Ibuprofen for Sudden Cardiac Arrest

INDICATIONS AND USAGE Ibuprofen Lysine Injection is indicated to close a clinically significant patent ductus arteriosus (PDA) in premature infants weighing between 500 and 1500 g, who are no more than 32 weeks gestational age when usual medical management (e.g., fluid restriction, diuretics, respiratory support, etc.) is ineffective. The clinical trial was conducted among infants with an asymptomatic PDA. However, the consequences beyond 8 weeks after treatment have not been evaluated; therefore, treatment should be reserved for infants with clear evidence of a clinically significant PDA. Ibuprofen Lysine Injection is a nonsteroidal anti-inflammatory drug indicated to close a clinically significant patent ductus arteriosus (PDA) in premature infants weighing between 500 and 1500 g, who are no more than 32 weeks gestational age when usual medical management is ineffective. The clinical trial was conducted among infants with an asymptomatic PDA. However, the consequences beyond 8 weeks after treatment have not been evaluated; therefore, treatment should be reserved for infants with clear evidence of a clinically significant PDA. (1)

DOSAGE AND ADMINISTRATION Use the lowest effective dosage for shortest duration consistent with individual patient treatment goals. ( 2.1 ) CALDOLOR Injection vials must be diluted before administration. ( 2.1 ) CALDOLOR Injection bags are ready to use. ( 2.1 ) Adult Pain: 400 mg to 800 mg intravenously over 30 minutes every 6 hours as necessary. ( 2.2 ) Adult Fever: 400 mg intravenously over 30 minutes, followed by 400 mg every 4 to 6 hours or 100-200 mg every 4 hours as necessary. ( 2.2 ) Pediatric (pain and fever) ages 12 to 17 years of age: 400 mg intravenously over 10 minutes every 4 to 6 hours as necessary. ( 2.3 ) Pediatric (pain and fever) aged 6 months to less than 12 years of age: 10 mg/kg intravenously over 10 minutes up to a maximum single dose of 400 mg every 4 to 6 hours as necessary. ( 2.3 ) Pediatric (pain and fever) aged 3 months to less than 6 months: 10 mg/kg intravenously over 10 minutes up to a maximum single dose of 100 mg. ( 2.3 ) 2.1 Important Dosage and Administration Instructions Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [ see Warnings and Precautions ( 5 ) ]. After observing the response to initial therapy with CALDOLOR, the dose and frequency should be adjusted to suit an individual patient's needs. Do not exceed 3200 mg total daily dose in adults. Do not exceed 40 mg/kg or 2,400 mg, whichever is less, total daily dose in pediatric patients 6 months to 17 years of age. The dosage is limited to a single dose not to exceed 10 mg/kg or 100 mg, whichever is less, in pediatric patients 3 months to less than 6 months of age. To reduce the risk of renal adverse reactions, patients must be well hydrated prior to administration of CALDOLOR. CALDOLOR injection 800 mg/8 mL (100 mg/mL) vials MUST BE DILUTED prior to administration. Dilute to a final concentration of 4 mg/mL or less. Appropriate diluents include 0.9% Sodium Chloride Injection USP (normal saline), 5% Dextrose Injection USP (D5W), or Lactated Ringers Solution. 100 mg dose: Dilute 1 mL of CALDOLOR in at least 100 mL of diluent 200 mg dose: Dilute 2 mL of CALDOLOR in at least 100 mL of diluent 400 mg dose: Dilute 4 mL of CALDOLOR in at least 100 mL of diluent 800 mg dose: Dilute 8 mL of CALDOLOR in at least 200 mL of diluent CALDOLOR injection 800 mg/200 mL (4 mg/mL) polypropylene flexible bags are ready to use, intended for 800 mg doses only. For weight-based dosing at 10 mg/kg ensure that the concentration of CALDOLOR is 4 mg/mL or less. Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit. If visibly opaque particles, discoloration or other foreign particulates are observed, the solution should not be used. Diluted solutions are stable for up to 24 hours at ambient temperature (approximately 20° C to 25° C) and room lighting. 