Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/3167
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Zithromax (Tablet, Film Coated)
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ZITHROMAX for oral suspension (single dose 1 g packet) can be taken with or without food after constitution. Not for pediatric use. For pediatric suspension, please refer to the INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION sections of the prescribing information for ZITHROMAX (azithromycin for oral suspension) 100 mg/5 mL and 200 mg/5 mL bottles. ZITHROMAX tablets may be taken without regard to food. However, increased tolerability has been observed when tablets are taken with food. The recommended dose of ZITHROMAX for the treatment of non-gonococcal urethritis and cervicitis due to C. trachomatis is: a single 1 gram (1000 mg) dose of ZITHROMAX. This dose can be administered as as one single dose packet (1 g).<br/>Prevention of Disseminated MAC Infections: The recommended dose of ZITHROMAX for the prevention of disseminated Mycobacterium avium complex (MAC) disease is: 1200 mg taken once weekly. This dose of ZITHROMAX may be combined with the approved dosage regimen of rifabutin.<br/>Treatment of Disseminated MAC Infections: ZITHROMAX should be taken at a daily dose of 600 mg, in combination with ethambutol at the recommended daily dose of 15 mg/kg. Other antimycobacterial drugs that have shown in vitro activity against MAC may be added to the regimen of azithromycin plus ethambutol at the discretion of the physician or health care provider.<br/>DIRECTIONS FOR ADMINISTRATION OF ZITHROMAX for oral suspension in the single dose packet (1 g): The entire contents of the packet should be mixed thoroughly with two ounces (approximately 60 mL) of water. Drink the entire contents immediately; add an additional two ounces of water, mix, and drink to assure complete consumption of dosage. The single dose packet should not be used to administer doses other than 1000 mg of azithromycin. This packet not for pediatric use.<br/>Renal Insufficiency: No dosage adjustment is recommended for subjects with renal impairment (GFR���80mL/min). The mean AUCwas similar in subjects with GFR 10���80 mL/min compared to subjects with normal renal function, whereas it increased 35% in subjects with GFR<10mL/min compared to subjects with normal renal function. Caution should be exercised when azithromycin is administered to subjects with severe renal impairment.<br/>Hepatic Insufficiency: The pharmacokinetics of azithromycin in subjects with hepatic impairment have not been established. No dosage adjustment recommendations can be made in patients with impaired hepatic function.
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ZITHROMAX (azithromycin tablets and azithromycin for oral suspension) contain the active ingredient azithromycin, an azalide, a subclass of macrolide antibiotics, for oral administration. Azithromycin has the chemical name (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-��-L-ribo-hexopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-��-D-xylo-hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one. Azithromycin is derived from erythromycin; however, it differs chemically from erythromycin in that a methyl-substituted nitrogen atom is incorporated into the lactone ring. Its molecular formula is CHNO, and its molecular weight is 749.0. Azithromycin has the following structural formula: Azithromycin, as the dihydrate, is a white crystalline powder with a molecular formula of CHNO���2HO and a molecular weight of 785.0. ZITHROMAX tablets contain azithromycin dihydrate equivalent to 600 mg azithromycin. The tablets are supplied as white, modified oval-shaped, film-coated tablets. They also contain the following inactive ingredients: dibasic calcium phosphate anhydrous, pregelatinized starch, sodium croscarmellose, magnesium stearate, sodium lauryl sulfate and an aqueous film coat consisting of hypromellose, titanium dioxide, lactose and triacetin. ZITHROMAX for oral suspension is supplied in a single dose packet containing azithromycin dihydrate equivalent to 1 g azithromycin. It also contains the following inactive ingredients: colloidal silicon dioxide, sodium phosphate tribasic, anhydrous; spray dried artificial banana flavor, spray dried artificial cherry flavor, and sucrose.
