Label: PENTAMIDINE ISETHIONATE inhalant

For Oral Inhalation Only

Pentamidine Isethionate for inhalation, an antifungal agent, is a nonpyrogenic lyophilized product. After reconstitution with Sterile Water for Injection, USP, Pentamidine Isethionate is administered by inhalation via the Respirgard ® II nebulizer [Marquest, Englewood, CO] (see DOSAGE AND ADMINISTRATION).

Pentamidine isethionate, 4,4’-[1,5-pentane-diylbis(oxy)]bis-benzenecarboximidamid, is a white crystalline powder soluble in water and glycerin and insoluble in ether, acetone, and chloroform.

C 19H 24N 4O 2•2C 2H 6O 4S 592.68

Each vial contains 300 mg pentamidine isethionate.

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.

Pentamidine Isethionate is contraindicated in patients with a ­history of an anaphylactic reaction to inhaled or parenteral pentamidine isethionate.

The potential for development of acute PJP still exists in patients receiving Pentamidine Isethionate prophylaxis. Therefore, any patient with symptoms suggestive of the presence of a pulmonary infection, including but not limited to dyspnea, fever or cough, should receive a thorough medical evaluation and appropriate diagnostic tests for possible acute PJP as well as for other opportunistic and nonopportunistic pathogens. The use of Pentamidine Isethionate may alter the clinical and radiographic features of PJP and could result in an atypical presentation, including but not limited to mild disease or focal ­infection.

Prior to initiating Pentamidine Isethionate prophylaxis, symptomatic patients should be evaluated appropriately to exclude the presence of PJP. The recommended dose of Pentamidine Isethionate for the prevention of PJP is insufficient to treat acute PJP.

IMPORTANT: DO NOT MIX THE PENTAMIDINE ISETHIONATE SOLUTION WITH ANY OTHER DRUGS. DO NOT USE THE RESPIRGARD® II NEBULIZER TO ADMINISTER A BRONCHODILATOR. (See DOSAGE AND ADMINISTRATION).

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.

Overdosage has not been reported with Pentamidine Isethionate. The symptoms and signs of overdosage are not known.

A serious overdosage, to the point of producing systemic drug levels similar to those following parenteral administration, would have the potential of producing similar types of serious systemic toxicity. (See PRECAUTIONS).

Available clinical pharmacology data (see CLINICAL PHARMACOLOGY) suggest that a dose up to 40 times the recommended Pentamidine Isethionate dosage would be required to produce systemic levels similar to a single 4 mg/kg intravenous dose.

IMPORTANT: PENTAMIDINE ISETHIONATE MUST BE DISSOLVED ONLY IN STERILE WATER FOR INJECTION, USP. DO NOT USE SALINE SOLUTION FOR RECONSTITUTION BECAUSE THE DRUG WILL PRECIPITATE. DO NOT MIX THE PENTAMIDINE ISETHIONATE SOLUTION WITH ANY OTHER DRUGS. DO NOT USE THE RESPIRGARD® II NEBULIZER TO ADMINISTER A BRONCHODILATOR.

Pentamidine Isethionate 300 mg lyophilized product is supplied as:
Single-dose glass vial (NDC 39822-3030-01), individually packaged as 1 vial per carton (NDC 39822-3030-02)

Store dry product at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

Protect the dry product and the reconstituted solution from light.

Manufactured for:
XGen Pharmaceuticals DJB, Inc.
Big Flats, NY 14814

Rx only

Revised: September 2022

PENH-PI-05

PC5142A

PACKAGE LABEL – PRINCIPAL DISPLAY – Pentamidine Isethionate 300 mg Single Dose Vial Label

NDC 39822-3030-1

Pentamidine Isethionate

300 mg

Lyophilized

For Inhalation Solution

Single-Dose Vial

Rx only

CARTON – PRINCIPAL DISPLAY – Pentamidine Isethionate 300 mg Single Dose Vial Carton

NDC 39822-3030-2

Pentamidine Isethionate

300 mg

Lyophilized

For Inhalation Solution

Single-Dose Vial Carton

Rx only