Zithromax is a macrolide antibacterial drug 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. Sexually Transmitted Diseases Non-gonococcal urethritis and cervicitis due to Chlamydia trachomatis Mycobacterial Infections 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 MAC disease in persons with advanced HIV infection see. Treatment of Disseminated MAC Disease Zithromax, taken in combination with ethambutol, is indicated for the treatment of disseminated MAC infections in persons with advanced HIV infection see and.

Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of Zithromax and other antibacterial drugs, Zithromax should be used only to treat 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. Zithromax Dosage and Administration see Zithromax for oral suspension (single dose 1 g packet) can be taken with or without food after constitution. However, increased tolerability has been observed when tablets are taken with food.

Zithromax for oral suspension (single dose 1 g packet) is not for pediatric use. For pediatric suspension see the prescribing information for Zithromax (azithromycin for oral suspension) 100 mg/5 mL and 200 mg/5 mL bottles. 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 ensure complete consumption of dosage. The single dose packet should not be used to administer doses other than 1000 mg of azithromycin.

Sexually Transmitted Diseases 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 one single dose packet (1 g). Mycobacterial Infections 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. 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. Dosage Forms and Strengths 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 for oral suspension 1000 mg/5 mL is supplied in single -dose packets containing azithromycin dihydrate equivalent to 1 gram of azithromycin. Contraindications Hypersensitivity Zithromax is contraindicated in patients with known hypersensitivity to azithromycin, erythromycin, any macrolide, or ketolide drug. Hepatic Dysfunction Zithromax is contraindicated in patients with a history of cholestatic jaundice/hepatic dysfunction associated with prior use of azithromycin.

Warnings and Precautions Hypersensitivity Serious allergic reactions, including angioedema, anaphylaxis, and dermatologic reactions including Acute Generalized Exanthematous Pustulosis (AGEP), Stevens-Johnson Syndrome, and toxic epidermal necrolysis, have been reported rarely in patients on azithromycin therapy. see Fatalities have been reported. Cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) have also been reported. Despite initially successful symptomatic treatment of the allergic symptoms, when symptomatic therapy was discontinued, the allergic symptoms recurred soon thereafter in some patients without further azithromycin exposure.

These patients required prolonged periods of observation and symptomatic treatment. The relationship of these episodes to the long tissue half-life of azithromycin and subsequent prolonged exposure to antigen is presently unknown. If an allergic reaction occurs, the drug should be discontinued and appropriate therapy should be instituted. Physicians should be aware that allergic symptoms may reappear when symptomatic therapy is discontinued. Hepatotoxicity Abnormal liver function, hepatitis, cholestatic jaundice, hepatic necrosis, and hepatic failure have been reported, some of which have resulted in death. Discontinue azithromycin immediately if signs and symptoms of hepatitis occur. Infantile Hypertrophic Pyloric Stenosis (IHPS) Following the use of azithromycin in neonates (treatment up to 42 days of life), IHPS has been reported.

Direct parents and caregivers to contact their physician if vomiting or irritability with feeding occurs. QT Prolongation Prolonged cardiac repolarization and QT interval, imparting a risk of developing cardiac arrhythmia and torsades de pointes, have been seen with treatment with macrolides, including azithromycin. Cases of torsades de pointes have been spontaneously reported during postmarketing surveillance in patients receiving azithromycin.

MEAN (CV%) PK PARAMETER DOSE/DOSAGE FORM (serum, except as indicated) Subjects Day No. C max ( mcg/mL) T max (hr) C 24 (mcg/mL) AUC (mcg∙hr/mL) T ½ (hr) Urinary Excretion (% of dose) AUC 0–24; 0–last.

500 mg/250 mg capsule 12 1 0.41 2.5 0.05 2.6 – 4.5 and 250 mg on Days 2–5 12 5 0.24 3.2 0.05 2.1 – 6.5 1200 mg/600 mg tablets 12 1 0.66 2.5 0.074 6.8 40 –%CV (62%) (79%) (49%) (64%) (33%) 600 mg tablet/day 7 1 0.33 2.0 0.039 2.4%CV 25% (50%) (36%) (19%) 7 22 0.55 2.1 0.14 5.8 84.5 -%CV (18%) (52%) (26%) (25%) - 600 mg tablet/day (leukocytes) 7 22 252 10.9 146 4763 82.8 -%CV (49%) (28%) (33%) (42%) -With a regimen of 500 mg on Day 1 and 250 mg/day on Days 2–5, C min and C max remained essentially unchanged from Day 2 through Day 5 of therapy. However, without a loading dose, azithromycin C min levels required 5 to 7 days to reach steady state. In asymptomatic HIV-positive adult subjects receiving 600 mg Zithromax tablets once daily for 22 days, steady state azithromycin serum levels were achieved by Day 15 of dosing. 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. Absorption The 1 gram single -dose packet is bioequivalent to four 250 mg azithromycin capsule When the oral suspension of azithromycin was administered with food, the C max increased 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 C max by 31% (CV=43%) while the extent of absorption (AUC) was unchanged (mean ratio of AUCs=1.00; CV=55%).

