      Document 0143
 DOCN  DRG0143
 UNIQUE IDENTIFIER        DRG-0104
 NAME OF SUBSTANCE        Azithromycin [USAN 1996]
 REGISTRY NUMBER          83905-01-5
 RELATED REGISTRY NUMBER  117772-70-0 (Dihydrate)
 STANDARD CHEMICAL NAME   1-Oxa-6-azacyclopentadecan-15-one,13-((2,6-di-
                          deoxy
                          -3-C-methyl-3-0-methyl-alpha-L-ribo-hexopyran-
                          osyl)
                          -oxy)2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,-
                          14-
                          heptamethyl-11-((3,4,6-trideoxy-3-(dimethylam-
                          ino) -beta-D-xylo-hexopyranosyl)oxy) [USAN
                          1996]
 SYNONYMS                 Zithromax [USAN 1996]
 SYNONYMS                 Sumamed [Merck Index 1989]
 SYNONYMS                 N-Methyl-11-aza-10-deoxo-10-dihydroerythromyc-
                          in A [Merck Index 1989]
 SYNONYMS                 9-Deoxo-9a-methyl-9a-aza-homoerythromycin A
                          [Merck Index 1989]
 PROTOCOL ID NUMBERS      FDA 058A
 PROTOCOL ID NUMBERS      NIAID 91 CC-100
 PROTOCOL ID NUMBERS      NIAID ACTG 156
 PROTOCOL ID NUMBERS      NIAID 92 I-165
 PROTOCOL ID NUMBERS      NIAID DATRI 001
 PROTOCOL ID NUMBERS      FDA 058F
 PROTOCOL ID NUMBERS      FDA 058G
 PROTOCOL ID NUMBERS      FDA 058D
 PROTOCOL ID NUMBERS      FDA 058C
 PROTOCOL ID NUMBERS      FDA 058H
 PROTOCOL ID NUMBERS      FDA 058I
 PROTOCOL ID NUMBERS      FDA 058J
 PROTOCOL ID NUMBERS      FDA 226A
 PROTOCOL ID NUMBERS      FDA 226B
 PROTOCOL ID NUMBERS      FDA 226C
 PROTOCOL ID NUMBERS      FDA 226D
 PROTOCOL ID NUMBERS      NIAID ACTG 135
 SECONDARY SOURCE ID      CP-62993 [USAN 1996]
 SECONDARY SOURCE ID      XZ-450 [USAN 1996]
 PHARMACOLOGICAL ACTION   MODE OF ACTION: Similar to erythromycin,
                          which binds to the 50 S ribosomal subunits of
                          susceptible bacteria and suppresses protein
                          synthesis. Azithromycin appears to bind to
                          the same receptor as erythromycin. These
                          drugs may be bactericidal or bacteriostatic.
                          The in vitro spectrum of azithromycin is
                          greater than that of erythromycin. It retains
                          the erythromycin spectrum eg, (gram-positive
                          coverage) while showing significant
                          improvement in activity against gram-negative
                          organisms. Appears to have better side effect
                          profile and greater acid stability than
                          erythromycin. Azithromycin is well absorbed
                          in humans and has a remarkable affinity for
                          tissue. The half-life of the drug in humans
                          appears to vary between 5 and 11 hours,
                          depending on the dose. Peak concentrations
                          are attained between 1.5 and 3.3 hours after
                          oral administration. The drug is protein
                          bound in serum and appears to be eliminated
                          slowly, possibly because of low serum
                          clearance and extensive distribution in the
                          tissues. Thus, detectable levels  of the drug
                          can be found in the urine 7 to 14 days after
                          the administration of a single dose. The
                          relatively long half life, affinity for
                          tissues, and the slow elimination of
                          azithromycin indicate potential for
                          once-a-day dosing. Biliary excretion,
                          predominantly as unchanged drug, is a major
                          route of elimination. Over a 7 day period,
                          about 6% of the administered dose appears as
                          unchanged drug in the urine. In patients with
                          non-inflamed meninges only very low
                          concentrations were noted in the CSF (less
                          than 0.01 mcg/ml). Studies suggest that the
                          drug attains active concentrations in the
                          inflamed central nervous system. In one study
                          involving ten healthly male volunteers, a
                          single 500 mg oral dose resulted in a peak
                          concentration of 0.4 mg/l. The mean serum
                          concentrations were <50 % than those after an
                          IV dose. Oral bioavailability is 37 %. Within
                          72 hours after dosing, 4.5% (oral) and 12.2%
                          (IV) was excreted in the urine. The half-life
                          depended on the sampling time and was quite
                          variable, ranging from 11 to 57 hours when
                          sampling 8 hours to 6 days post-dose. Serum
                          protein binding varied by drug concentration
                          ranging from 51% at 0.02 mcg/ml to 7% at 2.0
                          mcg/ml. Concentrations of azithromycin varied
                          between 1 and 9 mg/kg in various tissues and
                          were 10 to 100 times higher than serum sample
                          after a 500 mg dose.
