Azithromycin (oral)

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Vignesh Ponnusamy, M.B.B.S. [1]

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a

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macrolide antibacterial

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sexually transmitted diseases, mycobacterial infections, community-acquired pneumonia, and pelvic inflammatory disease

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diarrhea, nausea, abdominal pain, and vomiting

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• Content

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Sexually Transmitted Diseases

• Non-gonococcal urethritis and cervicitis due to Chlamydia trachomatis

• 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.

Community-Acquired Pneumonia

• The recommended dose of ZITHROMAX (azithromycin for injection) for the treatment of adult patients with community-acquired pneumonia due to the indicated organisms is: 500 mg as a single daily dose by the intravenous route for at least two days. Intravenous therapy should be followed by azithromycin by the oral route at a single, daily dose of 500 mg, administered as two 250-mg tablets to complete a 7- to 10-day course of therapy. The timing of the switch to oral therapy should be done at the discretion of the physician and in accordance with clinical response.

Pelvic Inflammatory Disease

• The recommended dose of ZITHROMAX (azithromycin for injection) for the treatment of adult patients with pelvic inflammatory disease due to the indicated organisms is: 500 mg as a single daily dose by the intravenous route for one or two days. Intravenous therapy should be followed by azithromycin by the oral route at a single, daily dose of 250 mg to complete a 7-day course of therapy. The timing of the switch to oral therapy should be done at the discretion of the physician and in accordance with clinical response. If anaerobic microorganisms are suspected of contributing to the infection, an antimicrobial agent with anaerobic activity should be administered in combination with ZITHROMAX.

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Condition1

• Developed by:

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• Dosing Information

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Condition2

There is limited information regarding Off-Label Guideline-Supported Use of Azithromycin (oral) in adult patients.

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Condition1

• Dosing Information

• Dosage

Condition2

There is limited information regarding Off-Label Non–Guideline-Supported Use of Azithromycin (oral) in adult patients.

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Condition1

• Dosing Information

• Dosage

Condition2

There is limited information regarding FDA-Labeled Use of Azithromycin (oral) in pediatric patients.

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Condition1

• Developed by:

• Class of Recommendation:

• Strength of Evidence:

• Dosing Information

• Dosage

Condition2

There is limited information regarding Off-Label Guideline-Supported Use of Azithromycin (oral) in pediatric patients.

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Condition1

• Dosing Information

• Dosage

Condition2

There is limited information regarding Off-Label Non–Guideline-Supported Use of Azithromycin (oral) in pediatric patients.

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• 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.

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Precautions

• Hypersensitivity

• Serious allergic reactions, including angioedema, anaphylaxis, and dermatologic reactions including Stevens-Johnson Syndrome and toxic epidermal necrolysis, have been reported rarely in patients on azithromycin therapy.
• Fatalities have 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.

• 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. Providers should consider the risk of QT prolongation which can be fatal when weighing the risks and benefits of azithromycin for at-risk groups including:
  • patients with known prolongation of the QT interval, a history of torsades de pointes, congenital long QT syndrome, bradyarrhythmias or uncompensated heart failure
  • patients on drugs known to prolong the QT interval
  • patients with ongoing proarrhythmic conditions such as uncorrected hypokalemia or hypomagnesemia, clinically significant bradycardia, and in patients receiving Class IA (quinidine, procainamide) or Class III (dofetilide, amiodarone, sotalol) antiarrhythmic agents.

• Elderly patients may be more susceptible to drug-associated effects on the QT interval.

• Clostridium difficile-Associated Diarrhea (CDAD)

• CDAD has been reported with use of nearly all antibacterial agents, including ZITHROMAX, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon, leading to overgrowth of C. difficile.
• C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antibacterial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.
• If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

• Exacerbation of Myasthenia Gravis

• Exacerbations of symptoms of myasthenia gravis and new onset of myasthenic syndrome have been reported in patients receiving azitrhromycin therapy.

• Use in Sexually Transmitted Infections

• ZITHROMAX, (single dose 1 g packet) at the recommended dose, should not be relied upon to treat gonorrhea or syphilis. Antibacterial 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 should have a serologic test for syphilis and appropriate cultures for gonorrhea performed at the time of diagnosis. Appropriate antibacterial therapy and follow-up tests for these diseases should be initiated if infection is confirmed.