2.2 Adults For Analgesia (pain) : The dose is 400 mg to 800 mg intravenously every 6 hours as necessary. Infusion time must be at least 30 minutes. Maximum daily dose is 3,200 mg. For Fever : The dose is 400 mg intravenously, followed by 400 mg every 4 to 6 hours or 100 mg to 200 mg every 4 hours as necessary. Infusion time must be at least 30 minutes. Maximum daily dose is 3,200 mg. 2.3 Pediatric Patients For Analgesia (pain) and Fever: Ages 12 to 17 years The dose is 400 mg intravenously every 4 to 6 hours as necessary. Infusion time must be at least 10 minutes. Maximum daily dose is 40 mg/kg or 2,400 mg, whichever is less. Ages 6 months to less than 12 years The dose is 10 mg/kg intravenously up to a maximum single dose of 400 mg every 4 to 6 hours as necessary. Infusion time must be at least 10 minutes. Maximum daily dose is 40 mg/kg or 2,400 mg, whichever is less. Pediatric Dosing as Necessary for Fever and Pain * Maximum daily dose is 40 mg/kg or 2,400 mg, whichever is less. Age Group Dose Dosing Interval Min infusion time Max daily dose 6 months to less than 12 years 10 mg/kg up to 400 mg max Every 4 to 6 hours as necessary 10 minutes *40 mg/kg or 2,400 mg 12 to 17 years 400 mg Every 4 to 6 hours as necessary 10 minutes *40 mg/kg or 2,400 mg Ages 3 months to less than 6 months The dose is a single dose at 10 mg/kg intravenously up to a maximum single dose of 100 mg. Infusion time must be at least 10 minutes.

WARNINGS Cardiovascular Effects Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as ibuprofen, increases the risk of serious gastrointestinal (GI) events [ see Warnings ]. Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [ see Contraindications ]. Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Avoid the use of ibuprofen tablets in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If ibuprofen tablets are used in patients with a recent MI, monitor patients for signs of cardiac ischemia. Hypertension NSAIDs including ibuprofen tablets, can lead to onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including ibuprofen tablets, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy. Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of ibuprofen may blunt the CV effects of several therapeutic agents used to treat these medical conditions [e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers (ARBs)] [see Drug Interactions ]. Avoid the use of ibuprofen tablets in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If ibuprofen tablets are used in patients with severe heart failure, monitor patients for signs of worsening heart failure. Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation NSAIDs, including ibuprofen tablets, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3 to 6 months, and in about 2 to 4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk. NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients treated with neither of these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be taken in treating this population. To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulcerations and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high-risk patients, alternate therapies that do not involve NSAIDs should be considered. Renal Effects Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. Advanced Renal Disease No information is available from controlled clinical studies regarding the use of ibuprofen tablets in patients with advanced renal disease. Therefore, treatment with ibuprofen tablets is not recommended in these patients with advanced renal disease. If ibuprofen tablet therapy must be initiated, close monitoring of the patients renal function is advisable. Anaphylactoid Reactions As with other NSAIDs, anaphylactoid reactions m

DRUG INTERACTION ACE-inhibitors Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors. Aspirin Pharmacodynamic studies have demonstrated interference with the antiplatelet activity of aspirin when ibuprofen 400 mg, given three times daily, is administered with enteric coated low-dose aspirin. The interaction exists even following a once-daily regimen of ibuprofen 400 mg, particularly when ibuprofen is dosed prior to aspirin. The interaction is alleviated if immediate-release low-dose aspirin is dosed at least 2 hours prior to a once daily regimen of ibuprofen; however, this finding cannot be extended to enteric-coated low-dose aspirin [see Clinical Pharmacology /Pharmacodynamics]. Because there may be an increased risk of cardiovascular events due to the interference of ibuprofen with the antiplatelet effect of aspirin, for patients taking low-dose aspirin for cardio protection who require analgesics, consider use of an NSAID that does not interfere with the