The majority of side effects observed in controlled clinical trials involving patients (adults and children) treated with oral ZITHROMAX (azithromycin dihydrate) were of a mild and transient nature. Approximately 0.7% of both adult patients (n=3812) and children (n=2878) from the 5-day multiple dose clinical trials discontinued ZITHROMAX therapy because of drug related side effects. Among adults receiving ZITHROMAX intravenously, 1.2% of CAP, and 2% of PID patients discontinued treatment. Discontinuation rates were slightly higher for PID patients receiving concomitant metronidazole therapy (4%).
In adults given 500 mg/day for 3 days, the discontinuation rate due to treatment-related side effects was 0.4%. In clinical trials in children given 30 mg/kg, orally either as a single dose (n= 487) or over 3 days, (n=1729) discontinuation from therapy due to treatment-related side effects was approximately 1%.
Most of the side effects leading to discontinuation in patients on oral or intravenous therapy were related to the gastrointestinal tract, e.g., nausea, vomiting, diarrhea, along with abdominal pain, rashes and increases in aminotransferases and/or alkaline phosphatase levels in adult patients receiving intravenous ZITHROMAX. Potentially serious treatment-related side effects including angioedema and cholestatic jaundice occurred in less than 1% of patients.
Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.
In adult patients, the most common treatment-related side effects in patients receiving the 3 or 5 day oral multiple-dose regimens of ZITHROMAX were related to the gastrointestinal system with diarrhea/loose stools (4-5%), nausea (3-4%), abdominal pain (2-3%) and vomiting (1%).
| Allergic: | pruritus |
| Cardiovascular: | hypertension |
| Gastrointestinal: | dry mouth, esophagitis, gastroenteritis, rectal hemorrhage, cholestatic jaundice |
| Genitourinary: | mennorhagia, urinary frequency, vaginitis |
| Nervous system: | dizziness |
| Special senses: | conjunctivitis |
In adult patients (n=904), side effects that occurred on the single one-gram dosing regimen of ZITHROMAX with a frequency greater than 1% included diarrhea (6.1%), nausea (4.9%), abdominal pain (4.9%), vomiting (1.7%), vaginitis (1.3%), loose stools (1.2%), and dyspepsia (1.1%).
Overall, the most common side effects in patients receiving a single 2-gram dose of ZITHROMAX were related to the gastrointestinal system. Side effects that occurred in patients in this study with a frequency of a 1% or greater included nausea (18.2%), diarrhea/loose stools (13.8%), vomiting (6.7%), abdominal pain (6.7%), vaginitis (2.2%), dyspepsia (1.1%), and dizziness (1.3%). The majority of these complaints were mild in nature.
Chronic therapy with ZITHROMAX 1200 mg weekly regimen: The nature of side effects seen with the 1200 mg weekly dosing regimen for the prevention of Mycobacterium avium complex infection in severely immunocompromised HIV-infected patients were similar to those seen with short-term dosing regimens.