 PHARMACOLOGICAL ACTION    Concentrations were lowest in fat, muscle,
                          bone, and gastric mucosa. Food decreases
                          absorption of azithromycin; the Cmax can be
                          lowered by 50% and the AUC by 43%. [PDR 1995]
                          [Facts and Comparisons 1995] [Antimicrob
                          Agents Chemother 1988 May; Aruaja, et al.,
                          32(5)]
 DISEASES STUDIED/TREATED Under investigation for the treatment of
                          Mycobacterium avium complex, toxoplasmosis,
                          and cryptosporidiosis [AmFAR Tx Dir
                          1995;7(4)]
 DISEASES STUDIED/TREATED In addition, azithromycin is available
                          through a compassionate-use protocol for the
                          treatment of toxoplasmosis,
                          cryptosporidiosis, and MAC [AmFAR Tx Dir
                          1995;7(4)]
 CLASSIFICATION CODE      Antibacterial [USAN 1996]
 OTHER MAJOR USES         Used to treat bacterial upper and lower
                          respiratory tract infections, skin and skin
                          structure infections, and sexually
                          transmitted diseases [PDR 1995]
 SUBSTANCE INTERACTIONS   Possibly interacts with theophylline,
                          warfarin, digoxin, ergotamine,
                          dihydroergotamine, triazolam, and drugs
                          metabolized by the cytochrome P450 system.
                          [PDR 1995]
 ADVERSE EFFECTS          Adverse effects include diarrhea/loose stools
                          (5%), nausea (3%), abdominal pain (3%). The
                          remaining side effects were seen at an
                          occurrence rate of less than 1%:
                          palpitations, chest pain, dyspepsia,
                          flatulence, vomiting, melena, cholestatic
                          jaundice, monilia, vaginitis, nephritis,
                          dizziness, headache, vertigo, somnolence,
                          fatigue, rash, photosensitivity, and
                          angioedema. [PDR 1995]
 CONTRAINDICATIONS        Contraindicated in patients with
                          hypersensitivity to azithromycin,
                          erythromycin, or any macrolide antibiotics.
