Pentamidine isethionate, an aromatic diamidine derivative, is an antiprotozoal and antifungal agent.1, 2, 3, 219
Pneumocystis jirovecii Pneumonia
Pentamidine isethionate is used as an alternative for treatment of Pneumocystis jirovecii (formerly Pneumocystis carinii ) pneumonia (PCP) and prevention of P. jirovecii infections.1, 134, 155, 156, 219 Pentamidine is designated an orphan drug by the US Food and Drug Administration (FDA) for treatment and prevention of PCP in patients at high risk for the disease.79
Treatment of Pneumocystis jirovecii Pneumonia
Parenteral pentamidine is used alone as an alternative for treatment of PCP in patients who cannot tolerate or do not respond to co-trimoxazole, including adults, adolescents, and children with human immunodeficiency virus (HIV) infection.1, 80, 81, 82, 83, 84, 85, 86, 89, 90, 96, 134, 155, 156, 167, 277, 279, 354 Pentamidine administered by oral inhalation via nebulization (aerosolized pentamidine) should not be used for treatment of PCP.155
Co-trimoxazole is the drug of choice for treatment of mild, moderate, or severe PCP, including PCP in HIV-infected adults, adolescents, and children.134, 155, 156
The US Centers for Disease Control and Prevention (CDC), National Institutes of Health (NIH), and Infectious Diseases Society of America (IDSA) state that alternatives for treatment of moderate to severe PCP in HIV-infected adults and adolescents who cannot tolerate or have not responded to co-trimoxazole are IV pentamidine or a regimen of primaquine in conjunction with clindamycin.155 Some clinicians prefer the primaquine and clindamycin regimen in such patients since it may be more effective and may be associated with lower toxicity compared with IV pentamidine.155 For treatment of PCP in HIV-infected children who cannot tolerate co-trimoxazole or have not responded after 5-7 days of co-trimoxazole, CDC, NIH, IDSA, and the American Academy of Pediatrics (AAP) recommend IV pentamidine;156 these experts state that treatment in such children can be switched to an appropriate oral regimen (e.g., atovaquone) after an initial response is obtained with IV pentamidine.156
Parenteral pentamidine is associated with a cure rate of approximately 50-70% in patients with PCP,82, 83, 85, 86, 89, 90, 134, 199 and has been effective in some patients whose infection did not respond to initial co-trimoxazole treatment.86, 89, 90, 199 In patients with PCP who respond to pentamidine, a therapeutic clinical response manifested by defervescence and improved respiratory function may be apparent within 24-48 hours, but is generally evident within 2-8 days after initiation of the drug.82, 85, 89, 90 While improvement in pulmonary radiographic signs generally occurs within several days to a week after the clinical response,82, 89, 90 complete clearing of radiographic signs may not occur for up to 20-30 days or longer.89, 90
Prior to the commercial availability of co-trimoxazole, pentamidine was considered the drug of choice for treatment of PCP;80, 81, 82, 83, 84, 85 however, because co-trimoxazole has excellent tissue penetration and is associated with rapid clinical response (e.g., 3-5 days in patients with mild to moderate PCP), co-trimoxazole became the drug of choice for treatment of PCP in most patients.89, 90, 134, 187, 199 Results of limited comparative studies suggest that pentamidine is about as effective as167 or slightly less effective188 than co-trimoxazole for treatment of PCP in patients with AIDS and the drugs produce a similar incidence of adverse reactions, including those severe enough to require discontinuance of treatment.167, 188
Prevention of Pneumocystis jirovecii Infections
Pentamidine administered by oral inhalation via nebulization (aerosolized pentamidine) is used for prevention of initial episodes of PCP (primary prophylaxis) in patients at high risk (e.g., HIV-infected patients with CD4+ T-cell counts of 200/mm3 or less)155, 156, 216, 219, 220, 221, 231, 278, 285, 295, 324, 342, 357 and for prevention of recurrence (secondary prophylaxis) in those with a history of PCP.155, 156, 177, 187, 193, 195, 198, 208, 219, 220, 221, 231, 285, 325
Prevention of Initial Episode (Primary Prophylaxis)
CDC, NIH, and IDSA recommend that primary prophylaxis to prevent initial episodes of PCP be initiated in HIV-infected adults and adolescents with CD4+ T-cell counts less than 200/mm3 or a history of oropharyngeal candidiasis.155 These experts state that primary PCP prophylaxis should be considered in HIV-infected adults and adolescents with CD4+ T-cell percentages less than 14% or a history of an AIDS-defining illness who would not otherwise qualify for prophylaxis and also should be considered in those with CD4+ T-cell counts greater than 200/mm3 but less than 250/mm3 if frequent monitoring of CD4+ T-cell counts (e.g., every 3 months) is not possible.155
CDC, NIH, and IDSA state that primary PCP prophylaxis should be discontinued in HIV-infected adults and adolescents who have responded to antiretroviral therapy and have CD4+ T-cell counts that have remained greater than 200/mm3 for longer than 3 months.155 Discontinuance of primary PCP prophylaxis is recommended in these individuals since it appears to add little benefit in terms of disease prevention (PCP, toxoplasmosis, bacterial infections) and discontinuance reduces the medication burden, cost, and potential for drug toxicity, drug interactions, and selection of drug-resistant pathogens.155 Primary PCP prophylaxis should be reinitiated if CD4+ T-cell counts decrease to less than 200/mm3.155
Co-trimoxazole is the drug of choice for primary PCP prophylaxis in HIV-infected adults and adolescents.155 CDC, NIH, and IDSA recommend that co-trimoxazole prophylaxis be continued, if clinically feasible, in individuals who experience adverse reactions to the drug that are not life-threatening; however, co-trimoxazole prophylaxis should be permanently discontinued and an alternative used in those with life-threatening adverse reactions to the drug.155
Alternative regimens recommended by CDC, NIH, and IDSA for primary PCP prophylaxis in HIV-infected adults and adolescents who cannot tolerate co-trimoxazole are dapsone alone, dapsone in conjunction with pyrimethamine (and leucovorin), aerosolized pentamidine, atovaquone alone, or atovaquone in conjunction with pyrimethamine (and leucovorin).155 In HIV-infected adults or adolescents who cannot tolerate co-trimoxazole and are seropositive for Toxoplasma gondii , dapsone with pyrimethamine (and leucovorin), atovaquone alone, or atovaquone with pyrimethamine (and leucovorin) would provide prophylaxis against both PCP and toxoplasmosis.155
In an 18-month, randomized, dose-response study in which 408 HIV-infected patients with or without a history of previous PCP received orally inhaled pentamidine isethionate 30 mg every 2 weeks, 150 mg every 2 weeks, or 300 mg every 4 weeks via a Respirgard® II nebulizer, the risk of developing PCP (either as an initial episode or as recurrence) was reduced by 50-70% in patients receiving the 300-mg dosage regimen compared with patients receiving the 30-mg regimen.219, 231, 237, 278 Although not statistically significant, a dose-response effect also was apparent in patients receiving the 300-mg regimen versus the 150-mg regimen,219, 231, 278 and the benefit of the 300-mg dosage was evident even after considering the effect of zidovudine in patients receiving the antiretroviral concurrently.219, 231, 278 Although the pentamidine dosage had no effect on reduction of overall mortality in this study, mortality was low in all 3 dosage groups.219, 278 In a study in which oral inhalation therapy with pentamidine isethionate (300 mg every 4 weeks via a Respirgard® II nebulizer) was limited to HIV-infected adults at high risk of PCP (e.g., those with AIDS, advanced AIDS-related complex [ ARC], CD4+ T-cell count less than 200/ mm3) but with no history of previous PCP (primary prevention), the 1-year estimated risk of developing PCP was reduced by about 70% relative to placebo.295
Prevention of Recurrence (Secondary Prophylaxis)
CDC, NIH, and IDSA recommend that HIV-infected adults and adolescents who have a history of PCP receive long-term suppressive or chronic maintenance therapy (secondary prophylaxis) to prevent recurrence.155
Secondary PCP prophylaxis generally is administered for life, unless immune recovery occurs as a result of antiretroviral therapy.155 CDC, NIH, and IDSA state that secondary PCP prophylaxis generally can be discontinued in HIV-infected adults and adolescents who have responded to antiretroviral therapy and have CD4+ T-cell counts that have remained greater than 200/mm3 for longer than 3 months, but should be reinitiated if CD4+ T-cell counts decrease to less than 200/mm3.155 In addition, these experts state that it may be prudent to continue secondary PCP prophylaxis for life (regardless of CD4+ T-cell count) if PCP occurred or recurred when CD4+ T-cell counts were greater than 200/mm3.155
Co-trimoxazole is the drug of choice for secondary PCP prophylaxis in HIV-infected adults and adolescents.155 CDC, NIH, and IDSA recommend that co-trimoxazole prophylaxis be continued, if clinically feasible, in individuals who experience adverse reactions to the drug that are not life-threatening; however, co-trimoxazole prophylaxis should be permanently discontinued and an alternative used in those with life-threatening adverse reactions to the drug.155
Alternative regimens recommended by CDC, NIH, and IDSA for secondary PCP prophylaxis in HIV-infected adults and adolescents who cannot tolerate co-trimoxazole are the same as those recommended for primary prophylaxis and include dapsone alone, dapsone in conjunction with pyrimethamine (and leucovorin), aerosolized pentamidine, atovaquone alone, or atovaquone in conjunction with pyrimethamine (and leucovorin).155 In HIV-infected adults or adolescents who cannot tolerate co-trimoxazole and are seropositive for T. gondii , dapsone with pyrimethamine (and leucovorin), atovaquone alone, or atovaquone with pyrimethamine (and leucovorin) would provide prophylaxis against both PCP and toxoplasmosis.155
Primary and Secondary Prophylaxis in Children
CDC, NIH, IDSA, and AAP recommend that primary prophylaxis to prevent initial episodes of PCP be initiated in HIV-infected children 1 to less than 6 years of age with CD4+ T-cell counts less than 500/mm3 or CD4+ T-cell percentages less than 15% and in HIV-infected children 6-12 years of age with CD4+ T-cell counts less than 200/mm3 or CD4+ T-cell percentages less than 15%.156 These experts recommend that all HIV-infected infants younger than 1 year of age (regardless of CD4+ T-cell count or percentage) receive primary PCP prophylaxis.156 In addition, infants born to HIV-infected mothers should be considered for primary PCP prophylaxis beginning at 4-6 weeks of age and those with indeterminate HIV status should continue to receive prophylaxis until they are determined to be non-HIV-infected or presumptively non-HIV-infected.156 Those found to be HIV-infected should receive primary PCP prophylaxis throughout the first year of life; at 1 year of age, the need for continued PCP prophylaxis should be reassessed based on age-specific CD4+ T-cell thresholds.156
HIV-infected children who have a history of PCP should receive long-term suppressive or chronic maintenance therapy (secondary prophylaxis) to prevent recurrence.156
CDC, NIH, IDSA, and AAP state that, in HIV-infected children who have received at least 6 months of antiretroviral therapy, discontinuance of primary or secondary PCP prophylaxis should be considered in those 1 to less than 6 years of age if CD4+ T-cell counts have remained at 500/mm3 or greater or CD4+ T-cell percentages have remained at 15% or greater for more than 3 consecutive months and in those 6-12 years of age if CD4+ T-cell counts have remained at 200/mm3 or greater or CD4+ T-cell percentages have remained at 15% or greater for more than 3 consecutive months.156 If primary or secondary PCP prophylaxis is discontinued in HIV-infected children, CD4+ T-cell counts and CD4+ T-cell percentages should be assessed every 3 months and PCP prophylaxis reinitiated if indicated based on age-specific CD4+ T-cell thresholds.156