Study 155 | Study 174 | ||||
|---|---|---|---|---|---|
| Placebo (n=91) | Azithromycin 1200 mg weekly (n=89) | Azithromycin 1200 mg weekly (n=233) | Rifabutin 300 mg daily (n=236) | Azithromycin & Rifabutin (n=224) | |
| Mean Duration of Therapy (days) | 303.8 | 402.9 | 315 | 296.1 | 344.4 |
| Discontinuation of Therapy (%) | 2.3 | 8.2 | 13.5 | 15.9 | 22.7 |
| Autonomic Nervous System | |||||
| Mouth Dry | 0 | 0 | 0 | 3.0 | 2.7 |
| Central Nervous System | |||||
| Dizziness | 0 | 1.1 | 3.9 | 1.7 | 0.4 |
| Headache | 0 | 0 | 3.0 | 5.5 | 4.5 |
| Gastrointestinal | |||||
| Diarrhea | 15.4 | 52.8 | 50.2 | 19.1 | 50.9 |
| Loose Stools | 6.6 | 19.1 | 12.9 | 3.0 | 9.4 |
| Abdominal Pain | 6.6 | 27 | 32.2 | 12.3 | 31.7 |
| Dyspepsia | 1.1 | 9 | 4.7 | 1.7 | 1.8 |
| Flatulence | 4.4 | 9 | 10.7 | 5.1 | 5.8 |
| Nausea | 11 | 32.6 | 27.0 | 16.5 | 28.1 |
| Vomiting | 1.1 | 6.7 | 9.0 | 3.8 | 5.8 |
| General | |||||
| Fever | 1.1 | 0 | 2.1 | 4.2 | 4.9 |
| Fatigue | 0 | 2.2 | 3.9 | 2.1 | 3.1 |
| Malaise | 0 | 1.1 | 0.4 | 0 | 2.2 |
| Musculoskeletal | |||||
| Arthralgia | 0 | 0 | 3.0 | 4.2 | 7.1 |
| Psychiatric | |||||
| Anorexia | 1.1 | 0 | 2.1 | 2.1 | 3.1 |
| Skin & Appendages | |||||
| Pruritus | 3.3 | 0 | 3.9 | 3.4 | 7.6 |
| Rash | 3.2 | 3.4 | 8.1 | 9.4 | 11.1 |
| Skin discoloration | 0 | 0 | 0 | 2.1 | 2.2 |
| Special Senses | |||||
| Tinnitus | 4.4 | 3.4 | 0.9 | 1.3 | 0.9 |
| Hearing Decreased | 2.2 | 1.1 | 0.9 | 0.4 | 0 |
| Taste Perversion | 0 | 0 | 1.3 | 2.5 | 1.3 |
| |||||
Side effects related to the gastrointestinal tract were seen more frequently in patients receiving azithromycin than in those receiving placebo or rifabutin. In one of the studies, 86% of diarrheal episodes were mild to moderate in nature with discontinuation of therapy for this reason occurring in only 9/233 (3.8%) of patients.
The most common side effects (greater than 1%) in adult patients who received sequential I.V./oral ZITHROMAX in studies of community-acquired pneumonia were related to the gastrointestinal system: diarrhea/loose stools (4.3%), nausea (3.9%), abdominal pain (2.7%), and vomiting (1.4%). Approximately 12% of patients experienced a side effect related to the intravenous infusion; most common were pain at the site and/or during the infusion (6.5%) and local inflammation (3.1%).
In adult women who received sequential I.V./oral ZITHROMAX in studies of pelvic inflammatory disease, the most common side effects (greater than 1%) were related to the gastrointestinal system. Diarrhea (8.5%) and nausea (6.6%) were most frequently reported, followed by vaginitis (2.8%), abdominal pain (1.9%), anorexia (1.9%), rash and pruritus (1.9%). When azithromycin was co-administered with metronidazole in these studies, a higher proportion of women experienced side effects of nausea (10.3%), abdominal pain (3.7%), vomiting (2.8%) and application site reaction, stomatitis, dizziness, or dyspnea (all at 1.9%).
| Allergic: | bronchospasm |
| Gastrointestinal: | dyspepsia, flatulence, mucositis, oral moniliasis, and gastritis |
| Nervous System: | headache, somnolence |
| Special Senses: | taste perversion |
In children enrolled in controlled clinical trials in acute otitis media and S. pyogenes pharyngitis, the type of side effects were comparable to those seen in adults (see below).
Different side effect incidence rates for the dosage regimens recommended in children were observed.
