When was zithromax approved

The pore size is in the nanometer range and is ideally suited for the slow release of the active medication once the microsphere has passed through the stomach. Because of this sustained release mechanism, most of the drug is released into the lower gastrointestinal tract, reducing gastrointestinal side-effects, and allowing for a higher dose to be administered Breen et al Azithromycin extended release delivers 2 g of azithromycin in one dose while the immediate release 3- and 5-day courses deliver 1.

This 2 g extended-release dose results in higher peak serum concentrations and pharmacokinetic parameters of azithromycin compared with conventional preparations. The peak serum concentrations 24 hour AUC 0—24 on day 1 are 3-fold higher for azithromycin extended release 2 g vs the traditional 1.

Drug levels are also higher at sites of infection, namely lung tissue and white blood cells. Sixty-four adults undergoing lung resection were randomly given 2 g azithromycin extended release or mg azithromycin. In another study 24 healthy adults were randomly given 2 g azithromycin extended release or mg azithromycin daily for 3 days and white blood cell pharmacokinetics in polymorphonuclear leukocytes were analyzed daily for 7 days.

The front loaded dose resulted in significantly higher white blood cell peak concentrations Pfizer Inc, data on file. Three industry-sponsored clinical trials have been performed comparing 2 g azithromycin extended release with other FDA-approved antibiotics for community-acquired pneumonia and acute bacterial sinusitis.

Two trials were published in for the treatment of community-acquired pneumonia CAP. The primary endpoint was clinical response at test of cure which occurred 14—21 days after initiation of therapy. Patients were all older than 18 years of age and had a clinical diagnosis of mild to moderate CAP a Fine mortality risk class of I, II, or III including a chest radiograph with radiographic pneumonia.

One hundred and eighty of the azithromycin-treated patients and of the levofloxacin-treated patients completed the study. All azithromycin patients were compliant with treatment while 10 of the levofloxacin-treated patients did not complete all seven days of therapy. Chlamydophila pneumoniae was most common, followed by Staphylococcus aureus, Haemophilus parainfluenzae, Mycoplasma pneumoniae, Staphylococcus pneumoniae, and Haemophilus influenzae.

None of the S. Five of these seven patients received azithromycin. At the test of cure the clinical cure rate was statistically equivalent with a cure rate of The bacteriological cure rate was also equivalent with a cure rate of Two of the subjects with azithromycin-resistant pneumococcus were clinical failures but one of these had clearance of organisms in the sputum.

This largely occurred on days one and two of treatment. The second study with CAP, by Drehobl et al , compared a single dose of azithromycin microspheres with clarithromycin extended release 1 g daily for 7 days. The study design was identical to the previous study and randomized patients, of which were treated and met all inclusion criteria.

The primary endpoint, again the clinical response at test of cure which occurred 14—21 days after initiation of therapy, was equivalent for the two arms; There were six S. Two were collected from the azithromycin-treated group and one of these was a clinical failure. This patient also had two other co-pathogens.

Four were collected from the clarithromycin-treated group and two of these were clinical failures. All patients completed the azithromycin antibiotic course while 15 of subjects did not complete the 7-day clarithromycin course. These episodes were all mild or moderate Drehobl et al The acute bacterial sinusitis study was performed by Murray et al and again was an international, multi-center, double-blinded, placebo-controlled trial.

Five hundred and forty-one patients with clinical signs and symptoms and radiographic evidence of acute bacterial sinusitis were randomized and met all inclusion criteria. Patients were excluded if they had received any systemic antibiotic therapy in the previous week, had recurrent, complicated, or nosocomial rhinosinusitis, or had undergone recent within 3 months nasal or sinus surgery. The primary outcome was clinical cure resolution of signs and symptoms or improvement with no need for further antibiotics at 17—24 days after the first antibiotic dose.

Azithromycin and levofloxacin were equally effective in providing a clinical cure: Of 81 S. 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 has been discontinued. 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. 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.

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:. Clostridium difficile -associated diarrhea 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. Hypertoxin producing strains of C. 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. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C.

Exacerbation of symptoms of myasthenia gravis and new onset of myasthenic syndrome have been reported in patients receiving azithromycin therapy.

Antibacterial agents used to treat non-gonococcal urethritis may mask or delay the symptoms of incubating syphilis. All patients with sexually transmitted urethritis or cervicitis should have a serologic test for syphilis and appropriate testing 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. Prescribing ZITHROMAX in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

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 side effects were mild to moderate in severity and were reversible upon discontinuation of the drug. Potentially serious adverse reactions of angioedema and cholestatic jaundice were reported. Approximately 0. Most of the adverse reactions leading to discontinuation were related to the gastrointestinal tract, e. Gastrointestinal: Dyspepsia, flatulence, vomiting, melena, and cholestatic jaundice.

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. The majority of these complaints were mild in nature. Single and Multiple-dose regimens: The types of adverse reactions in pediatric patients were comparable to those seen in adults, with different incidence rates for the dosage regimens recommended in pediatric patients.

Gastrointestinal: Dyspepsia, constipation, anorexia, enteritis, flatulence, gastritis, jaundice, loose stools, and oral moniliasis.

Nervous System: Headache otitis media dosage , hyperkinesia, dizziness, agitation, nervousness, and insomnia. General: Fever, face edema, fatigue, fungal infection, malaise, and pain. Skin and Appendages: Eczema, fungal dermatitis, pruritus, sweating, urticaria, and vesiculobullous rash. 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.