Co-trimoxazole is the drug of choice for primary and secondary PCP prophylaxis in HIV-infected infants and children.156 CDC, NIH, IDSA, and AAP recommend that co-trimoxazole be continued, if clinically feasible, in individuals who experience adverse reactions to the drug that are not life-threatening; however, co-trimoxazole should be permanently discontinued and an alternative used in those with life-threatening adverse reactions to the drug.155, 156
Alternative regimens recommended by CDC, NIH, IDSA, and AAP for primary and secondary PCP prophylaxis in HIV-infected infants and children who cannot tolerate co-trimoxazole are dapsone (1 month of age or older), atovaquone (1 month of age or older), or aerosolized pentamidine (5 years of age or older†).156
Pentamidine is used for treatment of early or first-stage (hemolymphatic) trypanosomiasis caused by Trypanosoma brucei gambiense † (West African trypanosomiasis, gambiense sleeping sickness)2, 41, 42, 43, 44, 100, 101, 102, 103, 107, 134, 367, 368, 369 and has been used as an alternative for treatment of early or first-stage (hemolymphatic) trypanosomiasis caused by Trypanosoma brucei rhodesiense † (East African trypanosomiasis, rhodesiense sleeping sickness).43, 44, 134, 149, 150, 367
Pentamidine penetrates the CNS poorly and is not effective for and should not be used for treatment of second-stage (meningoencephalitic) T. b. gambiense or T. b. gambiense infections when trypanosomes have invaded the CNS.15, 42, 43, 44, 100, 101, 102, 103, 105, 146, 367, 368, 369
T. b. gambiense and T. b. rhodesiense are transmitted to humans by the bite of infected tsetse flies;44, 105, 377 transmission via blood or perinatal transmission from mother to infant is rare.377
Trypanosoma brucei gambiense Infections
T. b. gambiense is endemic in West and Central Africa,44, 105, 377 and more than 95% of reported trypanosomiasis cases involve T. b. gambiense .44 T. b. gambiense infection occurs only rarely in short-term travelers to endemic areas, but has been reported in immigrants and expatriates from such areas.44, 105, 368
Pentamidine usually is the drug of choice for treatment of first-stage (hemolymphatic) trypanosomiasis caused by T. b. gambiense .44, 134, 367, 368 Suramin (not commercially available in the US, but may be available from CDC) also is effective for these first-stage infections, but is considered an alternative since pentamidine is better tolerated.134, 367
For treatment of T. b. gambiense infection with CNS involvement, eflornithine (with or without nitfurtimox) or melarsoprol (drugs not commercially available in the US, but may be available from CDC) usually is recommended.44, 134, 368, 369 In untreated patients, CNS invasion and symptoms may not occur for months or years after infection with T. b. gambiense .42, 44
For assistance with diagnosis or treatment of T. b. gambiense trypanosomiasis in the US, clinicians can contact CDC Parasitic Diseases Hotline at 404-718-4745 from 8:00 a.m. to 4:00 p.m. Eastern Standard Time or CDC Emergency Operation Center at 770-488-7100 after business hours and on weekends and holidays.382 CDC Drug Service should be contacted at 404-639-3670 for information on how to obtain antiparasitic drugs not commercially available in the US.382
Trypanosoma brucei rhodesiense Infections
T. b. rhodesiense is endemic in Eastern and Southern Africa.44, 105, 377 The disease has been reported occasionally in short-term travelers to endemic areas, especially tourists visiting wildlife reserves in such areas.44, 105, 368 T. b. rhodesiense infections are reported much less frequently than T. b. gambiense infections, but usually are associated with more rapidly progressive disease.44, 105, 377
For treatment of first-stage (hemolymphatic) trypanosomiasis caused by T. b. rhodesiense , suramin (not commercially available in the US, but may be available from CDC) usually is the drug of choice.44, 134, 367, 368 Pentamidine has been recommended as an alternative to suramin for treatment of first-stage T. b. rhodesiense infection because it is better tolerated,43, 44, 367 but pentamidine may be less active against this infection than against T. b. gambiense infection.41, 42, 43, 44
Melarsoprol (not commercially available in the US, but may be available from CDC) usually is the drug of choice for treatment of T. b. rhodesiense infection with CNS involvement.134, 367, 368 Clinicians should consider that CNS invasion may occur as soon as 3 weeks to 2 months after infection with T. b. rhodesiense .44, 105
For assistance with diagnosis or treatment of T. b. rhodesiense trypanosomiasis in the US, clinicians can contact CDC Parasitic Diseases Hotline at 404-718-4745 from 8:00 a.m. to 4:00 p.m. Eastern Standard Time or CDC Emergency Operation Center at 770-488-7100 after business hours and on weekends and holidays.382 CDC Drug Service should be contacted at 404-639-3670 for information on how to obtain antiparasitic drugs not commercially available in the US.382
Pentamidine has been used for treatment of cutaneous and mucocutaneous leishmaniasis† caused by various Leishmania species46, 55, 56, 57, 105, 114, 126, 154, 256, 369, 371, 372, 373, 374 and also has been used for treatment of visceral leishmaniasis† (also known as kala-azar).46, 113, 126, 136, 137, 138, 152, 153, 371, 372, 375, 376
Leishmaniasis is caused by more than 15 different species of Leishmania that are transmitted to humans by the bite of infected sand flies.46, 105, 126, 371, 372, 373, 377 Leishmania also can be transmitted via blood (e.g., blood transfusions, needles shared by IV drug abusers) and transmitted perinatally from mother to infant.46, 105, 155, 371, 377 In the Eastern Hemisphere, leishmaniasis is found most frequently in parts of Asia, the Middle East, Africa, and southern Europe; in the Western Hemisphere, the disease is found most frequently in Mexico and Central and South America and has been reported occasionally in Texas and Oklahoma.377 Leishmaniasis has been reported in short-term travelers to endemic areas and in immigrants and expatriates from such areas,46, 105, 372, 373, 377 and also has been reported in US military personnel and contract workers serving or working in endemic areas (e.g., Iraq, Afghanistan).46, 105, 377
Leishmania infection in humans may cause uncomplicated cutaneous leishmaniasis, diffuse cutaneous leishmaniasis, mucosal leishmaniasis, visceral leishmaniasis, or post-kala-azar leishmaniasis and may be termed Old World (Eastern Hemisphere) or New World (Western Hemisphere).46, 105, 126, 155, 371, 372, 373, 374, 375, 377 The specific form of leishmaniasis and disease severity depend on the Leishmania species involved, geographic area of origin, location of sand fly bite, and patient factors (e.g., nutritional and immune status).46, 105, 126, 371, 372, 373, 374, 375 Treatment of leishmaniasis (e.g., drug, dosage, duration of treatment) must be individualized based on the region where the disease was acquired, likely infecting species, drug susceptibilities reported in the area of origin, form of the disease, and patient factors (e.g., age, pregnancy, immune status).46, 105, 134, 155, 371, 372, 374, 375, 377 No single treatment approach is appropriate for all possible clinical presentations.46 Consultation with clinicians experienced in management of leishmaniasis is recommended.105, 134, 371, 377
For assistance with diagnosis or treatment of leishmaniasis in the US, clinicians can contact CDC Parasitic Diseases Hotline at 404-718-4745 from 8:00 a.m. to 4:00 p.m. Eastern Standard Time or CDC Emergency Operation Center at 770-488-7100 after business hours and on weekends and holidays.382 CDC Drug Service should be contacted at 404-639-3670 for information on how to obtain antiparasitic drugs not commercially available in the US.382
Cutaneous and Mucocutaneous Leishmaniasis
Although some cases of cutaneous leishmaniasis (usually Old World) may subside or resolve spontaneously over months or years, treatment of cutaneous leishmaniasis is recommended if there are multiple or large lesions, lesions are disabling or disfiguring or fail to heal within 6 months, the patient is immunocompromised, or dissemination to mucosal leishmaniasis is likely (e.g., New World disease caused by L. braziliensis or L. panamensis ).105, 126, 271, 369, 371, 372, 373, 374 Local treatment (e.g., topical paromomycin [not commercially available in the US], thermotherapy, intralesional pentavalent antimonials [not commercially available in the US], cryotherapy) may be appropriate in selected cases.46, 126, 134, 155, 373, 374 For systemic treatment of cutaneous leishmaniasis, pentavalent antimonials (i.e., sodium stibogluconate or meglumine antimonate [drugs not commercially available in the US, but may be available from CDC]) usually are used.126, 134, 256, 271, 369, 371, 372, 373, 374 Other treatment options for cutaneous leishmaniasis include amphotericin B, miltefosine, pentamidine, and ketoconazole,46, 126, 134, 155, 369, 371, 373, 374 especially when antimonials cannot be used because of tolerance or resistance.372, 373 Pentamidine may be particularly useful for and has been recommended for treatment of New World cutaneous leishmaniasis† caused by L. guyanensis or L. panamensis .46, 369, 372, 373, 374 Variable efficacy and potential adverse effects limit usefulness of pentamidine for other types of cutaneous leishmaniasis.46, 372, 373, 374
For treatment of mucosal leishmaniasis, pentavalent antimonials (i.e., sodium stibogluconate or meglumine antimonate [drugs not commercially available in the US, but may be available from CDC]), amphotericin B, or miltefosine usually are used.46, 126, 134, 256, 271, 369, 373, 374 Although data are limited, pentamidine also has been used as an alternative for these infections.46, 126, 369, 374
Pentavalent antimonials (i.e., sodium stibogluconate or meglumine antimonate [drugs not commercially available in the US, but may available from CDC]) have historically been considered the drugs of first choice for initial treatment of visceral leishmaniasis;46, 58, 126, 256, 271, 371, 375, 376 however, drug resistance and treatment failures have become a major concern in some areas (e.g., India, Nepal).126, 256, 375, 376 Relapse of visceral leishmaniasis is common in immunocompromised patients (e.g., HIV-infected patients), regardless of treatment regimen.155, 256
Other treatment options for visceral leishmaniasis include amphotericin B, miltefosine, or paromomycin.126, 134, 155, 256, 271, 371, 375, 376 Pentamidine has been used for treatment of visceral leishmaniasis, especially when antimonials may be not be effective because of resistance,46, 52, 53, 54, 126, 136, 153, 375, 376 but pentamidine is not usually recommended for treatment of visceral leishmaniasis, including in HIV-infected individuals, because of variable or suboptimal efficacy and potential adverse effects.134, 155, 371, 375, 376
Because of its activity against Babesia infections in animals,61, 62, 63 pentamidine has been used in a small number of patients for treatment of babesiosis† caused by B. microti ;115, 116, 117, 118, 119 however, efficacy has not been established115, 120 and use of the drug alone has not been shown to be effective.282 Although parenteral pentamidine used in conjunction with co-trimoxazole has been beneficial for treatment of infection caused by B. divergens in at least one patient,178, 282 potential adverse effects associated with pentamidine limit use of this regimen.178
When anti-infective treatment of babesiosis is indicated, IDSA and other clinicians recommend either a regimen of clindamycin and quinine or a regimen of atovaquone and azithromycin.105, 134, 178
Reconstitution and Administration
Pentamidine isethionate is administered by deep IM injection or slow IV infusion.1 The drug should not be administered by rapid IV injection or infusion.124 (See Cautions: Cardiovascular Effects.)
