT - A neonate was born with a profound, reversible neutropenia after his mother took sulphasalazine and prednisolone throughout the pregnancy (Levi et al, 1988).
    D) METHEMOGLOBINEMIA
    1) CASE REPORTS
    a) SULFAMETHOXAZOLE -
    1) Methemoglobinemia has been reported in a patient who ingested 30 tablets of Azo-Gantanol(R) (sulfamethoxazole 0.5 g/phenazopyridine 100 mg) (Fraser, 1969).
    2) Methemoglobinemia (methemoglobin level of 18.3%) associated with cyanosis of 24 hours' duration was reported in a 22-year-old female 8 days after receiving sulfamethoxazole and trimethoprim therapy for urinary tract infection (Damergis et al, 1983).

Dermatologic

    3.14.1) SUMMARY
    A) Various dermatological reactions, including rash, pruritus, erythema nodosum, and quite severe and often fatal erythema multiforme of the Stevens-Johnson type have been reported.
    1) The Stevens-Johnson and Lyell's Syndromes are usually associated with the use of a long-acting sulfonamide, although other sulfonamides have been reported to cause these reactions.
    2) This serious reaction has been reported even with the use of ophthalmic preparations. Rashes and fever appear ten days after initiation of therapy and reoccur immediately upon additional courses of the therapy.
    3.14.2) CLINICAL EFFECTS
    A) DERMATITIS
    1) Typical skin reactions associated with sulfonamide therapy include urticarial, erythematous, maculopapular, morbilliform, pruritus, and photosensitivity reactions (Rietschel, 1997; (Frisch, 1973) Weinstein et al, 1960).
    2) Exfoliative manifestations are rare (Frisch, 1973; Rallison et al, 1961).
    3) CASE REPORT - Generalized erythema of the skin and purple-black discoloration of the scrotum were seen in a 78-year-old man within 48 hours of starting a regimen of co-trimoxazole (no dose given) and flucloxacillin (500 mg every 8 hours) (Rudra et al, 1989).
    B) STEVENS-JOHNSON SYNDROME
    1) The Stevens Johnson and Lyell's syndromes are severe and sometimes fatal and usually associated with the use of the long-acting sulfonamides although other sulfonamides have been reported to cause these reactions (Carroll et al, 1966).
    2) A case of Stevens-Johnson syndrome has been reported with the use of the ophthalmic preparation of sulfacetamide (Gottschalk & Stone, 1976; Rubin, 1977).
    3) Rashes and fever appear after 10 days after initiation of therapy and reoccur immediately upon additional courses of therapy.

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) TRANSFUSION REACTION DUE TO SERUM PROTEIN REACTION
    1) CASE REPORT - Han et al (1969) reported a 38-year-old black male who developed a serum-sickness-like syndrome 2 weeks after starting sulfapyridine (2 g/day).
    a) The syndrome included hemolytic anemia, plasmacytosis, lymphocytosis, and multiclonal gammaglobulinopathy with appearance of cryoglobulin and elevation of immunoglobulin.
    B) DRUG-INDUCED LUPUS ERYTHEMATOSUS
    1) CASE REPORT - Lupus erythematosus was associated with the therapeutic use of sulfamethoxypyridazine 500 mg daily in a 55-year-old female (Rallison et al, 1961).

