      Document 0222
 DOCN  DRG0222
 UNIQUE IDENTIFIER        DRG-0025
 NAME OF SUBSTANCE        Pentamidine [USAN 1995]
 REGISTRY NUMBER          100-33-4
 STANDARD CHEMICAL NAME   4,4'-(Pentamethylenedioxy)dibenzamidine [USAN
                          1996]
 SYNONYMS                 Nebupent (aerosol) (isethionate) [USAN 1995]
 SYNONYMS                 Pentamidine Isethionate [USP DI 1995]
 SYNONYMS                 Pentam [USP DI 1995]
 SYNONYMS                 Lomidine (mesylte) [Merck Index 1989]
 SYNONYMS                 4,4'-Diamidino-alpha,omega-diphenoxypentane
                          isethionate [Merck Index 1989]
 SYNONYMS                 Pneumopent (aerosol) (isethionate) [ USAN
                          1995]
 SYNONYMS                 Aeropent (isethionate) [Merck Index 1989]
 SYNONYMS                 Benambax (isethionate) [Merck Index 1989]
 SYNONYMS                 Pentacarinat
                          (aerosol/intravenous/intramuscular) [USP DI
                          1995]
 SYNONYMS                 Pentamidine mesylate [Merck Index 1989]
 PROTOCOL ID NUMBERS      NIAID ACTG 021
 PROTOCOL ID NUMBERS      NIAID ACTG 029
 PROTOCOL ID NUMBERS      NIAID ACTG 030
 PROTOCOL ID NUMBERS      NIAID ACTG 040
 PROTOCOL ID NUMBERS      NIAID ACTG 041
 PROTOCOL ID NUMBERS      NIAID ACTG 048
 PROTOCOL ID NUMBERS      NIAID ACTG 079
 PROTOCOL ID NUMBERS      NIAID ACTG 081
 PROTOCOL ID NUMBERS      NIAID ACTG 115
 PROTOCOL ID NUMBERS      NIAID ACTG 142
 PROTOCOL ID NUMBERS      NIAID 88 CC-85
 PROTOCOL ID NUMBERS      NIAID 91 CC-207
 PROTOCOL ID NUMBERS      NCI 90 C-34
 PROTOCOL ID NUMBERS      FDA 022A
 PROTOCOL ID NUMBERS      FDA 022B
 PROTOCOL ID NUMBERS      FDA 022C
 PROTOCOL ID NUMBERS      FDA 022D
 PROTOCOL ID NUMBERS      FDA 022E
 PROTOCOL ID NUMBERS      FDA 023A
 PROTOCOL ID NUMBERS      FDA 023B
 PROTOCOL ID NUMBERS      FDA 053B
 PROTOCOL ID NUMBERS      NIAID ACTG 189
 PROTOCOL ID NUMBERS      NIAID CPCRA 013
 IND NUMBER               31,372
 IND NUMBER               31,914
 IND NUMBER               32,622
 IND NUMBER               30,006
 SECONDARY SOURCE ID      MB 800 (as isethionate) [USAN 1995]
 SECONDARY SOURCE ID      RP 2512 (as isethionate) [USAN 1995]
 PHARMACOLOGICAL ACTION   MODE OF ACTION: This is not fully understood
                          and little is known about pentamidine's
                          pharmacokinetics. In vitro studies with
                          mammalian tissues and the protozoan Crithidia
                          oncopelti indicate that this drug interferes
                          with nuclear metabolism producing inhibition
                          of the synthesis of DNA, RNA, phospholipids,
                          and proteins. Preliminary studies in 7
                          patients treated with daily intramuscular
                          injections at 4 mg/kg for 10-12 days gave
                          drug plasma levels between 0.3-0.5 mcg/ml
                          which did not appreciably change with time
                          after injection or from day-to-day; higher
                          plasma levels were found in patients having
                          an elevated blood urea nitrogen level;
                          decreasing amounts of the drug were excreted
                          in urine up to 6-8 weeks after cessation of
                          treatment. The drug also may interfere with
                          folate transformation. It is poorly absorbed
                          in the gastrointestinal tract (must be given
                          parenterally) and is rapidly bound to tissues
                          following parenteral administration.  In
                          humans, it appears to be stored in the body
                          to some extent, only small amounts appear in
                          the blood for a short time following a single
                          dose, and does not cross the blood-brain
                          barrier. Time to peak serum concentration
                          following intramuscular administration is
                          0.5-1 hour. Serum levels peaked at 30 min
                          after intravenous dosing then fell rapidly to
                          very low levels, with apparent uptake in
                          kidneys, liver, and lungs. Slow renal
                          clearance with decreasing amounts of
                          pentamidine in the urine for 6-8 weeks after
                          discontinuing its use. Aerosolized
                          pentamidine is taken up by lung alveoli, and
                          is associated with less systemic absorption.