Pentamidine isethionate also is administered by oral inhalation via nebulization (aerosolized pentamidine) using a Respirgard® II jet nebulizer.219
IV infusion (not IM injection) is usually recommended for treatment of Pneumocystis jirovecii (formerly Pneumocystis carinii ) pneumonia (PCP);134, 155, 156 oral inhalation via nebulization is used only for prevention of PCP.155, 156, 219
Because sudden, severe hypotensive reactions can occur following IM or IV administration of pentamidine, the patient should be in a supine position and blood pressure should be monitored closely during administration of the drug and several times thereafter until blood pressure is stable.1 Equipment and supportive therapy to treat a hypotensive reaction should be readily available.1 (See Precautions Related to Parenteral Pentamidine under Cautions: Precautions and Contraindications.)
Reconstituted and diluted solutions of pentamidine should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.1
For IM injection, a vial of pentamidine isethionate lyophilized powder labeled as containing 300 mg of the drug for IM or IV use should be reconstituted by adding 3 mL of sterile water for injection at 22-30°C to provide a solution containing approximately 100 mg/mL.1 The powder for IM or IV use should be reconstituted using only sterile water for injection; sodium chloride injection should not be used since precipitation of the drug will occur.1
The desired dose of reconstituted solution should then be withdrawn and administered by deep IM injection.1 Unused portions of reconstituted solution should be discarded.1
Some clinicians suggest that local adverse effects (e.g., sterile abscess, pain) associated with IM administration of pentamidine may be minimized by using the Z-track technique of injection, in which the subcutaneous tissue over the site of injection is firmly pushed aside before inserting the needle at a 90-degree angle, preferably into the upper outer quadrant of the buttock.321 (See Cautions: Local Effects.)
For IV infusion, a vial of pentamidine isethionate lyophilized powder labeled as containing 300 mg of the drug for IM or IV use should be reconstituted by adding 3-5 mL of sterile water for injection or 5% dextrose injection at 22-30°C 1 (e.g., using 3, 4, or 5 mL of diluent will provide solutions containing approximately 100, 75, or 60 mg/mL, respectively). The powder for IM or IV use should be reconstituted using only sterile water for injection; sodium chloride injection should not be used since precipitation of the drug will occur.1
The desired dose of reconstituted solution should then be withdrawn and diluted in 50-250 mL of 5% dextrose injection.1
The reconstituted and diluted solution of pentamidine should be administered by slow IV infusion over 60-120 minutes.1 Rapid IV infusion should be avoided.1 (See Cautions: Cardiovascular Effects.)
The IV needle or catheter should be positioned carefully and closely observed throughout the period of administration.1 Extravasation should be avoided;1 if extravasation occurs, the infusion should be immediately discontinued and restarted at another site.1 (See Cautions: Local Effects.)
Oral Inhalation via Nebulization
For oral inhalation via nebulization (aerosolized pentamidine), a vial of pentamidine isethionate lyophilized powder labeled as containing 300 mg of the drug for oral inhalation solution should be reconstituted by adding 6 mL of sterile water for injection.219 The powder for oral inhalation solution should be reconstituted using only sterile water for injection; sodium chloride injection should not be used since precipitation of the drug will occur.219
Prior to administration of pentamidine oral inhalation solution, the manufacturer's information on administering pentamidine via the Respirgard® II jet nebulizer should be reviewed to assure thorough familiarity with the use and operation of the nebulizer.231, 255
The entire contents of the reconstituted vial of pentamidine should be placed into the reservoir of the Respirgard® II jet nebulizer and delivered 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, an air compressor delivering 40-50 PSI may be used 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
Pentamidine for oral inhalation solution should not be admixed with any other drugs, and the Respirgard® II jet nebulizer should not be used to administer a bronchodilator.219
Pneumocystis jirovecii Pneumonia
Treatment of Pneumocystis jirovecii Pneumonia
When parenteral pentamidine isethionate is used for treatment of PCP in adults and adolescents, including those with human immunodeficiency virus (HIV) infection, the usual dosage is 4 mg/kg once daily given IV or IM.1, 155 The US Centers for Disease Control and Prevention (CDC), National Institutes of Health (NIH), and Infectious Diseases Society of America (IDSA) recommend that the drug be given IV for treatment of moderate to severe PCP in HIV-infected adults and adolescents and also state that dosage in these patients can be reduced to 3 mg/kg IV once daily if necessary because of toxicity.155
When parenteral pentamidine isethionate is used for treatment of PCP in children and infants 4 months of age or older, including those with HIV infection, the usual dosage is 4 mg/kg once daily given IV or IM.1, 156 CDC, NIH, IDSA, and American Academy of Pediatrics (AAP) recommend that the drug be given IV for treatment of PCP in HIV-infected children and also state that patients who have clinical improvement after 7-10 days of IV pentamidine can be switched to an appropriate oral regimen (e.g., atovaquone) to complete 21 days of treatment.156
CDC, NIH, IDSA, and AAP recommend a total treatment duration of 21 days.155, 156 The manufacturer recommends a treatment duration of 14-21 days and states that parenteral pentamidine has been continued for longer than 21 days, but such treatment may be associated with increased toxicity.1
Prevention of Pneumocystis jirovecii Infections
When pentamidine isethionate is administered by oral inhalation via nebulization (aerosolized pentamidine) for prevention of initial episodes (primary prophylaxis) of PCP in adults, adolescents, and children 5 years of age or older†, including HIV-infected individuals, the usual dosage is 300 mg once every 4 weeks (once monthly).155, 156, 219 CDC, NIH, and IDSA state that primary PCP prophylaxis should be discontinued in HIV-infected adults and adolescents if CD4+ T-cell counts have remained greater than 200/mm3 for longer than 3 months in response to antiretroviral therapy, but should be reinitiated if CD4+ T-cell counts decrease to less than 200/mm3.155 In HIV-infected children who have received at least 6 months of antiretroviral therapy, CDC, NIH, IDSA, and AAP state that discontinuance of primary PCP prophylaxis should be considered based on age-related CD4+ T-cell counts or CD4+ T-cell percentages, but should be reinitiated if these parameters decrease below the age-related thresholds.156 (See Prevention of Pneumocystis jirovecii Infections under Uses: Pneumocystis jirovecii Pneumonia.)
When pentamidine isethionate is administered by oral inhalation via nebulization (aerosolized pentamidine) for prevention of recurrence (secondary prophylaxis) of PCP in adults, adolescents, and children 5 years of age or older†, including HIV-infected individuals, the usual dosage is 300 mg once every 4 weeks (once monthly).155, 156, 219 CDC, NIH, and IDSA state that secondary PCP prophylaxis generally can be discontinued in HIV-infected adults and adolescents if CD4+ T-cell counts have remained greater than 200/mm3 for longer than 3 months in response to antiretroviral therapy, but should be reinitiated if CD4+ T-cell counts decrease to less than 200/mm3.155 However, secondary PCP prophylaxis probably should be continued for life (regardless of CD4+ T-cell count) if PCP occurred or recurred when CD4+ T-cell counts were greater than 200/mm3.155 In HIV-infected children who have received at least 6 months of antiretroviral therapy, CDC, NIH, IDSA, and AAP state that discontinuance of secondary PCP prophylaxis should be considered based on age-related CD4+ T-cell counts or CD4+ T-cell percentages, but should be reinitiated if these parameters decrease below the age-related thresholds.156 (See Prevention of Pneumocystis jirovecii Infections under Uses: Pneumocystis jirovecii Pneumonia.)
For treatment of first-stage (hemolymphatic) trypanosomiasis caused by Trypanosoma brucei gambiense † (West African trypanosomiasis, gambiense sleeping sickness), the World Health Organization (WHO) and others recommend that adults and children receive pentamidine isethionate in a dosage of 4 mg/kg once daily for 7-10 days given IM44, 134, 367, 368, 369 or, alternatively, by IV infusion over 2 hours.44, 367, 368
If pentamidine isethionate is used as an alternative for treatment of first-stage (hemolymphatic) trypanosomiasis caused by T. b. rhodesiense † (East African trypanosomiasis, rhodesiense sleeping sickness), WHO recommends that adults and children receive 4 mg/kg once daily for 7 days given IM or, alternatively, by IV infusion over 2 hours.44
For treatment of cutaneous leishmaniasis† caused by various Leishmania species, some clinicians recommend that adults and children receive pentamidine isethionate in a dosage of 2-3 mg/kg IM or IV once daily or every other day for 4-7 doses.134, 369 Others recommend 3-4 mg/kg IM or IV once every other day for 4-10 doses.373, 374 For treatment of New World cutaneous leishmaniasis caused by L. guyanensis or L. panamensis , WHO recommends that pentamidine isethionate be given in a dosage of 4 mg/kg IM or IV once every other day for 3 doses.46
If pentamidine isethionate is used as an alternative for treatment of visceral leishmaniasis†, some clinicians recommend a dosage of 4 mg/kg IM or IV once every other day or 3 times weekly for 15-20 doses.375
Dosage in Renal and Hepatic Impairment
The manufacturer of parenteral pentamidine isethionate states that efficacy and safety of alternative dosage regimens have not been established in patients with impaired renal or hepatic function, and the drug should be used with caution in such patients.1 (See Precautions Related to Parenteral Pentamidine under Cautions: Precautions and Contraindications.)
When IV pentamidine isethionate is used for treatment of PCP in HIV-infected adults and adolescents with renal impairment, some experts recommend that those with creatinine clearances of 10-50 mL/minute receive a dosage of 3 mg/kg once every 24 hours and that those with creatinine clearances less than 10 mL/minute receive 4 mg/kg once every 48 hours.155
The most common adverse effects reported with parenteral pentamidine isethionate are nephrotoxic effects;1, 83, 84, 85, 86, 89, 96, 167, 169, 188, 202, 269 the most common adverse effects reported with pentamidine isethionate administered by oral inhalation via nebulization (aerosolized pentamidine) are cough and bronchospasm.219, 220, 222, 231, 278, 279
Nephrotoxicity is common in patients receiving parenteral pentamidine for treatment of Pneumocystis jirovecii (formerly Pneumocystis carinii ) pneumonia (PCP).83, 84, 89, 96, 169, 188, 202, 269, 279 Pentamidine-induced nephrotoxicity is manifested by impaired renal function, increased serum creatinine concentration and/or BUN concentrations, and azotemia.1, 83, 84, 85, 86, 89, 90, 167, 279 Renal impairment usually is mild to moderate in severity and reversible following discontinuance of pentamidine;52, 83, 84, 85, 89, 188 however, acute renal failure1 or severe renal insufficiency84 requiring discontinuance of the drug may occur. Nephrotoxicity and hyperkalemia both may occur more frequently in patients with acquired immunodeficiency syndrome (AIDS)258, 259, 269, 272, 273 than in other patients treated with parenteral pentamidine;1, 83, 84, 89, 96, 169, 188, 202 hyperkalemia has been severe in some patients.259 (See Precautions Related to Parenteral Pentamidine under Cautions: Precautions and Contraindications.) Rarely, pentamidine-induced acute renal failure has been associated with myoglobinuria163 or gross hematuria.164 The risk and degree of pentamidine-induced renal impairment may be increased in the presence of dehydration158 or by concomitant use of other nephrotoxic drugs.83, 84, 85 (See Drug Interactions: Nephrotoxic Drugs.)
