NebuPent (pentamidine isethionate), an antipro-tozoal agent, is a nonpyrogenic lyophilizedprod-uct. After reconstitution with Sterile Water for Injection, USP, NebuPent is administered by inhalation via the Respirgard®II nebulizer [Marquest, Englewood, CO] (see DOSAGE AND ADMINISTRATION).

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

C₁₉H₂₄N₄O₂•2C₂H₆O₄S      592.68

Each vial contains 300 mg pentamidine isethionate.

Last updated on RxList: 12/15/2008

NebuPent is indicated for the prevention of Pneumocystis carinii pneumonia (PCP) in high-risk, HIVinfected patients defined by one or both of the following criteria:

1. a history of one or more episodes of PCP
2. a peripheral CD4+ (T4 helper/inducer) lymphocyte count less than or equal to 200/mm³.

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 PCP. The remaining patients without a history of PCP 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 NebuPent 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 PCP 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 PCP 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 NebuPent 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 PCP was low in all three dosage groups.

IMPORTANT: NEBUPENT 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 NEBUPENT SOLUTION WITH ANY OTHER DRUGS. DO NOT USE THE RESPIRGARD® II NEBULIZER TO ADMINISTER A BRONCHODILATOR.

Reconstitution

The contents of one vial (300 mg) must be dissolved in 6 mL Sterile Water for Injection, USP. Place the entire reconstituted contents of the vial into the Respirgard®II nebulizer reservoir for administration.

Dosage

The recommended adult dosage of NebuPent for the prevention of Pneumocystis carinii pneumonia is 300 mg once every four weeks administered via the Respirgard®II nebulizer.

The dose should be delivered until the nebulizer chamber is empty (approximately 30 to 45 minutes). The flow rate should be 5 to 7 liters per minute from a 40 to 50 pounds per square inch (PSI) air or oxygen source. Alternatively, a 40 to 50 PSI air compressor can be used with flow limited by setting the flowmeter at 5 to 7 liters per minute or by setting the pressure at 22 to 25 PSI. Low pressure (less than 20 PSI) compressors should not be used.

Stability

Freshly prepared solutions for aerosol use are recommended. After reconstitution with sterile water, the NebuPent solution is stable for 48 hours in the original vial at room temperature if protected from light.

Product No.	NDC No.
87715	63323-877-15	NebuPent (penta-midine isethionate) 300 mg lyophilized product in single dose vials, individually packaged.

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.

Abraxis Pharmaceutical Proucts, Schaumburg, IL 60173. Revised: December 2006. FDA revision date: 6/19/1996

Last updated on RxList: 12/15/2008

The most frequently reported unsolicited adverse events (1to 5%) in clinical trials, regardless of their relation to NebuPent 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, nonspecific 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, nonspecific 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 NebuPent 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.

While specific studies on drug interactions with NebuPent 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 NebuPent and other nephrotoxic drugs such as aminoglycosides, amphotericin B, cisplatin, foscarnet, or vancomycin should be closely monitored and avoided, if possible.

Last updated on RxList: 12/15/2008

The potential for development of acute PCP still exists in patients receiving NebuPent 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 PCP as well as for other opportunistic and nonopportunistic pathogens. The use of NebuPent may alter the clinical and radiographic features of PCP and could result in an atypical presentation, including but not limited to mild disease or focal infection.

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

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

Pulmonary

Inhalation of NebuPent may induce bronchospasm or cough. This has been noted particularly in some patients who have a history of smoking or asthma. In clinical trials, cough and bronchospasm were the most frequently reported adverse experiences associated with NebuPent administration (38% and15%, respectively of patients receiving the 300 mg dose); however less than1% of the doses were interrupted or terminated due to these effects. For the majority of patients, cough and bronchospasm were controlled by administration of an aerosolized bronchodilator (only1% of patients withdrew from the study due to treatment-associated cough or bronchospasm). In patients who experience bronchospasm or cough, administration of an inhaled bronchodilator prior to giving each NebuPent dose may minimize recurrence of the symptoms.

General

The extent and consequence of pentamidine accumulation following chronic inhalation therapy are not known. As a result, patients receiving NebuPent should be closely monitored for the development of serious adverse reactions that have occurred in patients receiving parenteral pentamidine, including hypotension, hypoglycemia, hyperglycemia, hypocalcemia, anemia, thrombocytopenia, leukopenia, hepatic or renal dysfunction, ventricular tachycardia, pancreatitis, Stevens-Johnson syndrome, hyperkalemia and abnormal ST segment of ECG.

Extrapulmonary infection with P. carinii has been reported infrequently. Most, but not all, of the cases have been reported in patients who have a history of PCP. The presence of extrapulmonary pneumocystosis should be considered when evaluating patients with unexplained signs and symptoms.