Reproductive

    3.20.1) SUMMARY
    A) Mafenide acetate, sulfADIAZINE, and sodium sulfacetamide are classified as FDA pregnancy category C. Silver sulfADIAZINE is classified as FDA pregnancy category B. At the time of this review, there are no adequate and well-controlled studies of mafenide acetate, sodium sulfacetamide, sulfADIAZINE, or silver sulfADIAZINE use in pregnant women. In animal studies, there was evidence of increased cleft palate and bony abnormalities with high oral doses of sulfonamides. Sulfonamides compete with bilirubin for binding to plasma albumin, which may result in kernicterus in the newborn.
    B) It is not known whether mafenide acetate, sodium sulfacetamide, or silver sulfADIAZINE are excreted in breast milk. However, other sulfonamides, including sulfADIAZINE, are excreted in breast milk. SulfADIAZINE is contraindicated as it may increase the risk of kernicterus.
    C) NOTE: For information on other sulfonamides, please refer to individual documents.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) SULFADIAZINE
    a) At the time of this review, no data were available to assess the teratogenic potential of sulfADIAZINE (Prod Info sulfadiazine oral tablet, 2008).
    B) ANIMAL STUDIES
    1) RATS AND MICE: In pregnant rats and mice, a significant increase in the incidence of cleft palate and other bony abnormalities in offspring was reported when certain sulfonamides of the short-, intermediate-, and long-acting types were administered at high oral doses of 7 to 25 times the human therapeutic dose, respectively (Prod Info sulfadiazine oral tablet, 2008).
    2) MAFENIDE ACETATE
    a) RATS: When rats were given up to 600 mg/kg/day of mafenide acetate during gestation, no adverse effects were seen in the offspring (Prod Info SULFAMYLON(R) topical solution, 2008).
    3) SILVER SULFADIAZINE
    a) RABBITS: When rabbits were given up to 3 to 10 times the concentration of silver sulfADIAZINE in silver sulfADIAZINE cream, no adverse effects were seen in the offspring (Prod Info SSD(R), SSD AF(R) topical cream, 2008).
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of exposure to sulfonamides, including MAFENIDE ACETATE, SILVER SULFADIAZINE, SODIUM SULFACETAMIDE, and SULFADIAZINE, during pregnancy in humans (Prod Info SULFAMYLON(R) topical cream, 2007; Prod Info SULFAMYLON(R) topical solution, 2008; Prod Info SSD(R), SSD AF(R) topical cream, 2008; Prod Info KLARON(R) topical lotion, 2006; Prod Info PLEXION(R), PLEXION TS(R), PLEXION SCT(R) cleanser, cleansing cloths, topical suspension, 2007; Prod Info sulfadiazine oral tablet, 2008).
    B) PREGNANCY CATEGORY
    1) The manufacturers have classified MAFENIDE ACETATE, SODIUM SULFACETAMIDE, and SULFADIAZINE as FDA pregnancy category C (Prod Info SULFAMYLON(R) topical cream, 2007; Prod Info SULFAMYLON(R) topical solution, 2008; Prod Info KLARON(R) topical lotion, 2006; Prod Info PLEXION(R), PLEXION TS(R), PLEXION SCT(R) cleanser, cleansing cloths, topical suspension, 2007; Prod Info sulfadiazine oral tablet, 2008).
    2) The manufacturer has classified SILVER SULFADIAZINE as FDA pregnancy category B (Prod Info SSD(R), SSD AF(R) topical cream, 2008).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of exposure to sulfonamides, including MAFENIDE ACETATE, SILVER SULFADIAZINE, and SODIUM SULFACETAMIDE, during lactation in humans (Prod Info SULFAMYLON(R) topical cream, 2007; Prod Info SULFAMYLON(R) topical solution, 2008; Prod Info SSD(R), SSD AF(R) topical cream, 2008; Prod Info KLARON(R) topical lotion, 2006; Prod Info PLEXION(R), PLEXION TS(R), PLEXION SCT(R) cleanser, cleansing cloths, topical suspension, 2007).
    B) KERNICTERUS
    1) Although no adverse effects have been observed with sulfonamides, these agents can compete with bilirubin for binding to plasma albumin, and possibly result in kernicterus in the newborn (Hensleigh & Kauffman, 1977; Heinonen et al, 1977).
    2) Some sulfonamides, including sulfADIAZINE, are excreted in breast milk. Sulfadiazine use in nursing mothers is contraindicated due to the potential for kernicterus (Prod Info sulfadiazine oral tablet, 2008).
    C) SULFADIAZINE
    1) Sulfonamides are excreted in breast milk. Use while nursing is not recommended as it may cause kernicterus (Prod Info sulfadiazine oral tablet, 2008). Particularly avoid breastfeeding in infants that are glucose-6-phosphate dehydrogenase deficient, premature, or less than 1-month old. Monitor nursing infants for side effects including jaundice, bloody diarrhea and hemolysis (Anon, 2002).
    3.20.5) FERTILITY
    A) LACK OF INFORMATION
    1) There are no long-term animal studies that evaluate the effects of sulfonamides on fertility (Prod Info SULFAMYLON(R) topical cream, 2007; Prod Info SULFAMYLON(R) topical solution, 2008; Prod Info SSD(R), SSD AF(R) topical cream, 2008; Prod Info KLARON(R) topical lotion, 2006; Prod Info PLEXION(R), PLEXION TS(R), PLEXION SCT(R) cleanser, cleansing cloths, topical suspension, 2007).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) The hepatotoxicity and nephrotoxicity of these pharmaceuticals may alter lab tests of liver function and kidney function. These systems as well as the hematopoietic should be monitored.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) The hepatotoxicity and nephrotoxicity associated with these pharmaceuticals may alter lab tests of liver function and kidney function including alkaline phosphatase, bilirubin, transaminase, cephalin flocculation, BUN, creatinine, urine protein, etc.
    2) Monitor liver function and kidney function in long term treatment.
    B) HEMATOLOGIC
    1) Monitor the hematopoietic system in long term treatment, even at normal doses.
    2) Monitor methemoglobin levels in cyanotic patients.