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Pharmacokinetics: Following oral administration, azithromycin is rapidly absorbed and widely distributed throughout the body. Rapid distribution of azithromycin into tissues and high concentration within cells result in significantly higher azithromycin concentrations in tissues than in plasma or serum. The 1 g single dose packet is bioequivalent to four 250 mg azithromycin capsules. The pharmacokinetic parameters of azithromycin in plasma after dosing as per labeled recommendations in healthy young adults and asymptomatic HIV-seropositive adults (age 18���40 years old) are portrayed in the following chart: In these studies (500 mg Day 1, 250 mg Days 2���5), there was no significant difference in the disposition of azithromycin between male and female subjects. Plasma concentrations of azithromycin following single 500 mg oral and I.V. doses declined in a polyphasic pattern resulting in an average terminal half-life of 68 hours. With a regimen of 500 mg on Day 1 and 250 mg/day on Days 2���5, Cand Cremained essentially unchanged from Day 2 through Day 5 of therapy. However, without a loading dose, azithromycin Clevels required 5 to 7 days to reach steady-state. In asymptomatic HIV-seropositive adult subjects receiving 600-mg ZITHROMAX tablets once daily for 22 days, steady state azithromycin serum levels were achieved by Day 15 of dosing. When azithromycin capsules were administered with food, the rate of absorption (C) of azithromycin was reduced by 52% and the extent of absorption (AUC) by 43%. When the oral suspension of azithromycin was administered with food, the Cincreased by 46% and the AUC by 14%. The absolute bioavailability of two 600 mg tablets was 34% (CV=56%). Administration of two 600 mg tablets with food increased Cby 31% (CV=43%) while the extent of absorption (AUC) was unchanged (mean ratio of AUCs=1.00; CV=55%). The AUC of azithromycin in 250 mg capsules was unaffected by coadministration of an antacid containing aluminum and magnesium hydroxide with ZITHROMAX (azithromycin); however, the Cwas reduced by 24%. Administration of cimetidine (800 mg) two hours prior to azithromycin had no effect on azithromycin absorption. When studied in healthy elderly subjects from age 65 to 85 years, the pharmacokinetic parameters of azithromycin (500 mg Day 1, 250 mg Days 2���5) in elderly men were similar to those in young adults; however, in elderly women, although higher peak concentrations (increased by 30 to 50%) were observed, no significant accumulation occurred. The high values in adults for apparent steady-state volume of distribution (31.1 L/kg) and plasma clearance (630 mL/min) suggest that the prolonged half-life is due to extensive uptake and subsequent release of drug from tissues. Selected tissue (or fluid) concentration and tissue (or fluid) to plasma/serum concentration ratios are shown in the following table: The extensive tissue distribution was confirmed by examination of additional tissues and fluids (bone, ejaculum, prostate, ovary, uterus, salpinx, stomach, liver, and gallbladder). As there are no data from adequate and well-controlled studies of azithromycin treatment of infections in these additionalbody sites, the clinical significance of these tissue concentration data is unknown. Following a regimen of 500 mg on the first day and 250 mg daily for 4 days, only very low concentrations were noted in cerebrospinal fluid (less than 0.01��g/mL) in the presence of non-inflamed meninges. Following oral administration of a single 1200 mg dose (two 600 mg tablets), the mean maximum concentration in peripheral leukocytes was 140��g/mL. Concentrations remained above 32��g/mL for approximately 60 hr. The mean half-lives for 6 males and 6 females were 34 hr and 57 hr, respectively. Leukocyte to plasma Cratios for males and females were 258 (��77%) and 175 (��60%), respectively, and the AUC ratios were 804 (��31%) and 541 (��28%), respectively. The clinical relevance of these findings is unknown. Following oral administration of multiple daily doses of 600 mg (1 tablet/day) to asymptomatic HIV-seropositive adults, mean