Pentamidine Isethionate

Overdosage has not been reported with NebuPent (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 NebuPent (pentamidine isethionate) dosage would be required to produce systemic levels similar to a single 4 mg/kg intravenous dose.

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

Pentamidine may affect blood sugar levels. Contact your doctor if you experience any low blood sugar symptoms including

• increased appetite;
• headache;
• chills, pale skin, shakes, cold sweats; or
• anxiety.

Pentamidine may affect blood sugar levels. Contact your doctor if you experience any high blood sugar symptoms including

• increased thirst;
• loss of appetite;
• increase in amount or frequency or urination;
• fruity smelling breath; or
• drowsiness.

Your doctor may want you to have regular blood, heart function, and blood sugar evaluations during treatment with pentamidine to monitor progress and side effects.

Before taking this medication, tell your doctor if you have:

• diabetes;
• heart problems
• blood pressure or circulation problems;
• kidney disease;
• pancreatitis;
• asthma;
• recent radiation therapy or treatment with chemotherapy;
• a history of dehydration; or
• special dietary restrictions.

You may not be able to take pentamidine, or you may require a dosage adjustment or special monitoring during treatment if you have any of the conditions listed above.

Pentamidine may affect blood sugar levels. Contact your doctor if you experience any low blood sugar symptoms including

• increased appetite;
• headache;
• chills, pale skin, shakes, cold sweats; or
• anxiety.

Pentamidine may affect blood sugar levels. Contact your doctor if you experience any high blood sugar symptoms including

• increased thirst;
• loss of appetite;
• increase in amount or frequency or urination;
• fruity smelling breath; or
• drowsiness.

Your doctor may want you to have regular blood, heart function, and blood sugar evaluations during treatment with pentamidine to monitor progress and side effects.

Talk to your doctor if you develop an infection of any kind.

Pentamidine is in the FDA pregnancy category C. This means that it is not known whether pentamidine will harm an unborn baby. Do not take this medication without first talking to your doctor if you are pregnant.

It is not known whether pentamidine passes into breast milk. Do not take this medication without first talking to your doctor if you are breast-feeding a baby.

Since the medication will be administered by a healthcare provider, missing a dose should not occur. If you have any questions contact your doctor.

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

Read the entire FDA prescribing information for Nebupent (Pentamidine Isethionate)

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© Nebupent Patient Information is supplied by Cerner Multum, Inc. and Nebupent Consumer information is supplied by First Databank, Inc., used under license and subject to their respective copyrights.

Contraindications

• IV or IM: Known hypersensitivity to pentamidine.1

• Oral inhalation via nebulization: History of anaphylactic reaction to pentamidine administered parenterally or by oral inhalation.219

Warnings/Precautions

Warnings

IV or IM: Hypotension, which may develop suddenly and may be moderate to severe, can occur.1 15 41 43 52 83 86 124 159 167 188 202 279 Fatalities due to severe hypotension or cardiac arrhythmias reported.1 202 Hypotensive reactions most likely with rapid IV injection or infusion.1 15 21 124 159 188 202 279

Oral inhalation via nebulization: Hypotension, hypertension, and cardiac arrhythmias also reported rarely.219 278

When administering IM or IV, place patient in a supine position.1 Monitor BP during and after administration until stable; perform ECG before, during, and after administration.1

Appropriate equipment for maintenance of an adequate airway and other supportive measures and agents (e.g., IV fluids, vasopressor agents)124 159 for management of hypotensive reactions should be readily available.1

Use with caution in patients with hypertension, hypotension, or ventricular tachycardia.1

IV: Extravasation may result in ulceration, tissue necrosis, and/or sloughing at injection site; long-term sequelae reported.1 Properly position and closely observe IV needle and catheter throughout infusion; if extravasation occurs, immediately discontinue infusion and restart in another vein.1 Phlebitis also reported.183

IM: Sterile abscess and/or necrosis,1 81 83 86 124 pain,1 83 124 erythema,85 89 tenderness,85 89 and induration at injection site.1 85 89

Hypoglycemia, which may be severe and has been fatal in some cases, reported with IM or IV pentamidine.1 31 32 33 34 35 81 83 84 85 86 89 90 165 167 169 180 188 202 243 Has been associated with pancreatic islet cell necrosis and inappropriately high plasma insulin concentrations.1

Hyperglycemia1 81 83 167 and insulin-dependent diabetes mellitus1 31 35 52 275 (which appears to be permanent in some cases)52 has occurred with or without preceding hypoglycemia1 275 and ketoacidosis1 in patients receiving parenteral pentamidine.31 52

Hypoglycemia,203 217 219 277 279 hyperglycemia,219 275 and diabetes219 also have occurred in patients receiving pentamidine by oral inhalation via nebulization.