Methods

    A) CHROMATOGRAPHY
    1) A method of quantification of sulfanilamide and sulfiSOXAZOLE by high performance thin layer chromatography was described by Sherma & Duncan (1986).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) The hepatotoxicity and nephrotoxicity of these pharmaceuticals may alter lab tests of liver function and kidney function. These systems as well as the hematopoietic should be monitored.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatment is symptomatic and supportive. For ANURIA or AGRANULOCYTOSIS, dialysis and/or isolation should be considered.
    B) MONITORING OF PATIENT
    1) Obtain a baseline CBC, electrolytes including glucose level and hepatic enzymes and renal function tests. Monitor methemoglobin levels in symptomatic or cyanotic patients.
    C) ACUTE ALLERGIC REACTION
    1) The drug should be immediately discontinued and the patient observed for the possibility of anaphylactic shock. In this situation the normal treatment for anaphylaxis is carried out with the establishment of an open airway, epinephrine and diphenhydramine.
    D) ANAPHYLAXIS
    1) SUMMARY
    a) Mild to moderate allergic reactions may be treated with antihistamines with or without inhaled beta adrenergic agonists, corticosteroids or epinephrine. Treatment of severe anaphylaxis also includes oxygen supplementation, aggressive airway management, epinephrine, ECG monitoring, and IV fluids.
    2) BRONCHOSPASM
    a) ALBUTEROL
    1) ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007). CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 mg/kg (up to 10 mg) every 1 to 4 hours as needed, or 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    3) CORTICOSTEROIDS
    a) Consider systemic corticosteroids in patients with significant bronchospasm.
    b) PREDNISONE: ADULT: 40 to 80 milligrams/day. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 to 2 divided doses divided twice daily (National Heart,Lung,and Blood Institute, 2007).
    4) MILD CASES
    a) DIPHENHYDRAMINE
    1) SUMMARY: Oral diphenhydramine, as well as other H1 antihistamines can be used as indicated (Lieberman et al, 2010).
    2) ADULT: 50 milligrams orally, or 10 to 50 mg intravenously at a rate not to exceed 25 mg/min or may be given by deep intramuscular injection. A total of 100 mg may be administered if needed. Maximum daily dosage is 400 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    3) CHILD: 5 mg/kg/24 hours or 150 mg/m(2)/24 hours. Divided into 4 doses, administered intravenously at a rate not exceeding 25 mg/min or by deep intramuscular injection. Maximum daily dosage is 300 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    5) MODERATE CASES
    a) EPINEPHRINE: INJECTABLE SOLUTION: It should be administered early in patients by IM injection. Using a 1:1000 (1 mg/mL) solution of epinephrine. Initial Dose: 0.01 mg/kg intramuscularly with a maximum dose of 0.5 mg in adults and 0.3 mg in children. The dose may be repeated every 5 to 15 minutes, if no clinical improvement. Most patients respond to 1 or 2 doses (Nowak & Macias, 2014).
    6) SEVERE CASES
    a) EPINEPHRINE
    1) INTRAVENOUS BOLUS: ADULT: 1 mg intravenously as a 1:10,000 (0.1 mg/mL) solution; CHILD: 0.01 mL/kg intravenously to a maximum single dose of 1 mg given as a 1:10,000 (0.1 mg/mL) solution. It can be repeated every 3 to 5 minutes as needed. The dose can also be given by the intraosseous route if IV access cannot be established (Lieberman et al, 2015). ALTERNATIVE ROUTE: ENDOTRACHEAL ADMINISTRATION: If IV/IO access is unavailable. DOSE: ADULT: Administer 2 to 2.5 mg of 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube. CHILD: DOSE: 0.1 mg/kg to a maximum of 2.5 mg administered as a 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube (Lieberman et al, 2015).
    2) INTRAVENOUS INFUSION: Intravenous administration may be considered in patients poorly responsive to IM or SubQ epinephrine. An epinephrine infusion may be prepared by adding 1 mg (1 mL of 1:1000 (1 mg/mL) solution) to 250 mL D5W, yielding a concentration of 4 mcg/mL, and infuse this solution IV at a rate of 1 mcg/min to 10 mcg/min (maximum rate). CHILD: A dosage of 0.01 mg/kg (0.1 mL/kg of a 1:10,000 (0.1 mg/mL) solution up to 10 mcg/min (maximum dose 0.3 mg) is recommended for children (Lieberman et al, 2010). Careful titration of a continuous infusion of IV epinephrine, based on the severity of the reaction, along with a crystalloid infusion can be considered in the treatment of anaphylactic shock. It appears to be a reasonable alternative to IV boluses, if the patient is not in cardiac arrest (Vanden Hoek,TL,et al).
    7) AIRWAY MANAGEMENT
    a) OXYGEN: 5 to 10 liters/minute via high flow mask.
    b) INTUBATION: Perform early if any stridor or signs of airway obstruction.
    c) CRICOTHYROTOMY: Use if unable to intubate with complete airway obstruction (Vanden Hoek,TL,et al).
    d) BRONCHODILATORS are recommended for mild to severe bronchospasm.
    e) ALBUTEROL: ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007).
    f) ALBUTEROL: CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    8) MONITORING
    a) CARDIAC MONITOR: All complicated cases.
    b) IV ACCESS: Routine in all complicated cases.
    9) HYPOTENSION
    a) If hypotensive give 500 to 2000 milliliters crystalloid initially (20 milliliters/kilogram in children) and titrate to desired effect (stabilization of vital signs, mentation, urine output); adults may require up to 6 to 10 L/24 hours. Central venous or pulmonary artery pressure monitoring is recommended in patients with persistent hypotension.
    1) VASOPRESSORS: Should be used in refractory cases unresponsive to repeated doses of epinephrine and after vigorous intravenous crystalloid rehydration (Lieberman et al, 2010).
    2) DOPAMINE: Initial Dose: 2 to 20 micrograms/kilogram/minute intravenously; titrate to maintain systolic blood pressure greater than 90 mm Hg (Lieberman et al, 2010).
    10) H1 and H2 ANTIHISTAMINES
    a) SUMMARY: Antihistamines are second-line therapy and are used as supportive therapy and should not be used in place of epinephrine (Lieberman et al, 2010).
    1) DIPHENHYDRAMINE: ADULT: 25 to 50 milligrams via a slow intravenous infusion or IM. PEDIATRIC: 1 milligram/kilogram via slow intravenous infusion or IM up to 50 mg in children (Lieberman et al, 2010).
    b) RANITIDINE: ADULT: 1 mg/kg parenterally; CHILD: 12.5 to 50 mg parenterally. If the intravenous route is used, ranitidine should be infused over 10 to 15 minutes or diluted in 5% dextrose to a volume of 20 mL and injected over 5 minutes (Lieberman et al, 2010).
    c) Oral diphenhydramine, as well as other H1 antihistamines, can also be used as indicated (Lieberman et al, 2010).
    11) DYSRHYTHMIAS
    a) Dysrhythmias and cardiac dysfunction may occur primarily or iatrogenically as a result of pharmacologic treatment (epinephrine) (Vanden Hoek,TL,et al). Monitor and correct serum electrolytes, oxygenation and tissue perfusion. Treat with antiarrhythmic agents as indicated.
    12) OTHER THERAPIES
    a) There have been a few reports of patients with anaphylaxis, with or without cardiac arrest, that have responded to vasopressin therapy that did not respond to standard therapy. Although there are no randomized controlled trials, other alternative vasoactive therapies (ie, vasopressin, norepinephrine, methoxamine, and metaraminol) may be considered in patients in cardiac arrest secondary to anaphylaxis that do not respond to epinephrine (Vanden Hoek,TL,et al).
    E) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    F) DIURESIS
    1) If kidney function is normal, administer 0.45% sodium chloride in D5W and a diuretic such as furosemide 1 mg/kg to a maximum of 40 mg/dose to obtain a urine flow of 3 to 6 mL/kg/hour to increase renal excretion.
    G) METHEMOGLOBINEMIA
    1) SUMMARY
    a) Determine the methemoglobin concentration and evaluate the patient for clinical effects of methemoglobinemia (ie, dyspnea, headache, fatigue, CNS depression, tachycardia, metabolic acidosis). Treat patients with symptomatic methemoglobinemia with methylene blue (this usually occurs at methemoglobin concentrations above 20% to 30%, but may occur at lower methemoglobin concentrations in patients with anemia, or underlying pulmonary or cardiovascular disorders). Administer oxygen while preparing for methylene blue therapy.
    2) METHYLENE BLUE
    a) INITIAL DOSE/ADULT OR CHILD: 1 mg/kg IV over 5 to 30 minutes; a repeat dose of up to 1 mg/kg may be given 1 hour after the first dose if methemoglobin levels remain greater than 30% or if signs and symptoms persist. NOTE: Methylene blue is available as follows: 50 mg/10 mL (5 mg/mL or 0.5% solution) single-dose ampules (Prod Info PROVAYBLUE(TM) intravenous injection, 2016) and 10 mg/1 mL (1% solution) vials (Prod Info methylene blue 1% intravenous injection, 2011). REPEAT DOSES: Additional doses may be required, especially for substances with prolonged absorption, slow elimination, or those that form metabolites that produce methemoglobin. NOTE: Large doses of methylene blue may cause methemoglobinemia or hemolysis (Howland, 2006). Improvement is usually noted shortly after administration if diagnosis is correct. Consider other diagnoses or treatment options if no improvement has been observed after several doses. If intravenous access cannot be established, methylene blue may also be given by intraosseous infusion. Methylene blue should not be given by subcutaneous or intrathecal injection (Prod Info methylene blue 1% intravenous injection, 2011; Herman et al, 1999). NEONATES: DOSE: 0.3 to 1 mg/kg (Hjelt et al, 1995).
    b) CONTRAINDICATIONS: G-6-PD deficiency (methylene blue may cause hemolysis), known hypersensitivity to methylene blue, methemoglobin reductase deficiency (Shepherd & Keyes, 2004)
    c) FAILURE: Failure of methylene blue therapy suggests: inadequate dose of methylene blue, inadequate decontamination, NADPH dependent methemoglobin reductase deficiency, hemoglobin M disease, sulfhemoglobinemia, or G-6-PD deficiency. Methylene blue is reduced by methemoglobin reductase and nicotinamide adenosine dinucleotide phosphate (NADPH) to leukomethylene blue. This in turn reduces methemoglobin. Red blood cells of patients with G-6-PD deficiency do not produce enough NADPH to convert methylene blue to leukomethylene blue (do Nascimento et al, 2008).
    d) DRUG INTERACTION: Concomitant use of methylene blue with serotonergic drugs, including serotonin reuptake inhibitors (SRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), norepinephrine-dopamine reuptake inhibitors (NDRIs), triptans, and ergot alkaloids may increase the risk of potentially fatal serotonin syndrome (U.S. Food and Drug Administration, 2011; Stanford et al, 2010; Prod Info methylene blue 1% IV injection, 2011).
    3) TOLUIDINE BLUE OR TOLONIUM CHLORIDE (GERMANY)
    a) DOSE: 2 to 4 mg/kg intravenously over 5 minutes. Dose may be repeated in 30 minutes (Nemec, 2011; Lindenmann et al, 2006; Kiese et al, 1972).
    b) SIDE EFFECTS: Hypotension with rapid intravenous administration. Vomiting, diarrhea, excessive sweating, hypotension, dysrhythmias, hemolysis, agranulocytosis and acute renal insufficiency after overdose (Dunipace et al, 1992; Hix & Wilson, 1987; Winek et al, 1969; Teunis et al, 1970; Marquez & Todd, 1959).
    c) CONTRAINDICATIONS: G-6-PD deficiency; may cause hemolysis.
    H) CHRONIC POISONING
    1) Discontinue use of the drug. Symptomatic and supportive treatment should be followed until the patient is asymptomatic.
    I) ACETYLCYSTEINE
    1) Intravenous N-acetylcysteine 24 g over 3 days was reported to be effective in treating hepatitis cause by sulfasalazine in a 37-year-old woman (Gabay et al, 1993).
    J) SEIZURE
    1) Seizures were reported in one patient following sufasalazine 50 g and paraceteamol 50 g (Dunn, 1998).
    2) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    3) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    4) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    5) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    6) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    7) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

