Pentamidine for Pneumocystis Infections

INDICATIONS AND USAGE Pentamidine Isethionate is indicated for the prevention of Pneumocystis jiroveci pneumonia (PJP) in high-risk, HIV-infected patients defined by one or both of the following criteria: i. a history of one or more episodes of PJP ii. a peripheral CD4+ (T4 helper/inducer) lymphocyte count less than or equal to 200/mm 3 . These indications are based on the results of an 18-month randomized, dose-response trial in high risk HIV-infected patients and on existing epidemiological data from natural history studies. The patient population of the controlled trial consisted of 408 patients, 237 of whom had a history of one or more episodes of PJP. The remaining patients without a history of PJP included 55 patients with Kaposi’s sarcoma and 116 patients with other AIDS diagnoses, ARC or asymptomatic HIV infection. Patients were randomly assigned to receive Pentamidine isethionate via the Respirgard ® II nebulizer at one of the following three doses: 30 mg every two weeks (n=135), 150 mg every two weeks (n=134) or 300 mg every four weeks (n=139). The results of the trial demonstrated a significant protective effect (p<0.01) against PJP with the 300 mg every four week dosage regimen compared to the 30 mg every two week dosage regimen. The 300 mg dose regimen reduced the risk of developing PJP by 50 to 70% compared to the 30 mg regimen. A total of 293 patients (72% of all patients) also received zidovudine at sometime during the trial. The analysis of the data demonstrated the efficacy of the 300 mg dose even after adjusting for the effect of zidovudine. The results of the trial further demonstrate that the dose and frequency of dosing are important to the efficacy of Pentamidine Isethionate prophylaxis in that multiple analyses consistently demonstrated a trend toward greater efficacy with 300 mg every four weeks as compared to 150 mg every two weeks. No dose-response was observed for reduction in overall mortality; however, mortality from PJP was low in all three dosage groups.

DOSAGE AND ADMINISTRATION CAUTION: DO NOT USE SODIUM CHLORIDE INJECTION, USP FOR INITIAL RECONSTITUTION BECAUSE PRECIPITATION WILL OCCUR. Pentamidine isethionate should be administered IM or IV only. The recommended regimen for adults and pediatric patients beyond 4 months of age is 4 mg/kg once a day for 14 to 21 days. Therapy for longer than 21 days with pentamidine isethionate has also been used but may be associated with increased toxicity. Intramuscular Injection The contents of one vial (300 mg) should be dissolved in 3 mL of Sterile Water for Injection, USP at 22° to 30°C (72° to 86°F). The calculated daily dose should then be withdrawn and administered by deep IM injection. Intravenous Injection The contents of one vial (300 mg) should first be dissolved in 3 to 5 mL of Sterile Water for Injection, USP, or 5% Dextrose Injection, USP at 22°to 30°C (72° to 86°F). The calculated dose of pentamidine isethionate should then be withdrawn and diluted further in 50 to 250 mL of 5% Dextrose Injection, USP. The diluted IV solutions containing pentamidine isethionate should be infused over a period of 60 to 120 minutes. Aseptic technique should be employed in preparation of all solutions. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Stability After reconstitution with sterile water, the pentamidine isethionate solution is stable for 48 hours in the original vial at room temperature if protected from light. To avoid crystallization,store at 22° to 30°C (72° to 86°F). Intravenous infusion solutions of pentamidine isethionate at 1 mg/mL and 2.5 mg/mL prepared in 5% Dextrose Injection, USP are stable at room temperature for up to 24 hours. Intravenous (IV) solutions of pentamidine isethionate have been shown to be incompatible with fluconazole and foscarnet sodium. IV solutions of pentamidine isethionate have been shown to be compatible with IV solutions of zidovudine (AZT) and diltiazem hydrochloride.

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.

Drug Interactions While specific studies on drug interactions with pentamidine isethionate have not been conducted, the majority of patients in clinical trials received concomitant medications, including zidovudine, with no reported interactions. Because the nephrotoxic effects may be additive, the concomitant or sequential use of pentamidine isethionate and other nephrotoxic drugs such as aminoglycosides, amphotericin B, cisplatin, foscarnet, or vancomycin should be closely monitored and avoided, if possible.

ADVERSE REACTIONS The most frequently reported unsolicited adverse events (1 to 5%) in clinical trials, regardless of their relation to Pentamidine Isethionate therapy were as follows (n=931): Body as a Whole: Night sweats. Gastrointestinal: Diarrhea and nausea. Hematologic: Anemia. Infection: Bronchitis, non-specific herpes, ­herpes zoster, non-specific influenza, oral Candida, pharyngitis, sinusitis, and upper ­respiratory tract. Nervous System: Headache. Respiratory System: Chest pain, cough, and wheezing. Special Senses: Bad taste. Adverse events 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, non-specific allergy, body odor, facial edema, fever, leg edema, lethargy, low body temperature, and temperature abnormality. Cardiovascular: Cerebrovascular accident, hypotension, hypertension, palpitations, poor circulation, syncope, tachycardia, vasodilatation and vasculitis. Gastrointestinal: Abdominal cramps, abdominal pain, constipation, dry mouth, dyspepsia, gastritis, gastric ulcer, gingivitis, hiatal hernia, hypersalivation, oral ulcer/abscess, splenomegaly, and vomiting. Hematological: Eosinophilia, neutropenia, non-specific cytopenia, pancytopenia, and thrombocytopenia. Hepatic: Hepatitis, hepatomegaly, and hepatic dysfunction. Infection: Bacterial pneumonia, central venous line related sepsis, cryptococcal meningitis, cytomegalovirus (CMV) colitis, CMV retinitis, esophageal Candida, histoplasmosis, Kaposi’s sarcoma, non-specific mycoplasma, oral herpes, non-specific otitis, non-specific pharyngitis, pharyngeal herpes, non-specific serious infection, tonsillitis, tuberculosis, and viral encephalitis. Metabolic: Hyperglycemia, hypoglycemia, and hypocalcemia. Musculoskeletal: Arthralgia, gout, and myalgia. Neurological: Anxiety, confusion, depression, drowsiness, emotional lability, hallucination, hypesthesia, insomnia, memory loss, neuralgia, neuropathy, non-specific neuropathy, nervousness, paranoia, paresthesia, peripheral neuropathy, seizure, tremors, unsteady gait, and vertigo. Reproductive: Miscarriage. 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, non-specific sputum, and tachypnea. Skin: Desquamation, dry and breaking hair, dry skin, erythema, non-specific dermatitis, pruritus, rash, and urticaria. Special senses: Blepharitis, blurred vision, conjunctivitis, contact lens discomfort, eye pain or discomfort, hemianopsia, loss of taste, non-specific odor, and smell. Urogenital: Flank pain, incontinence, nephritis, renal failure, and renal pain. In a clinical trial where some adverse events were solicited by investigators, the incidences were as follows: Cough (62.7%) Decreased appetite (50.0%) Dizziness or light-headedness (45.1%) Fatigue (65.7%) Fever (51.0%) Non-specific serious infection (15.2%) Shortness of breath (48.3%) Wheezing (32.4%) From post-marketing clinical experience with Pentamidine Isethionate the following spontaneous adverse events have been reported: anaphylaxis, colitis, diabetes, dyspnea, esophigitis, hematochezia, increased blood urea nitrogen (BUN) and serum creatinine levels, melena, pancreatitis (see WARNINGS ), syndrome of inappropriate antidiuretic hormone (SIADH), and torsade 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.