• Development of Drug-Resistant Bacteria

• Prescribing ZITHROMAX in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

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• Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

• In clinical trials, most of the reported adverse reactions 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 adverse reactions. Serious adverse reactions included angioedema and cholestatic jaundice. Most of the adverse reactions leading to discontinuation were related to the gastrointestinal tract, e.g., nausea, vomiting,,diarrhea, or abdominal pain.

• Multiple-dose regimen

• Overall, the most common adverse reactions 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 adverse reactions occurred in patients on the multiple-dose regimen of ZITHROMAX with a frequency greater than 1%. Adverse reactions that occurred with a frequency of 1% or less included the following:

Cardiovascular

Palpitations and 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.

• Chronic therapy with 1200 mg weekly regimen

• The nature of adverse reactions 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 [see Clinical Studies (14)].

• Chronic therapy with 600 mg daily regimen combined with ethambutol

• The nature of adverse reactions 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 adverse reactions 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 adverse reactions considered related to study drug occurred in 8 of 88 (9.1%) of subjects.

• Single 1 gram dose regimen

• Overall, the most common adverse reactions 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.
• Adverse reactions that occurred in patients on the single 1 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%).

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• The following adverse reactions have been identified during post approval use of azithromycin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Adverse reactions reported with azithromycin during the postmarketing period in adult and/or pediatric patients for which a causal relationship may not be established include:

Allergic

Arthralgia, edema, urticaria, and angioedema.

Cardiovascular

Arrhythmias, including ventricular tachycardia, and hypotension. There have been reports of QT prolongation and torsades de pointes.

Gastrointestinal

Anorexia, constipation, dyspepsia, flatulence, vomiting/diarrhea pseudomembranous colitis, pancreatitis, oral candidiasis, pyloric stenosis, and tongue discoloration.

General

Asthenia, paresthesia, fatigue, malaise, and anaphylaxis

Genitourinary

Interstitial nephritis, acute renal failure, and vaginitis.

Hematopoietic

Thrombocytopenia.

Liver/Biliary

Abnormal liver function, hepatitis, cholestatic jaundice, hepatic necrosis, and hepatic failure.

Nervous System

Convulsions, dizziness/vertigo, headache, somnolence, hyperactivity, nervousness, agitation, and syncope.

Psychiatric

Aggressive reaction and anxiety.

Skin/Appendages

Pruritus, and serious skin reactions including erythema multiforme, Stevens-Johnson Syndrome , and toxic epidermal necrolysis .

Special Senses

Hearing disturbances including hearing loss, deafness, and/or tinnitus, and reports of taste/smell perversion and/or loss.

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• Nelfinavir

• Co-administration of nelfinavir at steady-state with a single oral dose of azithromycin resulted in increased azithromycin serum concentrations. Although a dose adjustment of azithromycin is not recommended when administered in combination with nelfinavir, close monitoring for known adverse reactions of azithromycin, such as liver enzyme abnormalities and hearing impairment, is warranted. [see Adverse Reactions (6)].

• Warfarin

• Spontaneous post-marketing reports suggest that concomitant administration of azithromycin may potentiate the effects of oral anticoagulants such as warfarin, although the prothrombin time was not affected in the dedicated drug interaction study with azithromycin and warfarin. Prothrombin times should be carefully monitored while patients are receiving azithromycin and oral anticoagulants concomitantly.

• Potential Drug-Drug Interaction with Macrolides

• Interactions with the following drugs listed below have not been reported in clinical trials with azithromycin; however, no specific drug interaction studies have been performed to evaluate potential drug-drug interaction. However, drug interactions have been observed with other macrolide products. Until further data are developed regarding drug interactions when digoxin or phenytoin are used with azithromycin careful monitoring of patients is advised.

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• Pregnancy Category B

• Reproduction studies have been performed in rats and mice at doses up to moderately maternally toxic dose levels (i.e., 200 mg/kg/day). These daily doses in rats and mice, based on body surface area, are estimated to be 3.2 and 1.6 times, respectively, an adult daily dose of 600 mg. In the animal studies, no evidence of harm to the fetus due to azithromycin was found. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, azithromycin should be used during pregnancy only if clearly needed.

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• Australian Drug Evaluation Committee (ADEC) Pregnancy Category

There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Azithromycin (oral) in women who are pregnant.

|useInLaborDelivery= There is no FDA guidance on use of Azithromycin (oral) during labor and delivery.

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Azithromycin has been reported to be excreted in breast milk in small amounts. Caution should be exercised when azithromycin is administered to a nursing woman.