Enhanced Elimination

    A) HEMODIALYSIS
    1) SULFISOXAZOLE
    a) Hemodialysis and peritoneal dialysis will remove sulfiSOXAZOLE from the blood (USPDI, 1988).

Abstracts

Case Reports

    A) ADULT
    1) SULFAMETHOXAZOLE/TRIMETHOPRIM - An iatrogenic overdose of IV trimethoprim/sulfamethoxazole (20 mg/kg/dose of trimethoprim) every 6 hours for 11 doses resulted in agitation, disorientation, and psychosis over 2 days, and a tonic-clonic seizure after 7 doses in a 35-year-old.
    a) The white blood cell count and neutrophils reached a nadir of 600 and 300, respectively, 5 days after discontinuation (Personal Communication, 1988).
    2) SULFAMETHOXAZOLE/TRIMETHOPRIM - Ingestion of an overdose of 20 tablets (8 grams sulfamethoxazole/1.6 grams trimethoprim) resulted in an elevated serum creatinine within 48 hours (2.9 mg/dL), and obstruction of the Foley catheter with urine sediment in a 70-year-old man.
    a) He was being treated for urinary retention secondary to CHF. Lower abdominal pain was also present. Renal function improved by the fourth day (Goff, 1989).
    3) SULFAMETHOXAZOLE/PHENAZOPYRIDINE - A 23-year-old male developed mild occipital headache, dizziness, and cyanosis (methemoglobinemia) following a suicidal ingestion of 30 tablets of Azo Gantanol(R) (Fraser, 1969).
    B) PEDIATRIC
    1) CASE REPORT
    a) MULTI-ORGAN TOXICITY - A 13-year-old previously healthy male receiving trimethoprim/sulfamethoxazole for a sinus infection developed a cytotoxic reaction which included simultaneous renal, hepatic, thyroid, hematologic, and cutaneous toxicity (Pickert et al, 1994).
    1) The authors concluded that the toxicity occurred due to the inability to detoxify reactive metabolic intermediates resulting from biotransformation of the parent drug. This may have allowed the transformation of the parent compound to cytotoxic metabolites, such as hydroxylamines.

Range Of Toxicity

Summary

    A) Since many of the adverse effects appear to be hypersensitivity reactions, there is no specific toxic dose. The incidence of the adverse effects appears to increase with increased sulfonamide dosage.