maximum concentration in peripheral leukocytes was 252��g/mL (��49%). Trough concentrations in peripheral leukocytes at steady-state averaged 146��g/mL (��33%). The mean leukocyte to serum Cratio was 456 (��38%) and the mean leukocyte to serum AUC ratio was 816 (��31%). The clinical relevance of these findings is unknown. The serum protein binding of azithromycin is variable in the concentration range approximating human exposure, decreasing from 51% at 0.02��g/mL to 7% at 2��g/mL. Biliary excretion of azithromycin, predominantly as unchanged drug, is a major route of elimination. Over the course of a week, approximately 6% of the administered dose appears as unchanged drug in urine.<br/>Renal Insufficiency: Azithromycin pharmacokinetics was investigated in 42 adults (21 to 85 years of age) with varying degrees of renal impairment. Following the oral administration of a single 1.0 g dose of azithromycin (4��250 mg capsules), the mean Cand AUCincreased by 5.1% and 4.2%, respectively in subjects with GFR 10 to 80 mL/min compared to subjects with normal renal function (GFR>80 mL/min). The mean Cand AUCincreased 61% and 35%, respectively in subjects with end-stage renal disease (GFR<10 mL/min) compared to subjects with normal renal function (GFR>80 mL/min). Based upon the pharmacokinetic data for azithromycin in subjects with renal impairment, no dose adjustment for Zmax is recommended in patients with GFR>10 mL/min.<br/>Hepatic Insufficiency: The pharmacokinetics of azithromycin in subjects with hepatic impairment has not been established. The effect of azithromycin on the plasma levels or pharmacokinetics of theophylline administered in multiple doses adequate to reach therapeutic steady-state plasma levels is not known.<br/>Mechanism of Action: Azithromycin acts by binding to the 50S ribosomal subunit of susceptible microorganisms and, thus, interfering with microbial protein synthesis. Nucleic acid synthesis is not affected. Azithromycin concentrates in phagocytes and fibroblasts as demonstrated by in vitro incubation techniques. Using such methodology, the ratio of intracellular to extracellular concentration was>30 after one hour incubation. In vivo studies suggest that concentration in phagocytes may contribute to drug distribution to inflamed tissues.<br/>Microbiology: Azithromycin has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section. Aerobic Gram-Positive Microorganisms NOTE: Azithromycin demonstrates cross-resistance with erythromycin-resistant gram-positive strains. Most strains of Enterococcus faecalis and methicillin-resistant staphylococci are resistant to azithromycin. Aerobic Gram-Negative Microorganisms "Other" Microorganisms Beta-lactamase production should have no effect on azithromycin activity. Azithromycin has been shown to be active in vitro and in the prevention and treatment of disease caused by the following microorganisms: Mycobacteria The following in vitro data are available, but their clinical significance is unknown. Azithromycin exhibits in vitro minimal inhibitory concentrations (MICs) of 2.0��g/mL or less against most (���90%) strains of the following microorganisms; however, the safety and effectiveness of azithromycin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled trials. Aerobic Gram-Positive Microorganisms Aerobic Gram-Negative Microorganisms Anaerobic Microorganisms "Other" Microorganisms<br/>Susceptibility Testing of Bacteria Excluding Mycobacteria: The in vitro potency of azithromycin is markedly affected by the pH of the microbiological growth medium during incubation. Incubation in a 10% COatmosphere will result in lowering of media pH (7.2 to 6.6) within 18 hours and in an apparent reduction of the in vitro potency of azithromycin. Thus, the initial pH of the growth medium should be 7.2���7.4, and the COcontent of the incubation atmosphere should be as low as practical. Azithromycin can be solubilized for in vitro susceptibility testing by dissolving in a minimum amount of 95% ethanol and diluting to working concentration with water.