Flank pain,219 incontinence,219 increased BUN and serum creatinine concentrations,219 nephritis,219 renal failure,219 renal pain,219 and syndrome of inappropriate antidiuretic hormone secretion (SIADH)219 have been reported rarely in patients receiving pentamidine administered by oral inhalation via nebulization.219, 244
Hypotension, which may develop suddenly and may be moderate to severe (e.g., less than 60 mm Hg systolic), can occur following a single IM or IV dose of pentamidine.1, 15, 41, 43, 52, 83, 86, 124, 159, 167, 188, 202, 279 Deaths resulting from severe hypotension and cardiac arrhythmias have been reported in patients receiving the drug IM or IV.1, 202 The risk of hypotensive reactions following IM or IV administration of pentamidine has not been directly compared, but some data suggest that there is no difference in the frequency of these reactions following either route of administration when IV infusions of the drug are administered over a period of at least 60 minutes.124, 159 Hypotensive reactions may be particularly likely to occur following rapid IV injection or infusion.1, 15, 21, 124, 159, 188, 202, 279 To minimize the risk of this adverse effect when pentamidine is administered IV, infusions of the drug should be given over a period of 60-120 minutes.1, 124 In some patients, hypotension was not ameliorated by adjustment of the infusion rate, persisted beyond completion of the infusion, and required volume expansion for correction.279
Cardiorespiratory arrest (following rapid IV injection),188 ventricular tachycardia,1, 201, 202 atypical ventricular tachycardia (torsades de pointes),1, 175, 352 ECG abnormalities (abnormal ST segment),1, 52, 175 facial flushing,83 cerebrovascular accident,1 hypertension,1 palpitations,1 syncope,1 vasodilation,1 and vasculitis1 have also been reported in patients receiving parenteral pentamidine.
Cerebrovascular accident, hypotension, hypertension, palpitations, poor circulation, syncope, tachycardia, torsades de pointes, vasodilatation, and vasculitis have been reported rarely in patients receiving pentamidine administered by oral inhalation via nebulization.219, 278
Hypersensitivity and Dermatologic Effects
There have been rare reports of anaphylaxis1 and anaphylactoid reactions with shock52, 53 with parenteral pentamidine. Stevens-Johnson syndrome1, 83 and toxic epidermal necrolysis125 have been reported.
Anaphylaxis, allergic reaction, and nonspecific allergy have been reported in patients receiving pentamidine administered by oral inhalation via nebulization.219
Pruritus1, 83, 101, 210 and local or generalized urticaria1, 52, 124, 167, 210 or rash1, 83, 124, 167, 279, 337 (e.g., maculopapular, pruritic)124, 337 occur infrequently in patients receiving parenteral pentamidine.
Rash,174, 193, 219, 242 including severely pruritic, maculopapular eruption on the upper chest and back,242 also has occurred when the drug was administered by oral inhalation via nebulization.
Erythema, dry skin, dry and breaking hair, dermatitis, and desquamation have been reported occasionally in patients receiving pentamidine.1, 219, 278
Following IM injection of pentamidine, adverse effects at the site of injection, including sterile abscess and/or necrosis,1, 81, 83, 86, 124 pain,1, 83, 124 erythema,85, 89 tenderness,85, 89 and induration,1, 85, 89 have been reported in 10-20% of patients.1, 83, 84, 85, 86, 89, 124 To minimize some of these local adverse effects associated with IM administration of the drug, some clinicians recommend that the Z-track technique of injection be used.321 (See Parenteral Administration under Dosage and Administration: Reconstitution and Administration.)
Phlebitis may occur following IV administration of pentamidine.1, 83 Extravasation, sometimes resulting in ulceration, tissue necrosis, and/or sloughing at the injection site, has been reported in patients receiving pentamidine.1 Surgical debridement and skin grafting have been necessary in a few patients; long-term sequelae have occurred.1 Because prevention is the most effective means of limiting the severity of pentamidine extravasation, the IV needle or catheter should be properly positioned and closely observed throughout the infusion.1 If extravasation occurs, the infusion should be discontinued immediately and restarted in another vein; management of the extravasation site is symptomatic.1
Hypoglycemia and Diabetogenic Effects
Hypoglycemia, which may be severe (e.g., blood glucose concentration less than 25 mg/dL) and/or prolonged, appears to occur in at least 5-10% of patients receiving parenteral pentamidine.1, 31, 32, 33, 34, 35, 81, 83, 84, 85, 86, 89, 90, 165, 167, 169, 180, 188, 202, 243 Hyperglycemia1, 81, 83, 167 insulin-dependent diabetes mellitus1, 31, 35, 52, 275 (which appears to be permanent in some cases),52 with or without preceding hypoglycemia,1, 275 and ketoacidosis,1 have also occurred in patients receiving parenteral pentamidine;1, 31, 52 these adverse effects sometimes occurred several months after discontinuance of parenteral pentamidine.1, 31, 52 The exact mechanism(s) is not clearly established, but pentamidine-induced hypoglycemia has been associated with pancreatic islet cell necrosis and inappropriately high plasma insulin concentrations1 and the drug may produce insulin-dependent diabetes mellitus via direct toxic effects on beta cells of the pancreas.31, 36, 37, 170, 180, 202
Hypoglycemia,203, 217, 219, 277, 279 hyperglycemia,219, 275 and diabetes219 also have occurred when pentamidine was administered by oral inhalation via nebulization.
Although pentamidine-induced hypoglycemia may occur after initial doses of the drug,31 it generally occurs after at least 5-7 days of treatment31, 32, 33, 83, 85, 165, 180, 202 and can even occur up to several days after the drug is discontinued.165, 180 The duration of hypoglycemia appears to be quite variable, persisting for one or more days up to several weeks.165 While often asymptomatic,83, 85, 89, 188 pentamidine-induced hypoglycemia is occasionally severe1, 31, 33, 34, 165, 188, 202 and has resulted in death.1, 180, 188, 202 Some data suggest that the occurrence of hypoglycemia caused by the drug in patients with AIDS may be associated with the development of nephrotoxicity.165, 202 Other apparent risk factors associated with the occurrence of hypoglycemia reportedly include duration of treatment (or total cumulative dosage) and previous treatment with the drug (particularly within the prior 3 months).202
Management of pentamidine-induced hypoglycemia depends on the severity and duration of the reaction.31, 32, 33, 34, 35, 85, 165, 169 Hypoglycemia is usually, but not always,33, 34, 169 readily controlled by administration of IV dextrose;31, 32, 33, 85 in some cases, large dosages of IV dextrose and/or supplemental IV dextrose therapy for several days or longer may be required.33, 34, 85, 165, 169 In a few cases of recurring, severe hypoglycemia, short-term therapy with oral diazoxide was useful.31, 33
Leukopenia (e.g., neutropenia)1, 174, 188, 202, 279 and thrombocytopenia,1, 83, 167, 188, 202, 279 which can be severe (e.g., leukocyte count less than 1000/mm3, platelet count less than 20,000/mm3), occur occasionally in patients receiving parenteral pentamidine.1, 83, 188, 202 Leukopenia occurs more frequently than thrombocytopenia.1, 135, 279 Anemia,1, 83, 167 defibrination,1 eosinophilia,1 pancytopenia,1 and prolonged clotting time1 have been reported rarely in patients receiving parenteral pentamidine.1 Severe thrombocytopenic purpura also has been reported rarely.127 Although decreased serum folate concentrations (associated with megaloblastic changes in bone marrow in at least one case) have been observed rarely in patients receiving parenteral pentamidine,81, 83 it is not clear whether the drug can cause folic acid deficiency.
Anemia has been reported occasionally in patients receiving pentamidine by oral inhalation via nebulization;219 eosinophilia, neutropenia, nonspecific cytopenia, pancytopenia, and thrombocytopenia also have been reported.219
Adverse GI effects reported with parenteral pentamidine or oral inhalation of the drug via nebulization include abdominal cramping or pain,1, 44, 52, 219 anorexia or decreased appetite,1, 53, 219 diarrhea,1, 52, 219 dry mouth,1, 219 dyspepsia,1, 219 hematochezia,1, 219 increased sputum production (hypersalivation),1, 208, 209, 219 loss of taste,219 melena,1, 219 nausea,1, 52, 83, 90, 167, 202, 219, 278, 279 splenomegaly,1, 219 and vomiting.1, 15, 44, 52, 83, 90, 167, 219, 279 An unpleasant (e.g., metallic) taste (dysgeusia) sensation in the mouth or unpleasant feeling on the tongue also have been reported.1, 83, 219, 279 Dysgeusia may be more severe and persistent with IV than oral inhalation therapy.279
Gingivitis,219 oral ulcer or abscess,219 gastritis,219 gastric ulcer,219 hiatal hernia,219 esophagitis,219 constipation,219 colitis,219 and numb lips278 also have been reported in patients receiving pentamidine by oral inhalation via nebulization.
Acute pancreatitis1, 128, 166, 168, 322, 335 (sometimes fatal)168 has occurred with parenteral pentamidine; acute pancreatitis also has been reported rarely with pentamidine oral inhalation therapy.219, 246, 274 (See Cautions: Precautions and Contraindications.)
Elevated liver function test results, including increased serum AST and ALT concentrations,1, 83 occur occasionally in patients receiving parenteral pentamidine.1, 83, 167, 169, 174, 202 Hepatitis,1, 219 hepatomegaly,1, 219 and hepatic dysfunction1, 219 have been reported in patients receiving pentamidine parenterally or by oral inhalation via nebulization.
Cough and bronchospasm are frequent effects attributed to pentamidine oral inhalation therapy.219, 231, 277, 278, 279 Cough and bronchospasm also have been reported with parenteral pentamidine.1, 210
Cough174, 176, 190, 191, 193, 208, 217, 219, 278 has occurred in up to 63% of patients receiving pentamidine by oral inhalation via nebulization (38% of patients in initial clinical trials).219 Cough is most likely in and may be most severe in patients who smoke,176, 193, 217, 219 and occasionally may be severe enough to require discontinuance of oral inhalation therapy.190, 191, 278 Bronchospasm174, 177, 192, 193, 208, 217, 278, 279 has occurred in patients receiving pentamidine oral inhalation via nebulization (15% of patients in initial clinical trials),219 and is most likely in those with a history of smoking or asthma.174, 208, 217, 219 Although the exact cause of this bronchospasm has not been elucidated, it has been suggested that it may result, at least in part, from local histamine release179 and/or anticholinesterase activity209 induced by the drug.
Cough or bronchospasm occurring during pentamidine oral inhalation therapy can be controlled in most patients by interruption of oral inhalation therapy and administration of a bronchodilator.193, 219, 278, 279 Coughing also may be controlled by slowing the delivery or intensity of the aerosol stream.193, 195, 217 In patients who experience cough or bronchospasm with pentamidine oral inhalation, use of an orally inhaled bronchodilator prior to each dose may minimize recurrence of these symptoms.176, 177, 193, 208, 219, 279, 315, 316 Limited evidence suggests that pretreatment with orally inhaled cromolyn sodium is less effective than bronchodilators in preventing such bronchoconstriction.315, 316
Other adverse respiratory effects reported in patients receiving parenteral pentamidine or pentamidine administered by oral inhalation via nebulization include asthma,1, 219 bronchitis,1, 219 chest congestion or tightness,1, 219 coryza,1, 219 cyanosis,1, 219 dyspnea,1, 219 eosinophilic or interstitial pneumonitis,1, 219 gagging,1, 219, 278 hemoptysis,1, 219 hyperventilation,1, 219 laryngitis1, 191, 219 (sometimes severe),191 laryngospasm,1, 219 nonspecific lung disorder,1, 219 nasal congestion,1, 219 pleuritis,1, 219 pneumothorax,1, 215, 219 rales,1, 219 rhinitis,1, 219 shortness of breath,1, 219 tachypnea,1, 219 and wheezing.219 Bronchial bleeding during bronchoscopy245 or severe pulmonary hemorrhage following bronchoscopic biopsy190 also have occurred in association with pentamidine oral inhalation therapy.
Anxiety,1, 219 confusion,1, 219 depression,1, 219 dizziness,1, 219, 278 drowsiness,1, 219 emotional lability,1, 219 hallucinations,1, 219 hypesthesia,1, 219 insomnia,1, 219 memory loss,1, 219 nervousness,1, 219 neuralgia,1, 219 neuropathy (peripheral or nonspecific),1, 219 paranoia,1, 219 paresthesia,1, 219 seizure,1, 219 tremors,1, 219 unsteady gait,1, 219, 278 and vertigo1, 219 have been reported in patients receiving parenteral pentamidine and pentamidine oral inhalation therapy.