Therapeutic Dose

    7.2.1) ADULT
    A) SPECIFIC SUBSTANCE
    1) MAFENIDE
    a) TOPICAL SOLUTION: For a 5% topical solution add 50 g of mafenide acetate powder (supplied in a sterile packet) to be mixed in a 1000 mL of sterile water or 0.9% sodium chloride. To be used as a topical solution ONLY; discard an open container after 48 hours (Prod Info SULFAMYLON(R) topical solution, 2008).
    2) SULFADIAZINE
    a) ORAL: Initial Dose: 2 to 4 g. Maintenance Therapy: 2 to 4 g, divided into 3 to 6 doses, every 24 hours (Prod Info sulfadiazine oral tablet, 2008).
    3) SULFACETAMIDE
    a) TOPICAL: Apply foam to affected area 1 to 2 times daily; massage the foam into the affected area (Prod Info ROSULA(R) topical aerosol, foam, 2009).
    7.2.2) PEDIATRIC
    A) SPECIFIC SUBSTANCE
    1) SULFADIAZINE
    a) OVER 2 MONTHS OF AGE
    1) LOADING DOSE: 75 mg/kg orally (Prod Info sulfadiazine oral tablet, 2008).
    2) MAINTENANCE DOSE: 150 mg/kg/day or 4 g/m(2)/day in 4 to 6 divided doses (maximum daily dose: 6 g per 24 hours) (Prod Info sulfadiazine oral tablet, 2008).
    b) RHEUMATIC FEVER PROPHYLAXIS
    1) CHILDREN LESS THAN 30 KG: 500 mg every 24 hours (Prod Info sulfadiazine oral tablet, 2008).
    2) CHILDREN GREATER THAN 30 KG: 1 g every 24 hours (Prod Info sulfadiazine oral tablet, 2008).

Maximum Tolerated Exposure

    A) SPECIFIC SUBSTANCE
    1) MAFENIDE ACETATE
    a) ANIMAL DATA - Single oral doses of 2000 mg/kg of mafenide acetate as a 5% solution in rats did not cause mortality or symptoms of toxicity (Prod Info Sulfamylon(R), mafenide acetate, 1998).
    2) SULFAMETHOXAZOLE/TRIMETHOPRIM
    a) An iatrogenic overdose of intravenous trimethoprim/sulfamethoxazole (20 milligrams/kilogram/dose of trimethoprim) every 6 hours for 11 doses resulted in: agitation, disorientation, and psychosis over 2 days, and a tonic-clonic seizure after 7 doses in a 35-year-old woman with Pneumocystis carinii pneumonia (Personal Communication, 1988).
    b) Ingestion of 8 grams of sulfamethoxazole and 1.6 grams of trimethoprim resulted in renal insufficiency in an elderly man (Goff, 1989).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Synthetic modification of the parent compound, sulfanilamide (p-amino benzenesulfonamide), has resulted in many compounds of varying pharmacologic activity.
    B) This class of drugs has low water-solubility and forms soluble salts. They are partially acetylated in the body. Some longer acting compounds undergo glucuronide conjugation.
    C) Sulfonamides are bacteriostatic in normal doses and bacteriocidal in extremely high concentrations. Evidence indicates that they act as antimetabolites of PABA, interfering with its use. They inhibit folic acid synthesis.

Toxicologic Mechanism

    A) The metabolites are believed to be responsible for many toxic reactions, especially hypersensitivity. One study compared the acetylation phenotype of 21 patients with known hypersensitivity reactions to that of race-matched controls. Nineteen (90%) of the patients were slow acetylators; a significantly greater number than was seen in the control group (55%) (Rieder et al, 1991).
    1) Lymphocytes from patients with known history of hypersensitivity reactions became significantly more toxic than lymphocytes from controls when they were exposed to hydroxylamine, a reactive intermediate of sulfamethoxazole (Rieder et al, 1989).

Physicochemical

Physical Characteristics

    A) SILVER SULFADIAZINE: white powder (JEF Reynolds , 1988)
    B) SULFACETAMIDE: odorless, acid-saline tasting, white or yellow-white crystalline powder (JEF Reynolds , 1988)
    C) SULFADIAZINE: odorless, tasteless, white, pink-white, or yellow-white powder (JEF Reynolds , 1988)
    D) SULFAMETHIZOLE: odorless, bitter tasting, colorless, white, or creamy-white powder (JEF Reynolds , 1988)
    E) SULFAMETHOXAZOLE: practically odorless, white or off-white crystalline powder (USPDI, 1988)
    F) SULFANILAMIDE: odorless, bitter taste followed by sweet aftertaste, white crystalline powder (JEF Reynolds , 1988)
    G) SULFAPYRIDINE: odorless, slightly bitter tasting, white or yellow-white powder (JEF Reynolds , 1988)
    H) SULFISOXAZOLE: odorless, white or yellow-white crystalline powder (USPDI, 1988)

Molecular Weight

    A) SILVER SULFADIAZINE: 357.1 (JEF Reynolds , 1988)
    B) SULFACETAMIDE: 214.2 (JEF Reynolds , 1988)
    C) SULFACYTINE: 294.33 (USPDI, 1988)
    D) SULFADIAZINE: 250.3 (JEF Reynolds , 1988)
    E) SULFAMETHIZOLE: 270.3 (JEF Reynolds , 1988)
    F) SULFAMETHOXAZOLE: 253.28 (USPDI, 1988)
    G) SULFANILAMIDE: 172.2 (JEF Reynolds , 1988)
    H) SULFAPYRIDINE: 249.3 (JEF Reynolds , 1988)
    I) SULFISOXAZOLE: 267.30 (USPDI, 1988)

Animal Toxicology

Clinical Effects

    11.1.3) CANINE/DOG
    A) POLYARTHRITIS - Some large breed dogs, especially Dobermann pinschers, may develop a non-septic polyarthritis 1 to 3 weeks after initiation of sulfonamide-trimethoprim therapy (Cribb, 1989; Giger et al, 1985).
    1) Fever is usually present. This reaction has also been reported in a Pekingese (Little & Carmichael, 1990).
    B) HEPATOTOXICOSIS - Elevated liver enzymes, icterus, and vomiting were seen in a 7-month-old Schnauzer who received 30 mg/kg every 12 hours for 12 weeks (Rowland et al, 1992).
    11.1.5) EQUINE/HORSE
    A) There have been occasional reports (5) sent to the Suspected Adverse Reaction Scheme for Veterinary Medicines, the Veterinary Medicines Directorate, that intravenously given long acting sulfonamides caused apnea, collapse, and cardiac arrest in horses (Gray, 1989).

