PENTAMIDINE ISETHIONATE

WARNINGS Fatalities due to severe hypotension, hypoglycemia, acute pancreatitis and cardiac arrhythmias have been reported in patients treated with pentamidine isethionate, both by the IM and IV routes. Severe hypotension may result after a single IM or IV dose and is more likely with rapid IV administration (see PRECAUTIONS ). The administration of the drug should, therefore, be limited to the patients in whom Pneumocystis carinii has been demonstrated. Patients should be closely monitored for the development of serious adverse reactions (see PRECAUTIONS and ADVERSE REACTIONS ). Extravasations have been reported which, in some instances, proceeded to ulceration, tissue necrosis and/or sloughing at the injection site. While not common, surgical debridement and skin grafting has been necessary in some of these cases; long-term sequelae have been reported. Prevention is the most effective means of limiting the severity of extravasation. The intravenous needle or catheter must be properly positioned and closely observed throughout the period of pentamidine isethionate administration. If extravasation occurs, the injection should be discontinued immediately and restarted in another vein. Because there are no known local treatment measures which have proven to be useful, management of the extravasation should be symptomatic.

ADVERSE REACTIONS CAUTION : Fatalities due to severe hypotension, hypoglycemia, acute pancreatitis and cardiac arrhythmias have been reported in patients treated with pentamidine isethionate, both by the IM and IV routes. Nephrotoxic events (increased creatinine, impaired renal function, azotemia, and renal failure) are common with the parenteral administration of pentamidine isethionate. The administration of the drug should, therefore, be limited to the patients in whom Pneumocystis carinii has been demonstrated. The most frequently reported spontaneous adverse events (1 to 30%) reported in clinical trials, regardless of their relation to pentamidine isethionate therapy were as follows (n=424): Cardiovascular: -Hypotension 5.0% Gastrointestinal: -Anorexia/Nausea 5.9% Hematologic: -Anemia 1.2% -Leukopenia 10.4% -Thrombocytopenia 2.6% Hepatic: -Elevated liver function tests 8.7% Metabolic: -Hypoglycemia 5.9% Neurologic: -Confusion/hallucinations 1.7% Skin: -Sterile abscess and/or necrosis, pain, or induration at the site of IM injection 11.1% -Rash 3.3% Special Senses: -Bad taste 1.7% Urogenital: -Azotemia 8.5% -Elevated serum creatinine 23.6% -Elevated blood urea nitrogen 6.6% -Impaired renal function 28.8% Adverse events with a frequency of less than 1% incidence were as follows (No causal relationship to treatment has been established for these adverse events): Body as a whole: Allergic reaction (i.e. urticaria, itching, rash), anaphylaxis, arthralgia, chills, extrapulmonary pneumocystosis, headache, night sweats, and Stevens-Johnson syndrome. Cardiovascular: Abnormal ST segment of electrocardiogram, cardiac arrhythmias, cerebrovascular accident, hypertension, palpitations, phlebitis, syncope, tachycardia, vasodilatation, vasculitis and ventricular tachycardia. Gastrointestinal: Abdominal pain, diarrhea, dry mouth, dyspepsia, hematochezia, hypersalivation, melena, pancreatitis, splenomegaly, and vomiting. Hematological: Defibrination, eosinophilia, neutropenia, pancytopenia, and prolonged clotting time. Hepatic: Hepatic dysfunction, hepatitis and hepatomegaly Metabolic: Hyperglycemia, hyperkalemia, hypocalcemia, and hypomagnesemia. Neurological: Anxiety, confusion, depression, dizziness, drowsiness, emotional lability, hypesthesia, insomnia, memory loss, neuropathy, nervousness, neuralgia, paranoia, paresthesia, peripheral neuropathy, seizure, tremors, unsteady gait, and vertigo. Respiratory system: Asthma, bronchitis, bronchospasm, chest congestion, chest tightness, coryza, cyanosis, eosinophilic or interstitial pneumonitis, gagging, hemoptysis, hyperventilation, laryngitis, laryngospasm, non-specific lung disorder, nasal congestion, pleuritis, pneumothorax, rales, rhinitis, shortness of breath, and tachypnea. Skin: Desquamation, dry and breaking hair, dry skin, erythema, dermatitis, pruritus, rash, and urticaria. Special senses: Blepharitis, blurred vision, conjunctivitis, contact lens discomfort, eye pain or discomfort, loss of hearing, loss of taste, and loss of smell. Urogenital: Flank pain, hematuria, incontinence, nephritis, renal dysfunction and renal failure. From post-marketing clinical experience with pentamidine isethionate, the following adverse events have been reported: cough, diabetes mellitus/ketoacidosis, dyspnea, infiltration (extravasation–see WARNINGS ), and torsades de pointes. To report SUSPECTED ADVERSE REACTIONS, contact XGen Pharmaceuticals DJB, Inc. at 1-866-390-4411 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

