1) Pulmonary toxicity developed in a 27-year-old man who had been receiving sulfasalazine for the treatment of ulcerative proctosigmoiditis. Two weeks prior to admission, the dose of sulfasalazine was increased from 1 g twice daily to 1 g 4 times daily. Upon evaluation, the patient had multiple bilateral peripheral wedge-shaped infiltrates with central cavitation of the right lower lobe. Other symptoms included abdominal cramping, nausea, fatigue, myalgias, and nonproductive cough. No infectious etiology could be identified. Wegner's Granulomatosis (WG) was considered since the centrally accentuated antineutrophil cytoplasmic antibody test (c-ANCA) was positive and characteristic of WG. An open lung biopsy was also consistent with WG. However, once the patient was off sulfasalazine, the pulmonary infiltrates cleared and the patient was asymptomatic. Due to the timeline between the disappearance of disease and the discontinuation of sulfasalazine, the c-ANCA was thought to be a false-positive and the pulmonary toxicity was due to sulfasalazine (Salerno et al, 1996).

1) Neurotoxicity developed in a 46-year-old woman who had been taking sulfasalazine 15 g/day for 3 weeks to control her rheumatoid arthritis. She presented with a severe reaction, characterized by dysphasia, seizures, and rash. Tests for perinuclear antineutrophil cytoplasmic antibodies (pANCA) were positive. Her condition improved spontaneously upon withdrawal of sulfasalazine (Hill et al, 1994).
2) A 63-year-old woman developed sensorimotor neuropathy approximately 2 weeks after starting sulfasalazine 1 g 4 times daily for colitis. Withdrawal of the drug resulted in a delayed recovery. The patient was determined to be a slow acetylator (Price, 1985).
3) Acute encephalopathy developed in a 30-year-old man with Crohn disease who had taken sulfasalazine 3 g daily for 1 month. The development of a toxic hepatitis and dermatitis prompted discontinuance of the sulfasalazine therapy. Four days after these symptoms, the patient manifested neurological symptoms which included acute monoparesis, stupor, and coma. CNS symptoms resolved with methylprednisolone treatment (Schoonjans et al, 1993).
4) Supranuclear hemiparesis developed in a 13-year-old girl after 12 months with sulfasalazine 1.5 g daily for the treatment of Crohn disease. Discontinuation of sulfasalazine resulted in complete resolution of the hemiparesis within 3 months (Hermann, 1984).
5) Aseptic meningitis developed in a 41-year-old man receiving sulfasalazine 500 mg twice daily for rheumatoid arthritis. Twelve days after initiation of therapy, the patient presented with sudden onset of severe headache, fever, photophobia, and bitemporal pain. Lumbar puncture and CFS culture tests were negative; therefore, the patient was diagnosed with aseptic meningitis. CNS symptoms resolved with the discontinuance of sulfasalazine therapy. Headache and fever symptoms appeared with rechallenge of sulfasalazine therapy. The temporal relationship suggested aseptic meningitis secondary to sulfasalazine (Alloway & Mitchell, 1993).
6) A report described 3 cases of sulfasalazine-induced neurotoxicity that included ataxia, neck stiffness, headache, confusion, and grand mal seizures (Taffet & Das, 1983).

1) Hepatotoxicity developed in a 20-year-old woman with early Crohn disease who was treated with sulfasalazine 2 g/day in divided doses. She presented with a 7-day history of nausea, vomiting, fever, diarrhea, and abdominal pain 25 days after starting sulfasalazine. The laboratory data was consistent with a mixed hepatocellular and cholestatic pattern. Sulfasalazine was restarted and after taking 4 doses, the patient had a diffuse urticarial rash, fever, and diffuse abdominal tenderness. Sulfasalazine was again discontinued, and the patient was assessed asymptomatic with normal liver tests 4 weeks later (Gulley et al, 1979).
2) A 59-year-old woman with psoriatic arthritis developed fever, confusion, a widespread erythematous macular rash, and hepatomegaly after receiving sulfasalazine for 7 days. Laboratory results showed evidence of intravascular coagulation with abnormal liver enzymes levels. She developed renal failure and died 48 hours after admission. At autopsy, the liver was enlarged (2150 g) and histological examination revealed cirrhosis, extensive areas of necrosis, collapse of the reticulum framework, and numerous apoptotic bodies (Pears & Morley, 1989).
3) Fulminant hepatic failure and necrotizing pancreatitis occurred in a 37-year-old man with ulcerative colitis. Approximately 3 weeks prior to development of fulminant hepatic failure and necrotizing pancreatitis, the patient was treated with sulfasalazine 4 g/day. An exploratory laparotomy revealed severe necrotizing pancreatitis with phlegmon, in addition to hepatic necrosis. Electron microscopy of the liver was consistent with drug injury. The patient died after 2 months of hospitalization (Rubin, 1994).
4) CHILDREN: Two children (a 13-year-old boy and a 14-year-old girl), developed hepatotoxicity 11 to 14 days after exposure to sulfasalazine. They presented with fever, headache, abdominal pain, diarrhea, a red pruritic rash of the abdomen, face, and throat, and cervical lymphadenopathy. Laboratory tests revealed leukopenia with left shift, eosinophilia, thrombocytopenia, and elevated liver enzymes. Liver biopsy showed pericholangitis and portal and parenchymal inflammation without cholestasis. Following the discontinuation of sulfasalazine, they recovered gradually over the next 2 weeks (Losek & Werlin, 1981; Boyer et al, 1989).