Distribution The serum protein binding of azithromycin is variable in the concentration range approximating human exposure, decreasing from 51% at 0.02 µg/mL to 7% at 2 µg/mL. The antibacterial activity of azithromycin is pH related and appears to be reduced with decreasing pH. However, the extensive distribution of drug to tissues may be relevant to clinical activity. Azithromycin has been shown to penetrate into tissues in humans, including skin, lung, tonsil, and cervix. 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 additional body sites, the clinical importance of these tissue concentration data is unknown.

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 hr of incubation. In vivo studies suggest that concentration in phagocytes may contribute to drug distribution to inflamed tissues. Following oral administration of a single 1200 mg dose (two 600 mg tablets), the mean maximum concentration in peripheral leukocytes was 140 µg/mL.

Concentration remained above 32 µg/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 C max ratios 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-positive adults, mean maximum concentration in peripheral leukocytes was 252 µg/mL (±49%). Trough concentrations in peripheral leukocytes at steady-state averaged 146 µg/mL (±33%). The mean leukocyte-to-serum C max ratio was 456 (±38%) and the mean leukocyte to serum AUC ratio was 816 (±31%).

The clinical relevance of these findings is unknown. Metabolism In vitro and in vivo studies to assess the metabolism of azithromycin have not been performed. Elimination Plasma concentrations of azithromycin following single 500 mg oral and IV doses declined in a polyphasic pattern resulting in an average terminal half-life of 68 hr. 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.

Specific Populations 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 C max and AUC 0–120 increased 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 C max and AUC 0–120 increased 61% and 35%, respectively, in subjects with end-stage renal disease (GFR 80 mL/min). Hepatic Insufficiency The pharmacokinetics of azithromycin in subjects with hepatic impairment has not been established. Gender There are no significant differences in the disposition of azithromycin between male and female subjects. No dosage adjustment is recommended on the basis of gender. Geriatric Patients Pharmacokinetic parameters in older volunteers (65 to 85 years old) were similar to those in younger volunteers (18 to 40 years old) for the 5-day therapeutic regimen.

Dosage adjustment does not appear to be necessary for older patients with normal renal and hepatic function receiving treatment with this dosage regimen. see Pediatric Patients For information regarding the pharmacokinetics of Zithromax (azithromycin for oral suspension) in pediatric patients, see the prescribing information for Zithromax (azithromycin for oral suspension) 100 mg/5 mL and 200 mg/5 mL bottles. Drug-drug Interactions Drug interaction studies were performed with azithromycin and other drugs likely to be co-administered. The effects of co-administration of azithromycin on the pharmacokinetics of other drugs are shown in Table 1 and the effects of other drugs on the pharmacokinetics of azithromycin are shown in Table 2. Co-administration of azithromycin at therapeutic doses had a modest effect on the pharmacokinetics of the drugs listed in Table 1. No dosage adjustment of drugs listed in Table 1 is recommended when co-administered with azithromycin.

Co-administration of azithromycin with efavirenz or fluconazole had a modest effect on the pharmacokinetics of azithromycin. Nelfinavir significantly increased the C max and AUC of azithromycin. No dosage adjustment of azithromycin is recommended when administered with drugs listed in Table 2.

Drug Interactions: Pharmacokinetic Parameters for Azithromycin in the Presence of Co-administered Drugs. Cumulative Incidence Rate,%: Placebo (n=89) Month MAC Free and Alive MAC Adverse Experience Lost to Follow-up 6 69.7 13.5 6.7 10.1 12 47.2 19.1 15.7 18.0 18 37.1 22.5 18.0 22.5 Cumulative Incidence Rate,%: Azithromycin (n=85) Month MAC Free and Alive MAC Adverse Experience Lost to Follow-up 6 84.7 3.5 9.4 2.4 12 63.5 8.2 16.5 11.8 18 44.7 11.8 25.9 17.6 The difference in the one -year cumulative incidence rates of disseminated MAC disease (placebo – azithromycin) is 10.9%.

This difference is statistically significant (p=0.037) with a 95% confidence interval for this difference of 0.8%, 20.9%. The comparable number of patients experiencing adverse events and the fewer number of patients lost to follow-up on azithromycin should be taken into account when interpreting the significance of this difference. In Study 174, 223 patients randomized to receive rifabutin, 223 patients randomized to receive azithromycin, and 218 patients randomized to receive both rifabutin and azithromycin met the entrance criteria. Cumulative incidences at 6, 12, and 18 months of the possible outcomes are recorded in the following table.