                          Bronchoalveolar fluid was found to contain
                          70-fold higher levels of pentamidine from
                          aerosolized pentamidine compared to standard
                          intravenous therapy. [PDR 1995]
 DISEASES STUDIED/TREATED Pneumocystis carinii pneumonia (PCP) [PDR
                          1995]
 DISEASES STUDIED/TREATED FDA approved 10/16/84 for PCP treatment (IM
                          and IV);
 DISEASES STUDIED/TREATED FDA approved 6/15/89 for PCP prophylaxis
                          (aerosol) [FDA Office of AIDS and Special
                          Health Issues]
 CLASSIFICATION CODE      Antiprotozoal [USP DI 1995]
 SUBSTANCE INTERACTIONS   No clinically significant interactions have
                          been documented in patients receiving
                          prophylactic aerosolized pentamidine.
                          Parenteral pentamidine has interacted with
                          blood dyscrasia-causing medications, bone
                          marrow depressants, nephrotoxic medications
                          (concurrent use with pentamidine may increase
                          the risk for nephrotoxicity). Concurrent use
                          of pentamidine with radiation therapy may
                          increase the bone marrow-depressant effect.
                          Combination with didanosine may result in
                          pancreatitis; concurrent use with foscarnet
                          may result in severe, but reversible,
                          hypocalcemia, hypomagnesemia and
                          nephrotoxicity. [USP DI 1995]
 ADVERSE EFFECTS          Since fatalities due to severe hypotension,
                          hypoglycemia, and cardiac arrhythmias have
                          been reported in patients treated with this
                          drug both by the intramuscular and
                          intravenous routes, its use should be limited
                          to patients in whom Pneumocystis carinii has
                          been demonstrated. Of 424 patients (most
                          having AIDS) who were treated with
                          pentamidine isethionate, 57.5 percent
                          developed some adverse reaction, with the
                          most severe being: leukopenia, hypoglycemia,
                          thrombocytopenia, hypotension, acute renal
                          failure, hypocalcemia, Stevens-Johnson
                          syndrome, and ventricular tachycardia. More
                          frequent side effects include: anxiety,
                          chills, cold sweats, cool pale skin,
                          headache, increased hunger, nausea,
                          nervousness, shakiness, blurred vision,
                          confusion, dizziness, fainting or
                          lightheadedness, drowsiness, flushed dry
                          skin, fruit-like breath odor, increased
                          thirst, increased urination, appetite loss,
                          hallucinations, rapid/irregular pulse, skin
                          rash, sore throat and fever, unusual
                          bleeding/bruising, or unusual
                          tiredness/weakness.  Other sources have
                          reported that use of pentamidine may cause
                          pain, swelling, and sterile abscess, or
                          induration at site of intramuscular
                          injection; thrombophlebitis and generalized
                          or localized urticarial eruptions with
                          intravenous administration; severe
                          hypotension with single intramuscular
                          injection following rapid intravenous
                          infusion; hypoglycemia; diabetes mellitus;
                          toxicity to pancreas beta cells; mild
                          impairment of renal function in absence of
                          other neurotoxic drugs; elevation of liver
                          enzymes; hematologic disturbances with
                          neutropenia and thrombocytopenia, fever,