Monitor blood glucose concentrations before, during (daily or every other day), and after IM or IV pentamidine.1 135 169 165 180

Use with caution in patients with hypoglycemia or hyperglycemia.1

Acute pancreatitis1 128 166 168 322 335 (sometimes fatal)168 reported with IM or IV pentamidine. Acute pancreatitis also reported rarely in patients receiving pentamidine by oral inhalation via nebulization.219 246 274

Use with caution in patients with pancreatitis.1 Discontinue if acute pancreatitis occurs.166 219

Use IM or IV pentamidine for treatment of PCP only in patients in whom the presence of P. jirovecii has been demonstrated.1

Prior to initiating pentamidine oral inhalation via nebulization for prevention of PCP, evaluate symptomatic patients to rule out P. jirovecii infection.219 Dosage of orally inhaled pentamidine used for prevention of PCP is insufficient for treatment of PCP.219

Patients receiving the drug for prevention of PCP may still develop acute PCP.219 278 Extrapulmonary and/or disseminated P. jirovecii infection also reported occasionally during PCP prophylaxis,200 219 231 236 239 240 249 276 278 usually in patients with a history of PCP.219 236 240 249 276

Monitor patients receiving PCP prophylaxis for signs and symptoms of pulmonary infection (e.g., fever, cough, dyspnea); evaluate those with signs or symptoms to rule out infection caused by P. jirovecii or other opportunistic or nonopportunistic pathogens.219 223 239 247 249 If PCP develops, discontinue prophylaxis and initiate treatment with co-trimoxazole, parenteral pentamidine, or another effective regimen.195 221 223 247 248 PCP prophylaxis can be reinstituted when treatment is complete.221 247

Cough and bronchospasm reported frequently when pentamidine administered by oral inhalation via nebulization,219 231 277 278 279 especially in those with a history of smoking or asthma.174 208 211 212 217 Bronchospasm also reported after parenteral administration.1 210

Cough or bronchospasm in patients receiving pentamidine by oral inhalation can be controlled in most patients by interrupting pentamidine treatment and administering a bronchodilator.193 211 212 219 278 279 Coughing also may be controlled by slowing the delivery or intensity of the pentamidine aerosol stream.193 195 211 212 217

Pretreatment with an orally inhaled bronchodilator may minimize occurrence of coughing and bronchospasm.176 177 193 208 211 212 279 315 316

Sensitivity Reactions

IM or IV: Anaphylaxis,1 anaphylactoid reactions with shock,52 53 Stevens-Johnson syndrome,1 83 and toxic epidermal necrolysis reported.125 Use with caution in patients with Stevens-Johnson syndrome.1 219

Oral inhalation via nebulization: Anaphylaxis, allergic reaction, and nonspecific allergy reported.219

Pruritus,1 83 83 101 210 local or generalized urticaria,1 52 124 167 210 rash1 83 124 167 279 337 (e.g., maculopapular, pruritic)124 337 also reported with IM or IV administration.

Rash,174 193 219 242 including severely pruritic, maculopapular eruption on upper chest and back,242 also reported in patients receiving the drug by oral inhalation via nebulization.1 219 278

Major Toxicities

IM or IV: Nephrotoxicity (increase in Scr and/or BUN, azotemia, renal insufficiency, renal failure) reported.1 52 83 84 85 86 89 90 96 167 169 188 202 271 279

Oral inhalation via nebulization: Flank pain,219 incontinence,219 increased BUN and Scr,219 nephritis,219 renal failure,219 renal pain,219 and syndrome of inappropriate antidiuretic hormone secretion (SIADH)219 reported rarely.219 244

Monitor renal function (BUN, Scr) before, during (daily or every other day), and after therapy.1 135 165 169 Consider monitoring serum potassium concentrations, particularly in AIDS patients.258 259

Ensure that patients are well hydrated; monitor fluid status.258 259 (See Renal Impairment under Cautions.)

IM or IV: Elevated liver function test results reported.1 83 167 169 174 202

Hepatitis,1 219 hepatomegaly,1 219 and hepatic dysfunction1 219 reported in patients receiving the drug parenterally or by oral inhalation via nebulization.

Monitor hepatic function (serum bilirubin, alkaline phosphatase, AST, ALT) before, during, and after therapy.1 (See Hepatic Impairment under Cautions.)

IM or IV: Leukopenia (e.g., neutropenia)1 188 202 279 and thrombocytopenia,1 83 167 188 202 279 which can be severe (e.g., leukocyte count <1000/mm3, platelet count <20,000/mm3),1 occur occasionally.1 83 188 202 Anemia,1 83 167 167 eosinophilia,1 pancytopenia,1 and prolonged clotting time1 reported rarely.1

Oral inhalation via nebulization: Anemia reported occasionally; eosinophilia, neutropenia, nonspecific cytopenia, pancytopenia, and thrombocytopenia also reported.219

Monitor CBCs and platelet counts.1 Use with caution in patients with leukopenia, thrombocytopenia, or anemia.1 219

General Precautions

Consider that serious adverse effects reported with parenteral pentamidine also may occur when the drug is administered by oral inhalation via nebulization.174 203 219

Monitor renal function (BUN, Scr) before, during (daily or every other day), and after IM or IV pentamidine;1 135 165 169 consider monitoring serum potassium concentrations, particularly in AIDS patients.258 259 Also monitor renal function and for hyperkalemia in patients receiving the drug by oral inhalation via nebulization.219 (See Renal Impairment under Cautions.)