Cardiovascular: Arrhythmias including ventricular tachycardia and hypotension. There have been reports of QT prolongation and torsades de pointes. Genitourinary: Interstitial nephritis and acute renal failure and vaginitis. The majority of subjects with elevated serum creatinine also had abnormal values at baseline. When follow-up was provided, changes in laboratory tests appeared to be reversible.

In multiple-dose clinical trials involving more than patients, four patients discontinued therapy because of treatment-related liver enzyme abnormalities and one because of a renal function abnormality. In multiple-dose clinical trials involving approximately pediatric patients, no patients discontinued therapy because of treatment-related laboratory abnormalities.

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.

Spontaneous postmarketing 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. Interactions with digoxin, colchicine or phenytoin have not been reported in clinical trials with azithromycin. 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, colchicine or phenytoin are used with azithromycin careful monitoring of patients is advised. Available data from published literature and postmarketing experience over several decades with azithromycin use in pregnant women have not identified any drug-associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes see Data.

Developmental toxicity studies with azithromycin in rats, mice, and rabbits showed no drug-induced fetal malformations at doses up to 4, 2, and 2 times, respectively, an adult human daily dose of mg based on body surface area. Decreased viability and delayed development were observed in the offspring of pregnant rats administered azithromycin from day 6 of pregnancy through weaning at a dose equivalent to 4 times an adult human daily dose of mg based on body surface area see Data.

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U. Available data from published observational studies, case series, and case reports over several decades do not suggest an increased risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes with azithromycin use in pregnant women.

Limitations of these data include the lack of randomization and inability to control for confounders such as underlying maternal disease and maternal use of concomitant medications. Based on body surface area, this dose is approximately 4 rats and 2 mice times an adult human daily dose of mg. Maternal toxicity reduced food consumption and body weight gain; increased stress at parturition was observed at the higher dose.

Azithromycin is present in human milk see Data. Non-serious adverse reactions have been reported in breastfed infants after maternal administration of azithromycin see Clinical Considerations. There are no available data on the effects of azithromycin on milk production. Azithromycin breastmilk concentrations were measured in 20 women after receiving a single 2 g oral dose of azithromycin during labor.

Breastmilk samples collected on days 3 and 6 postpartum as well as 2 and 4 weeks postpartum revealed the presence of azithromycin in breastmilk up to 4 weeks after dosing. In another study, a single dose of azithromycin mg was administered intravenously to 8 women prior to incision for cesarean section. Breastmilk colostrum samples obtained between 12 and 48 hours after dosing revealed that azithromycin persisted in breastmilk up to 48 hours. Safety and effectiveness in the treatment of pediatric patients with acute otitis media, acute bacterial sinusitis and community-acquired pneumonia under 6 months of age have not been established.

Use of ZITHROMAX for the treatment of acute bacterial sinusitis and community-acquired pneumonia in pediatric patients 6 months of age or greater is supported by adequate and well-controlled trials in adults. 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 response 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. Adverse reactions experienced at higher than recommended doses were similar to those seen at normal doses particularly nausea, diarrhea, and vomiting. In the event of overdosage, general symptomatic and supportive measures are indicated as required.

ZITHROMAX azithromycin tablets and azithromycin for oral suspension contain the active ingredient azithromycin, a macrolide antibacterial drug, for oral administration. 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 Azithromycin has the following structural formula:.

After constitution, each 5 mL of suspension contains mg or mg of azithromycin. Azithromycin is a macrolide antibacterial drug. QTc interval prolongation was studied in a randomized, placebo-controlled parallel trial in healthy subjects who received either chloroquine mg alone or in combination with oral azithromycin mg, mg, and mg once daily. Co-administration of azithromycin increased the QTc interval in a dose- and concentration- dependent manner. Two azithromycin mg tablets are bioequivalent to a single mg tablet.

In a two-way crossover study, 12 adult healthy volunteers 6 males, 6 females received mg of azithromycin administered in single daily doses over either 5 days two mg tablets on day 1, followed by one mg tablet on days 2—5 or 3 days mg per day for days 1—3. 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.

Acute bacterial sinusitis due to Haemophilus influenzae, Moraxella catarrhalis. Community-acquired pneumonia due to Chlamydophila pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae, or Streptococcus pneumoniae in patients appropriate for oral therapy. Uncomplicated skin and skin structure infections due to S taphylococcus aureus, Streptococcus pyogenes, or Streptococcus agalactiae.

Urethritis and cervicitis due to Chlamydia trachomatis or Neisseria gonorrhoeae Genital ulcer disease in men due to H aemophilus ducreyi chancroid.

Due to the small number of women included in clinical trials, the efficacy of azithromycin in the treatment of chancroid in women has not been established. Mechanism of Action Azithromycin is a macrolide antibacterial drug.

Side Effects Adverse effects associated with the use of Zithramax may include, but are not limited to, the following: diarrhea nausea abdominal pain vomiting Clinical Trial Results Adult Patients Acute Bacterial Exacerbations of Chronic Bronchitis In a randomized, double-blind controlled clinical trial of acute exacerbation of chronic bronchitis AECB , azithromycin mg once daily for 3 days was compared with clarithromycin mg twice daily for 10 days.

Pediatric Patients From the perspective of evaluating pediatric clinical trials, Days were considered on-therapy evaluations because of the extended half-life of azithromycin.

For the patients who were evaluated for clinical efficacy, the clinical success rate i. The combined clinical success rate i. For this reason, Protocol 3 was not considered to be an independent study. Ninety-two 92 patients were evaluable for clinical and microbiologic efficacy. Each patient received active drug and placebo matched for the comparator.