Cases of acute pancreatitis have been reported in patients receiving aerosolized pentamidine. NebuPent should be discontinued if signs or symptoms of acute pancreatitis develop.

Carcinogenesis, Mutagenesis and Impairment of Fertility

No studies have been conducted to evaluate the potential of pentamidine isethionate as a carcinogen or mutagen or to determine its effects on fertility.

Pregnancy–Pregnancy Category C

Animal reproduction studies have not been conducted with NebuPent. It is also not known whether NebuPent can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. NebuPent should be given to a pregnant woman only if clearly needed. NebuPent should not be given to a pregnant woman unless the potential benefits are judged to outweigh the unknown risks.

Nursing Mothers

It is not known whether NebuPent is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from Nebu- Pent, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Because many drugs are excreted in human milk, NebuPent should not be given to a nursing mother unless the potential benefits are judged to outweigh the unknown risks.

Pediatric Use

The safety and effectiveness of NebuPent in pediatric patients (birth to 16 years of age) have not been established.

Last updated on RxList: 12/15/2008

Once the diagnosis of Pneumocystis carinii pneumonia has been firmly established, there are no absolute contraindications to the use of pentamidine isethionate.

Last updated on RxList: 12/8/2004

Microbiology

Pentamidine isethionate, an aromatic diamidine, is known to have activity against Pneumocystis carinii. The mode of action is not fully understood. In vitro studies indicate that the drug interferes with protozoal nuclear metabolism by inhibition of DNA, RNA, phospholipid and protein synthesis.

Pharmacokinetics

In 5 AIDS patients with suspected Pneumocystis carinii pneumonia (PCP), the mean concentrations of pentamidine determined 18 to 24 hours after inhalation therapy were 23.2 ng/mL (range 5.1 to 43.0 ng/mL) in bronchoalveolar lavage fluid and 705 ng/mL (range 140 to 1336 ng/mL) in sediment after administration of a 300 mg single dose via the Respirgard®II nebulizer. In 3 AIDS patients with suspected PCP, the mean concentrations of pentamidine determined 18 to 24 hours after a 4 mg/kg intravenous dose were 2.6 ng/mL (range 1.5 to 4.0 ng/mL) in bronchoalveolar lavage fluid and 9.3 ng/mL (range 6.9 to 12.8 ng/mL) in sediment. In the patients who received aerosolized pentamidine, the peak plasma levels of pentamidine were at or below the lower limit of detection of the assay (2.3 ng/mL).

Following a single 2-hour intravenous infusion of 4 mg/kg of pentamidine isethionate to 6 AIDS patients, the mean plasma Cmax, T 1/2 and clearance were 612 ± 371 ng/mL, 6.4 ± 1.3 hr and 248 ± 91 L/hr respectively. In another study of aerosolized pentamidine in 13 AIDS patients with acute PCP who received 4 mg/kg/day administered via the Ultra Vent®jet nebulizer, peak plasma levels of pentamidine averaged18.8 ± 11.9 ng/mL after the first dose. During the next 14 days of repeated dosing, the highest observed Cmax averaged 20.5 ± 21.2 ng/mL. In a third study, following daily administration of 600 mg of inhaled pentamidine isethionate with the Respirgard®II nebulizer for 21days in11patients with acute PCP, mean plasma levels measured shortly after the 21st dose averaged 11.8 ± 10.0 ng/mL. Plasma concentrations after aerosol administration are substantially lower than those observed after a comparable intravenous dose. The extent of pentamidine accumulation and distribution following chronic inhalation therapy are not known.

In rats, intravenous administration of a 5 mg/kg dose resulted in concentrations of pentamidine in the liver and kidney that were 87.5 and 62.3-fold higher, respectively, than levels in those organs following 5 mg/kg administered as an aerosol.

No pharmacokinetic data are available following aerosol administration of pentamidine in humans with impaired hepatic or renal function.

Last updated on RxList: 12/15/2008

No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.

Last updated on RxList: 12/15/2008

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

PENTAMIDINE ISETHIONATE - INHALATION

(pen-TAM-ih-deen eye-seth-EYE-oh-nate)

COMMON BRAND NAME(S): Nebupent

USES: Pentamidine isethionate inhalation (prophylaxis) is used to prevent a serious lung infection (Pneumocystis pneumonia-PCP) in patients with acquired immunodeficiency syndrome (AIDS). It is used when the usual medications can not be used. Pentamidine belongs to a class of drugs known as antimicrobials. It works by killing the organism that causes the infection.