1) Bilateral renal calculi occurred in a 19-year-old patient receiving sulfasalazine therapy for juvenile rheumatoid arthritis (dose or length of therapy was not reported). The condition was successfully treated with extracorporeal shock wave lithotripsy. Analysis of the fragments with thin layer chromatography and nuclear magnetic resonance revealed acetylsulfapyridine, a metabolite of sulfasalazine. The patient was subsequently followed for 2 years with no recurrence of renal calculi formation (Erturk et al, 1994).
2) A 46-year-old man on sulfasalazine for ulcerative colitis developed left ureteric pain during a hospital admission for rehydration and adjustment of sulfasalazine therapy (dose not given). Intravenous urography revealed partial obstruction in the left mid-ureter and left renal pelvis. A calculus passed 5 days after the onset of pain was found to contain sulfur and chloride. Sulfasalazine was discontinued and a repeat intravenous urogram 1 month after the original episode showed multiple filling defects in the left lower pole calix. During the following month, he passed flakes of black material. Withdrawal of the drug and rehydration allowed the calculi to be passed spontaneously (Sillar & Kleinig, 1993).

1) Two men (a 20-year-old and a 59-year-old ) developed agranulocytosis after taking sulfasalazine 3 to 4 g/day for 4 to 8 weeks. Both patients discontinued taking sulfasalazine before admission and recovered following aggressive therapy (Hutchinson & Wyld, 1983).
2) A fatal case of agranulocytosis was reported in a 53-year-old woman treated with sulfasalazine 1.5 g daily for rheumatoid arthritis. After 52 days of therapy, sulfasalazine was discontinued secondary to neutropenia. Seven days after discontinuation, the patient was admitted to the hospital with agranulocytosis and sepsis. Bone marrow showed disappearance of the myeloid lineage, and the patient died on the third hospital day, despite antibiotic therapy. The authors reviewed 23 documented cases of agranulocytosis and stated that this complication usually occurs after a mean duration of treatment of 3.5 weeks (range: 2 to 233 weeks), with a mean cumulative dose of 115 g (range: 20 to 316 g), and that rapid myeloid recovery is usually observed before 10 days (Guillemin et al, 1989).
3) A 17-year-old woman receiving sulfasalazine developed agranulocytosis 1 month after the start of therapy. Initially, the patient was admitted for septic-like symptoms (ie, fever, rigors, abdominal pains), but further evaluation revealed severe leukopenia (ie, 0.4 x 10(9)/L) with an absolute neutrophil count of 0. A bone marrow aspirate demonstrated granulocytic aplasia and reduced iron stores. Filgrastim 300 mcg daily normalized the white blood cell (WBC) and absolute neutrophil counts within 5 days. All signs and symptoms of septicemia disappeared as the WBC improved, and the patient was eventually discharged from the hospital 9 days after admission (Crawford & Laurence, 1996).
4) A 64-year-old man with ulcerative colitis developed agranulocytosis after 5 weeks of sulfasalazine therapy. He presented with fever and skin rash, and bone marrow aspiration revealed severe myeloid hypoplasia. He was subsequently treated with mesalamine enemas, without adverse effects. This report adds evidence that sulfapyridine is the toxic component of sulfasalazine and produces the majority of toxic effects, including blood dyscrasias (Jacobson et al, 1985).
5) Agranulocytosis was described in a 79-year-old woman following sulfasalazine therapy (500 mg twice daily for approximately 2 months) for diverticulitis. She had discontinued sulfasalazine approximately 9 days prior to admission. Presenting symptoms consisted of hoarseness, fever, odynophagia, and malaise, with WBC of 600/mm(3) (neutrophils 0%, bands 8%, lymphocytes 67%, monocytes 25%); maturation arrest was demonstrated on bone marrow aspirate and biopsy. The patient gradually recovered without sequelae after 9 days of hospitalization . Although this case strongly suggests the association between sulfasalazine and agranulocytosis, a definite cause-effect relationship was not established (Derry & Schwinghammer, 1988).
6) A fatal case of agranulocytosis was reported in a 77-year-old woman with rheumatoid arthritis treated with sulfasalazine 2 g daily for 3 weeks. After 3 weeks of treatment, she developed malaise, anorexia, fever, and rigors. Her medication was discontinued at this time. After a week of illness, she was admitted to the hospital. On examination, she had fever, jaundice, oral ulcers, cutaneous cellulitis, abdominal distension and tenderness, and active arthritis. A bone marrow aspirate showed absence of myeloid precursors, scanty megakaryocyte, and a gross reactive plasmacytosis. Despite aggressive management, there was persistent agranulocytosis and multiorgan failure. The patient died on the 10th day of hospitalization (Canvin et al, 1993).
7) Lymphocyte sensitization to sulfasalazine was demonstrated by analyzing the in vitro proliferation of peripheral blood lymphocytes from a 41-year-old woman who developed severe agranulocytosis following therapy of ulcerative colitis with sulfasalazine 3 g daily . The authors concluded that a cell-mediated mechanism is involved in sulfasalazine-induced agranulocytosis (Victorino et al, 1990).