Acute Otitis Media: For the recommended total dosage regimen of 30 mg/kg, the most frequent side effects (≥1%) attributed to treatment were diarrhea, abdominal pain, vomiting, nausea and rash. The incidence, based on dosing regimen, is described in the table below:
| Regimen | Subjects | Overall ADR Incidence | Diarrhea | Abdominal pain | Vomiting | Nausea | Rash |
|---|---|---|---|---|---|---|---|
| 1-Day | 487 | 14% | 4% | 1% | 5% | 1% | 1% |
| 3-Day | 1395 | 7% | 3% | 2% | 1% | < 1% | < 1% |
| 5-Day | 1888 | 6% | 2% | 1% | 1% | 1% | < 1% |
Community-Acquired Pneumonia: For the recommended total dosage regimen of 30 mg/kg, the most frequent side effects attributed to treatment were diarrhea/loose stools, abdominal pain, vomiting/nausea and rash. The incidence is described in the table below:
| Dosage Regimen | Subjects | Overall ADR Incidence | Diarrhea/ Loose stools | Abdominal Pain | Vomiting | Nausea | Rash |
|---|---|---|---|---|---|---|---|
| 5-day | 323 | 12% | 5.8% | 1.9% | 1.9% | 1.9% | 1.6% |
Pharyngitis/tonsillitis: For the recommended total dosage regimen of 60 mg/kg, the most frequent side effects attributed to treatment were diarrhea, vomiting, abdominal pain, nausea and headache. The incidence is described in the table below:
| Regimen | Subjects | Overall ADR Incidence | Diarrhea | Abdominal pain | Vomiting | Nausea | Rash | Headache |
|---|---|---|---|---|---|---|---|---|
| 5-Day | 447 | 17% | 5% | 3% | 6% | 2% | < 1% | 1% |
Side effects that occurred with a frequency of 1% or less in patients included the following:
| Allergic: | Allergic reaction, photosensitivity, angioedema, erythema multiforme, pruritus and urticaria. |
| Cardiovascular: | Palpitations, chest pain; |
| Gastrointestinal: | Dyspepsia, flatulence, melena, constipation, anorexia, enteritis, loose stools, oral moniliasis and gastritis; |
| General: | Fatigue, face edema, fever, fungal infection, pain and malaise; |
| Genitourinary: | Monilia, vaginitis and nephritis; |
| Hematologic and Lymphatic: | Anemia, leukopenia |
| Liver/Biliary | Liver function test abnormal, jaundice and cholestatic jaundice. |
| Nervous System: | Dizziness, vertigo, somnolence, agitation, nervousness, insomnia and hyperkinesia; |
| Respiratory: | Cough increased, pharyngitis, pleural effusion and rhinitis; |
| Skin and Appendages: | Eczema, fungal dermatitis, sweating and vesiculobullous rash |
Clinically significant abnormalities (irrespective of drug relationship) occurring during the clinical trials in patients were reported as follows:
With an incidence of greater than 1%: decreased hemoglobin, hematocrit, lymphocytes, monocytes, albumin and blood glucose, elevated serum creatine phosphokinase, potassium, ALT (SGPT), GGT and AST (SGOT), BUN, creatinine, blood glucose, platelet count, eosinophils and monocytes.
With an incidence of less than 1%: leukopenia, neutropenia, decreased platelet count, elevated serum alkaline phosphatase, bilirubin, LDH and phosphate.
The majority of subjects with elevated serum creatine 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 4500 patients, 3 patients discontinued therapy because of treatment-related liver enzyme abnormalities, one for treatment-related elevated transaminases and triglycerides and one because of a renal function abnormality.
In these immunocompromised patients with advanced HIV infection, it was sometimes necessary to assess laboratory abnormalities developing on study with additional criteria if baseline values were outside the normal range.
Study 155 | Study 174 | |||||
|---|---|---|---|---|---|---|
| Criteriaa | Placebo (n=88) | Azithromycin 1200 mg weekly (n=89) | Azithromycin 1200 mg weekly (n=208) | Rifabutin 300 mg daily (n=205) | Azithromycin & Rifabutin (n=199) | |
| Hemoglobin | <0.8xLLNb | 31% | 30% | 19% | 26% | 21% |
| Platelet Count | <0.75xLLN | 19% | 16% | 11% | 10% | 16% |
| WBC Count | <0.75xLLN | 48% | 49% | 60% | 53% | 60% |
| Neutrophils | <0.5xLLN | 16% | 28% | 23% | 20% | 29% |
| <500/mm3 | 6% | 13% | 5% | 6% | 8% | |
| AST (SGOT) | >2.0xULNc | 28% | 39% | 33% | 18% | 30% |
| >200 U/L | 10% | 8% | 8% | 3% | 6% | |
| ALT (SGPT) | >2.0xULN | 24% | 34% | 31% | 15% | 27% |
| >250 U/L | 2% | 6% | 8% | 2% | 6% | |
| ||||||
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/mm3).
