(azithromycin dihydrate TABLET, SUSPENSION)
12 CLINICAL PHARMACOLOGY
12 CLINICAL PHARMACOLOGY
12.2 Pharmacodynamics
Based on animal models of infection, the antibacterial activity of azithromycin appears to correlate with the ratio of area under the concentration-time curve to minimum inhibitory concentration (AUC/MIC) for certain pathogens (S. pneumoniae and S. aureus). The principal pharmacokinetic/pharmacodynamic parameter best associated with clinical and microbiological cure has not been elucidated in clinical trials with azithromycin.
Cardiac Electrophysiology
QTc interval prolongation was studied in a randomized, placebo-controlled parallel trial in 116 healthy subjects who received either chloroquine (1000 mg) alone or in combination with oral azithromycin (500 mg, 1000 mg, and 1500 mg once daily). Co-administration of azithromycin increased the QTc interval in a dose- and concentration- dependent manner. In comparison to chloroquine alone, the maximum mean (95% upper confidence bound) increases in QTcF were 5 (10) ms, 7 (12) ms and 9 (14) ms with the co-administration of 500 mg, 1000 mg and 1500 mg azithromycin, respectively.
12.3 Pharmacokinetics
Following oral administration of a single 500 mg dose (two 250 mg tablets) to 36 fasted healthy male volunteers, the mean (SD) pharmacokinetic parameters were AUC0–72=4.3 (1.2) mcg∙hr/mL; Cmax=0.5 (0.2) mcg/mL; Tmax=2.2 (0.9) hours. Two azithromycin 250 mg tablets are bioequivalent to a single 500 mg tablet.
In a two-way crossover study, 12 adult healthy volunteers (6 males, 6 females) received 1500 mg of azithromycin administered in single daily doses over either 5 days (two 250 mg tablets on day 1, followed by one 250 mg tablet on days 2–5) or 3 days (500 mg per day for days 1–3). Due to limited serum samples on day 2 (3-day regimen) and days 2–4 (5-day regimen), the serum concentration-time profile of each subject was fit to a 3-compartment model and the AUC0–∞ for the fitted concentration profile was comparable between the 5-day and 3-day regimens.
| 3-Day Regimen | 5-Day Regimen | |||
|---|---|---|---|---|
| ||||
Pharmacokinetic Parameter [mean (SD)] | Day 1 | Day 3 | Day 1 | Day 5 |
Cmax (serum, mcg/mL) | 0.44 (0.22) | 0.54 (0.25) | 0.43 (0.20) | 0.24 (0.06) |
Serum AUC0–∞ (mcg∙hr/mL) | 17.4 (6.2)* | 14.9 (3.1)* | ||
Serum T1/2 | 71.8 hr | 68.9 hr | ||
Absorption
The absolute bioavailability of azithromycin 250 mg capsules is 38%.
In a two-way crossover study in which 12 healthy subjects received a single 500 mg dose of azithromycin (two 250 mg tablets) with or without a high fat meal, food was shown to increase Cmax by 23% but had no effect on AUC.
When azithromycin oral suspension was administered with food to 28 adult healthy male subjects, Cmax increased by 56% and AUC was unchanged.
Distribution
The serum protein binding of azithromycin is variable in the concentration range approximating human exposure, decreasing from 51% at 0.02 mcg/mL to 7% at 2 mcg/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 human tissues, 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 significance of these tissue concentration data is unknown.
Following a regimen of 500 mg on the first day and 250 mg daily for 4 days, very low concentrations were noted in cerebrospinal fluid (less than 0.01 mcg/mL) in the presence of noninflamed meninges.
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 a mean apparent plasma clearance of 630 mL/min and terminal elimination half-life of 68 hr. The prolonged terminal half-life is thought to be due to extensive uptake and subsequent release of drug from tissues. 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
Patients with Renal Impairment
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), mean Cmax and AUC0–120 increased by 5.1% and 4.2%, respectively, in subjects with mild to moderate renal impairment (GFR 10 to 80 mL/min) compared to subjects with normal renal function (GFR >80 mL/min). The mean Cmax and AUC0–120 increased 61% and 35%, respectively, in subjects with severe renal impairment (GFR <10 mL/min) compared to subjects with normal renal function (GFR >80 mL/min).
Patients with Hepatic Impairment
The pharmacokinetics of azithromycin in subjects with hepatic impairment has not been established.
