ZMAX SIDE EFFECTS

SIDE EFFECTS

Clinical Trials Experience

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.

Adults

The data described below reflect exposure to Zmax in 728 adult patients. All patients received a single 2 g oral dose of Zmax. The population studied had community-acquired pneumonia and acute bacterial sinusitis.

In controlled clinical trials with Zmax, the majority of the reported treatment-related adverse reactions were gastrointestinal in nature and mild to moderate in severity.

Overall, the most common treatment-related adverse reactions in adult patients receiving a single 2 g dose of Zmax were diarrhea/loose stools (12%), nausea (4%), abdominal pain (3%), headache (1%), and vomiting (1%). The incidence of treatment-related gastrointestinal adverse reactions was 17% for Zmax and 10% for pooled comparators.

Treatment-related adverse reactions following Zmax treatment that occurred with a frequency of < 1% included the following:

Cardiovascular: Palpitations, chest pain

Gastrointestinal: Constipation, dyspepsia, flatulence, gastritis, oral moniliasis

Genitourinary: Vaginitis

Nervous system: Dizziness, vertigo

General: Asthenia

Allergic: Rash, pruritus, urticaria

Special senses: Taste perversion

Pediatric Patients

The data described below reflect exposure to Zmax in 907 pediatric patients. The population was 3 months to 12 years of age. All patients received a single 60 mg/kg oral dose of Zmax.

As in adults, the most common treatment-related adverse reactions in pediatric subjects were gastrointestinal in nature. The pediatric subjects all received a single 60 mg/kg dose (equivalent to 27 mg/lb) of Zmax.

In a trial with 450 pediatric subjects (ages 3 months to 48 months), vomiting (11%), diarrhea (10%) loose stools (9%), and abdominal pain (2%) were the most frequently reported treatment-related gastrointestinal adverse reactions. Many treatment related gastrointestinal adverse reactions with an incidence greater than 1% began on the day of dosing in these subjects [43% (68/160)] and most [53% (84/160)] resolved within 48 hr of onset. Treatment-related adverse events that were not gastrointestinal, occurring with a frequency > 1% were: rash (5%), anorexia (2%), fever (2%), and dermatitis (2%).

In a second trial of 337 pediatric subjects, ages 2 years to 12 years, the most frequently reported treatment-related adverse reactions also included vomiting (14%), diarrhea (7%), loose stools (2%), nausea (4%) and abdominal pain (4%).

A third trial investigated the tolerability of two different concentrations of azithromycin oral suspension in 120 pediatric subjects (ages 3 months to 48 months), all of whom were treated with azithromycin. The study evaluated the hypothesis that a more dilute, less viscous formulation (the recommended 27 mg/mL concentration of Zmax) is less likely to induce vomiting in young children than a more concentrated suspension used in other pediatric studies. The vomiting rate for subjects taking the dilute concentration azithromycin was 3% (2/61). The rate was numerically lower but not statistically different from the vomiting for the more concentrated suspension Across both treatment arms, the only treatment-related adverse events with a frequency of > 1% were vomiting (6%, 7/120) and diarrhea (2%, 2/120).

Treatment-related adverse reactions with a frequency of < 1% following Zmax treatment in all 907 pediatric subjects in the Phase 3 studies were:

Body as a whole: Chills, fever, flu syndrome, headache;

Digestive: Abnormal stools, constipation, dyspepsia, flatulence, gastritis, gastrointestinal disorder, hepatitis;

Hematologic and lymphatic: Leukopenia;

Nervous system: Agitation, emotional liability, hostility, hyperkinesia, insomnia, irritability, paresthesia, Somnolence;

Respiratory: Asthma, bronchitis, cough, dyspnea, pharyngitis, rhinitis;

Skin and appendages: Dermatitis, fungal dermatitis, maculopapular rash, pruritus, urticaria;

Special senses: Otitis media, taste perversion;

Urogenital: Dysuria.

Postmarketing Experience With Other Azithromycin Products

Because these reactions are reported voluntarily from a population of uncertain size, reliably estimating their frequency or establishing a causal relationship to drug exposure is not always possible.

Adverse events reported with azithromycin immediate release formulations during the postmarketing period for which a causal relationship may not be established include:

Allergic: Arthralgia, edema, urticaria and angioedema

Cardiovascular: Palpitations and 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 rare reports of tongue discoloration

General: Asthenia, paresthesia, fatigue, malaise and anaphylaxis

Genitourinary: Interstitial nephritis, acute renal failure and vaginitis

Hematopoietic: Thrombocytopenia, mild neutropenia

Liver/biliary: Adverse reactions related to hepatic dysfunction have been reported in postmarketing experience with azithromycin.

Nervous system: Convulsions, dizziness/vertigo, headache, somnolence, hyperactivity, nervousness, agitation and syncope

Psychiatric: Aggressive reaction and anxiety

Skin/appendages: Pruritus, rash, photosensitivity, serious skin reactions including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and DRESS.

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

Laboratory Abnormalities

In subjects with normal baseline values, the following clinically significant laboratory abnormalities (irrespective of drug relationship) were reported in Zmax clinical trials in adults and pediatric patients:

Adults

Laboratory abnormalities with an incidence of greater than or equal to 1%: reduced lymphocytes and increased eosinophils; reduced bicarbonate. Laboratory abnormalities with an incidence of less than 1%: leukopenia, neutropenia, elevated bilirubin, AST, ALT, BUN, creatinine, alterations in potassium. Where follow-up was provided, changes in laboratory tests appeared to be reversible.

Pediatric Patients

Laboratory abnormalities with an incidence of greater than or equal to 1%: elevated eosinophils, BUN, and potassium; decreased lymphocytes; and alterations in neutrophils; with an incidence of less than 1%: elevated SGOT, SGPT and creatinine; decreased potassium; and alterations in sodium and glucose.

SRC: NLM .