PROPHYLAXIS AGAINST DISSEMINATED MAC ABNORMAL LABORATORY VALUES Placebo Azithromycin 1200 mg weekly Rifabutin 300 mg daily Azithromycin & Rifabutin excludes subjects outside of the relevant normal range at baseline Upper Limit of Normal Hemoglobin 5 × ULN 1/41 2% 8/158 5% 3/121 3% 6/114 5% SGPT 5 × ULN 0/49 0% 8/166 5% 3/130 2% 5/117 4% Alk Phos 5 × ULN 1/80 1% 4/247 2% 2/172 1% 3/164 2% Treatment of Disseminated MAC Disease One randomized, double -blind clinical trial (Study 189) was performed in patients with disseminated MAC. In this trial, 246 HIV -infected patients with disseminated MAC received either azithromycin 250 mg daily (N=65), azithromycin 600 mg daily (N=91), or clarithromycin 500 mg twice a day (N=90), each administered with ethambutol 15 mg/kg daily, for 24 weeks. Blood cultures and clinical assessments were performed every 3 weeks through week 12 and monthly thereafter through week 24.

After week 24, patients were switched to any open -label therapy at the discretion of the investigator and followed every 3 months through the last follow -up visit of the trial. Patients were followed from the baseline visit for a period of up to 3.7 years (median: 9 months). MAC isolates recovered during treatment or post-treatment were obtained whenever possible.

The primary endpoint was sterilization by week 24. Sterilization was based on data from the central laboratory, and was defined as two consecutive observed negative blood cultures for MAC, independent of missing culture data between the two negative observations. Analyses were performed on all randomized patients who had a positive baseline culture for MAC. The azithromycin 250 mg arm was discontinued after an interim analysis at 12 weeks showed a significantly lower clearance of bacteremia compared to clarithromycin 500 mg twice a day. Efficacy results for the azithromycin 600 mg daily and clarithromycin 500 mg twice a day treatment regimens are described in the following table.

Azithromycin 600 mg (N=68) Clarithromycin 500 mg twice a day (N=57) groups stratified by MAC colony counts at baseline no. (%) subjects in stratified group sterile at week 24 no. (%) subjects in stratified group sterile at week 24 ≤10 cfu/mL 10/15 (66.7%) 12/17 (70.6%) 11–100 cfu/mL 13/28 (46.4%) 13/19 (68.4%) 101–1,000 cfu/mL 7/19 (36.8%) 5/13 (38.5%) 1,001–10,000 cfu/mL 1/5 (20.0%) 1/5 (20%) 10,000 cfu/mL 0/1 (0.0%) 1/3 (33.3%) Susceptibility Pattern of MAC Isolates Susceptibility testing was performed on MAC isolates recovered at baseline, at the time of breakthrough on therapy or during post-therapy follow-up. The T100 radiometric broth method was employed to determine azithromycin and clarithromycin MIC values. Azithromycin MIC values ranged from 256 µg/mL and clarithromycin MICs ranged from 32 µg/mL. The individual MAC susceptibility results demonstrated that azithromycin MIC values could be 4 to 32 -fold higher than clarithromycin MIC values. During treatment and post-treatment follow -up for up to 3.7 years (median: 9 months) in Study 189, a total of 6/68 (9%) and 6/57 (11%) of the patients randomized to azithromycin 600 mg daily and clarithromycin 500 mg twice a day respectively, developed MAC blood culture isolates that had a sharp increase in MIC values.

Rational Math

All twelve MAC isolates had azithromycin MICs ≥256 µg/mL and clarithromycin MICs 32 µg/mL. These high MIC values suggest development of drug resistance. However, at this time, specific breakpoints for separating susceptible and resistant MAC isolates have not been established for either macrolide. REFERENCES.

Griffith DE, Aksamit T, Brown-Elliot BA, et al. An official ATS/IDSA statement: Diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med.

2007; 175:367–416. How Supplied/Storage and Handling 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. Boxes of 10 single -dose packets (1 g) NDC 0069-3051-07 Boxes of 3 single -dose packets (1 g) NDC 0069-3051-75 Store single -dose packets between 5° and 30°C (41° and 86°F).

Patient Counseling Information Zithromax tablets may be taken with or without food. However, increased tolerability has been observed when tablets are taken with food. Zithromax for oral suspension in single 1 g packets can be taken with or without food after constitution. Patients should also be cautioned not to take aluminum- and magnesium-containing antacids and azithromycin simultaneously. The patient should be directed to discontinue azithromycin immediately and contact a physician if any signs of an allergic reaction occur.

Direct parents or caregivers to contact their physician if vomiting and irritability with feeding occurs in the infant. Patients should be counseled that antibacterial drugs, including Zithromax, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Zithromax is prescribed to treat bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed.

Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Zithromax or other antibacterial drugs in the future. Diarrhea is a common problem caused by antibacterial which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibacterials, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibacterial. If this occurs, patients should contact their physician as soon as possible.

Rx only Licensed from Pliva This product's label may have been updated. For current full prescribing information, please visit www.pfizer.com LAB-0022-19.0 PRINCIPAL DISPLAY PANEL - 600 mg Tablet Bottle Label NDC 0069-3080-30 Pfizer Zithromax ® (azithromycin) tablets 600 mg. 30 Tablets Rx only.

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