1) A 22-year-old woman with rheumatoid arthritis developed hepatitis, generalized, exfoliative dermatitis, and Coombs positive autoimmune hemolytic anemia after receiving sulfasalazine 1 g twice daily . She improved following therapy with prednisolone (Vyse & So, 1992).
2) A 58-year-old woman developed hemolytic anemia about 14 months after initiation of sulfasalazine 2 to 6 g daily. On admission, hemoglobin level was 6.3 g/100 mL, reticulocytes 60%, and methyl violet staining revealed typical Heinz bodies in most of the erythrocytes. Direct and indirect Coombs tests were negative. All 3 major immunoglobulins were totally absent from the serum. No deficiency of glucose-6-phosphate dehydrogenase or other erythrocyte enzymes or pathological hemoglobin were found. Sulfasalazine therapy was stopped, and subsequently the Heinz bodies disappeared with hemoglobin and reticulocyte levels returning to normal. All the enzymatic, osmotic, and hemolytic abnormalities disappeared (Kaplinsky & Frankl, 1978).

1) A 68-year-old man with intermittent diarrhea unresponsive to kaolin and Lomotil(R) developed megaloblastic anemia after taking sulfasalazine 4 g/day for 5 months. His hemoglobin decreased from 14.5 g/dL to 7.9 g/dL. Bone marrow aspiration demonstrated changes of megaloblastic erythropoiesis. Discontinuation of sulfasalazine and treatment with folic acid 10 mg/day resulted in a gradual rise in the patient's hemoglobin to 13 g/dL and improvement in the patient's clinical condition (Schneider & Beeley, 1977).
2) A 33-year-old woman with ulcerative proctitis developed megaloblastic anemia after taking sulfasalazine 2.5 g twice daily for 7 years. Clinical and lab findings revealed hemoglobin 12.6 g/dL, mean cell volume 108 micron(3), serum B12 600 ng/L, serum folate 0.8 mcg/L, and a red blood cell folate of 88 mcg/L (radioassay). Sulfasalazine was discontinued and folic acid 5 mg/day orally was administered. Laboratory findings returned to normal with hemoglobin at 13.8 gm/dL (Kane & Boots, 1977).

