Pentamidine Isethionate

Class: Antiprotozoals, Miscellaneous
VA Class: AP100
Chemical Name: 4,4′-[1,5-Pentanediylbis(oxy)]bisbenzenecarboximidamide dimethanesulfonate
CAS Number: 140-64-7
Brands: NebuPent, Pentam 300

Introduction

Antiprotozoal; aromatic diamidine-derivative.^{1 2 3 4}

Uses for Pentamidine Isethionate

Pneumocystis jiroveci (Pneumocystis carinii) Pneumonia

Treatment of Pneumocystis jiroveci (formerly Pneumocystis carinii) pneumonia (PCP); designated an orphan drug by FDA for this use.^{1 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 96 156 157 167 344}

Parenteral pentamidine is an alternative to co-trimoxazole (the drug of choice) for treatment of pneumocystis pneumonia; can be used in patients who do not respond to or cannot tolerate co-trimoxazole,^{88 89 90 91 186 187 199 303 310 311} including those with a history of severe allergic reactions to either component of co-trimoxazole (i.e., sulfonamides or trimethoprim).^{88 186 199 310 311}

Prevention of initial episodes of pneumocystis pneumonia (primary prophylaxis) in immunocompromised individuals at increased risk, including HIV-infected individuals; pentamidine oral inhalation designated an orphan drug by FDA for this use.^{79 216 219 220 221 230 231 278 285 295 342 343 347 356 357} Pentamidine given by oral inhalation is one of several alternatives that can be used in adults, adolescents, and children who cannot tolerate co-trimoxazole (the drug of choice).^{299 300 303 351 356 358}

Long-term suppressive or chronic maintenance therapy (secondary prophylaxis) to prevent recurrence following an initial episode of pneumocystis pneumonia in immunocompromised patients, including HIV-infected individuals; pentamidine oral inhalation designated an orphan drug by the FDA for this use.^{79 177 178 187 193 195 198 208 212 213 219 220 221 230 231 285 343 347 356} Pentamidine given by oral inhalation is one of several alternatives that can be used in adults, adolescents, and children who cannot tolerate co-trimoxazole (the drug of choice).^{299 300 303 351 356 358}

African Trypanosomiasis

Treatment of trypanosomiasis caused by Trypanosoma brucei gambiense† (Gambian sleeping sickness, West African trypanosomiasis).^{2 15 41 42 43 44 100 101 102 103 105 106 107 145 146} A drug of choice in early (hemolymphatic) stage of T. b. gambiense infection.^{41 43 44 91 105 303} Should not be used for late disease with CNS involvement since pentamidine penetrates the CNS poorly.^{15 43 44 100 101 102 103 105 146 303}

Has been used with some success for treatment of trypanosomiasis caused by T. b. rhodesiense† (Rhodesian sleeping sickness, East African trypanosomiasis).^{15 43 44 91 105 106 149 150} Other drugs preferred (e.g., suramin or melarsoprol [drugs not commercially available in US, but may be available from CDC]).^{91 303}

Leishmaniasis

Has been effective for treatment of cutaneous and mucocutaneous leishmaniasis† caused by various Leishmania spp.^{15 46 47 55 56 57 114 154 155 265 303} Usual drugs of choice are pentavalent antimony compounds (e.g., sodium stibogluconate or meglumine antimonate [drugs not commercially available in the US]);^{91 265 303 b} pentamidine is an alternative and may be a drug of choice in patients who fail to respond to antimony compounds.^{91 303 b}

Has been effective for treatment of visceral leishmaniasis (kala-azar) caused by Leishmania donovani†.^{15 46 47 113 136 137 138 152 153 265} Usual drugs of choice for initial treatment of visceral leishmaniasis caused by L. donovani (usually endemic in Asia and Africa), L. infantum (usually endemic in the Mediterranean basin), or L. chagasi (usually endemic in Latin America) are pentavalent antimony compounds,^{46 113 265} but resistance and treatment failures are becoming increasingly common.²⁶⁵ Both IV amphotericin B and parenteral pentamidine are considered alternatives and have been effective in patients who failed to respond to antimony compounds.^{46 47 91 113 265 303}

Pentamidine Isethionate Dosage and Administration

Administration

Administer by slow IV infusion or IM injection or by oral inhalation via nebulization.^{1 219}

IV (not IM) route usually is recommended for treatment of pneumocystis pneumonia;^{91 199} oral inhalation is used for prophylaxis of pneumocystis pneumonia.^{91 356}

Since severe hypotensive reactions can occur following IV or IM administration of pentamidine, patients should be in a supine position and BP should be monitored closely during and after parenteral administration of the drug.¹ (See Hypotension and Other Cardiovascular Effects under Cautions.)