Fatigue was reported in about 66% of patients receiving pentamidine by oral inhalation via nebulization in initial clinical trials.219
Other adverse effects reported in patients receiving parenteral pentamidine or pentamidine by oral inhalation via nebulization include arthralgia,1, 219 body odor,219 chills,1 edema (facial or leg),219 fever,1, 83, 219, 279 gout,219 headache,219 hypocalcemia1, 83, 167, 219 (sometimes severe),1 hypomagnesemia,1 lethargy,219 low or abnormal body temperature,219 myalgia,219 miscarriage,219 night sweats,1, 219 nonspecific odor,219 and extrapulmonary pneumocystosis (sometimes fatal).1, 219, 231, 236, 239, 240, 276, 278 (See Precautions Related to Pentamidine Oral Inhalation via Nebulization under Cautions: Precautions and Contraindications.)
Blepharitis,1, 219 blurred vision,1, 219 conjunctivitis,1, 204, 219 contact lens discomfort,1, 219 eye pain or discomfort,1, 219 hemianopsia,219 loss of hearing,1 bad taste,219 and loss of taste or smell1, 219 also have been reported in patients receiving pentamidine.
Environmental Exposure of Health-care Personnel and Visitors
When pentamidine is administered by oral inhalation via nebulization, health-care personnel and visitors or other individuals present during administration of the drug may be at risk of environmental exposure to aerosolized pentamidine204, 205, 247, 251, 252, 261, 263, 264, 285, 294, 378, 380, 381 and may also be at risk of exposure to pathogens (e.g., Mycobacterium tuberculosis ) that can be transmitted by patients who cough during the oral inhalation procedure.250, 264, 266, 285, 380
There is evidence from several studies that measurable levels of pentamidine can be present in room air when pentamidine is administered by oral inhalation via nebulization.261, 294, 378, 380, 381 This level may depend on several factors, including room ventilation, proper use of the nebulizer, and variations in treatment practices (e.g., turning off the nebulizer 2-5 minutes before the mouthpiece is removed from the patient).261, 264, 294, 378, 381 In one study, area air samples were collected using an ambient air sampler over a 4-hour period in an unventilated treatment room where patients received a median dose of 150 mg of aerosolized pentamidine isethionate over 35-40 minutes via a nebulizer (Respirgard® II, which included an expiratory filter); pentamidine concentrations in area air samples averaged about 45 ng/m3during this period.261 Theoretical estimates based on exposure data from this study indicate that the amount of aerosolized pentamidine isethionate that potentially could be deposited in the lungs of health-care personnel would be 22 ng per 8-hour workday or 4.9 mcg per 225-day workyear,261 assuming continuous exposure during each 8-hour period.135 Although it was postulated that the relatively low estimated amounts of drug deposited in the lungs following environmental exposure and the low systemic absorption of pentamidine from the lungs might minimize risk,261 the potential risk for extrapulmonary toxicity that this or other exposure would represent remains to be established.135, 261 In another study in a limited number of health-care personnel and other individuals with varying levels of potential exposure to patients receiving the drug via a jet nebulizer (Respirgard® II or AeroTech® II, with expiratory filters), the likelihood of a positive urinary sample for pentamidine appeared to be increased by increasing degrees of potential exposure, with treatment providers being at greatest risk for measurable exposure and personnel simply working in the vicinity of the treatment area or in other areas of the institution being at minimal risk.294 In this study, approximately 90% of positive samples occurred in treatment providers; urinary concentrations in positive samples ranged from 0.15-8.19 ng/mL, and the number of treatment exposures in providers ranged from 1 monthly in various areas of the institution to 80 monthly in designated rooms with 6 or 35 exchanges of nonrecirculated air per hour.294
Adverse effects that have been 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 numbness of the mouth and nose;263 bitter metallic taste; burning sensation of the eyes, nose, and throat;264 sinus irritation;264 increased mucous dischar nasal stuffiness; sneezing;264 shortness of breath;262, 264, 338 cough;264 tightness of the chest;264, 338 acute bronchospasm;262 wheezing; hoarseness; fatigue; headache;264 and light-headedness.264 Asymptomatic reduction in carbon monoxide diffusion capacity was reported in a nonsmoking, apparently otherwise healthy, respiratory therapist following occupational exposure over a 14-month period to aerosolized pentamidine that was being administered to patients via a Respirgard® II jet nebulizer;251 this individual's diffusion capacity improved upon removal from exposure and remained stable despite reexposure when ventilation fans were installed in the area used for administration of orally inhaled pentamidine.251 Reduction in diffusion capacity also has been reported in other health-care personnel.338, 381
Because of concerns about the potential risks of environmental exposure to aerosolized pentamidine by health-care personnel and visitors while in contact with patients undergoing oral inhalation therapy with the drug and because of the lack of data on potential effects of pentamidine on the fetus or pregnancy,205, 247, 251, 252, 261, 264, 285, 294 environmental exposure to aerosolized pentamidine by pregnant women205, 261, 264 and possibly those planning to become pregnant (e.g., within 8 weeks of potential exposure)264 should be avoided. (See Pregnancy under Cautions: Pregnancy, Fertility, and Lactation.)
Exposure to tuberculosis is possible in settings where cough-inducing procedures, including administration of aerosolized pentamidine, are performed on patients with undiagnosed M. tuberculosis infection.250, 264, 266, 285 Therefore, it has been suggested that appropriate diagnostic procedures be performed to rule out potentially infectious tuberculosis (e.g., sputum smear, tuberculin skin test, chest radiographs) or other active pulmonary infections prior to initiation of pentamidine oral inhalation therapy.250, 266, 285 Antituberculosis therapy should be initiated before pentamidine oral inhalation therapy is started in patients with suspected or confirmed potentially infectious tuberculosis.135, 250, 266, 285 While the risk of tuberculosis transmission to individuals in contact with HIV-infected patients undergoing pentamidine prophylaxis has not been elucidated and some evidence suggests that it may be low overall in some areas135, 267 (but variable depending on demographics and other factors),250, 267 epidemiologic studies in one health clinic in which a substantial number of employees developed significant (positive) reactions to a tuberculin skin test (Mantoux) within a 6-month period suggest that occupational exposure to patients with positive M. tuberculosis sputum cultures who were receiving pentamidine oral inhalation therapy may have contributed to transmission of the infection.250 Inadequate fresh air ventilation in this clinic probably contributed substantially to transmission of tuberculosis;135, 250, 266 several months after installation of adequate ventilation in the facility, no additional significant reactions to a tuberculin skin test were observed.250 Therefore, adequate air exchange and exhaust to the outside and away from intake vents should be ensured in rooms and booths used for administering aerosolized pentamidine.135, 250, 261, 266 However, it should be recognized that such ensurance cannot completely eliminate the risk of transmission.266 Other appropriate preventive measures (e.g., minimizing contact of coughing patients with health-care personnel and others,250, 266 appropriate use of ultraviolet air disinfection,266, 268 use of properly constructed and vented and/or filtered [using high-efficiency particulate air filters] administration booths)135, 266 aimed at reducing the risk of tuberculosis transmission in this setting also should be considered.
The potential risks, particularly long-term and cumulative effects, associated with environmental exposure to aerosolized pentamidine have not been elucidated,205, 247, 251, 252, 261, 264, 285, 378, 380, 381 and health-care facilities should have procedures to minimize environmental exposure to aerosolized pentamidine.205, 251, 261, 262, 264, 378, 380, 381 Whenever possible, patients receiving pentamidine oral inhalation via nebulization should be located in rooms where potential exposure to personnel and other patients is minimized (e.g., using separate treatment rooms with closed doors, using properly constructed and vented and/or filtered [with an exhaust HEPA filter] booths or hoods, using nebulizers that have an expiratory filter [e.g., Respirgard® II], instructing the patient to turn off the nebulizer when the mouthpiece is removed).205, 252, 264, 378, 381 Proper room ventilation can reduce ambient concentrations of the drug.205, 251, 261, 262, 264, 380, 381 Some clinicians suggest that use of gowns, gloves, goggles, and masks by health-care personnel be considered, although the level of protection provided is not known205, 251, 261, 262, 264, 380 and some experts state that measures aimed at isolating and engineering out potential exposure generally should be emphasized over personal protective apparel and equipment.135 Use of surgical masks by health-care personnel caring for pentamidine-treated patients probably is unlikely to provide an effective means for reducing environmental exposure to the drug;261 therefore, if a face mask is used, alternative, appropriately designed (e.g., for adequate particle-size filtration) and well-fitted face masks (e.g., 3M Company model 9970 or 9920) should be employed since they are more likely to substantially reduce respiratory exposure levels.135, 261 In addition, health-care personnel administering aerosolized pentamidine should 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 and exposure of health-care personnel to the same risks of adverse effects as patients receiving orally inhaled pentamidine prophylaxis.247, 261
Precautions and Contraindications
Parenteral pentamidine isethionate is contraindicated in patients with a history of hypersensitivity to the drug.1
Pentamidine isethionate administered by oral inhalation via nebulization is contraindicated in patients with a history of anaphylactic reaction following parenteral or oral inhalation of the drug.219
Precautions Related to Parenteral Pentamidine
Parenteral pentamidine isethionate should be used with caution in patients with hypertension, hypotension, ventricular tachycardia, pancreatitis, Stevens-Johnson syndrome, hyperglycemia, hypoglycemia, hypocalcemia, leukopenia, thrombocytopenia, anemia, or hepatic or renal dysfunction.1
Parenteral pentamidine causes adverse effects in a high percentage of patients,1, 83, 85, 86, 279 and deaths resulting from severe hypotension, hypoglycemia, acute pancreatitis, or cardiac arrhythmias have occurred in patients receiving the drug IM or IV.1 Therefore, parenteral pentamidine should be used for treatment of PCP only after presence of the organism has been demonstrated.1 In addition, patients receiving the drug should be closely monitored for the development of severe adverse reactions (e.g., leukopenia, hypoglycemia, nephrotoxicity).1, 180
Because sudden, severe hypotension can occur following a single IM or IV dose of pentamidine, patients receiving the drug should be in a supine position and blood pressure should be monitored closely during administration of the drug and several times thereafter until blood pressure is stable.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 whenever pentamidine is administered parenterally.1 Since cardiac arrhythmias have been reported in patients receiving pentamidine, the manufacturers recommend that ECGs be performed before, during, and after parenteral therapy with the drug.1