One-, Three- and Five-Day Regimens
Laboratory data collected from 64 subjects receiving azithromycin in comparative clinical trials employing the 1-day regimen (30 mg/kg as a single dose), 1198 and 169 subjects receiving azithromycin respectively employing the two 3-day regimens (30 mg/kg or 60 mg/kg in divided doses over 3 days) were similar for regimens of azithromycin and all comparators combined, with most clinically significant laboratory abnormalities occurring at incidences of 1-5%.
Similar results were obtained in subjects receiving the two 5-day regimens. Overall, 1948 and 421 patients were exposed to 30 mg/kg or 60 mg/kg, respectively in divided doses over 5 days. The data collected in the subset of azithromycin patients assessed for laboratory abnormalities were similar to those in all comparators combined with most clinically significant laboratory abnormalities occurring at incidences of 1-5%.
In a single center clinical trial, a decrease in absolute neutrophils was observed in the range of 21-29% for azithromycin regimens of 30 mg/kg given either as a single dose or over 3 days, as well as the comparator. No patients had significant neutropenia defined as an absolute neutrophil count <500 cells/mm3 (see 14 CLINICAL TRIALS).
In clinical trials involving approximately 4700 pediatric patients, no patients discontinued therapy because of treatment-related laboratory abnormalities.
With an incidence of 4-6%, elevated ALT, AST, and creatinine.
With an incidence of 1-3%, elevated LDH and bilirubin.
With an incidence of less than 1%, leukopenia, neutropenia, decreased platelet count, and elevated serum alkaline phosphatase.
In multiple dose clinical trials involving more than 750 patients treated with sequential I.V./oral ZITHROMAX less than 2% of patients discontinued therapy because of treatment-related liver enzyme abnormalities.
When follow-up was provided, changes in laboratory tests appeared to be reversible for both oral and I.V. dosing.
The following adverse experiences have been reported in patients under conditions (e.g., open trials, marketing experience) where a causal relationship is uncertain or in patients treated with significantly higher than the recommended doses for prolonged periods.
In addition, because these reactions are reported voluntarily from a population of uncertain size, reliably estimating their frequency is not always possible.
| Allergic: | Arthralgia, edema, anaphylaxis (with rare reports of fatalities) (see 7 WARNINGS AND PRECAUTIONS), serum sickness, urticaria, vasculitis, angioedema; |
| Blood and the lymphatic system disorders: | Agranulocytosis, haemolytic anaemia, thrombocytopenia |
| Cardiovascular: | Cardiac arrhythmias (including ventricular tachycardia), palpitations, hypotension. There have been rare reports of QT prolongation and torsade de pointes in patients receiving therapeutic doses of azithromycin, including a pediatric case report of QT interval prolongation which reversed to normal upon discontinuation (see 7 WARNINGS AND PRECAUTIONS). |
| Gastrointestinal: | Anorexia, constipation, hypoglycaemia, dehydration, vomiting/diarrhea rarely resulting in dehydration, pancreatitis, pseudomembranous colitis, rare reports of tongue discoloration, pyloric stenosis / infantile hypertrophic pyloric stenosis (IHPS); |
| General: | Asthenia, paresthesia, muscle pain; |
| Genitourinary: | Interstitial nephritis, acute renal failure, nephrotic syndrome; |
| Liver/Biliary: | Hepatitis fulminant. Abnormal liver function including drug-induced hepatitis and cholestatic jaundice have been reported. There have also been rare cases of hepatic necrosis and hepatic failure, which have resulted in death (see 7 WARNINGS AND PRECAUTIONS). |
| Musculoskeletal and connective tissue disorders: | myasthenia gravis |
| Nervous System: | Hyperactivity, hypoaesthesia, seizure, convulsions, and syncope |
| Psychiatric Disorders: | Aggressive reaction, anxiety, nervousness, agitation, delirium, hallucinations |
| Skin/Appendages: | Serious skin reactions including erythema multiforme, exfoliative dermatitis, Acute Generalized Exanthematous Pustulosis (AGEP), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) (see 7 WARNINGS AND PRECAUTIONS). |
| Special Senses: | Hearing disturbances including hearing loss, hearing impaired, deafness and / or tinnitus, vertigo, taste/smell perversion and/or loss, abnormal vision. |
The majority of side effects observed in controlled clinical trials involving patients (adults and children) treated with oral ZITHROMAX (azithromycin dihydrate) were of a mild and transient nature. Approximately 0.7% of both adult patients (n=3812) and children (n=2878) from the 5-day multiple dose clinical trials discontinued ZITHROMAX therapy because of drug related side effects. Among adults receiving ZITHROMAX intravenously, 1.2% of CAP, and 2% of PID patients discontinued treatment. Discontinuation rates were slightly higher for PID patients receiving concomitant metronidazole therapy (4%).