<table border="0" width="35%"><tbody><tr><td>Cardiovascular:</td><td/></tr><tr><td styleCode="Botrule">-Hypotension</td><td styleCode="Botrule">5.0%</td></tr><tr><td>Gastrointestinal:</td><td/></tr><tr><td styleCode="Botrule">-Anorexia/Nausea</td><td styleCode="Botrule">5.9%</td></tr><tr><td>Hematologic:</td><td/></tr><tr><td>-Anemia</td><td>1.2%</td></tr><tr><td>-Leukopenia</td><td>10.4%</td></tr><tr><td styleCode="Botrule">-Thrombocytopenia</td><td styleCode="Botrule">2.6%</td></tr><tr><td>Hepatic:</td><td/></tr><tr><td styleCode="Botrule">-Elevated liver function tests</td><td styleCode="Botrule">8.7%</td></tr><tr><td>Metabolic:</td><td/></tr><tr><td styleCode="Botrule">-Hypoglycemia</td><td styleCode="Botrule">5.9%</td></tr><tr><td>Neurologic:</td><td/></tr><tr><td styleCode="Botrule">-Confusion/hallucinations</td><td styleCode="Botrule">1.7%</td></tr><tr><td>Skin:</td><td/></tr><tr><td>-Sterile abscess and/or necrosis, pain, or induration at the site of IM injection</td><td>11.1%</td></tr><tr><td styleCode="Botrule">-Rash</td><td styleCode="Botrule">3.3%</td></tr><tr><td>Special Senses:</td><td/></tr><tr><td styleCode="Botrule">-Bad taste</td><td styleCode="Botrule">1.7%</td></tr><tr><td>Urogenital:</td><td/></tr><tr><td>-Azotemia</td><td>8.5%</td></tr><tr><td>-Elevated serum creatinine</td><td>23.6%</td></tr><tr><td>-Elevated blood urea nitrogen</td><td>6.6%</td></tr><tr><td>-Impaired renal function</td><td>28.8%</td></tr></tbody></table>

<table><colgroup><col/><col/></colgroup><tbody><tr><td styleCode="Botrule Toprule Lrule Rrule " valign="top"><paragraph>Body as a whole:</paragraph></td><td styleCode="Botrule Toprule Lrule Rrule " valign="top"><paragraph>Allergic reaction (i.e. urticaria, itching, rash), anaphylaxis, arthralgia, chills, extrapulmonary pneumocystosis, headache, night sweats, and Stevens-Johnson syndrome.</paragraph></td></tr><tr><td styleCode="Botrule Toprule Lrule Rrule " valign="top"><paragraph>Cardiovascular:</paragraph></td><td styleCode="Botrule Toprule Lrule Rrule " valign="top"><paragraph>Abnormal ST segment of electrocardiogram, cardiac arrhythmias, cerebrovascular accident, hypertension, palpitations, phlebitis, syncope, tachycardia, vasodilatation, vasculitis and ventricular tachycardia.</paragraph></td></tr><tr><td styleCode="Botrule Toprule Lrule Rrule " valign="top"><paragraph>Gastrointestinal:</paragraph></td><td styleCode="Botrule Toprule Lrule Rrule " valign="top"><paragraph>Abdominal pain, diarrhea, dry mouth, dyspepsia, hematochezia, hypersalivation, melena, pancreatitis, splenomegaly, and vomiting.</paragraph></td></tr><tr><td styleCode="Botrule Toprule Lrule Rrule " valign="top"><paragraph>Hematological:</paragraph></td><td styleCode="Botrule Toprule Lrule Rrule " valign="top"><paragraph>Defibrination, eosinophilia, neutropenia, pancytopenia, and prolonged clotting time.</paragraph></td></tr><tr><td styleCode="Botrule Toprule Lrule Rrule " valign="top"><paragraph>Hepatic:</paragraph></td><td styleCode="Botrule Toprule Lrule Rrule " valign="top"><paragraph>Hepatic dysfunction, hepatitis and hepatomegaly</paragraph></td></tr><tr><td styleCode="Botrule Toprule Lrule Rrule " valign="top"><paragraph>Metabolic:</paragraph></td><td styleCode="Botrule Toprule Lrule Rrule " valign="top"><paragraph>Hyperglycemia, hyperkalemia, hypocalcemia, and hypomagnesemia.</paragraph></td></tr><tr><td styleCode="Botrule Toprule Lrule Rrule " valign="top"><paragraph>Neurological:</paragraph></td><td styleCode="Botrule Toprule Lrule Rrule " valign="top"><paragraph>Anxiety, confusion, depression, dizziness, drowsiness, emotional lability, hypesthesia, insomnia, memory loss, neuropathy, nervousness, neuralgia, paranoia, paresthesia, peripheral neuropathy, seizure, tremors, unsteady gait, and vertigo.</paragraph></td></tr><tr><td styleCode="Botrule Toprule Lrule Rrule " valign="top"><paragraph>Respiratory system:</paragraph></td><td styleCode="Botrule Toprule Lrule Rrule " valign="top"><paragraph>Asthma, bronchitis, bronchospasm, chest congestion, chest tightness, coryza, cyanosis, eosinophilic or interstitial pneumonitis, gagging, hemoptysis, hyperventilation, laryngitis, laryngospasm, non-specific lung disorder, nasal congestion, pleuritis, pneumothorax, rales, rhinitis, shortness of breath, and tachypnea.</paragraph></td></tr><tr><td styleCode="Botrule Toprule Lrule Rrule " valign="top"><paragraph>Skin:</paragraph></td><td styleCode="Botrule Toprule Lrule Rrule " valign="top"><paragraph>Desquamation, dry and breaking hair, dry skin, erythema, dermatitis, pruritus, rash, and urticaria.</paragraph></td></tr><tr><td styleCode="Botrule Toprule Lrule Rrule " valign="top"><paragraph>Special senses:</paragraph></td><td styleCode="Botrule Toprule Lrule Rrule " valign="top"><paragraph>Blepharitis, blurred vision, conjunctivitis, contact lens discomfort, eye pain or discomfort, loss of hearing, loss of taste, and loss of smell.</paragraph></td></tr><tr><td styleCode="Botrule Toprule Lrule Rrule " valign="top"><paragraph>Urogenital:</paragraph></td><td styleCode="Botrule Toprule Lrule Rrule " valign="top"><paragraph>Flank pain, hematuria, incontinence, nephritis, renal dysfunction and renal failure.</paragraph></td></tr></tbody></table>