<br/>In Vitro Activity of Azithromycin Against Mycobacteria: Azithromycin has demonstrated in vitro activity against Mycobacterium avium complex (MAC) organisms. While gene probe techniques may be used to distinguish between M. avium and M. intracellulare, many studies only reported results on M. avium complex (MAC) isolates. Azithromycin has also been shown to be active against phagocytized M. avium complex (MAC) organisms in mouse and human macrophage cell cultures as well as in the beige mouse infection model. Various in vitro methodologies employing broth or solid media at different pHs, with and without oleic acid-albumin dextrose-catalase (OADC), have been used to determine azithromycin MIC values for Mycobacterium avium complex strains. In general, azithromycin MIC values decreased 4 to 8 fold as the pH of Middlebrook 7H11 agar media increased from 6.6 to 7.4. At pH 7.4, azithromycin MIC values determined with Mueller-Hinton agar were 4 fold higher than that observed with Middlebrook 7H12 media at the same pH. Utilization of oleic acid-albumin-dextrose-catalase (OADC) in these assays has been shown to further alter MIC values. The relationship between azithromycin and clarithromycin MIC values has not been established. In general, azithromycin MIC values were observed to be 2 to 32 fold higher than clarithromycin independent of the susceptibility method employed. The ability to correlate MIC values and plasma drug levels is difficult as azithromycin concentrates in macrophages and tissues.<br/>Drug Resistance: Complete cross-resistance between azithromycin and clarithromycin has been observed with Mycobacterium avium complex (MAC) isolates. In most isolates, a single point mutation at a position that is homologous to the Escherichia coli positions 2058 or 2059 on the 23S rRNA gene is the mechanism producing this cross-resistance pattern.Mycobacterium avium complex (MAC) isolates exhibiting cross-resistance show an increase in azithromycin MICs to���128��g/mL with clarithromycin MICs increasing to���32��g/mL. These MIC values were determined employing the radiometric broth dilution susceptibility testing method with Middlebrook 7H12 medium. The clinical significance of azithromycin and clarithromycin cross-resistance is not fully understood at this time but preclinical data suggest that reduced activity to both agents will occur after M. avium complex strains produce the 23S rRNA mutation.<br/>Susceptibility testing for Mycobacterium avium complex (MAC): The disk diffusion techniques and dilution methods for susceptibility testing against Gram-positive and Gram-negative bacteria should not be used for determining azithromycin MIC values against mycobacteria. In vitro susceptibility testing methods and diagnostic products currently available for determining minimal inhibitory concentration (MIC) values against Mycobacterium avium complex (MAC) organisms have not been standardized or validated. Azithromycin MIC values will vary depending on the susceptibility testing method employed, composition and pH of media and the utilization of nutritional supplements. Breakpoints to determine whether clinical isolates of M. avium or M. intracellulare are susceptible or resistant to azithromycin have not been established. The clinical relevance of azithromycin in vitro susceptibility test results for other mycobacterial species, including Mycobacterium tuberculosis, using any susceptibility testing method has not been determined.
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ZITHROMAX 600 mg tablets (engraved on front with "PFIZER" and on back with "308") are supplied as white, modified oval-shaped, film-coated tablets containing azithromycin dihydrate equivalent to 600 mg azithromycin. These are packaged in bottles of 30 tablets. ZITHROMAX tablets are supplied as follows: Bottles of 30 NDC 0069-3080-30 Tablets should be stored at or below 30��C (86��F). ZITHROMAX for oral suspension is supplied in single dose packets containing azithromycin dihydrate equivalent to 1 gram of azithromycin as follows: Boxes of 10 Single Dose Packets (1 g) NDC 0069-3051-07Boxes of 3 Single Dose Packets (1 g) NDC 0069-3051-75 Store single dose packets between 5��and 30��C (41��and 86��F).