In adults given 500 mg/day for 3 days, the discontinuation rate due to treatment-related side effects was 0.4%. In clinical trials in children given 30 mg/kg, orally either as a single dose (n= 487) or over 3 days, (n=1729) discontinuation from therapy due to treatment-related side effects was approximately 1%.
Most of the side effects leading to discontinuation in patients on oral or intravenous therapy were related to the gastrointestinal tract, e.g., nausea, vomiting, diarrhea, along with abdominal pain, rashes and increases in aminotransferases and/or alkaline phosphatase levels in adult patients receiving intravenous ZITHROMAX. Potentially serious treatment-related side effects including angioedema and cholestatic jaundice occurred in less than 1% of patients.
Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.
In adult patients, the most common treatment-related side effects in patients receiving the 3 or 5 day oral multiple-dose regimens of ZITHROMAX were related to the gastrointestinal system with diarrhea/loose stools (4-5%), nausea (3-4%), abdominal pain (2-3%) and vomiting (1%).
| Allergic: | pruritus |
| Cardiovascular: | hypertension |
| Gastrointestinal: | dry mouth, esophagitis, gastroenteritis, rectal hemorrhage, cholestatic jaundice |
| Genitourinary: | mennorhagia, urinary frequency, vaginitis |
| Nervous system: | dizziness |
| Special senses: | conjunctivitis |
In adult patients (n=904), side effects that occurred on the single one-gram dosing regimen of ZITHROMAX with a frequency greater than 1% included diarrhea (6.1%), nausea (4.9%), abdominal pain (4.9%), vomiting (1.7%), vaginitis (1.3%), loose stools (1.2%), and dyspepsia (1.1%).
Overall, the most common side effects in patients receiving a single 2-gram dose of ZITHROMAX were related to the gastrointestinal system. Side effects that occurred in patients in this study with a frequency of a 1% or greater included nausea (18.2%), diarrhea/loose stools (13.8%), vomiting (6.7%), abdominal pain (6.7%), vaginitis (2.2%), dyspepsia (1.1%), and dizziness (1.3%). The majority of these complaints were mild in nature.
Chronic therapy with ZITHROMAX 1200 mg weekly regimen: The nature of side effects seen with the 1200 mg weekly dosing regimen for the prevention of Mycobacterium avium complex infection in severely immunocompromised HIV-infected patients were similar to those seen with short-term dosing regimens.