References

General Bibliography

    1) AMA Department of DrugsAMA Department of Drugs: AMA Evaluations Subscription, American Medical Association, Chicago, IL, 1992.
    2) Adams JG, Heller P, & Abramson RK: Sulfonamide-induced hemolytic anemia and hemoglobin hasharon. Arch Intern Med 1977; 137:1449-1451.
    3) Alaspaa AO, Kuisma MJ, Hoppu K, et al: Out-of-hospital administration of activated charcoal by emergency medical services. Ann Emerg Med 2005; 45:207-12.
    4) Anon: Breastfeeding and Maternal Medication. World Health Organization, Geneva, Switzerland, 2002.
    5) Arem R, Garber AJ, & Field JB: Sulfonamide-induced hypoglycemia in chronic renal failure. Arch Intern Med 1983; 143:827-829.
    6) Ball P: Toxicity of sulphonamide-diaminopyrimidine combinations: implications for future use. J Antimicrob Chemother 1986; 17:694-696.
    7) Berg PA & Daniel PT: Co-trimoxazole-induced hepatic injury - an analysis of cases with hypersensitivity-like reactions. Infection 1987; 15(Suppl 5):S259-S264.
    8) Bovino JA & Marcus DF: The mechanism of transient myopia induced by sulfonamide therapy. Am J Ophthamol 1982; 94:99-102.
    9) Brophy GM, Bell R, Claassen J, et al: Guidelines for the evaluation and management of status epilepticus. Neurocrit Care 2012; 17(1):3-23.
    10) Carroll OM, Bryan PA, & Robinson RJ: Stevens-Johnson syndrome associated with long-acting sulfonamides. JAMA 1966; 195:691-693.
    11) Chamberlain JM, Altieri MA, & Futterman C: A prospective, randomized study comparing intramuscular midazolam with intravenous diazepam for the treatment of seizures in children. Ped Emerg Care 1997; 13:92-94.
    12) Chin RF , Neville BG , Peckham C , et al: Treatment of community-onset, childhood convulsive status epilepticus: a prospective, population-based study. Lancet Neurol 2008; 7(8):696-703.
    13) Choonara IA & Rane A: Therapeutic drug monitoring of anticonvulsants state of the art. Clin Pharmacokinet 1990; 18:318-328.
    14) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    15) Craft AW, Brocklebank JT, & Jackson RH: Acute renal failure and hypoglycaemia due to sulphadiazine poisoning. Postgrad Med J 1977; 53:103-104.
    16) Cribb AE: J Am Vet Med Assoc 1989; 195:1612.
    17) Dagnone D, Matsui D, & Rieder MJ: Assessment of the palatability of vehicles for activated charcoal in pediatric volunteers. Pediatr Emerg Care 2002; 18:19-21.
    18) Damergis JA, Stoker JM, & Abadie JL: Methemoglobinemia after sulfamethoxazole and trimethorpim therapy. JAMA 1983; 249:590-591.
    19) Dunipace AJ, Beaven R, Noblitt T, et al: Mutagenic potential of toluidine blue evaluated in the Ames test. Mutat Res 1992; 279(4):255-259.
    20) Dunn RJ: Massive sulfasalazine and paracetamol ingestion causing acidosis, hyperglycemia, coagulopathy, and methemoglobinemia. Clin Tox 1998; 36:239-242.
    21) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    22) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    23) Frankel MC, Leslie BR, & Sax FL: Trimethoprim-sulfamethoxazole-related hypoglycemia in a patient with renal failure. State J Med 1984; 84:30-31.
    24) Fraser DG: Suicide attempt with azogantanol resulting in methemoglobinemia. Milit Med 1969; 134:679-681.
    25) Frisch JM: Clinical experience with adverse reactions to trimethoprim-sulfamethoxazole. J Infect Dis 1973; 128(Suppl):S607-S611.
    26) Gabay C, De Bandt M, & Palazzo E: Sulphasalazine-related life-threatening side effects: is N-acetylcysteine of therapeutic value?. Clin Exp Rheumatol 1993; 11:417-420.
    27) Giger U, Werner LL, & Millichamp NJ: J Am Vet Med Assoc 1985; 186:479.
    28) Gilman AG, Goodman LS, & Rall TW: The Pharmacologic Basis of Therapeutics, 7th ed, MacMillan Publishing Company, New York, NY, 1985.
    29) Goff D: Renal failure induced by co-trimoxazole. Hosp Ther 1989; 14:61-68.
    30) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    31) Gottschalk HR & Stone OJ: Stevens-Johnson syndrome from ophthalmic sulfonamide. Arch Dermatol 1976; 112:513.
    32) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    33) Grant WM: Toxicology of the Eye, 3rd ed, Charles C Thomas, Springfield, IL, 1986.
    34) Gray A: Adverse reaction to potentiated sulphonamides in horses (letter). Vet Rec 1989; 125:138.
    35) Guenther Skokan E, Junkins EP, & Corneli HM: Taste test: children rate flavoring agents used with activated charcoal. Arch Pediatr Adolesc Med 2001; 155:683-686.
    36) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    37) Hegenbarth MA & American Academy of Pediatrics Committee on Drugs: Preparing for pediatric emergencies: drugs to consider. Pediatrics 2008; 121(2):433-443.
    38) Heimpel H & Raghavachar A: Hematological side effects of co-trimoxazole. Infection 1987; 15(Suppl 5):S248-S252.
    39) Heinonen OP, Slone D, & Shapiro SHeinonen OP, Slone D, & Shapiro S: Birth Defects and Drugs in Pregnancy, Publishing Sciences Group, Inc., Littleton, MA, 1977.
    40) Hekster CA & Vree TB: Clinical pharmacokinetics of sulphonamides and their N(4)-acetyl derivatives. Antibiotics Chemother 1982; 31:22-118.
    41) Hensleigh PA & Kauffman RE: Maternal absorption and placental transfer of sulfasalazine. Am J Obstet Gynecol 1977; 127:443-444.
    42) Herman MI, Chyka PA, & Butlse AY: Methylene blue by intraosseous infusion for methemoglobinemia. Ann Emerg Med 1999; 33:111-113.