Because parenteral pentamidine often causes nephrotoxicity,1, 83, 84, 85, 86, 89, 96 renal function should be frequently and carefully monitored in patients receiving the drug.1 Limited evidence suggests that nephrotoxicity associated with parenteral pentamidine may occur more frequently in patients with AIDS258, 259 than in other patients treated with the drug1, 83, 84, 89, 96, 169, 188, 202 and may be accompanied by severe, sometimes life-threatening, hyperkalemia despite modest elevations in BUN and/or serum creatinine concentration.258, 259, 269, 272, 273 Therefore, some clinicians suggest that, in addition to routine monitoring of renal function, serum potassium concentrations should be monitored and patients well hydrated during pentamidine therapy, particularly in AIDS patients.258, 259 The manufacturers recommend that BUN and serum creatinine concentrations be determined prior to initiation of parenteral pentamidine therapy, daily during therapy with the drug, and after the drug is discontinued.;1 some clinicians suggest that renal function may be monitored less frequently during therapy (e.g., every other day),135, 165, 169 unless substantial increases in serum creatinine concentration become evident during treatment and/or other nephrotoxic drugs are administered concomitantly.169 In addition, to minimize the risk and degree of pentamidine-induced nephrotoxicity, fluid status should be carefully monitored in patients with PCP, particularly patients with AIDS who may be at high risk of dehydration as a result of diarrhea, fever, and poor oral intake.158 Concurrent administration of IV sodium chloride injection with each dose of parenteral pentamidine has been reported to decrease the incidence and/or severity of adverse effects (e.g., GI symptoms) associated with pentamidine administration.257
Since pentamidine commonly causes hypoglycemia1, 31, 32, 33, 34, 35, 81, 83, 84, 85, 86, 89, 90, 165, 180, 188, 202, 243 (which can occur up to several days after the drug is discontinued)165, 180 and has diabetogenic effects1, 31, 35, 52 (which may not be preceded by hypoglycemia1 and which can sometimes occur several months after therapy with the drug),1, 31, 52 blood glucose concentration should be frequently and carefully monitored in patients receiving the drug parenterally.1, 180 The manufacturers recommend that blood glucose concentration be determined before, daily during, and after parenteral pentamidine therapy.1 Some clinicians suggest that blood glucose concentration may be monitored less frequently during therapy (e.g., every other day),135, 169 but should be determined daily in patients with a history of diabetes mellitus or hypoglycemia or in those with poor oral intake169 and should be determined whenever signs and/or symptoms suggestive of hypoglycemia occur.135
The manufacturers and some clinicians also recommend that complete blood counts, platelet counts, liver function tests (including serum bilirubin, alkaline phosphatase, AST, and ALT concentrations), and serum calcium concentrations be determined before and at periodic intervals during and after pentamidine therapy.1, 169
Because acute pancreatitis has been reported rarely in patients receiving parenteral pentamidine,128, 166, 168 some clinicians suggest that periodic monitoring of serum amylase concentrations may be warranted in patients receiving the drug.246, 274 Pentamidine should be discontinued if signs or symptoms of acute pancreatitis develop.166
Precautions Related to Pentamidine Oral Inhalation via Nebulization
Although pentamidine isethionate administered by oral inhalation via nebulization is generally considered not to be associated with substantial risk of serious adverse effects,174, 177, 187, 193, 195, 198, 199, 220, 221, 224, 226, 231, 247, 253, 277, 278, 279 the extent and consequences of accumulation of pentamidine following chronic oral inhalation therapy are not known.219 Therefore, patients receiving pentamidine oral inhalation therapy should be closely monitored for development of serious adverse effects that have been reported with parenteral pentamidine (e.g., hypotension, hypoglycemia, hyperglycemia, hypocalcemia, anemia, thrombocytopenia, leukopenia, hepatic or renal dysfunction, ventricular tachycardia, pancreatitis, Stevens-Johnson syndrome, hyperkalemia, ECG abnormalities [abnormal ST segment]).174, 203, 219
Prior to initiating prophylaxis with pentamidine oral inhalation via nebulization, symptomatic patients should be evaluated appropriately to exclude the presence of PCP.219 Dosage of pentamidine isethionate oral inhalation therapy recommended for prevention of PCP is insufficient for treatment of PCP.219
Patients receiving pentamidine oral inhalation via nebulization for prevention of PCP may still develop acute PCP.219, 278 Relapse of PCP with atypical clinical or radiographic features (e.g., mild disease, granulomatous pulmonary lesions, focal infection confined to the upper lobes of the lung) may occur;200, 219, 220, 241, 265, 281 such relapses have been treated successfully with parenteral pentamidine, suggesting that inadequate dosage or drug distribution rather than drug resistance is responsible for failure of prophylaxis.248
Extrapulmonary and/or disseminated infection caused by P. jirovecii , which can be fatal,236 has been reported occasionally in patients receiving pentamidine oral inhalation therapy for prevention of PCP;200, 219, 231, 236, 239, 240, 249, 276, 278 most cases have occurred in patients with a history of PCP.219, 236, 240, 249, 276 The presence of extrapulmonary pneumocystosis should be considered when evaluating patients with unexplained signs and symptoms.219
Patients receiving pentamidine by oral inhalation via nebulization for prevention of PCP should be monitored closely for signs and symptoms of pulmonary infection (e.g., fever, cough, dyspnea); those who exhibit such signs or symptoms should have thorough medical evaluations and appropriate diagnostic tests to rule out infection caused by P. jirovecii or other opportunistic or nonopportunistic pathogens.219, 223, 239, 247, 249 If PCP develops in a patient receiving prophylaxis with pentamidine oral inhalation therapy, prophylaxis should be discontinued and treatment with co-trimoxazole, parenteral pentamidine, or other effective treatment regimen should be initiated.195, 221, 223, 247, 248 Upon completion of treatment, PCP prophylaxis can be reinstituted.221, 247
Because acute pancreatitis has been reported rarely in patients receiving orally inhaled pentamidine,219, 246, 274 some clinicians suggest that periodic monitoring of serum amylase concentrations may be warranted in patients receiving the drug.246, 274 Pentamidine should be discontinued if signs or symptoms of acute pancreatitis develop.166, 219
Safety and efficacy of parenteral pentamidine isethionate has been established for treatment of PCP in children and infants older than 4 months of age,1, 81, 83, 85, 86, 89, 90, 130 and there appear to be no unusual risks associated with use of the drug in this age group.1, 85, 89, 90, 130, 134 Parenteral pentamidine isethionate also has been used effectively and apparently without unusual risks in children for treatment of first-stage (hemolymphatic) African trypanosomiasis†100, 101, 134 and treatment of leishmaniasis†.53, 134
The manufacturer states that safety and efficacy of orally inhaled pentamidine isethionate have not been established in children 16 years of age or younger.219 The US Centers for Disease Control and Prevention (CDC), National Institutes of Health (NIH), Infectious Diseases Society of America (IDSA), and American Academy of Pediatrics (AAP) recommend pentamidine administered by oral inhalation via nebulization as an alternative for prevention of PCP in children 5 years of age or older† who are capable of effectively using a nebulizer.105, 156 (See Primary and Secondary Prophylaxis in Children under Pneumocystis jirovecii Pneumonia: Prevention of Pneumocystis jirovecii Infections, in Uses.)
Mutagenicity and Carcinogenicity
Pentamidine was not mutagenic in the Ames bacteria ( Salmonella typhimurium ) test and did not induce an increase in chromosomal aberrations in Chinese hamster ovary (CHO) cells or human lymphocytes in vitro.219, 252
Studies have not been performed to date to evaluate the carcinogenic potential of pentamidine isethionate.1, 219
Pregnancy, Fertility, and Lactation
In a study in pregnant rats, IV pentamidine 4 mg/kg daily was embryolethal; teratogenicity was not observed in this study.219 It is not known whether pentamidine isethionate can cause fetal harm when administered to pregnant women,1, 205, 219 and parenteral pentamidine or pentamidine administered by oral inhalation via nebulization should be used during pregnancy only when clearly needed.1, 219
For treatment of first-stage (hemolymphatic) trypanosomiasis† or treatment of leishmaniasis† in pregnant women, the World Health Organization (WHO) states that parenteral pentamidine should not be used during the first trimester of pregnancy, but may be used after the first trimester.44, 46
Although fetal exposure would theoretically not be substantial, some clinicians recommend 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 Cautions: Environmental Exposure of Health-Care Personnel and Visitors.)
It is not known whether pentamidine isethionate affects fertility in humans.1, 219
It is not known whether pentamidine isethionate is distributed into milk.1, 219 Because of the potential for serious adverse reactions to pentamidine isethionate in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.1, 219 The manufacturers state that pentamidine isethionate should not be administered parenterally or by oral inhalation via nebulization in nursing mothers unless potential benefits outweigh potential risks.1, 219
Concurrent or sequential use of pentamidine isethionate and other nephrotoxic drugs (e.g., aminoglycosides, amphotericin B, capreomycin, colistin [commercially available in the US as colistimethate sodium], cisplatin, foscarnet, polymyxin B, vancomycin) should be closely monitored or avoided, if possible, since nephrotoxic effects may be additive.1, 83, 84, 85, 219
Pentamidine appears to affect the results of bronchoalveolar lavage and induced sputum diagnostic tests for Pneumocystis jirovecii (formerly Pneumocystis carinii ) in patients receiving prophylaxis with the drug administered by oral inhalation via nebulization.281, 318 The diagnostic yield of bronchoalveolar lavage in patients receiving the drug via oral inhalation was 62% compared with 100% in patients not receiving oral inhalation therapy;281 similar decreases in diagnostic yield have been observed for induced sputum tests.318 It is suggested that in the case of bronchoalveolar lavage, both bronchoalveolar and transbronchial biopsy specimens be obtained to optimize the diagnosis of P. jirovecii pneumonia (PCP);281 however, the yield from these tests is still considered high enough to maintain their diagnostic utility in these patients.281
Renal and hepatic impairment, hypotension, and cardiopulmonary arrest occurred following inadvertent administration of a 1.6-g dose of IV pentamidine isethionate in a 17-month-old infant.1 Treatment included cardiopulmonary resuscitation, intubation, epinephrine, atropine, intubation, and 4 hours of charcoal hemoperfusion (resulting in a reduction in serum pentamidine concentrations).1 The patient recovered from this event, but later died from an unknown cause.1 One patient with Pneumocystis jirovecii (formerly Pneumocystis carinii ) pneumonia (PCP) inadvertently received a 2-g IM dose of the drug, reportedly without ill effect.83 In general, overdosage of pentamidine isethionate would be expected to produce effects that are extensions of common adverse reactions.134, 135, 141
Overdosage of pentamidine isethionate administered by oral inhalation via nebulization has not been reported to date and the signs and symptoms of such an overdose are not known.219 Currently available pharmacokinetic data181, 219 suggest that a dose up to 40 times the recommended dose of orally inhaled pentamidine isethionate would be required to produce plasma concentrations similar to those of a single IV dose of 4 mg/kg;219 such an overdosage would have the potential of producing adverse effects similar to those seen after parenteral administration of the drug.219
In mice, the LD50 of pentamidine isethionate has been reported to be 15, 63, or 120 mg/kg following IV, intraperitoneal, or subcutaneous administration, respectively.142
The exact mechanism(s) of antiprotozoal action of pentamidine has not been fully elucidated.1, 2, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 44, 219 Several mechanisms of action may be involved, and the role of the mechanism(s) may vary among the different types of protozoa.2, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 The effects of pentamidine on various organisms (e.g., bacteria, protozoa) and cells (e.g., murine ascites tumor cells) have been studied to elucidate the mechanism(s) of action,2, 8, 9, 10, 11, 12, 13, 14, 19, 20, 21, 22, 23, 27 and most information on the antiprotozoal activity of aromatic diamidines such as pentamidine has been derived from studies involving Trypanosomatidae (e.g., Crithidia , Leishmania , Trypanosoma ).8, 9, 10, 11, 12, 13, 19, 20, 21, 22, 23, 27