                          [PDR 1995]
 CHEMICAL/PHYSICAL DATA   DRUG DESCRIPTION: An azalide, a subclass of
                          macrolide antibiotics [PDR 1995]
 CHEMICAL/PHYSICAL DATA   DRUG DESCRIPTION: Azithromycin is derived
                          from erythromycin [PDR 1995]
 CHEMICAL/PHYSICAL DATA   DRUG DESCRIPTION: However, azithromycin
                          differs chemically from erythromycin in that
                          a methyl-substituted nitrogen atom is
                          incorporated into the lactone ring [PDR 1995]
 CHEMICAL/PHYSICAL DATA   MOLECULAR FORMULA: C38H72N2O12 [Merck Index
                          1989]
 CHEMICAL/PHYSICAL DATA   MOLECULAR WEIGHT: 749.00 (anhydrous) [USAN
                          1996]
 CHEMICAL/PHYSICAL DATA   MELTING POINT: 113-115 C [Merck Index 1989]
 CHEMICAL/PHYSICAL DATA   ELEMENTAL COMPOSITION: C60.94%, H9.69%,
                          N3.74%, O25.63% [Merck Index 1989]
 CHEMICAL/PHYSICAL DATA   PHYSCICAL DESCRIPTION: White, crystalline
                          powder [PDR 1995]
 SUBSTANCE DELIVERY DATA  DOSAGE FORM: 250 mg gelatin capsules. [PDR
                          1995]
 SUBSTANCE DELIVERY DATA  MODE OF DELIVERY: Oral. [PDR 1995]
 SUBSTANCE DELIVERY DATA  STORAGE: Capsules should be stored below 30
                          C. [PDR 1995]
 MANUFACTURERS            Pfizer
 REFERENCES               Ives DV, Davis RB, Currier JS. Impact of
                          clarithromycin and azithromycin on patterns
                          of treatment and survival among AIDS patients
                          with disseminated Mycobacterium avium
                          complex. AIDS. 1995 Mar;9(3):261-6.
 REFERENCES               Ciaffi L, Franzetti F, Gervasoni C,
                          Romaniello A, Maillard M, Moro M, Ruggieri A,
                          Cernuschi M, Lazzarin A. Azithromycin versus
                          amoxicillin/clavulanate in community acquired
                          pneumonias of HIV-patients. Int Conf AIDS.
                          1994 Aug 7-12;10(2):135 (abstract no.
                          PB0554).
 REFERENCES               Verdon MS, Handsfield HH, Johnson RB. Pilot
                          study of azithromycin for treatment of
                          primary and secondary syphilis. Clin Infect
                          Dis. 1994 Sep;19(3):486-8.
 REFERENCES               Tyndall MW, Agoki E, Plummer FA, Malisa W,
                          Ndinya-Achola JO, Ronald AR. Single dose
                          azithromycin for the treatment of chancroid:
                          a randomized comparison with erythromycin.
                          Sex Transm Dis. 1994 Jul-Aug;21(4):231-4.
 REFERENCES               Godofsky EW. Treatment of presumed cerebral
                          toxoplasmosis with azithromycin [letter]. N
                          Engl J Med. 1994 Feb 24;330(8):575-6.
 REFERENCES               Benson CA. Treatment of disseminated disease
                          due to the Mycobacterium avium complex in
                          patients with AIDS. Clin Infect Dis. 1994
                          Apr;18 Suppl 3:S237-42.
 REFERENCES               Wallace MR, Mille LK, Nguyen MT, Shields AR.
                          Ototoxicity with azithromycin [letter].
                          Lancet. 1994 Jan 22;343(8891):241.
 REFERENCES               Saba J, Morlat P, Raffi F, Hazebroucq V, Joly
                          V, Leport C, Vilde JL. Pyrimethamine plus
                          azithromycin for treatment of acute
                          toxoplasmic encephalitis in patients with
                          AIDS. Eur J Clin Microbiol Infect Dis. 1993
                          Nov;12(11):853-6.
 REFERENCES               Dunne MW. Open label azithromycin in the
                          treatment of crytosporidiosis. Int Conf AIDS.
                          1993 Jun 6-11;9(1):385 (abstract no.
                          PO-B10-1500).
 REFERENCES               Kovacs JA, Polis MA, Baird B, Feuerstein I,
                          Fallon J, Walker RE, Davey RT, Lane HC, Masur
                          H. Evaluation of azithromycin or the
                          combination of 566C80 and pyrimethamine in
                          the treatment of toxoplasmosis. Int Conf
                          AIDS. 1992 Jul 19-24;8(2):B120 (abstract no.
                          PoB 3199).
 ENTRY MONTH              9103
 LAST REVISION DATE       951213
 

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