Study 155 | Study 174 | ||||
|---|---|---|---|---|---|
| Placebo (n=91) | Azithromycin 1200 mg weekly (n=89) | Azithromycin 1200 mg weekly (n=233) | Rifabutin 300 mg daily (n=236) | Azithromycin & Rifabutin (n=224) | |
| Mean Duration of Therapy (days) | 303.8 | 402.9 | 315 | 296.1 | 344.4 |
| Discontinuation of Therapy (%) | 2.3 | 8.2 | 13.5 | 15.9 | 22.7 |
| Autonomic Nervous System | |||||
| Mouth Dry | 0 | 0 | 0 | 3.0 | 2.7 |
| Central Nervous System | |||||
| Dizziness | 0 | 1.1 | 3.9 | 1.7 | 0.4 |
| Headache | 0 | 0 | 3.0 | 5.5 | 4.5 |
| Gastrointestinal | |||||
| Diarrhea | 15.4 | 52.8 | 50.2 | 19.1 | 50.9 |
| Loose Stools | 6.6 | 19.1 | 12.9 | 3.0 | 9.4 |
| Abdominal Pain | 6.6 | 27 | 32.2 | 12.3 | 31.7 |
| Dyspepsia | 1.1 | 9 | 4.7 | 1.7 | 1.8 |
| Flatulence | 4.4 | 9 | 10.7 | 5.1 | 5.8 |
| Nausea | 11 | 32.6 | 27.0 | 16.5 | 28.1 |
| Vomiting | 1.1 | 6.7 | 9.0 | 3.8 | 5.8 |
| General | |||||
| Fever | 1.1 | 0 | 2.1 | 4.2 | 4.9 |
| Fatigue | 0 | 2.2 | 3.9 | 2.1 | 3.1 |
| Malaise | 0 | 1.1 | 0.4 | 0 | 2.2 |
| Musculoskeletal | |||||
| Arthralgia | 0 | 0 | 3.0 | 4.2 | 7.1 |
| Psychiatric | |||||
| Anorexia | 1.1 | 0 | 2.1 | 2.1 | 3.1 |
| Skin & Appendages | |||||
| Pruritus | 3.3 | 0 | 3.9 | 3.4 | 7.6 |
| Rash | 3.2 | 3.4 | 8.1 | 9.4 | 11.1 |
| Skin discoloration | 0 | 0 | 0 | 2.1 | 2.2 |
| Special Senses | |||||
| Tinnitus | 4.4 | 3.4 | 0.9 | 1.3 | 0.9 |
| Hearing Decreased | 2.2 | 1.1 | 0.9 | 0.4 | 0 |
| Taste Perversion | 0 | 0 | 1.3 | 2.5 | 1.3 |
| |||||
Side effects related to the gastrointestinal tract were seen more frequently in patients receiving azithromycin than in those receiving placebo or rifabutin. In one of the studies, 86% of diarrheal episodes were mild to moderate in nature with discontinuation of therapy for this reason occurring in only 9/233 (3.8%) of patients.
The most common side effects (greater than 1%) in adult patients who received sequential I.V./oral ZITHROMAX in studies of community-acquired pneumonia were related to the gastrointestinal system: diarrhea/loose stools (4.3%), nausea (3.9%), abdominal pain (2.7%), and vomiting (1.4%). Approximately 12% of patients experienced a side effect related to the intravenous infusion; most common were pain at the site and/or during the infusion (6.5%) and local inflammation (3.1%).
In adult women who received sequential I.V./oral ZITHROMAX in studies of pelvic inflammatory disease, the most common side effects (greater than 1%) were related to the gastrointestinal system. Diarrhea (8.5%) and nausea (6.6%) were most frequently reported, followed by vaginitis (2.8%), abdominal pain (1.9%), anorexia (1.9%), rash and pruritus (1.9%). When azithromycin was co-administered with metronidazole in these studies, a higher proportion of women experienced side effects of nausea (10.3%), abdominal pain (3.7%), vomiting (2.8%) and application site reaction, stomatitis, dizziness, or dyspnea (all at 1.9%).
| Allergic: | bronchospasm |
| Gastrointestinal: | dyspepsia, flatulence, mucositis, oral moniliasis, and gastritis |
| Nervous System: | headache, somnolence |
| Special Senses: | taste perversion |
In children enrolled in controlled clinical trials in acute otitis media and S. pyogenes pharyngitis, the type of side effects were comparable to those seen in adults (see below).
Different side effect incidence rates for the dosage regimens recommended in children were observed.