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dailymed-ingredient:dibasic_calcium_phosphate_anhydrous,
dailymed-ingredient:hypromellose,
dailymed-ingredient:lactose,
dailymed-ingredient:magnesium_stearate,
dailymed-ingredient:pregelatinized_starch,
dailymed-ingredient:sodium_croscarmellose,
dailymed-ingredient:sodium_lauryl_sulfate,
dailymed-ingredient:titanium_dioxide,
dailymed-ingredient:triacetin
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azithromycin
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Zithromax (Tablet, Film Coated)
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In clinical trials, most of the reported side effects were mild to moderate in severity and were reversible upon discontinuation of the drug. Approximately 0.7% of the patients from the multiple-dose clinical trials discontinued ZITHROMAX (azithromycin) therapy because of treatment-related side effects. Most of the side effects leading to discontinuation were related to the gastrointestinal tract, e.g., nausea, vomiting, diarrhea, or abdominal pain. Rarely but potentially serious side effects were angioedema and cholestatic jaundice.<br/>Clinical:<br/>Multiple-dose regimen: Overall, the most common side effects in adult patients receiving a multiple-dose regimen of ZITHROMAX were related to the gastrointestinal system with diarrhea/loose stools (5%), nausea (3%), and abdominal pain (3%) being the most frequently reported. No other side effects occurred in patients on the multiple-dose regimen of ZITHROMAX with a frequency greater than 1%. Side effects that occurred with a frequency of 1% or less included the following: Cardiovascular: Palpitations, chest pain.Gastrointestinal: Dyspepsia, flatulence, vomiting, melena, and cholestatic jaundice.Genitourinary: Monilia, vaginitis, and nephritis.Nervous System: Dizziness, headache, vertigo, and somnolence.General: Fatigue.Allergic: Rash, photosensitivity, and angioedema.<br/>Chronic therapy with 1200 mg weekly regimen: The nature of side effects seen with the 1200 mg weekly dosing regimen for the prevention of Mycobacterium avium infection in severely immunocompromised HIV-infected patients were similar to those seen with short term dosing regimens.<br/>Chronic therapy with 600 mg daily regimen combined with ethambutol: The nature of side effects seen with the 600 mg daily dosing regimen for the treatment of Mycobacterium avium complex infection in severely immunocompromised HIV-infected patients were similar to those seen with short term dosing regimens. Five percent of patients experienced reversible hearing impairment in the pivotal clinical trial for the treatment of disseminated MAC in patients with AIDS. Hearing impairment has been reported with macrolide antibiotics, especially at higher doses. Other treatment related side effects occurring in>5% of subjects and seen at any time during a median of 87.5 days of therapy include: abdominal pain (14%), nausea (14%), vomiting (13%), diarrhea (12%), flatulence (5%), headache (5%) and abnormal vision (5%). Discontinuations from treatment due to laboratory abnormalities or side effects considered related to study drug occurred in 8/88 (9.1%) of subjects.<br/>Single 1-gram dose regimen: Overall, the most common side effects in patients receiving a single-dose regimen of 1 gram of ZITHROMAX were related to the gastrointestinal system and were more frequently reported than in patients receiving the multiple-dose regimen. Side effects that occurred in patients on the single one-gram dosing regimen of ZITHROMAX with a frequency of 1% or greater included diarrhea/loose stools (7%), nausea (5%), abdominal pain (5%), vomiting (2%), dyspepsia (1%), and vaginitis (1%).<br/>Post-Marketing Experience: Adverse events reported with azithromycin during the post-marketing period in adult and/or pediatric patients for which a causal relationship may not be established include: Allergic: Arthralgia, edema, urticaria, angioedema.Cardiovascular: Arrhythmias including ventricular tachycardia, hypotension. There have been rare reports of QT prolongation and torsades de pointes.Gastrointestinal: Anorexia, constipation, dyspepsia, flatulence, vomiting/diarrhea rarely resulting in dehydration, pseudomembranous colitis, pancreatitis, oral candidiasis and rare reports of tongue discoloration.General: Asthenia, paresthesia, fatigue, malaise and anaphylaxis (rarely fatal).Genitourinary: Interstitial nephritis and acute renal failure, vaginitis.Hematopoietic: Thrombocytopenia.Liver/Biliary: Abnormal liver function including hepatitis and cholestatic jaundice, as well as rare cases of hepatic necrosis and hepatic failure, some of which have resulted in death.Nervous System: Convulsions, dizziness/vertigo, headache, somnolence, hyperactivity, nervousness, agitation and syncope.Psychiatric: Aggressive reaction and anxiety.Skin/Appendages: Pruritus, rarely serious skin reactions including erythema multiforme, Stevens Johnson Syndrome, and toxic epidermal necrolysis.Special Senses: Hearing disturbances including hearing loss, deafness, and/or tinnitus, rare reports of taste/smell perversion and/or loss.