                          hypocalcemia, and hallucinations; leukopenia;
                          cardiac arrhythmias; pancreatitis.  Appeared
                          to be no more toxic than
                          trimethoprim/sulfamethoxazole (TMP/SMX);
                          potential alternative to sulfonamides and
                          TMP/SMX for pneumocystis pneumonia. [PDR
                          1995]
 CONTRAINDICATIONS        Once diagnosis of Pneumocystis carinii
                          pneumonia has been firmly established, there
                          are no absolute contraindications to the use
                          of pentamidine isethionate. [PDR 1995]
 CHEMICAL/PHYSICAL DATA   DRUG DESCRIPTION: Aromatic diamidine
                          derivative [PDR 1995]
 CHEMICAL/PHYSICAL DATA   MOLECULAR FORMULA: C19H24N4O2 (Pentamidine)
                          [USAN 1995]  C23H36N4O10S2 (Pentamidine
                          Isethionate) [USAN 1995]
 CHEMICAL/PHYSICAL DATA   MOLECULAR WEIGHT: 340.43 (Pentamidine) [USAN
                          1995]
 CHEMICAL/PHYSICAL DATA   MOLECULAR WEIGHT: 592.68 (Pentamidine
                          Isethionate) [PDR 1995]
 CHEMICAL/PHYSICAL DATA   PERCENT ELEMENTAL COMPOSITION: C67.04%,
                          H7.10%, N16.46%, O9.40% [Merck Index 1989]
 CHEMICAL/PHYSICAL DATA   MELTING POINT: (Pentamidine Isethionate):
                          About 180 C [Merck Index 1989]
 CHEMICAL/PHYSICAL DATA   SOLUBILITY: (Pentamidine Isethionate):
                          Soluble in water (about 1:10 at 25 C; about
                          1:4 at 100 C); soluble in glycerol
                          (solubility increases on warming); insoluble
                          in ether, acetone, chloroform, and liquid
                          petroleum [Merck Index 1989]
 CHEMICAL/PHYSICAL DATA   ACIDITY: Acidity of 5 percent (w/v) aqueous
                          solution (Pentamidine Isethionate): pH
                          4.5-6.5 [Merck Index 1983]
 CHEMICAL/PHYSICAL DATA   PHYSICAL DESCRIPTION: White crystalline
                          powder (Pentamidine Isethionate) [PDR 1995]
                          Hygroscopic, very bitter crystals; slight
                          butyric odor (Pentamidine Isethionate) [Merck
                          Index 1989]
 CHEMICAL/PHYSICAL DATA   STABILITY: The manufacturers instructions
                          vary with each brand of inhalation solution
                          or injection. In general solutions are stable
                          for 24 hours at room temperature or 48 hours
                          when refrigerated [USP DI 1995]
 SUBSTANCE DELIVERY DATA  DOSAGE FORM: Vials - 300 mg lyophilized
                          product, formulated in USP sterile water or 5
                          percent dextrose for injection/infusion.
                          (Note; 522 mg pentamidine isethionate is
                          equivalent to [PDR 1995]
 SUBSTANCE DELIVERY DATA  DOSAGE FORM: approximately 300 mg
                          pentamidine. [PDR 1995]
 SUBSTANCE DELIVERY DATA  MODE OF DELIVERY: Inhalation of aerosolized
                          mist of aqueous solution [NIAID ACTG 021]
                          Intravenous injection/infusion. Intramuscular
                          injection. [PDR 1995]
 SUBSTANCE DELIVERY DATA  STORAGE: Store dry, lyophilized product at
                          controlled room temperature (15-30 C; 59-86
                          F), protected from light; dextrose solutions
                          are stable at room temperature for up to 24
                          hours. [PDR 1995]
 SUBSTANCE DELIVERY DATA  STORAGE: Reconstituted with sterile water,
                          solution remains stable for up to 48 hours at
                          room temperature.  [PDR 1995]
 MANUFACTURERS            LyphoMed
 REFERENCES               Bozzette SA, Finkelstein DM, Spector SA,
                          Frame P, Powderly WG, He W, Phillips L,
                          Craven D, van der Horst C, Feinberg J. A
                          randomized trial of three antipneumocystis
                          agents in patients with advanced human
                          immunodeficiency virus infection. N Engl J
                          Med. 1995 Mar 16;332(11):693-9.