Male and Female Patients
There are no significant differences in the disposition of azithromycin between male and female subjects. No dosage adjustment is recommended based on gender.
Geriatric Patients
Pharmacokinetic parameters in older volunteers (65 to 85 years old) were similar to those in young adults (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 Geriatric Use (8.5)]
Pediatric Patients
In two clinical studies, azithromycin for oral suspension was dosed at 10 mg/kg on day 1, followed by 5 mg/kg on days 2 through 5 in two groups of pediatric patients (aged 1–5 years and 5–15 years, respectively). The mean pharmacokinetic parameters on day 5 were Cmax=0.216 mcg/mL, Tmax=1.9 hr, and AUC0–24=1.822 mcg∙hr/mL for the 1 to 5-year-old group and were Cmax=0.383 mcg/mL, Tmax=2.4 hr, and AUC0–24=3.109 mcg∙hr/mL for the 5 to 15-year-old group.
In another study, 33 pediatric patients received doses of 12 mg/kg/day (maximum daily dose 500 mg) for 5 days, of whom 31 patients were evaluated for azithromycin pharmacokinetics following a low fat breakfast. In this study, azithromycin concentrations were determined over a 24 hr period following the last daily dose. Patients weighing above 41.7 kg received the maximum adult daily dose of 500 mg. Seventeen patients (weighing 41.7 kg or less) received a total dose of 60 mg/kg. The following table shows pharmacokinetic data in the subset of pediatric patients who received a total dose of 60 mg/kg.
| Pharmacokinetic Parameter [mean (SD)] | 5-Day Regimen (12 mg/kg for 5 days) |
|---|---|
| N | 17 |
Cmax (mcg/mL) | 0.5 (0.4) |
Tmax (hr) | 2.2 (0.8) |
AUC0–24(mcg∙hr/mL) | 3.9 (1.9) |
Single dose pharmacokinetics of azithromycin in pediatric patients given doses of 30 mg/kg have not been studied. [see Dosage and Administration (2)]
Drug Interaction Studies
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 Cmax and AUC of azithromycin. No dosage adjustment of azithromycin is recommended when administered with drugs listed in Table 2. [see Drug Interactions (7.3)]
| Co-administered Drug | Dose of Co-administered Drug | Dose of Azithromycin | n | Ratio (with/without azithromycin) of Co-administered Drug Pharmacokinetic Parameters (90% CI); No Effect = 1.00 | |
|---|---|---|---|---|---|
| Mean Cmax | Mean AUC | ||||
| |||||
Atorvastatin | 10 mg/day for 8 days | 500 mg/day orally on days 6–8 | 12 | 0.83 | 1.01 |
Carbamazepine | 200 mg/day for 2 days, then 200 mg twice a day for 18 days | 500 mg/day orally for days 16–18 | 7 | 0.97 | 0.96 |
Cetirizine | 20 mg/day for 11 days | 500 mg orally on day 7, then 250 mg/day on days 8–11 | 14 | 1.03 | 1.02 |
Didanosine | 200 mg orally twice a day for 21 days | 1200 mg/day orally on days 8–21 | 6 | 1.44 | 1.14 |
Efavirenz | 400 mg/day for 7 days | 600 mg orally on day 7 | 14 | 1.04* | 0.95* |
Fluconazole | 200 mg orally single dose | 1200 mg orally single dose | 18 | 1.04 | 1.01 |
Indinavir | 800 mg three times a day for 5 days | 1200 mg orally on day 5 | 18 | 0.96 | 0.90 |
Midazolam | 15 mg orally on day 3 | 500 mg/day orally for 3 days | 12 | 1.27 | 1.26 |
Nelfinavir | 750 mg three times a day for 11 days | 1,200 mg orally on day 9 | 14 | 0.90 | 0.85 |
Sildenafil | 100 mg on days 1 and 4 | 500 mg/day orally for 3 days | 12 | 1.16 | 0.92 |
Theophylline | 4 mg/kg IV on days 1, 11, 25 | 500 mg orally on day 7, 250 mg/day on days 8–11 | 10 | 1.19 | 1.02 |
Theophylline | 300 mg orally twice a day for 15 days | 500 mg orally on day 6, then 250 mg/day on days 7–10 | 8 | 1.09 | 1.08 |
Triazolam | 0.125 mg on day 2 | 500 mg orally on day 1, then 250 mg/day on day 2 | 12 | 1.06* | 1.02* |
Trimethoprim/ | 160 mg/800 mg/day orally for 7 days | 1200 mg orally on day 7 | 12 | 0.85 | 0.87 |
Zidovudine | 500 mg/day orally for 21 days | 600 mg/day orally for 14 days | 5 | 1.12 | 0.94 |