IV Administration

Avoid extravasation; irritating to tissues.¹ Position the IV needle or catheter carefully; observe throughout the period of administration.¹ If extravasation occurs, immediately stop the infusion and restart at another site.¹ (See Local Effects under Cautions.)

Reconstitution and Dilution

Reconstitute vial containing 300 mg of pentamidine isethionate for injection with 3, 4, or 5 mL of sterile water for injection or 5% dextrose injection to provide a solution containing 100, 75, or 60 mg/mL, respectively.¹

Dilute an appropriate volume of the reconstituted solution in 50–250 mL of 5% dextrose injection.¹

Rate of Administration

IV infusions are given over 60–120 minutes to minimize the risk of hypotensive reactions.¹ Do not administer by rapid IV injection or infusion.^{1 124}

IM Administration

Administer by deep IM injection.¹ Local adverse effects may be minimized by using the Z-tract technique (firmly push subcutaneous tissue aside before inserting the needle at a 90-degree angle).³²¹

Reconstitution

Reconstitute vial containing 300 mg of pentamidine isethionate for injection with 3 mL of sterile water for injection to provide a solution containing 100 mg/mL.¹

Oral Inhalation

Following reconstitution of the powder for oral inhalation (NebuPent), the solution is administered using a Respirgard II jet nebulizer.^{219 231 255}

Consult the manufacturer's information for detailed administration instructions.^{219 231 255}

Pentamidine isethionate for oral inhalation solution should not be admixed with any other drugs; the Respirgard II jet nebulizer should not be used to administer a bronchodilator.²¹⁹

Reconstitution

Reconstitute vial containing 300 mg of pentamidine isethionate for oral inhalation (NebuPent) with 6 mL of sterile water for injection.²¹⁹ Do not use sodium chloride solution; precipitation will occur.²¹⁹

Rate of Administration

Place the reconstituted solution for oral inhalation into the reservoir of the Respirgard II jet nebulizer and deliver until the nebulizer chamber is empty (approximately 30–45 minutes) using a flow rate of 5–7 L/minute and an air or oxygen source at 40–50 PSI.^{219 231} Alternatively, use an air compressor delivering 40–50 PSI by setting the flowmeter at 5–7 L/minute or the pressure at 22–25 PSI; low-pressure (i.e., less than 20 PSI) air compressors should not be used.^{219 230}

Dosage

Available as pentamidine isethionate in the US; dosage expressed as pentamidine isethionate.^{1 219}

May be available outside the US as the mesylate salt; dosage of the mesylate salt is expressed as the base.^{160 206} Consider that dosages used in some published references may be unclear since the salt employed may not be specified.^{15 100 101 102 103 104 108 111 146 149 206 207}

Pediatric Patients

Pneumocystis jiroveci (Pneumocystis carinii) Pneumonia

Treatment

IV or IM

Children >4 months of age: 3–4 mg/kg once daily for 14–21 days.^{1 88 89 90 91 92 187 214 277 279}

Adolescents: 3–4 mg/kg once daily for 14–21 days.⁹¹

Some patients may require more prolonged treatment;^{156 157 165} manufacturer cautions that therapy for >21 days may be associated with increased toxicity.¹

Primary Prophylaxis

Inhalation

Children ≥5 years of age†: 300 mg every 4 weeks (once monthly).^{91 219 230 299 300 310 312 319 351 356} The child must be capable of effectively using a nebulizer; other appropriate agents (co-trimoxazole, dapsone, atovaquone) recommended for younger children.³⁵⁶

In HIV-infected children 1–5 years of age, primary prophylaxis should be initiated if CD4⁺ T-cell counts are <500/mm³ or CD4⁺ percentage is <15%.^{356 358} In HIV-infected children 6–12 years of age, primary prophylaxis should be initiated if CD4⁺ T-cell counts are <200/mm³ or CD4⁺ percentage is <15%.^{356 358}

Adolescents†: Dosage and criteria for initiation or discontinuance of primary prophylaxis in this age group are the same as those recommended for adults.³⁵⁶ (See Adult Dosage under Dosage and Administration.)