 REFERENCES               Rizzardi GP, Lazzarin A, Frigerio D, Maillard
                          M, Lucchini M, Musicco M, Moroni M. Two
                          dosages of inhaled pentamidine for secondary
                          prophylaxis of PCP. A 1-yr randomized
                          controlled trial. Int Conf AIDS. 1994 Aug
                          7-12;10(2):150 (abstract no. PBO612).
 REFERENCES               Dohn MN, Weinberg WG, Torres RA, Follansbee
                          SE, Caldwell PT, Scott JD, Gathe JC Jr,
                          Haghighat DP, Sampson JH, Spotkov J, et al.
                          Oral atovaquone compared with intravenous
                          pentamidine for Pneumocystis carinii
                          pneumonia in patients with AIDS. Ann Intern
                          Med. 1994 Aug 1;121(3):174-80.
 REFERENCES               May T, Beuscart C, Reynes J, Marchou B,
                          Leclercq P, Borsa Lebas F, Saba J, Micoud M,
                          Mouton Y, Canton P.
                          Trimethoprim-sulfamethoxazole versus
                          aerosolized pentamidine for primary
                          prophylaxis of Pneumocystis carinii
                          pneumonia: a prospective, randomized,
                          controlled clinical trial. J Acquir Immune
                          Defic Syndr. 1994 May;7(5):457-62.
 REFERENCES               Opravil M, Heald A, Lazzarin A, Hirschel B,
                          Luthy R. Dapsone-pyrimethamine (DP) vs.
                          aerosolized pentamidine (AP) for combined
                          prophylaxis of PCP and toxoplasmic
                          encephalitis (TE). Int Conf AIDS. 1993 Jun
                          6-11;9(1):373 (abstract no. PO-B10-1429).
 REFERENCES               Rizzardi GP, Frigerio D, Lazzarin A, Maillard
                          M, Musicco M, Moroni M. Prospective study on
                          primary prophylaxis for PCP: a 1-yr
                          randomized trial comparing aerosolized
                          pentamidine vs. daily cotrimoxazole. Int Conf
                          AIDS. 1993 Jun 6-11;9(1):388 (abstract no.
                          PO-B10-1519).
 REFERENCES               Lidman C, Berglund O, Tynell E, Lindback S,
                          Elvin K. Aerosolized pentamidine as primary
                          prophylaxis for Pneumocystis carinii
                          pneumonia: efficacy, mortality and morbidity.
                          AIDS. 1994 Jul;8(7):935-9.
 REFERENCES               Arasteh K, Vohringer H, Roth H, Bragas B,
                          Breuel H, L'age M. Phase I-trial for
                          evaluating the safety and tolerance of single
                          ascending doses of an aerosolized mixture of
                          pentamidine and
                          phosphatidylcholine-liposomes. Int Conf AIDS.
                          1993 Jun 6-11;9(1):431 (abstract no.
                          PO-B17-1777).
 REFERENCES               Mallolas J, Zamora L, Gatell JM, Miro JM,
                          Vernet E, Valls ME, Soriano E, SanMiguel JG.
                          Primary prophylaxis for Pneumocystis carinii
                          pneumonia: a randomized trial comparing
                          cotrimoxazole, aerosolized pentamidine and
                          dapsone plus pyrimethamine. AIDS. 1993
                          Jan;7(1):59-64.
 REFERENCES               Hardy WD, Feinberg J, Finkelstein DM, Power
                          ME, He W, Kaczka C, Frame PT, Homes M, Waskin
                          H, Fass RJ, et al. A controlled trial of
                          trimethoprim-sulfamethoxazole or aerosolized
                          pentamidine for secondary prophylaxis of
                          Pneumocystis carinii pneumonia in patients
                          with the acquired immunodeficiency syndrome.
                          N Engl J Med. 1992 Dec 24;327(26):1842-8.
 ENTRY MONTH              8906
 LAST REVISION DATE       951108
 

SOURCE: National Library of Medicine, Bethesda, MD.  Distributed by AEGIS.