Acute Otitis Media: For the recommended total dosage regimen of 30 mg/kg, the most frequent side effects (≥1%) attributed to treatment were diarrhea, abdominal pain, vomiting, nausea and rash. The incidence, based on dosing regimen, is described in the table below:
| Regimen | Subjects | Overall ADR Incidence | Diarrhea | Abdominal pain | Vomiting | Nausea | Rash |
|---|---|---|---|---|---|---|---|
| 1-Day | 487 | 14% | 4% | 1% | 5% | 1% | 1% |
| 3-Day | 1395 | 7% | 3% | 2% | 1% | < 1% | < 1% |
| 5-Day | 1888 | 6% | 2% | 1% | 1% | 1% | < 1% |
Community-Acquired Pneumonia: For the recommended total dosage regimen of 30 mg/kg, the most frequent side effects attributed to treatment were diarrhea/loose stools, abdominal pain, vomiting/nausea and rash. The incidence is described in the table below:
| Dosage Regimen | Subjects | Overall ADR Incidence | Diarrhea/ Loose stools | Abdominal Pain | Vomiting | Nausea | Rash |
|---|---|---|---|---|---|---|---|
| 5-day | 323 | 12% | 5.8% | 1.9% | 1.9% | 1.9% | 1.6% |
Pharyngitis/tonsillitis: For the recommended total dosage regimen of 60 mg/kg, the most frequent side effects attributed to treatment were diarrhea, vomiting, abdominal pain, nausea and headache. The incidence is described in the table below:
| Regimen | Subjects | Overall ADR Incidence | Diarrhea | Abdominal pain | Vomiting | Nausea | Rash | Headache |
|---|---|---|---|---|---|---|---|---|
| 5-Day | 447 | 17% | 5% | 3% | 6% | 2% | < 1% | 1% |
Side effects that occurred with a frequency of 1% or less in patients included the following:
| Allergic: | Allergic reaction, photosensitivity, angioedema, erythema multiforme, pruritus and urticaria. |
| Cardiovascular: | Palpitations, chest pain; |
| Gastrointestinal: | Dyspepsia, flatulence, melena, constipation, anorexia, enteritis, loose stools, oral moniliasis and gastritis; |
| General: | Fatigue, face edema, fever, fungal infection, pain and malaise; |
| Genitourinary: | Monilia, vaginitis and nephritis; |
| Hematologic and Lymphatic: | Anemia, leukopenia |
| Liver/Biliary | Liver function test abnormal, jaundice and cholestatic jaundice. |
| Nervous System: | Dizziness, vertigo, somnolence, agitation, nervousness, insomnia and hyperkinesia; |
| Respiratory: | Cough increased, pharyngitis, pleural effusion and rhinitis; |
| Skin and Appendages: | Eczema, fungal dermatitis, sweating and vesiculobullous rash |
Clinically significant abnormalities (irrespective of drug relationship) occurring during the clinical trials in patients were reported as follows:
With an incidence of greater than 1%: decreased hemoglobin, hematocrit, lymphocytes, monocytes, albumin and blood glucose, elevated serum creatine phosphokinase, potassium, ALT (SGPT), GGT and AST (SGOT), BUN, creatinine, blood glucose, platelet count, eosinophils and monocytes.
With an incidence of less than 1%: leukopenia, neutropenia, decreased platelet count, elevated serum alkaline phosphatase, bilirubin, LDH and phosphate.
The majority of subjects with elevated serum creatine 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 4500 patients, 3 patients discontinued therapy because of treatment-related liver enzyme abnormalities, one for treatment-related elevated transaminases and triglycerides and one because of a renal function abnormality.
In these immunocompromised patients with advanced HIV infection, it was sometimes necessary to assess laboratory abnormalities developing on study with additional criteria if baseline values were outside the normal range.
Study 155 | Study 174 | |||||
|---|---|---|---|---|---|---|
| Criteriaa | Placebo (n=88) | Azithromycin 1200 mg weekly (n=89) | Azithromycin 1200 mg weekly (n=208) | Rifabutin 300 mg daily (n=205) | Azithromycin & Rifabutin (n=199) | |
| Hemoglobin | <0.8xLLNb | 31% | 30% | 19% | 26% | 21% |
| Platelet Count | <0.75xLLN | 19% | 16% | 11% | 10% | 16% |
| WBC Count | <0.75xLLN | 48% | 49% | 60% | 53% | 60% |
| Neutrophils | <0.5xLLN | 16% | 28% | 23% | 20% | 29% |
| <500/mm3 | 6% | 13% | 5% | 6% | 8% | |
| AST (SGOT) | >2.0xULNc | 28% | 39% | 33% | 18% | 30% |
| >200 U/L | 10% | 8% | 8% | 3% | 6% | |
| ALT (SGPT) | >2.0xULN | 24% | 34% | 31% | 15% | 27% |
| >250 U/L | 2% | 6% | 8% | 2% | 6% | |
| ||||||
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/mm3).