Prevention of Recurrence (Secondary Prophylaxis)

Inhalation

Children ≥5 years of age†: 300 mg every 4 weeks (once monthly).^{91 219 221 230 299 300 310 312 319 351 356} The child must be capable of effectively using a nebulizer; other appropriate agents (co-trimoxazole, dapsone, atovaquone) recommended for younger children.³⁵⁶

The safety of discontinuing secondary prophylaxis in HIV-infected children receiving potent antiretroviral therapy has not been extensively studied.³⁶⁵ Children who have a history pneumocystis pneumonia should receive life-long suppressive therapy to prevent recurrence.³⁵⁶

Adolescents†: Dosage and criteria for initiation or discontinuance of secondary prophylaxis in this age group are the same as those recommended for adults.³⁵⁶ (See Adult Dosage under Dosage and Administration.)

African Trypanosomiasis†

Treatment of Trypanosoma brucei gambiense Infections†

IM

4 mg/kg once daily for 10 days recommended by CDC and others.^{91 143 214}

Leishmaniasis†

Treatment of Cutaneous Leishmaniasis†

IV or IM

2–3 mg/kg once daily or every other day for 4–7 doses.^{91 265}

Treatment of Visceral Leishmaniasis Caused by Leishmania donovani (Kala-azar)†

IV or IM

2–4 mg/kg once daily or every other day for 15–30 doses recommended by CDC and others.^{91 143 214} Some clinicians recommend 4 mg 3 times weekly for 15–25 doses.²⁶⁵

Adults

Pneumocystis jiroveci (Pneumocystis carinii) Pneumonia

Treatment

IV or IM

3–4 mg/kg once daily for 14–21 days.^{1 88 89 90 91 92 187 214 277 279}

Some patients may require more prolonged treatment;^{156 157 165} manufacturer cautions that therapy for >21 days may be associated with increased toxicity.¹

Primary Prophylaxis

Inhalation

300 mg every 4 weeks (once monthly).^{91 219 221 230 299 310 312 319 356}

Initiate primary prophylaxis in patients with CD4⁺ T-cell counts <200/mm³ or a history of oropharyngeal candidiasis.³⁵⁶ Also consider primary prophylaxis if CD4⁺ T-cell percentage is <14% or there is a history of an AIDS-defining illness.³⁵⁶

Primary prophylaxis can be discontinued in adults and adolescents responding to potent antiretroviral therapy who have a sustained (≥3 months) increase in CD4⁺ T-cell counts from <200/mm³ to >200/mm³.³⁵⁶ However, it should be restarted if CD4⁺ T-cell count decreases to <200/mm³.³⁵⁶

Prevention of Recurrence (Secondary Prophylaxis)

Inhalation

300 mg every 4 weeks (once monthly).^{91 219 230 299 310 312 319 356}

Initiate long-term suppressive therapy or chronic maintenance therapy (secondary prophylaxis) in those with a history of P. jiroveci pneumonia to prevent recurrence.³⁵⁶

Discontinuance of secondary prophylaxis is recommended in those who have a sustained (≥3 months) increase in CD4⁺ T-cell counts to >200/mm³ since such prophylaxis appears to add little benefit in terms of disease prevention and discontinuance reduces the medication burden, the potential for toxicity, drug interactions, selection of drug-resistant pathogens, and cost.³⁵⁶

Reinitiate secondary prophylaxis if CD4⁺ T-cell count decreases to <200/mm³ or if P. jiroveci pneumonia recurs at a CD4⁺ T-cell count >200/mm³.³⁵⁶ It probably is prudent to continue secondary prophylaxis for life in those who had P. jiroveci episodes when they had CD4⁺ T-cell counts >200/mm³.³⁵⁶

African Trypanosomiasis†

Treatment of Trypanosoma brucei gambiense Infections†

IM

4 mg/kg once daily for 10 days recommended by CDC and others.^{91 143 214}

Leishmaniasis†

Treatment of Cutaneous Leishmaniasis†

IV or IM

2–3 mg/kg once daily or every other day for 4–7 doses.^{91 265}

Treatment of Visceral Leishmaniasis Caused by Leishmania donovani (Kala-azar)†

IV or IM

2–4 mg/kg once daily or every other day for 15–30 doses recommended by CDC and others.^{91 143 214} Some clinicians recommend 4 mg 3 times weekly for 15–25 doses.²⁶⁵

Special Populations

Renal Impairment

Some clinicians suggest that dosage adjustment may be needed if parenteral pentamidine is used in patients with severe renal impairment.^{77 131 132 133 185} Manufacturer states that parenteral pentamidine should be used with caution in patients with renal impairment and that safety and efficacy of alternative dosage regimens have not been established in these patients.¹