Monitor hepatic function (serum bilirubin, alkaline phosphatase, AST, ALT) before, during, and after IM or IV pentamidine.1 Also monitor hepatic function in patients receiving the drug by oral inhalation via nebulization.219 (See Hepatic Impairment under Cautions.)

Monitor blood glucose concentrations before, during (daily or every other day), and after IM or IV pentamidine.1 135 169 165 180 Also monitor for hypoglycemia and hyperglycemia in patients receiving the drug by oral inhalation via nebulization.219

Because hypocalcemia has been reported, monitor serum calcium concentrations before, during, and after IM or IV pentamidine.1 83 167 Also monitor for hypocalcemia in patients receiving the drug by oral inhalation via nebulization.219

Potential risks of environmental exposure to aerosolized pentamidine in health-care personnel and visitors or other individuals present when patients are receiving pentamidine by oral inhalation via nebulization not known.205 211 212 247 251 252 261 264 285 378 380 381 Measurable levels of pentamidine can be present in room air when pentamidine is administered by oral inhalation via nebulization.261 294 378 380 381

Adverse effects reported in health-care personnel and others exposed to aerosolized pentamidine in the environment include eye irritation (e.g., conjunctivitis);204 263 perioral and perinasal paresthesia;263 burning sensation of the eyes, nose, and throat;264 sinus irritation;264 shortness of breath;262 264 338 cough;264 tightness of the chest;264 338 acute bronchospasm;262 headache;264 and light-headedness.264

Cough and bronchospasm frequently occur in patients receiving pentamidine by oral inhalation via nebulization;219 231 277 278 279 health-care personnel and other individuals present during administration of the drug may be at risk of exposure to pathogens that can be transmitted when patients cough (e.g., Mycobacterium tuberculosis).250 264 266 285 380

Because of concerns about potential risks of environmental exposure to aerosolized pentamidine and lack of data regarding potential effects of the drug on the fetus or pregnancy,205 247 251 252 261 264 285 294 some clinicians suggest that pregnant women205 261 264 and possibly those planning to become pregnant (e.g., within 8 weeks of potential exposure)264 avoid environmental exposure to aerosolized pentamidine.

Health-care personnel administering aerosolized pentamidine should be familiar with the manufacturer's instructions for use of the nebulizer delivery system; improper use potentially could result in release of substantial amounts of pentamidine into the environment.247 261

Because potential risks, particularly long-term and cumulative effects, associated with environmental exposure to aerosolized pentamidine not established,205 247 251 252 261 264 285 378 380 381 health-care facilities should have procedures to minimize environmental exposure to aerosolized pentamidine.205 251 261 262 264 378 380 381 Consult specialized sources for recommended procedures.211 212 251 261 262 264

Specific Populations

Category C.1 219

For treatment of first-stage (hemolymphatic) trypanosomiasis† or treatment of leishmaniasis† in pregnant women, WHO states do not use IM or IV pentamidine during first trimester of pregnancy, but may use after first trimester.44 46

Some clinicians suggest that pregnant women and possibly those planning to become pregnant (e.g., within 8 weeks of potential exposure) avoid environmental exposure to aerosolized pentamidine.205 261 264 (See Environmental Exposure of Health-care Personnel and Visitors under Cautions.)

Not known whether distributed into milk.1 219 Discontinue nursing or the drug.1 219

IM or IV: Safety and efficacy established for treatment of PCP in children >4 months of age;1 no unusual risks identified.85 89 90 130 Also has been used effectively and apparently without unusual risks in children for treatment of first-stage (hemolymphatic) African trypanosomiasis†100 101 and for treatment of leishmaniasis†.53

Oral inhalation via nebulization: Manufacturer states safety and efficacy not established in children ≤16 years of age.219 Recommended by CDC, NIH, IDSA, and AAP as an alternative for prevention of PCP in children ≥5 years of age† capable of effectively using the Respirgard II jet nebulizer.156

IM or IV: Use with caution in patients with hepatic impairment;1 219 safety and efficacy of alternative dosage regimens not established in these patients.1

Oral inhalation via nebulization: Pharmacokinetic data not available.219

IM or IV: Use with caution in patients with renal impairment;1 safety and efficacy of alternative dosage regimens not established in these patients.1 (See Renal Impairment under Dosage and Administration.)

Oral inhalation via nebulization: Pharmacokinetic data not available.219

Common Adverse Effects

IM or IV: Nephrotoxicity,1 83 84 85 86 89 96 167 169 188 202 271 hypotension,1 41 43 52 83 86 124 159 167 188 202 279 hepatic effects,1 83 167 169 174 202 GI effects (anorexia, nausea, vomiting),1 52 83 90 167 202 219 278 279 hematologic effects (leukopenia),1 188 202 279 hypoglycemia,1 31 32 33 34 35 81 83 84 85 86 89 90 165 167 169 180 188 202 243 injection site reactions.1 81 83 86 124

Oral inhalation via nebulization: Respiratory effects (cough, bronchospasm, wheezing, shortness of breath),219 222 231 278 279 GI effects (diarrhea, nausea, decreased appetite).219

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name