1) A 49-year-old man presented with a widespread eruption with mucous membrane involvement within 13 days of starting piroxicam 20 mg daily and sulfasalazine 1500 mg daily for psoriatic arthritis. Three days after admission, epidermal detachment of the trunk, face, and proximal limbs developed. He rapidly developed severe dyspnea requiring mechanical ventilation. He died of complications of sepsis (Jullien et al, 1995).
2) A 25-year-old woman with joint disease developed toxic epidermal necrolysis after receiving sulfasalazine 1500 mg daily for 12 days. Following supportive care for 3 weeks, she recovered completely (Jullien et al, 1995).
3) In 1 patient, a 63-year-old man, erythema multiforme was so severe that the patient began to slough large areas of skin and became hemodynamically compromised. A diagnosis of toxic epidermal necrolysis was made. Shortly after being admitted to the intensive care unit, the patient had a fatal cardiopulmonary arrest (Pearl et al, 1986)

1) Sulfasalazine-induced systemic lupus erythematosus (SLE) was reported in a 28-year-old woman receiving sulfasalazine 1 g twice daily for rheumatoid arthritis. Five months after starting therapy, the patient presented with fever, pleuritic chest pain, marked increase in joint pain, generalized lymphadenopathy, hepatosplenomegaly, and bilateral pleural rub. A diagnosis of systemic lupus erythematosus was made and sulfasalazine was discontinued. Follow-up 4 months later showed signs of improvement, except for progressive destruction of both hip joints (Siam & Hammoudeh , 1993). In a similar case, a 31-year-old woman with rheumatoid arthritis stabilized on sulfasalazine 1 g twice daily developed SLE after 5 years of therapy. The sulfasalazine was discontinued and high dose prednisolone was given. After 5 weeks of symptomatic therapy, the steroid dose was reduced and the patient was discharged on plaquenil (Walker & Carty, 1994).
2) Systemic lupus erythematosus occurred in a 43-year-old man with ulcerative colitis following administration of sulfasalazine 1 g 4 times daily for 8 years. The patient developed pneumonitis, bilateral pleural effusions, cardiac tamponade, and positive antinuclear antibodies (ANA). After discontinuation of sulfasalazine and following a 6-week course of corticosteroids, the syndrome resolved over a period of 4 to 6 months (Clementz & Dolin, 1988).
3) Sulfasalazine-induced lupus-like syndrome was reported in a patient with ulcerative colitis. Seven months after initiation of therapy with sulfasalazine 3 g daily, the patient presented with fever, joint pain, and weight loss. Chest x-ray showed bilateral pleural effusion, and echocardiographic examination revealed cardiac tamponade. An antinuclear antibody (ANA) titer was positive. Sulfasalazine therapy was discontinued and gradual clinical improvement occurred (Deboever et al, 1989).
4) A report described 2 cases of a lupus syndrome induced by sulfasalazine therapy. Patient 1 was a 68-year-old woman on sulfasalazine 1.5 g/day for 3 years. Six months later, after treatment with NSAIDs and hydroxychloroquine 200 mg twice daily due to skin lesions, the synovitis, pleuropericarditis, and cutaneous symptoms were totally resolved. One year after sulfasalazine discontinuation, lupus symptomatology did not recur and rheumatoid arthritis was quiescent. Patient 2 was a 61-year-old woman on sulfasalazine 2 g/day for 6 months who presented with acute polyarthritis, dramatic increased subcutaneous rheumatoid nodules, and necrotizing lesions in digits, feet, and sacral area. The patient did not fulfill the ARA's criteria for diagnosis of lupus. After 1 month of NSAID therapy, symptoms markedly improved and after 1 year the patient was doing well without drug therapy (Caulier et al, 1994).
5) A case report described a 46-year-old woman who had been taking sulfasalazine 1.5 g daily for rheumatoid arthritis. About 3 weeks after starting therapy, she developed a severe reaction, characterized by dysphasia, seizures, and a rash. Tests for perinuclear antineutrophil cytoplasmic antibodies (pANCA) were positive at this time. Her condition improved spontaneously upon withdrawal of sulfasalazine. After 1 year of follow-up, she had no further neurological problems and her arthritis was being controlled by diclofenac alone (Hill et al, 1994).

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).

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).

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).

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).

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).

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).

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).

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).

1) Safety and efficacy in pediatric patients have not been established (Prod Info Azulfidine(R) oral tablets, 2014; Prod Info Azulfidine EN-tabs(R) oral delayed release tablets, 2014).

1) INITIAL: 40 to 60 mg/kg orally every 24 hours, divided into 3 to 6 doses (Prod Info Azulfidine(R) oral tablets, 2014; Prod Info Azulfidine EN-tabs(R) oral delayed release tablets, 2014).
2) MAINTENANCE: 30 mg/kg orally every 24 hours, divided into 4 doses (Prod Info Azulfidine(R) oral tablets, 2014; Prod Info Azulfidine EN-tabs(R) oral delayed release tablets, 2014).
3) DELAYED-RELEASE TABLET: Swallow whole (Prod Info Azulfidine EN-tabs(R) oral delayed release tablets, 2014).