Cautions for Pentamidine Isethionate

Contraindications

• 
  

  Known hypersensitivity to pentamidine or any ingredient in the formulation.^{1 219}

  
  

Warnings/Precautions

Warnings

Hypotension and Other Cardiovascular Effects

Parenteral administration: Hypotension (which may develop suddenly and may be moderate to severe) may occur following IM or IV administration.^{1 15 41 43 52 83 86 87 124 159 167 188 202 279} 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}

When administering IV or IM pentamidine, place patient in a supine position.¹ Monitor blood pressure during and after administration until blood pressure is stable; monitor ECGs.¹

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

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

Local Effects

IV administration: Extravasation may result in ulceration, tissue necrosis, and/or sloughing at the injection site; long-term sequelae reported.¹ Manage symptomatically; surgical debridement and skin grafting may be needed.¹

IM administration: Sterile abscess,^{1 81 83 86 124} pain,^{1 83 124} erythema,^{85 89} tenderness,^{85 89} and induration at injection site.^{1 85 89}

Hypoglycemia and Diabetogenic Effects

Hypoglycemia^{1 31 32 33 34 35 81 83 84 85 86 87 88 89 90 95 165 167 169 180 188 202 243} (sometimes fatal) associated with pancreatic islet cell necrosis and high plasma insulin concentrations reported with IV or IM pentamidine.¹

Hyperglycemia^{1 81 83 167} and insulin-dependent diabetes mellitus^{1 31 35 52 275} (which appears to be permanent in some cases)⁵² has occurred with or without preceding hypoglycemia^{1 275} and ketoacidosis¹ in patients receiving parenteral therapy ^{31 52} or oral inhalation of the drug;²⁷⁵ these adverse effects sometimes occurred several months after discontinuance of parenteral therapy.^{1 31 52}

Monitor blood glucose concentrations before, during (daily or every other day), and after therapy.^{1 135 169 165 180 329}

Use with caution in patients with hypoglycemia or hyperglycemia.¹

Pancreatitis

Acute pancreatitis^{1 128 166 168 322 335} (sometimes fatal)¹⁶⁸ reported with IV or IM administration. Severe pancreatitis also reported rarely with orally inhaled pentamidine.^{219 246 274}

Use parenteral pentamidine with caution in patients with pancreatitis.¹ Discontinue orally inhaled pentamidine if acute pancreatitis occurs.²¹⁹

Selection and Use for Treatment or Prevention of Pneumocystis Pneumonia

Use pentamidine for treatment of pneumocystis pneumonia only in patients in whom the presence of P. jiroveci has been demonstrated.¹

Dosage of orally inhaled pentamidine used for prophylaxis is insufficient for treatment of acute pneumocystis pneumonia.²¹⁹ Prior to initiating primary prophylaxis, evaluate symptomatic patients to rule out P. jiroveci infection.²¹⁹

Consider that orally inhaled pentamidine may not be completely protective and some patients receiving the drug for prophylaxis may develop acute pneumocystis pneumonia.^{219 230 278} Extrapulmonary and/or disseminated infection also reported occasionally during prophylaxis,^{200 219 231 236 239 240 249 276 278} usually in patients with a history of pneumocystis pneumonia.^{219 236 240 249 276}

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

Respiratory Effects

Cough and bronchospasm reported frequently with orally inhaled pentamidine,^{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 the occurrence of coughing and bronchospasm.^{176 177 178 193 208 211 212 279 315 316}

Sensitivity Reactions

Parenteral administration: Allergic reactions reported, including pruritus,^{83 101 210} local or generalized urticaria,^{52 124 167 210} rash^{1 83 95 124 167 279 337} (e.g., maculopapular, pruritic),^{124 337} anaphylaxis,¹ Stevens-Johnson syndrome,^{1 83} and toxic epidermal necrolysis.¹²⁵ Use with caution in patients with Stevens-Johnson syndrome.^{1 219}

Oral inhalation: Allergic reactions reported.²¹⁹

Major Toxicities

Renal Effects

Parenteral administration: Nephrotoxicity (increase in Scr and/or BUN, azotemia, renal insufficiency, renal failure) reported.^{1 52 83 84 85 86 87 89 90 95 96 167 169 188 202 271 279}

Monitor renal function (BUN, Scr) before, during (daily or every other day), and after therapy.^{1 135 165 169 329} 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.)