antiplatelet effect of aspirin, or non-NSAID analgesics, where appropriate. When ibuprofen tablets are administered with aspirin, its protein binding is reduced, although the clearance of free ibuprofen tablets is not altered. The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of ibuprofen and aspirin is not generally recommended because of the potential for increased adverse effects. Diuretics Clinical studies, as well as post marketing observations, have shown that ibuprofen tablets can reduce the natriuretic effect-of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see WARNINGS, Renal Effects ), as well as to assure diuretic efficacy. Lithium Ibuprofen produced an elevation of plasma lithium levels and a reduction in renal lithium clearance in a study of eleven normal volunteers. The mean minimum lithium concentration increased 15% and the renal clearance of lithium was decreased by 19% during this period of concomitant drug administration. This effect has been attributed to inhibition of renal prostaglandin synthesis by ibuprofen. Thus, when ibuprofen and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity. (Read circulars for lithium preparation before use of such concurrent therapy.) Methotrexate NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate. Warfarin-type anticoagulants Several short-term controlled studies failed to show that ibuprofen tablets significantly affected prothrombin times or a variety of other clotting factors when administered to individuals on coumarin-type anticoagulants. However, because bleeding has been reported when ibuprofen tablets and other NSAIDs have been administered to patients on coumarin-type anticoagulants, the physician should be cautious when administering ibuprofen tablets to patients on anticoagulants. The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that the users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone. H-2 Antagonists In studies with human volunteers, co-administration of cimetidine or ranitidine with ibuprofen had no substantive effect on ibuprofen serum concentrations. Pregnancy Risk Summary Use of NSAIDs, including ibuprofen tablets, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of ibuprofen tablets use between about 20 and 30 weeks of gestation, and avoid ibuprofen tablets use at about 30 weeks of gestation and later in pregnancy [ see WARNINGS; Fetal Toxicity ]. Premature Closure of Fetal Ductus Arteriosus Use of NSAIDs, including ibuprofen tablets, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment Use of NSAIDs at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. Reproductive studies conducted in rats and rabbits have not demonstrated evidence of developmental abnormalities. However, animal reproduction studies are not always predictive of human response. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as ibuprofen, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as ibuprofen, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. The estimated background risk of major birth defects and miscarriage for the indicated population(s) is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAIDs in women at about 30 weeks gestation and later in pregnancy, because NSAIDs, including ibuprofen tablets, can cause premature closure of the fetal ductus arteriosus (see WARNINGS; Fetal Toxicity ) . Oligohydramnios/Neonatal Renal Impairment If an NSAID is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If ibuprofen tablets treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue ibuprofen tablets and follow up according to clinical practice (see WARNINGS; Fetal Toxicity ) . Data Human Data There are no adequate, well-controlled studies in pregnant women. Ibuprofen tablets should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus. Premature Closure of Fetal Ductus Arteriosus: Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. These adv

ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: Cardiovascular Thrombotic Events [see Warnings and Precautions ( 5.1 )] GI Bleeding, Ulceration and Perforation [see Warnings and Precautions ( 5.2 )] Hepatotoxicity [ see Warnings and Precautions ( 5.3 ) ] Hypertension [ see Warnings and Precautions ( 5.4 ) ] Heart Failure and Edema [ see Warnings and Precautions ( 5.5 ) ] Renal Toxicity and Hyperkalemia [ see Warnings and Precautions ( 5.6 ) ] Anaphylactic reactions [ see Warnings and Precautions ( 5.7 ) ] Serious Skin Reactions [ see Warnings and Precautions ( 5.9 ) ] Hematologic Toxicity [ see Warnings and Precautions ( 5.11 ) ] The most common adverse reactions are nausea, flatulence, vomiting, headache, hemorrhage and dizziness (>5%). The most common adverse reactions in pediatric patients are infusion site pain, vomiting, nausea, anemia and headache (≥2%). ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Cumberland Pharmaceuticals Inc. at 1-877-484-2700 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be compared directly to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adult Population During clinical development, 560 patients were exposed to CALDOLOR, 438 in pain and 122 with fever. In the pain studies, CALDOLOR was started intra-operatively and administered at a dose of 400 mg or 800 mg every six hours for up to three days. In the fever studies, CALDOLOR was administered at doses of 100 mg, 200 mg, or 400 mg every four or six hours for up to 3 days. The most frequent type of adverse reaction occurring with oral ibuprofen is gastrointestinal. Pain Studies The incidence rates of adverse reactions listed in the following table were derived from multi-center, controlled clinical studies in post-operative patients comparing CALDOLOR to placebo in patients also receiving morphine as needed for post-operative pain. Table 1: Post-operative Patients with Adverse Reactions Observed in ≥ 3% of Patients in any CALDOLOR Treatment Group in Pain Studies * * All patients received concomitant morphine during these studies. Event CALDOLOR Placebo (N=287) 400 mg (N=134) 800 mg (N=304) Any Reaction 118 (88%) 260 (86%) 258 (90%) Nausea 77 (57%) 161 (53%) 179 (62%) Vomiting 30 (22%) 46 (15%) 50 (17%) Flatulence 10 (7%) 49 (16%) 44 (15%) Headache 12 (9%) 35 (12%) 31 (11%) Hemorrhage 13 (10%) 13 (4%) 16 (6%) Dizziness 8 (6%) 13 (4%) 5 (2%) Edema peripheral 1 (<1%) 9 (3%) 4 (1%) Urinary retention 7 (5%) 10 (3%) 10 (3%) Anemia 5 (4%) 7 (2%) 6 (2%) Decreased hemoglobin 4 (3%) 6 (2%) 3 (1%) Dyspepsia 6 (4%) 4 (1%) 2 (<1%) Wound hemorrhage 4 (3%) 4 (1%) 4 (1%) Abdominal discomfort 4 (3%) 2 (<1%) 0 Cough 4 (3%) 2 (<1%) 1 (<1%) Hypokalemia 5 (4%) 3 (<1%) 8 (3%) Fever Studies Fever studies were conducted in febrile hospitalized patients with malaria and febrile hospitalized patients with varying causes of fever. In hospitalized febrile patients with malaria, the adverse reactions observed in at least two CALDOLOR-treated patients included abdominal pain and nasal congestion. In hospitalized febrile patients (all causes), adverse reactions observed in more than two patients in any given treatment group are presented in the table below. Table 2: Patients with Adverse Reactions Observed in ≥ 3% of Patients in any CALDOLOR Treatment Group in All-Cause Fever Study Event CALDOLOR Placebo N=28 100 mg N=30 200 mg N=30 400 mg N=31 Any Reaction 27 (87%) 25 (83%) 23 (74%) 25 (89%) Anemia 5 (17%) 6 (20%) 11 (36%) 4 (14%) Eosinophilia 7 (23%) 7 (23%) 8 (26%) 7 (25%) Hypokalemia 4 (13%) 4 (13%) 6 (19%) 5 (18%) Hypoproteinemia 3 (10%) 0 4 (13%) 2 (7%) Neutropenia 2 (7%) 2 (7%) 4 (13%) 2 (7%) Blood urea increased 0 0 3 (10%) 0 Hypernatremia 2 (7%) 0 3 (10%) 0 Hypertension 0 0 3 (10%) 0 Hypoalbuminemia 3 (10%) 1 (3%) 3 (10%) 1 (4%) Hypotension 0 2 (7%) 3 (10%) 1 (4%) Diarrhea 3 (10%) 3 (10%) 2 (7%) 2 (7%) Pneumonia bacterial 3 (10%) 1 (3%) 2 (7%) 0 Blood LDH increased 3 (10%) 2 (7%) 1 (3%) 1 (4%) Thrombocythemia 3 (10%) 2 (7%) 1 (3%) 0 Bacteremia 4 (13%) 0 0 0 Pediatric Population A total of 143 pediatric patients ages 6 months and older have received CALDOLOR in controlled clinical trials. The most common adverse reactions (incidence greater than or equal to 2%) in pediatric patients treated with CALDOLOR were infusion site pain, vomiting, nausea, anemia and headache. Twenty-one hospitalized patients ages 3 months to less than 6 months were treated with CALDOLOR for pain or fever in an open-label, non-controlled clinical study; 18 of 21 patients were treated with a single dose. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of ibuprofen. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Skin and Appendages: Exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and fixed drug eruption (FDE).