<br/>Laboratory Abnormalities: Significant abnormalities (irrespective of drug relationship) occurring during the clinical trials were reported as follows: With an incidence of 1���2%, elevated serum creatine phosphokinase, potassium, ALT (SGPT), GGT, and AST (SGOT). With an incidence of less than 1%, leukopenia, neutropenia, decreased platelet count, elevated serum alkaline phosphatase, bilirubin, BUN, creatinine, blood glucose, LDH, and phosphate. When follow-up was provided, changes in laboratory tests appeared to be reversible. In multiple-dose clinical trials involving more than 3000 patients, 3 patients discontinued therapy because of treatment-related liver enzyme abnormalities and 1 because of a renal function abnormality. In a phase I drug interaction study performed in normal volunteers, 1 of 6 subjects given the combination of azithromycin and rifabutin, 1 of 7 given rifabutin alone and 0 of 6 given azithromycin alone developed a clinically significant neutropenia (<500 cells/mm). Laboratory abnormalities seen in clinical trials for the prevention of disseminated Mycobacterium avium disease in severely immunocompromised HIV-infected patients are presented in the CLINICAL STUDIES section. Chronic therapy (median duration: 87.5 days, range: 1���229 days) that resulted in laboratory abnormalities in>5% subjects with normal baseline values in the pivotal trial for treatment of disseminated MAC in severely immunocompromised HIV infected patients treated with azithromycin 600 mg daily in combination with ethambutol include: a reduction in absolute neutrophils to<50% of the lower limit of normal (10/52, 19%) and an increase to five times the upper limit of normal in alkaline phosphatase (3/35, 9%). These findings in subjects with normal baseline values are similar when compared to all subjects for analyses of neutrophil reductions (22/75 [29%]) and elevated alkaline phosphatase (16/80 [20%]). Causality of these laboratory abnormalities due to the use of study drug has not been established.
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ZITHROMAX (azithromycin) is indicated for the treatment of patients with mild to moderate infections caused by susceptible strains of the designated microorganisms in the specific conditions listed below.<br/>Sexually Transmitted Diseases: Non-gonococcal urethritis and cervicitis due to Chlamydia trachomatis. ZITHROMAX, at the recommended dose, should not be relied upon to treat gonorrhea or syphilis. Antimicrobial agents used in high doses for short periods of time to treat non-gonococcal urethritis may mask or delay the symptoms of incubating gonorrhea or syphilis. All patients with sexually-transmitted urethritis or cervicitis shouldhave a serologic test for syphilis and appropriate cultures for gonorrhea performed at the time of diagnosis. Appropriate antimicrobial therapy and follow-up tests for these diseases should be initiated if infection is confirmed. Appropriate culture and susceptibility tests should be performed before treatment to determine the causative organism and its susceptibility to azithromycin. Therapy with ZITHROMAX may be initiated before results of these tests are known; once the results become available, antimicrobial therapy should be adjusted accordingly. To reduce the development of drug-resistant bacteria and maintain the effectiveness of Zithromax (azithromycin) and other antibacterial drugs, Zithromax (azithromycin) should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.<br/>Mycobacterial Infections:<br/>Prophylaxis of Disseminated Mycobacterium avium complex (MAC) Disease: ZITHROMAX, taken alone or in combination with rifabutin at its approved dose, is indicated for the prevention of disseminated Mycobacterium avium complex (MAC) disease in persons with advanced HIV infection.<br/>Treatment of Disseminated Mycobacterium avium complex (MAC) Disease: ZITHROMAX, taken in combination with ethambutol, is indicated for the treatment of disseminated MAC infections in persons with advanced HIV infection.
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Zithromax
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