Hepatic Effects

Parenteral administration: Elevated liver function test results reported.^{1 83 87 95 167 169 174 202} Monitor hepatic function (serum bilirubin, alkaline phosphatase, AST, ALT) before, during, and after therapy.¹ (See Hepatic Impairment under Cautions.)

Hematologic Effects

Parenteral administration: Leukopenia (e.g., neutropenia)^{1 95 188 202 279} and thrombocytopenia,^{1 83 95 167 188 202 279} which can be severe (e.g., leukocyte count <1000/mm³, platelet count <20,000/mm³),^{1 95} occur occasionally in patients receiving parenteral pentamidine.^{1 83 95 188 202} Anemia occurs rarely.^{1 83 167}

Oral inhalation: Neutropenia has occurred in several patients receiving the drug by oral inhalation,^{174 219} but these patients generally had low pretreatment leukocyte counts associated with zidovudine therapy.¹⁷⁴

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 with oral inhaled pentamidine.^{174 203 219}

Laboratory Monitoring

Monitor renal function (BUN, Scr) before, during (daily or every other day), and after parenteral therapy.^{1 135 165 169 329} Consider monitoring serum potassium concentrations, particularly in AIDS patients.^{258 259} Also monitor renal function and for hyperkalemia in patients receiving orally inhaled pentamidine.²¹⁹

Monitor hepatic function (serum bilirubin, alkaline phosphatase, AST, ALT) before, during, and after parenteral therapy.¹ Also monitor hepatic function in patients receiving orally inhaled pentamidine.²¹⁹ (See Hepatic Impairment under Cautions.)

Monitor blood glucose concentrations before, during (daily or every other day), and after parenteral therapy.^{1 135 169 165 180 329} Also monitor for hypoglycemia and hyperglycemia in patients receiving orally inhaled pentamidine.²¹⁹

Because hypocalcemia has been reported with parenteral pentamidine, monitor serum calcium concentrations before, during, and after therapy.^{1 83 167} Also monitor for hypocalcemia in patients receiving orally inhaled pentamidine.²¹⁹

Environmental Exposure of Health-care Personnel and Visitors

The potential risks of environmental exposure to aerosolized pentamidine by health-care personnel and visitors in contact with patients receiving pentamidine inhalation therapy are unknown.^{205 211 212 230 247 251 252 261 264 285} Adverse effects have been reported in health-care personnel and others exposed to aerosolized pentamidine (e.g., 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 light-headedness).²⁶⁴

CDC and others recommend that health-care personnel administering aerosolized pentamidine be familiar with the manufacturer's instructions for use of the nebulizer delivery system, since improper use of the nebulizer potentially could result in release of substantial amounts of pentamidine into the environment.^{230 247 261} Some clinicians suggest that pregnant women^{205 261 264} and possibly those planning to become pregnant (e.g., within 8 weeks of potential exposure)²⁶⁴ avoid environmental exposure to aerosolized pentamidine. Consult specialized sources for recommended procedures to minimize environmental exposure to drug.^{211 212 251 261 262 264}

Because cough and bronchospasm frequently occur in patients receiving orally inhaled pentamidine,^{219 231 277 278 279} health-care personnel who administer pentamidine inhalation therapy may be at risk of exposure to tuberculosis if the patient has undiagnosed Mycobacterium tuberculosis infection.^{230 250 264 266 285 310 311}

Specific Populations

Pregnancy

Category C.^{1 219}

Lactation

Not known whether pentamidine distributed into milk.^{134 219} Discontinue nursing or the drug.^{1 219}

Pediatric Use

Parenteral administration: Safety and efficacy established in children >4 months of age.¹ Has been used effectively for treatment of pneumocystis pneumonia in younger children^{1 81 83 85 86 87 89 90 130} (including neonates);^{1 83 85 86 90 130} no unusual risks associated with the drug identified.^{85 89 90 130 134} Also has been used effectively and apparently without unusual risks for treatment of African trypanosomiasis†^{91 100 101} and leishmaniasis†^{53 91} in children.

Oral inhalation: Safety and efficacy not established in children ≤16 years of age.²¹⁹ AAP, USPHS/IDSA, and others state that use of orally inhaled pentamidine can be considered in children ≥5 years of age who are capable of effectively using a nebulizer.^{299 300 303 356}

Hepatic Impairment

Caution in patients with hepatic impairment.^{1 219}