Zidovudine | 500 mg/day orally for 21 days | 1200 mg/day orally for 14 days | 4 | 1.31 | 1.30 |
| Co-administered Drug | Dose of Co-administered Drug | Dose of Azithromycin | n | Ratio (with/without co-administered drug) of Azithromycin Pharmacokinetic Parameters (90% CI); No Effect = 1.00 | |
|---|---|---|---|---|---|
| Mean Cmax | Mean AUC | ||||
| |||||
Efavirenz | 400 mg/day for 7 days | 600 mg orally on day 7 | 14 | 1.22 | 0.92* |
Fluconazole | 200 mg orally single dose | 1,200 mg orally single dose | 18 | 0.82 | 1.07 |
Nelfinavir | 750 mg three times a day for 11 days | 1,200 mg orally on day 9 | 14 | 2.36 | 2.12 |
12.4 Microbiology
Mechanism of Action
Azithromycin acts by binding to the 23S rRNA of the 50S ribosomal subunit of susceptible microorganisms inhibiting bacterial protein synthesis and impeding the assembly of the 50S ribosomal subunit.
Resistance
Azithromycin demonstrates cross resistance with erythromycin. The most frequently encountered mechanism of resistance to azithromycin is modification of the 23S rRNA target, most often by methylation. Ribosomal modifications can determine cross resistance to other macrolides, lincosamides, and streptogramin B (MLSB phenotype).
Antimicrobial Activity
Azithromycin has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections. [see Indications and Usage (1)]
Gram-Positive Bacteria
- Staphylococcus aureus
- Streptococcus agalactiae
- Streptococcus pneumoniae
- Streptococcus pyogenes
Gram-Negative Bacteria
- Haemophilus ducreyi
- Haemophilus influenzae
- Moraxella catarrhalis
- Neisseria gonorrhoeae
Other Bacteria
- Chlamydophila pneumoniae
- Chlamydia trachomatis
- Mycoplasma pneumoniae
The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for azithromycin against isolates of similar genus or organism group. However, the efficacy of azithromycin in treating clinical infections caused by these bacteria has not been established in adequate and well-controlled clinical trials.
Gram-Positive Bacteria
- Beta-hemolytic streptococci (Groups C, F, G)
- Viridans group streptococci
Gram-Negative Bacteria
- Bordetella pertussis
- Legionella pneumophila
Anaerobic Bacteria
- Prevotella bivia
- Peptostreptococcus species
Other Bacteria
- Ureaplasma urealyticum
PATIENT INFORMATION
Patient Information
ZITHROMAX® (Zith-roe-maks)
(azithromycin)
Tablets
ZITHROMAX®
(azithromycin)
Oral Suspension
Read this Patient Information leaflet before you start taking ZITHROMAX and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.
What is ZITHROMAX?
ZITHROMAX is a macrolide antibiotic prescription medicine used in adults 18 years or older to treat certain infections caused by certain germs called bacteria. These bacterial infections include:
- •
- acute worsening of chronic bronchitis
- •
- acute sinus infection
- •
- community-acquired pneumonia
- •
- infected throat or tonsils
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- skin infections
- •
- infections of the urethra or cervix
- •
- genital ulcers in men
ZITHROMAX is also used in children to treat:
- •
- ear infections
- •
- community-acquired pneumonia
- •
- infected throat or tonsils
Azithromycin should not be taken by people who cannot tolerate oral medications because they are very ill or have certain other risk factors including:
- •
- have cystic fibrosis
- •
- have hospital acquired infections
- •
- have known or suspected bacteria in the blood
- •
- need to be in the hospital
- •
- are elderly
- •
- have any medical problems that can lower the ability of the immune system to fight infections
ZITHROMAX is not for viral infections such as the common cold.
It is not known if ZITHROMAX is safe and effective for genital ulcers in women.
It is not known if ZITHROMAX is safe and effective for children with ear infections, sinus infections, and community-acquired pneumonia under 6 months of age.