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• In controlled clinical studies, azithromycin has been administered to pediatric patients ranging in age from 6 months to 12 years. For information regarding the use of ZITHROMAX (azithromycin for oral suspension) in the treatment of pediatric patients, [see Indications and Usage (1) and Dosage and Administration (2)] of the prescribing information for ZITHROMAX (azithromycin for oral suspension) 100 mg/5 mL and 200 mg/5 mL bottles.

• HIV-Infected Pediatric Patients: The safety and efficacy of azithromycin for the prevention or treatment of MAC in HIV-infected children have not been established. Safety data are available for 72 children 5 months to 18 years of age (mean 7 years) who received azithromycin for treatment of opportunistic infections. The mean duration of therapy was 242 days (range 3–2004 days) at doses of <1 to 52 mg/kg/day (mean 12 mg/kg/day). Adverse reactions were similar to those observed in the adult population, most of which involved the gastrointestinal tract. Treatment-related reversible hearing impairment in children was observed in 4 subjects (5.6%). Two (2.8%) children prematurely discontinued treatment due to adverse reactions: one due to back pain and one due to abdominal pain, hot and cold flushes, dizziness, headache, and numbness. A third child discontinued due to a laboratory abnormality (eosinophilia). The protocols upon which these data are based specified a daily dose of 10–20 mg/kg/day (oral and/or IV) of azithromycin.

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• In multiple-dose clinical trials of oral azithromycin, 9% of patients were at least 65 years of age (458/4949) and 3% of patients (144/4949) were at least 75 years of age. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

• Elderly patients may be more susceptible to development of torsades de pointes arrhythmias than younger patients. [see Warnings and Precautions (5.3)].

• ZITHROMAX 600 mg tablets contain 2.1 mg of sodium per tablet. ZITHROMAX for oral suspension 1 gram single-dose packets contain 37.0 mg of sodium per packet.

• Geriatric Patients with Opportunistic Infections, Including (MAC) Disease: Safety data are available for 30 patients (65–94 years old) treated with azithromycin at doses >300 mg/day for a mean of 207 days. These patients were treated for a variety of opportunistic infections, including MAC. The adverse reaction were generally similar to that seen in younger patients, except for a higher incidence of adverse reactions relating to the gastrointestinal system and to reversible impairment of hearing [see Dosage and Administration (2)].

|useInGender= There is no FDA guidance on the use of Azithromycin (oral) with respect to specific gender populations.

|useInRace= There is no FDA guidance on the use of Azithromycin (oral) with respect to specific racial populations.

|useInRenalImpair= There is no FDA guidance on the use of Azithromycin (oral) in patients with renal impairment.

|useInHepaticImpair= There is no FDA guidance on the use of Azithromycin (oral) in patients with hepatic impairment.

|useInReproPotential= There is no FDA guidance on the use of Azithromycin (oral) in women of reproductive potentials and males.

|useInImmunocomp= There is no FDA guidance one the use of Azithromycin (oral) in patients who are immunocompromised.

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• Oral

• Intravenous

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There is limited information regarding Monitoring of Azithromycin (oral) in the drug label.

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There is limited information regarding IV Compatibility of Azithromycin (oral) in the drug label.

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Acute Overdose

Signs and Symptoms

• Description

Management

• Description

Chronic Overdose

There is limited information regarding Chronic Overdose of Azithromycin (oral) in the drug label.

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• 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 extra-cellular concentration was >30 after one hour incubation. In vivo studies suggest that concentration in phagocytes may contribute to drug distribution to inflamed tissues.

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• ZITHROMAX (azithromycin tablets and oral suspension) contains the active ingredient azithromycin, a macrolide antibacterial drug , 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-α-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)-β-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 C38H72N2O12, and its molecular weight is 749.0. Azithromycin has the following structural formula:

File:Azithromycin (oral)01.png

This image is provided by the National Library of Medicine.

• Azithromycin, as the dihydrate, is a white crystalline powder with a molecular formula of C38H72N2O12∙2H2O and a molecular weight of 785.0.

• ZITHROMAX tablets contain azithromycin dihydrate equivalent to 600 mg azithromycin. 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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There is limited information regarding Pharmacodynamics of Azithromycin (oral) in the drug label.

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There is limited information regarding Pharmacokinetics of Azithromycin (oral) in the drug label.

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There is limited information regarding Nonclinical Toxicology of Azithromycin (oral) in the drug label.

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There is limited information regarding Clinical Studies of Azithromycin (oral) in the drug label.

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There is limited information regarding Patient Counseling Information of Azithromycin (oral) in the drug label.

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• Alcohol-Azithromycin (oral) interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

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