One-, Three- and Five-Day Regimens
Laboratory data collected from 64 subjects receiving azithromycin in comparative clinical trials employing the 1-day regimen (30 mg/kg as a single dose), 1198 and 169 subjects receiving azithromycin respectively employing the two 3-day regimens (30 mg/kg or 60 mg/kg in divided doses over 3 days) were similar for regimens of azithromycin and all comparators combined, with most clinically significant laboratory abnormalities occurring at incidences of 1-5%.
Similar results were obtained in subjects receiving the two 5-day regimens. Overall, 1948 and 421 patients were exposed to 30 mg/kg or 60 mg/kg, respectively in divided doses over 5 days. The data collected in the subset of azithromycin patients assessed for laboratory abnormalities were similar to those in all comparators combined with most clinically significant laboratory abnormalities occurring at incidences of 1-5%.
In a single center clinical trial, a decrease in absolute neutrophils was observed in the range of 21-29% for azithromycin regimens of 30 mg/kg given either as a single dose or over 3 days, as well as the comparator. No patients had significant neutropenia defined as an absolute neutrophil count <500 cells/mm3 (see 14 CLINICAL TRIALS).
In clinical trials involving approximately 4700 pediatric patients, no patients discontinued therapy because of treatment-related laboratory abnormalities.
With an incidence of 4-6%, elevated ALT, AST, and creatinine.
With an incidence of 1-3%, elevated LDH and bilirubin.
With an incidence of less than 1%, leukopenia, neutropenia, decreased platelet count, and elevated serum alkaline phosphatase.
In multiple dose clinical trials involving more than 750 patients treated with sequential I.V./oral ZITHROMAX less than 2% of patients discontinued therapy because of treatment-related liver enzyme abnormalities.
When follow-up was provided, changes in laboratory tests appeared to be reversible for both oral and I.V. dosing.
The following adverse experiences have been reported in patients under conditions (e.g., open trials, marketing experience) where a causal relationship is uncertain or in patients treated with significantly higher than the recommended doses for prolonged periods.
In addition, because these reactions are reported voluntarily from a population of uncertain size, reliably estimating their frequency is not always possible.
| Allergic: | Arthralgia, edema, anaphylaxis (with rare reports of fatalities) (see 7 WARNINGS AND PRECAUTIONS), serum sickness, urticaria, vasculitis, angioedema; |
| Blood and the lymphatic system disorders: | Agranulocytosis, haemolytic anaemia, thrombocytopenia |
| Cardiovascular: | Cardiac arrhythmias (including ventricular tachycardia), palpitations, hypotension. There have been rare reports of QT prolongation and torsade de pointes in patients receiving therapeutic doses of azithromycin, including a pediatric case report of QT interval prolongation which reversed to normal upon discontinuation (see 7 WARNINGS AND PRECAUTIONS). |
| Gastrointestinal: | Anorexia, constipation, hypoglycaemia, dehydration, vomiting/diarrhea rarely resulting in dehydration, pancreatitis, pseudomembranous colitis, rare reports of tongue discoloration, pyloric stenosis / infantile hypertrophic pyloric stenosis (IHPS); |
| General: | Asthenia, paresthesia, muscle pain; |
| Genitourinary: | Interstitial nephritis, acute renal failure, nephrotic syndrome; |
| Liver/Biliary: | Hepatitis fulminant. Abnormal liver function including drug-induced hepatitis and cholestatic jaundice have been reported. There have also been rare cases of hepatic necrosis and hepatic failure, which have resulted in death (see 7 WARNINGS AND PRECAUTIONS). |
| Musculoskeletal and connective tissue disorders: | myasthenia gravis |
| Nervous System: | Hyperactivity, hypoaesthesia, seizure, convulsions, and syncope |
| Psychiatric Disorders: | Aggressive reaction, anxiety, nervousness, agitation, delirium, hallucinations |
| Skin/Appendages: | Serious skin reactions including erythema multiforme, exfoliative dermatitis, Acute Generalized Exanthematous Pustulosis (AGEP), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) (see 7 WARNINGS AND PRECAUTIONS). |
| Special Senses: | Hearing disturbances including hearing loss, hearing impaired, deafness and / or tinnitus, vertigo, taste/smell perversion and/or loss, abnormal vision. |
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