    43) Hix WR & Wilson WR: Toluidine blue staining of the esophagus: a useful adjunct in the panendoscopic evaluation of patients with squamous cell carcinoma of the head and neck. Arch Otolaryngol Head Neck Surg 1987; 113(8):864-865.
    44) Hjelt K, Lund JT, Scherling B, et al: Methaemoglobinaemia among neonates in a neonatal intensive care unit. Acta Paediatr 1995; 84(4):365-370.
    45) Howland MA: Antidotes in Depth. In: Goldfrank LR, Flomenbaum N, Hoffman RS, et al, eds. Goldfrank's Toxicologic Emergencies. 8th ed., 8th ed. McGraw-Hill, New York, NY, 2006, pp 826-828.
    46) Hvidberg EF & Dam M: Clinical pharmacokinetics of anticonvulsants. Clin Pharmacokinet 1976; 1:161.
    47) JEF Reynolds : Martindale: The Extra Pharmacopeia. The Pharmaceutical Press. London, England (Internet Version). Edition expires 1988; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    48) Kaplan SA & Weinfeld RE: Pharmacokinetic profile of sulfisoxazole following intravenous, intramuscular, and oral administration to man. J Pharm Sci 1972; 61:773-778.
    49) Kiese M , Lorcher W , Weger N , et al: Comparative studies on the effects of toluidine blue and methylene blue on the reduction of ferrihaemoglobin in man and dog. Eur J Clin Pharmacol 1972; 4(2):115-118.
    50) Kleinman ME, Chameides L, Schexnayder SM, et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Part 14: pediatric advanced life support. Circulation 2010; 122(18 Suppl.3):S876-S908.
    51) Lee AJ & Maddix DS: Trimethoprim/sulfamethoxazole-induced hypoglycemia in a patient with acute renal failure. Ann Pharmacother 1997; 31:727-732.
    52) Levi S, Liberman M, & Levi AJ: Reversible congenital neutropenia associated with maternal sulphasalazine therapy. Eur J Pediatr 1988; 48:174-175.
    53) Lieberman P, Nicklas R, Randolph C, et al: Anaphylaxis-a practice parameter update 2015. Ann Allergy Asthma Immunol 2015; 115(5):341-384.
    54) Lieberman P, Nicklas RA, Oppenheimer J, et al: The diagnosis and management of anaphylaxis practice parameter: 2010 update. J Allergy Clin Immunol 2010; 126(3):477-480.
    55) Lindenmann J, Matzi V, Kaufmann P, et al: Hyperbaric oxygenation in the treatment of life-threatening isobutyl nitrite-induced methemoglobinemia--a case report. Inhal Toxicol 2006; 18(13):1047-1049.
    56) Little CJL & Carmichael S: Trimethoprim-sulphonamide hypersensitivity in dog. Vet Rec 1990; 127:459-460.
    57) Loddenkemper T & Goodkin HP: Treatment of Pediatric Status Epilepticus. Curr Treat Options Neurol 2011; Epub:Epub.
    58) Manno EM: New management strategies in the treatment of status epilepticus. Mayo Clin Proc 2003; 78(4):508-518.
    59) Marinella MA: Trimethoprim/sulfamethoxazole associated with hyperkalemia. WJM 1997; 167:356-358.
    60) Marquez A & Todd M: Acute hemolytic anemia and agranulocytosis following intravenous administration of toluidine blue. Am Pract 1959; 10:1548-1550.
    61) Martin G & Finberg: Propylene glycol: a potentially toxic vehicle in liquid dosage form. J Pediatr 1970; 77:877-878.
    62) Mermel LA, Doro JM, & Kabadi UM: Acute psychosis in a patient receiving trimethoprim-sulfamethoxazole intravenously. J Clin Psychiatry 1986; 47:269-270.
    63) National Heart,Lung,and Blood Institute: Expert panel report 3: guidelines for the diagnosis and management of asthma. National Heart,Lung,and Blood Institute. Bethesda, MD. 2007. Available from URL: http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf.
    64) Nelson E & O'Reilly I: Kinetics of sulfamethylthiadiazole acetylation and excretion in humans. J Pharm Sci 1961; 50:417-420.
    65) Nemec K: Antidotes in acute poisoning. Eur J Hosp Pharm Sci Pract 2011; 17(4):53-55.
    66) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    67) Nowak RM & Macias CG : Anaphylaxis on the other front line: perspectives from the emergency department. Am J Med 2014; 127(1 Suppl):S34-S44.
    68) Ohnhaus EE & Spring P: Elimination kinetics of sulfadiazine in patients with normal and impaired renal function. J Pharmacokinet Biopharm 1975; 3:171-179.
    69) Peberdy MA , Callaway CW , Neumar RW , et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care science. Part 9: post–cardiac arrest care. Circulation 2010; 122(18 Suppl 3):S768-S786.
    70) Personal Communication: Personal Communication: Andrew Sopchak, Pharm.D. Drug Information Service, Burroughs Wellcome, 1988.
    71) Pickert CB, Belsha CW, & Kearns GL: Multi-organ disease secondary to sulfonamide toxicity. Pediatrics 1994; 94:237-239.
    72) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    73) Product Information: GANTRISIN(R) pediatric oral suspension, sulfisoxazole pediatric oral suspension. Roche Laboratories, Nutley, NJ, 1997.
    74) Product Information: KLARON(R) topical lotion, sodium sulfacetamide topical lotion. Dermik Laboratories, Bridgewater, NJ, 2006.
    75) Product Information: PLEXION(R), PLEXION TS(R), PLEXION SCT(R) cleanser, cleansing cloths, topical suspension, sodium sulfacetamide cleanser, cleansing cloths, topical suspension. Medicis, Scottsdale, AZ, 2007.
    76) Product Information: PROVAYBLUE(TM) intravenous injection, methylene blue intravenous injection. American Regent (per FDA), Shirley, NY, 2016.
    77) Product Information: ROSULA(R) topical aerosol, foam, sulfacetamide sodium and sulfur topical aerosol, foam. PharmaDerm (per DailyMed), Melville, NY, 2009.
    78) Product Information: SSD(R), SSD AF(R) topical cream, silver sulfadiazine topical cream. Par Pharmaceutical Companies, Inc., Spring Valley, NY, 2008.