In vitro studies indicate that pentamidine interferes with protozoal nuclear metabolism by inhibition of DNA, RNA, phospholipid, and protein synthesis.1, 219 Mechanisms that may play a role include binding to nucleic acids, disruption of kinetoplast DNA, inhibition of RNA editing in trypanosomes, and inhibition of mRNA trans-splicing.44 In vitro, pentamidine has been shown to inhibit protein and nucleic acid synthesis in cell-free extracts of Crithidia oncopelti .8, 9 The drug has also been shown to bind to and aggregate ribosomes in cell-free extracts of C. oncopelti in vitro, but pentamidine-induced inhibition of protein and nucleic acid synthesis is not associated with marked ribosomal aggregation in intact organisms.9 In vitro, pentamidine has also been shown to inhibit polyamine synthesis in Leishmania spp.10 and DNA, RNA, protein, and phospholipid synthesis11 and thymidylate synthetase activity12 in C. fasciculata ; in addition, the drug partially inhibits respiration in C. fasciculata 11, 13 and in mitochondria-kinetoplast fractions obtained from the organism.13 The exact mechanism(s) by which pentamidine may impair energy-yielding reactions in trypanosomes is not known, but it has been suggested that the drug may inhibit oxidative phosphorylation.14 It has also been suggested that the susceptibility of different species of trypanosomes to pentamidine may be related to the relative importance of aerobic and anaerobic glycolysis in their metabolic processes,2, 15 with the drug being more active against those species that rely more on aerobic glycolysis.2, 16 There is also some evidence suggesting that susceptibility of different species and subspecies of trypanosomes to pentamidine may be correlated with the rate and/or extent of drug uptake by the organisms.74, 75, 76 The trypanosomicidal activity of pentamidine and related aromatic diamidine derivatives (e.g., diaminazene, hydroxystilbamidine) may be related in a large part to the ability of the drugs to bind to nucleic acids and DNA,15, 16, 17, 18 particularly that of mitochondrial kinetoplasts, and thereby produce disruptive effects including inhibition of DNA and RNA synthesis.15, 19, 20, 21, 22, 23 Ultrastructural studies in various trypanosomes indicate that pentamidine rapidly causes mitochondrial enlargement and fragmentation and condensation of kinetoplast DNA.19, 20, 21, 22, 23
In vitro, pentamidine appears to be directly lethal to Pneumocystis jirovecii (formerly Pneumocystis carinii ),28, 29, 30 although the drug only moderately inhibits glucose metabolism, protein and RNA synthesis, and intracellular amino acid transport in the organism at concentrations attainable in vivo.29
Pentamidine can cause hypotension, which can be severe.1, 15, 41, 43, 52, 83, 86, 124, 159 (See Cautions: Cardiovascular Effects.) The exact mechanism(s) of pentamidine-induced hypotension is not known, but studies in animals suggest that the drug has a direct vasodilatory action on peripheral small arteries and arterioles.2, 3, 38 It has also been suggested that histamine release may contribute to the hypotensive effect,15 since other aromatic diamidine derivatives have been shown to have histamine-releasing activity.39
Hypoglycemic and Diabetogenic Effects
Pentamidine can produce hypoglycemia, which may be severe and/or prolonged;1, 31, 32, 33, 34, 35, 165, 169, 180 in addition, the drug may produce hyperglycemia1, 81, 83, 167 and insulin-dependent diabetes mellitus,1, 31, 35, 52 with or without preceding hypoglycemia.1 (See Cautions: Hypoglycemic and Diabetogenic Effects.) The effect of pentamidine on blood glucose concentration can be multiphasic; an initial increase in blood glucose concentration may occur immediately following administration of the drug (possibly attributed to an adrenergic reaction), followed by a period of hypoglycemia lasting several hours and then hyperglycemia.31 Although the exact mechanism is not clearly established, pentamidine-induced hypoglycemia has been associated with pancreatic islet cell necrosis1, 180 and inappropriately elevated plasma insulin concentrations.1, 31, 33, 180 In vitro studies using pancreatic islet cells31, 36 and malignant insulinoma cells37 suggest that pentamidine causes an acute release of insulin from beta cells of the pancreas, possibly via a cytolytic effect,36, 37, 180 followed by inhibition of insulin release and by cytolysis of the cells.36, 37 The results of these in vitro studies and in vivo metabolic studies in patients receiving the drug indicate that pentamidine-induced diabetes mellitus probably results from a direct, selective cytotoxic effect of the drug on beta cells of the pancreas.31, 36, 37, 180
At concentrations greater than 1 mcg/mL in vitro, pentamidine inhibits platelet aggregation induced by thrombin, epinephrine, adenosine diphosphate (ADP), collagen, and ristocetin in a concentration-dependent manner, with complete inhibition occurring at a concentration of 10 mcg/mL.40 In vitro, the drug also prolongs thrombin time by a few seconds at a concentration of 5 mcg/mL and slightly prolongs prothrombin and partial thromboplastin times, but only at substantially higher concentrations.40 At concentrations attained in vivo, pentamidine probably does not affect platelet function or coagulation.40 Pentamidine also has inhibited cholinesterases in vitro.209
Pentamidine is active in vitro and/or in vivo against a variety of protozoa,2, 8, 9, 10, 11, 12, 13, 15, 22, 23, 27, 41, 42, 43, 44, 46, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 80, 81, 82, 83, 84, 85, 86, 89, 90, 96, 126 including Trypanosomatidae that are pathogenic to humans— Trypanosoma and Leishmania .2, 10, 15, 22, 23, 27, 41, 42, 43, 44, 46, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 126, 136, 137, 138, 147, 148, 149, 150, 151, 152, 153, 154
Pentamidine is active in vivo against the causative agents of African trypanosomiasis, including most strains of Trypanosoma brucei gambiense 2, 15, 41, 42, 43, 44, 146, 147, 148 and some strains of T. b. rhodesiense ,2, 15, 27, 41, 42, 43, 44, 59, 149, 150, 151 but is not active against T. cruzi (causative agent of American trypanosomiasis [Chagas disease]).2, 15, 59
Pentamidine is active in vitro10, 27, 48, 49, 60 and in vivo2, 15, 46, 52, 53, 54, 126, 136, 137, 138, 152, 153 against Leishmania donovani , including antimony-resistant strains of the organism.50, 52, 53, 54, 153 In vitro, pentamidine concentrations of 0.05-0.5 mcg/mL result in elimination of 85-90% of L. donovani amastigotes in human monocyte-derived macrophages and 20-40% of L. donovani promastigotes in cell-free media.49 The drug is also active in vivo against L. aethiopica 46, 55, 56, 126 and has some activity in vitro10, 23, 49, 50, 51 and possibly in vivo15 against L. tropica . In vitro, pentamidine concentrations of 0.1-0.5 mcg/mL result in elimination of about 85% of L. tropica amastigotes in human monocyte-derived macrophages and 10-20% of L. tropica promastigotes in cell-free media.49 Pentamidine also has some activity in vivo against L. braziliensis 46, 57, 58, 154 (including L. b. guyanensis )46, 57 and in vitro against L. mexicana 22, 50 (including L. m. amazonensis )22 and possibly in vivo against L. mexicana .46, 58
Pentamidine also is active in vitro against Crithidia fasciculata 11, 13 and C. oncopelti ,9 which are not pathogenic to humans.135
Pentamidine has been shown to have some activity against pathogenic strains of Acanthamoeba in vitro,280 against Babesia canis in dogs,61 and against B. microti in rodents.62, 63 The drug also has some antiplasmodial activity in animals.2, 27, 144 Pentamidine was inactive in vitro against pathogenic strains of Naegleria in one study.280
Pentamidine is active in vitro28, 29, 30 and in vivo1, 15, 80, 81, 82, 83, 84, 85, 86, 89, 90, 96 against Pneumocystis jirovecii (formerly Pneumocystis carinii ). In vitro, the drug appears to be directly lethal to the organism at concentrations attainable in vivo.28, 29, 30
Pentamidine is active in vitro64, 65 and in vivo66 against some strains of Candida albicans . The drug also has some activity in vitro against various Trichophyton , 65, 67 Microsporum ,65, 67 Cryptococcus ,65, 68 Blastomyces ,65, 67, 68 and Histoplasma ,67, 68 but usually only at very high concentrations.65, 67, 68
In vitro, pentamidine has some antibacterial activity against Escherichia coli 69, 70 and Staphylococcus aureus 69 and some antiviral activity.71
Little information is available on natural or acquired resistance of protozoa to pentamidine.72, 73, 74, 75, 76 Pentamidine resistance can be induced in vitro.44 Evidence from in vitro studies using Trypanosoma brucei brucei 74 and Crithidia oncopelti 76 with induced pentamidine resistance and T. b. brucei with a degree of natural resistance to the drug74 suggests that resistance to pentamidine results primarily because of reduced uptake of the drug by the organisms.44, 74, 75, 76 Studies using trypanosomes indicate that the P2 aminopurine transporter is important for uptake of pentamidine and loss of this transporter results in emergence of resistance.44 In addition, there is evidence that loss of the P2 transporter and the high-affinity pentamidine transporter appears to be associated with high-level resistance to both pentamidine and melarsoprol (not commercially available in the US, but may be available from the CDC).44 Trypanosomes resistant to pentamidine are generally cross-resistant to other aromatic diamidine derivatives (e.g., stilbamidine).73, 74, 76
Following daily IM administration of single 4-mg/kg doses of pentamidine isethionate (2.3 mg/kg of pentamidine) in an early study in patients with Pneumocystis jirovecii (formerly Pneumocystis carinii ) pneumonia (PCP), plasma pentamidine concentrations (determined using a fluorometric assay) after 1-10 days of therapy averaged 0.3-0.5 mcg/mL (range: 0.3-1.4 mcg/mL).77 In these patients, plasma drug concentrations did not vary appreciably throughout the day and did not increase with successive doses of the drug.77 Although plasma pentamidine concentrations generally did not increase immediately after administration of a dose, if an increase did occur, it was usually within 1 hour after administration.77 Highest plasma drug concentrations occurred in patients with varying degrees of renal impairment.1, 77
Following a single 4-mg/kg IM or IV (given as a 2-hour infusion) dose of pentamidine isethionate in patients with acquired immunodeficiency syndrome (AIDS) and PCP, peak plasma pentamidine concentrations (determined using an HPLC assay) averaged 209 ng/mL approximately 40 minutes after the IM dose and 612 ng/mL after completion of the IV infusion.1, 171 Following IV administration of pentamidine isethionate 3.7-4 mg/kg daily (given as a 4-hour infusion) in HIV-infected patients with PCP, mean peak plasma concentrations were 175.3, 210.9, or 256.7 ng/mL on day 1, 4, or 7, respectively.1 Data from this study suggest that steady state was not achieved by day 7.1
Following oral inhalation of pentamidine isethionate via nebulization (aerosolized pentamidine), bronchoalveolar lavage fluid concentrations of the drug are substantially higher (at least 5-10 times higher) than those attained following IV administration;174, 181, 182, 219, 277 however, plasma concentrations following oral inhalation are substantially lower than those attained with a comparable IV dose.219 In a small number of patients with AIDS and suspected PCP, concentrations of pentamidine determined 18-24 hours after oral inhalation of pentamidine isethionate 300 mg via a Respirgard® II jet nebulizer or IV administration of pentamidine isethionate 4 mg/kg averaged 23.2 ng/mL (range: 5.1-43 ng/mL) or 2.6 ng/mL (range: 1.5-4 ng/mL), respectively, in bronchoalveolar lavage fluid and 705 ng/mL (range: 140-1336 ng/mL) or 9.3 ng/mL (range: 6.9-12.8 ng/mL), respectively, in bronchoalveolar lavage sediment;181, 219 plasma pentamidine concentrations in all but one patient receiving pentamidine by oral inhalation were at or below the level of detection of the HPLC assay (2-3 ng/mL).181, 219 In other studies in patients receiving orally inhaled pentamidine isethionate 600 mg daily via the Respirgard® II jet nebulizer, mean plasma concentrations after the dose on day 21 reportedly averaged 11.8-13.8 ng/mL.219, 277 Pentamidine appears to undergo limited absorption from the respiratory tract into systemic circulation;174, 181, 182 peak plasma concentrations appear to occur at or near completion of oral inhalation administration and appear to be 5% or less of those attained following IV administration.182 The extent of pentamidine accumulation following chronic oral inhalation therapy is not known.219