HOW TO USE: This medication is usually given in the hospital or clinic by a health care professional once every 4 weeks. It is given with a special machine that turns the medication into a mist for breathing. Each treatment takes 30 to 45 minutes. You may also be given another inhaled medication (e.g., albuterol) to help open your airways before each treatment with pentamidine. Learn the proper way to mix and give this medication. Follow all instructions from the manufacturer.

Dosage is based on your medical condition and response to treatment.

Use this medication regularly to get the most benefit from it. To help you remember, mark your appointment dates on a calendar on your calendar the days you should receive each dose.

Immediately tell your doctor if you develop problems with breathing/cough/fever between treatments.

SIDE EFFECTS: Cough, upset stomach, loss of appetite, nausea, vomiting, diarrhea, headache, or unusual taste in the mouth may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor or respiratory therapist immediately if any of these unlikely but serious side effects occur: chest tightness, breathing problems.

Though very unlikely, it is possible that inhaled pentamidine may be absorbed into the bloodstream. Tell your doctor immediately if any of these rare but very serious side effects occur: abdominal pain, persistent vomiting, unusual bruising/bleeding, sudden fast/irregular heartbeat, tingling/numbness of the hands/area around the mouth, decrease in the amount of urine, signs of low blood pressure (e.g., severe dizziness, pale skin, fainting), signs of low blood sugar (e.g., severe hunger, dizziness, shakiness, trouble thinking, fainting), signs of high blood sugar (e.g., increase in the amount of urine, increased tiredness, fruity breath odor), signs of another infection (e.g., increased fever, chills, persistent sore throat), mental/mood changes (e.g., confusion, hallucinations), signs of low red blood cells (e.g., worsening breathing problems, bluish skin/nails).

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching, swelling, severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before using pentamidine inhalation, tell your doctor or pharmacist if you are allergic to it; or to pentamidine injection; or if you have any other allergies.

Before using this medication, tell your doctor, respiratory therapist, or pharmacist your medical history, especially of: Pneumocystis pneumonia while receiving inhaled pentamidine prophylaxis, asthma, smoking.

Though unlikely, it is possible that inhaled pentamidine will be absorbed into your bloodstream. For this reason, tell your doctor, pharmacist, or respiratory therapist your medical history, especially of: certain heart problems (QT prolongation in the EKG, torsade de pointes), other heart problems (e.g., ventricular tachycardia, slow heartbeat, heart failure), family history of certain heart problems (QT prolongation in the EKG, sudden cardiac death), problems with low blood sugar (hypoglycemia), low blood pressure, high blood pressure, diabetes, kidney problems, liver problems, low blood calcium/potassium/magnesium levels, inflamed pancreas (pancreatitis), low white blood cells, low blood clotting cells (platelets), low red blood cells (anemia).

This drug may make you dizzy or drowsy. Use caution while driving, using machinery, or doing any activity that requires alertness.

Though unlikely, caution is advised when using this drug in the elderly because they may be more sensitive to the effects on the kidneys, blood pressure, and blood sugar.

During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor.

It is not known whether this drug passes into breast milk. Since this medication may cause serious side effects in a nursing infant, breast-feeding is not recommended. If you are HIV-positive, avoid breast-feeding since breast milk can transmit HIV to a nursing infant. Consult your doctor for more information.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: drugs that may also have kidney side effects (e.g., amphotericin B, tobramycin, gentamicin, cisplatin, foscarnet, vancomycin), certain "water pills" (potassium-wasting diuretics such as hydrochlorothiazide, furosemide).

Rarely, inhaled pentamidine may affect the heart rhythm. Other drugs besides pentamidine may also affect the heart rhythm (QT prolongation in the EKG), including flecainide, tolterodine, vardenafil, thioridazine, amitriptyline, amiodarone, ziprasidone, dofetilide, cisapride, and erythromycin, among others. Before using pentamidine, report all medications you are currently using to your doctor or pharmacist. QT prolongation can infrequently result in serious (rarely fatal) fast/irregular heartbeat and other symptoms (e.g., severe dizziness, fainting) that require immediate medical attention. Ask your doctor or pharmacist for more details and for instructions on how you may reduce the risk of this effect.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center.

NOTES: Do not share this medication with others.

Keep all inhaled pentamidine/medical/lab appointments.

MISSED DOSE: If you miss a dose, make an appointment to receive it as soon as you remember, then resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature between 59-86 degrees F (15-30 degrees C). Mixed solutions may be stored in the original vial for up to 48 hours at room temperature. Discard after 48 hours. Protect mixed and unmixed pentamidine from light. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For information about enrolling in MedicAlert, call 1-800-854-1166 (USA) or 1-800-668-1507 (Canada).

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.