    79) Product Information: SULFAMYLON(R) topical cream, mafenide acetate topical cream. UDL Laboratories, Inc., Rockford, IL, 2007.
    80) Product Information: SULFAMYLON(R) topical solution, mafenide acetate topical solution. UDL Laboratories, Inc., Rockford, IL, 2008.
    81) Product Information: Sulfamylon(R), mafenide acetate. Bertek Pharmaceuticals, Inc, Sugar Land, TX, 1998.
    82) Product Information: diazepam IM, IV injection, diazepam IM, IV injection. Hospira, Inc (per Manufacturer), Lake Forest, IL, 2008.
    83) Product Information: diphenhydramine HCl intravenous injection solution, intramuscular injection solution, diphenhydramine HCl intravenous injection solution, intramuscular injection solution. Hospira, Inc. (per DailyMed), Lake Forest, IL, 2013.
    84) Product Information: dopamine hcl, 5% dextrose IV injection, dopamine hcl, 5% dextrose IV injection. Hospira,Inc, Lake Forest, IL, 2004.
    85) Product Information: lorazepam IM, IV injection, lorazepam IM, IV injection. Akorn, Inc, Lake Forest, IL, 2008.
    86) Product Information: methylene blue 1% IV injection, methylene blue 1% IV injection. American Regent, Inc (per manufacturer), Shirley, NY, 2011.
    87) Product Information: methylene blue 1% intravenous injection, methylene blue 1% intravenous injection. Akorn, Inc. (per manufacturer), Lake Forest, IL, 2011.
    88) Product Information: norepinephrine bitartrate injection, norepinephrine bitartrate injection. Sicor Pharmaceuticals,Inc, Irvine, CA, 2005.
    89) Product Information: sulfadiazine oral tablet, sulfadiazine oral tablet. Sandoz Inc. (per DailyMed), Princeton, NJ, 2008.
    90) Product Information: sulfamethoxazole and trimethoprim oral suspension, sulfamethoxazole and trimethoprim oral suspension. Hi-Tech Pharmacal Co., Inc (per DailyMed), Amityville, NY, 2010.
    91) Rallison ML, O'Brien J, & Good RA: Severe reactions to long-acting sulfonamides: erythema multiforme exudativum and lupus erythematosus following administration of sulfamethoxypyridazine and sulfadimethoxine. Pediatrics 1961; 28:908-917.
    92) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    93) Rieder MJ, Shear NH, & Kanee A: Prominence of slow acetylator phenotype among patients with sulfonamide hypersensitivity reactions. Clin Pharmacol Ther 1991; 49:13-17.
    94) Rieder MJ, Uetrecht J, & Shear NH: Diagnosis of sulfonamide hypersensitivity reactions by in vitro "rechallenge" with hydroxylamine metabolites. Ann Intern Med 1989; 110:286-289.
    95) Rowland PH, Center SA, & Dougherty SA: Presumptive trimethoprim-sulfadiazine-related hepatotoxicosis in a dog. JAVMA 1992; 200:348-350.
    96) Rubin Z: Ophthalmic sulfonamide-induced Stevens-Johnson syndrome. Arch Dermatol 1977; 113:235-236.
    97) Rudra T, Webb DB, & Evans AG: Acute tubular necrosis following co-trimoxazole therapy. Nephron 1989; 53:85-86.
    98) Scott R, Besag FMC, & Neville BGR: Buccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: a randomized trial. Lancet 1999; 353:623-626.
    99) Shepherd G & Keyes DC: Methylene blue. In: Dart,RC, ed. Medical Toxicology, 3rd ed. 3rd ed, Philadelphia, PA, 2004, pp -.
    100) Spiller HA & Rogers GC: Evaluation of administration of activated charcoal in the home. Pediatrics 2002; 108:E100.
    101) Sreenath TG, Gupta P, Sharma KK, et al: Lorazepam versus diazepam-phenytoin combination in the treatment of convulsive status epilepticus in children: A randomized controlled trial. Eur J Paediatr Neurol 2009; Epub:Epub.
    102) Stanford SC , Stanford BJ , & Gillman PK : Risk of severe serotonin toxicity following co-administration of methylene blue and serotonin reuptake inhibitors: an update on a case report of post-operative delirium. J Psychopharmacol 2010; 24(10):1433-1438.
    103) Stevenson DK, Christie DL, & Haas JE: Hepatic injury in a child caused by trimethoprim-sulfamethoxazole. Pediatrics 1978; 61:864-866.
    104) Teunis BS, Leftwich EI, & Pierce LE: Acute methemoglobinemia and hemolytic anemia due to toluidine blue. Arch Surg 1970; 101:527-531.
    105) Thakore S & Murphy N: The potential role of prehospital administration of activated charcoal. Emerg Med J 2002; 19:63-65.
    106) U.S. Food and Drug Administration: FDA Drug Safety Communication: Serious CNS reactions possible when methylene blue is given to patients taking certain psychiatric medications. U.S. Food and Drug Administration. Silver Spring, MD. 2011. Available from URL: http://www.fda.gov/Drugs/DrugSafety/ucm263190.htm. As accessed 2011-07-26.
    107) USPDI: Drug Information for the Health Care Professional, 8th ed, US Pharmaceutical Convention, Inc, Rockville, MD, 1988.
    108) Van Gerpen JA: Tremor caused by trimethoprim-sulfamethoxazole in a patient with AIDS. Neurology 1997; 48:537-538.
    109) Vanden Hoek,TL; Morrison LJ; Shuster M; et al: Part 12: Cardiac Arrest in Special Situations 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. American Heart Association. Dallas, TX. 2010. Available from URL: http://circ.ahajournals.org/cgi/reprint/122/18_suppl_3/S829. As accessed 2010-10-21.
    110) Vozeh S, Schmidlin O, & Taeschner W: Pharmacokinetic drug data. Clin Pharmacokin 1988; 254-282.
    111) Winek CL, Collom WD, & Martineau P: Toluidine blue intoxication. Clin Toxicol 1969; 2:1-3.
    112) do Nascimento TS, Pereira RO, de Mello HL, et al: Methemoglobinemia: from diagnosis to treatment. Rev Bras Anestesiol 2008; 58(6):651-664.