Distribution of pentamidine into human body tissues and fluids has not been well characterized, but the drug appears to be rapidly and extensively distributed and/or bound to tissues.77, 171, 183 Data from patients with AIDS indicate that following parenteral administration of pentamidine, highest concentrations of the drug (determined using a bioassay) are found in the liver, followed by the kidneys, adrenals, spleen, lungs, and pancreas.183 Further studies are needed, but these data also suggest that continued parenteral administration beyond the first week of therapy may not substantially increase accumulation of the drug in lung tissue.183 Since pentamidine is not effective for the treatment of trypanosomiasis involving the CNS, the drug has been believed to poorly penetrate the CNS;2, 15, 42, 43, 44, 100, 101, 102, 103 this is supported by limited data from patients with AIDS which indicate that pentamidine may distribute into the CNS in some patients, but only in very low concentrations and after prolonged therapy (a month or longer).183 Following intraperitoneal or IM administration of pentamidine isethionate in mice or rats, respectively, highest concentrations of the drug are found in the kidneys,77, 78 followed by the liver77, 78 and lungs.78 Following IV administration in dogs, highest concentrations of pentamidine are found in the liver, followed by the kidneys, lungs, and spleen; the drug is also distributed into bile and the CNS.172 IV administration of pentamidine isethionate 5 mg/kg in rats reportedly produced concentrations in the liver and kidney that were 87.5 and 62.3 times higher, respectively, than those produced by an identical dose of pentamidine isethionate administered by oral inhalation.219
Deposition of orally inhaled pentamidine shows considerable interindividual variation and appears to depend on several factors, including delivery device, particle size of aerosolized drug, dose, patient position, and nebulization efficiency.181, 182, 219, 284, 293, 296 Limited data from patients with HIV infections indicate that distribution of the drug in the lungs following oral inhalation via nebulization is more uniform when the patient is in the supine rather than the sitting position.284 In one study, differences in pulmonary deposition of pentamidine appeared to relate principally to aerosol delivery from the nebulizer system rather than from lung parameters (e.g., breathing pattern, pulmonary function tests, regional ventilation).296 In this study, the fraction of a dose deposited (amount deposited versus amount inhaled, not the amount deposited versus the amount of drug added to the nebulizer) averaged 62% in patients with HIV infection and did not differ substantially as a fraction of that inhaled for the Respirgard® II or AeroTech® II jet nebulizers, although the latter nebulizer was substantially more efficient in delivering the drug to the patient (i.e., the amount inhaled per minute was higher).296 In an in vitro study simulating clinical conditions, the amount of drug that would be delivered for oral inhalation versus that originally added to the nebulizer (nebulizer efficiency) averaged 4.6, 21, and 16% for the Respirgard® II, AeroTech® II, and FISONeb® nebulizers, respectively, at a simulated tidal volume of 750 cm3 and a frequency of 20 breaths/minute.293
In vitro, pentamidine is reportedly 69% bound to serum proteins.172 Pentamidine apparently crosses the placenta.355 In a child delivered by cesarean section from an HIV-infected woman receiving IV pentamidine (3.4 mg/kg daily), concentrations of the drug in cord blood were 13.2 ng/mL; the sample was obtained 16.5 hours after the mother's last dose and blood concentrations of the drug in the mother that day were 81.3 ng/mL.355 It is not known whether pentamidine isethionate is distributed into milk.134
Following a single pentamidine isethionate dose of 4 mg/kg given by IM injection or IV infusion over 2 hours in patients with AIDS and PCP who had normal renal function, plasma concentrations of the drug declined in a biphasic manner with a mean half-life of 54 or 18 minutes in the initial phase, respectively, and 9.4 or 6.4 hours in the elimination phase, respectively.1, 171 Pentamidine appears to be eliminated very slowly from tissues in which the drug principally accumulates (e.g., liver, lungs),182, 183 and terminal half-lives of 2.8-12 days have been reported with IV dosages of 2-4 mg/kg daily.1 Following a single pentamidine isethionate dose of 3-4.8 mg/kg given by IV infusion in patients with Trypanosoma brucei gambiense infection, the mean terminal elimination half-life was 11 days (range 4-19 days).370 Limited data suggest that the elimination half-life of pentamidine is not substantially altered in patients with mild to moderate renal impairment but may be prolonged up to 2 days or longer in patients with severe renal impairment.184, 185
In mice, pentamidine is excreted in urine and feces in a ratio of about 4:1, respectively;1, 77 the ratio remains constant for at least 90 hours after administration.77 In humans, pentamidine is excreted in urine, apparently as unchanged drug;77, 171, 185 it is not known if the drug is excreted in feces.24, 77, 171 Following daily IM administration of pentamidine isethionate in a study in patients with PCP who had varying degrees of renal function, 24-hour urinary drug excretion (determined using a fluorometric assay) after 1-10 days of therapy was generally 15-20% (range: 11-29%) of the daily dose; most urinary excretion occurred within the first 6 hours after administration of a dose.77 In several patients, decreasing amounts of pentamidine were excreted in urine for up to 6-8 weeks after discontinuance of the drug.77 Following a single 4-mg/kg IM or IV dose of pentamidine isethionate in patients with AIDS and PCP who had normal renal function, about 2.5-5% of the dose (determined using an HPLC assay) was excreted in urine as unchanged drug in 24 hours, mainly within the first 8 hours after administration of the drug;171 similar amounts (about 1-4% of the dose) were also excreted in urine as unchanged drug in 24 hours in patients with mild to moderate renal impairment.185 Studies in dogs and humans suggest that renal clearance accounts for about 5% or less of the total body clearance of the drug.171, 172, 185
Limited data suggest that pentamidine is not appreciably removed by hemodialysis or peritoneal dialysis.185
Data are not available regarding the pharmacokinetics of pentamidine isethionate after oral inhalation via nebulization in patients with hepatic or renal dysfunction.219
Pentamidine isethionate is an aromatic diamidine-derivative antiprotozoal and antifungal agent.1, 2, 3, 219 The presence of the benzenecarboximidamide (aromatic amidine, benzamidine) group is associated with pentamidine's trypanosomicidal activity, and the presence of both benzenecarboximidamide groups is necessary for this activity.4, 5
Pentamidine isethionate is commercially available as a sterile, lyophilized powder for preparation of solutions for IM or IV use1 and as a sterile, lyophilized powder for preparation of solutions for oral inhalation via nebulization (aerosolized pentamidine).219 Pentamidine isethionate occurs as white or almost white crystals or powder;1, 6 the drug is hygroscopic and may be odorless6 or have a slight butyric odor.7 The drug is soluble in water,1, 6, 7 having an aqueous solubility of approximately 100 mg/mL at 25°C,7 and is slightly soluble in alcohol.6, 7 Each 1.74 mg of pentamidine isethionate is equivalent to 1 mg of pentamidine.41, 43, 207 Pentamidine reportedly has a pKa1 and pKa2 of 11.4.19, 73
Following reconstitution with sterile water for injection or 5% dextrose injection, pentamidine isethionate solutions for parenteral use are clear134 and colorless.135 After reconstitution with sterile water for injection, solutions of the drug for parenteral use containing 60-100 mg/mL have a pH of approximately 5.4.134 Following reconstitution with 5% dextrose injection, pentamidine isethionate solutions for parenteral use containing 60 or 100 mg/mL have a pH of 4.09 or 4.38, respectively.134 Pentamidine isethionate solutions for parenteral use containing 100 mg/mL in sterile water for injection or 5% dextrose injection have osmolalities of 160 or 455 mOsm/kg, respectively.134
When pentamidine isethionate lyophilized powder for oral inhalation solution is reconstituted and administered using the Respirgard® II jet nebulizer, the resultant mist contains nebulized particles of the drug with a median mass aerodynamic diameter of 0.8-1.4 µm.176, 181, 224, 225, 234, 245, 285, 293, 296
Prior to reconstitution, pentamidine isethionate lyophilized powders should be stored at 20-25°C and protected from light.1, 219
Following reconstitution with sterile water for injection, pentamidine isethionate solutions for parenteral use containing 60-100 mg/mL are stable in the original vial for 48 hours at room temperature if protected from light;1 to avoid crystallization, reconstituted solutions should be stored at 22-30°C.1 Unused portions of the reconstituted solutions should be discarded.1 Reconstituted solutions of the drug for parenteral use that have been further diluted in 5% dextrose injection to a concentration of 1 or 2.5 mg/mL for IV infusion are stable for up to 24 hours at room temperature.1 Reconstituted solutions that have been diluted to a concentration of 1 or 2 mg/mL in 5% dextrose or 0.9% sodium chloride injection in PVC bags are reportedly stable for 48 hours exposed to normal fluorescent light at 22-26°C;162 some data suggest that small amounts of the drug may be adsorbed onto PVC infusion sets.162
Following reconstitution with sterile water for injection, pentamidine isethionate solutions for oral inhalation are stable in the original vial for 48 hours at room temperature if protected from light.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.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral Inhalation | For solution, for nebulization | 300 mg | ||
Parenteral | For injection | 300 mg* | Pentam® 300 | APP |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
1. APP Pharmaceuticals, LLC. Pentam® 300 (pentamidine isethionate) lyophilized powder, for injection for intramuscular or intravenous use prescribing information. Schaumburg, IL; 2008 Mar.
2. Schoenbach EB, Greenspan EM. The pharmacology, mode of action and therapeutic potentialities of stilbamidine, pentamidine, propamidine and other aromatic diamidines—a review. Medicine (Baltimore) . 1948; 27:327-77. [PubMed 18885033]
3. Wien R. The pharmacological actions of certain aromatic diamidines possessing trypanocidal activity. Ann Trop Med Parasit . 1943; 37:1-18.
4. Lourie EM, Yorke W. Studies in chemotherapy. XXI. The trypanocidal action of certain aromatic diamidines. Ann Trop Med Parasit . 1939; 33:289-304.
5. Ashley JN, Barber HJ, Ewins AJ et al. A chemotherapeutic comparison of the trypanocidal action of some aromatic diamidines. J Chem Soc . 1942; 20:103-16.
6. The British pharmacopoeia. London: Her Majesty's Stationery Office; 1980:330.
7. Windholz M, ed. The Merck index. 10th ed. Rahway, NJ: Merck & Co, Inc; 1983:1023.
8. Chesters JK. Protein synthesis by cell-free extracts of Crithidia oncopelti. Biochim Biophys Acta. 1966; 114:385-97.
9. Wallis DC. The effect of pentamidine on ribosomes of the parasitic flagellate Crithidia ( Strigomonas ) oncopelti. J Protozool. 1966; 13:234-9.
10. Bachrach U, Brem S, Wertman SB et al. Leishmania spp.: effect of inhibitors on growth and on polyamine and macromolecular syntheses. Exp Parasitol . 1979; 48:464-70. [PubMed 510448]
11. Gutteridge WE. Some effects of pentamidine di-isethionate on Crithidia fasciculata. J Protozool. 1969; 16:306-11.
12. Kaplan HG, Myers CE. Complex inhibition of thymidylate synthetase by aromatic diamidines: evidence for both rapid, freely reversible and slowly progressive, nonequilibrium inhibition. J Pharmacol Exp Ther . 1977; 201:554-63. [PubMed 864595]
13. Hill GC, Hutner SH. Effect of trypanocidal drugs on terminal respiration of Crithidia fasciculata. Exp Parasitol. 1968; 22:207-12.
14. Bornstein RS, Yarbro JW. An evaluation of the mechanism of action of pentamidine isethionate. J Surg Oncol . 1970; 2:393-8. [PubMed 5315524]
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