It is not known if ZITHROMAX is safe and effective for infected throat or tonsils in children under 2 years of age.
Who should not take ZITHROMAX?
Do not take ZITHROMAX if you:
- •
- have had a severe allergic reaction to certain antibiotics known as macrolides or ketolides including azithromycin and erythromycin.
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- have a history of cholestatic jaundice or hepatic dysfunction that happened with the use of azithromycin.
What should I tell my healthcare provider before taking ZITHROMAX?
Before you take ZITHROMAX, tell your healthcare provider if you:
- •
- have pneumonia
- •
- have cystic fibrosis
- •
- have known or suspected bacteremia (bacterial infection in the blood)
- •
- have liver or kidney problems
- •
- have an irregular heartbeat, especially a problem called "QT prolongation"
- •
- have a problem that causes muscle weakness (myasthenia gravis)
- •
- have any other medical problems
- •
- are pregnant or plan to become pregnant. It is not known if ZITHROMAX will harm your unborn baby.
- •
- are breastfeeding or plan to breastfeed. ZITHROMAX has been reported to pass into breast milk. Talk to your healthcare provider about the best way to feed your baby while you take ZITHROMAX.
Contact your healthcare provider immediately if you are giving ZITHROMAX to a young child (less than 6 weeks of age) and he or she vomits or becomes irritable when fed.
Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.
ZITHROMAX and other medicines may affect each other causing side effects. ZITHROMAX may affect the way other medicines work, and other medicines may affect how ZITHROMAX works.
Especially tell your healthcare provider if you take:
- •
- nelfinavir
- •
- a blood thinner (warfarin)
- •
- digoxin
- •
- colchicine
- •
- phenytoin
- •
- an antacid that contains aluminum or magnesium
Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine.
How should I take ZITHROMAX?
- •
- Take ZITHROMAX exactly as your healthcare provider tells you to take it.
- •
- ZITHROMAX can be taken with or without food.
- •
- If you take ZITHROMAX Oral Suspension, shake the bottle well just before you take it.
- •
- Do not skip any doses of ZITHROMAX or stop taking it, even if you begin to feel better, until you finish your prescribed treatment unless you have a serious allergic reaction or your healthcare provider tells you to stop taking ZITHROMAX. "See What are the possible side effects of ZITHROMAX?" If you skip doses, or do not complete the total course of ZITHROMAX your treatment may not work as well and your infection may be harder to treat. Taking all of your ZITHROMAX doses will help lower the chance that the bacteria will become resistant to ZITHROMAX.
- •
- If the bacteria becomes resistant to ZITHROMAX, ZITHROMAX and other antibiotic medicines may not work for you in the future.
- •
- If you take too much ZITHROMAX, call your healthcare provider or get medical help right away.
What are the possible side effects of ZITHROMAX?
ZITHROMAX can cause serious side effects, including:
- •
- Serious allergic reactions. Allergic reactions can happen in people taking azithromcyin the active ingredient in ZITHROMAX, even after only 1 dose. Stop taking ZITHROMAX and get emergency medical help right away if you have any of the following symptoms of a severe allergic reaction:
- o
- trouble breathing or swallowing
- o
- swelling of the lips, tongue, face
- o
- throat tightness, hoarseness
- o
- rapid heartbeat
- o
- faintness
- o
- skin rash (hives)
- o
- new onset of fever and swollen lymph nodes
- Stop taking ZITHROMAX at the first sign of a skin rash and call your healthcare provider. Skin rash may be a sign of a more serious reaction to ZITHROMAX.
- •
- Liver damage (hepatotoxicity). Hepatotoxicity can happen in people who take ZITHROMAX. Call your healthcare provider right away if you have unexplained symptoms such as:
|
|
- Stop taking ZITHROMAX and tell your healthcare provider right away if you have yellowing of your skin or white part of your eyes, or if you have dark urine. These can be signs of a serious reaction to ZITHROMAX (a liver problem).
- •
- Serious heart rhythm changes that can be life-threatening, including heart stopping (cardiac arrest), QT prolongation, torsades de pointes, feeling that your heart is pounding or racing (palpitations), chest discomfort, or irregular heartbeat.
Tell your healthcare provider right away if you or your child feel a fast or irregular heartbeat, get dizzy or faint. ZITHROMAX may cause a rare heart problem known as prolongation of the QT interval. This condition can cause an abnormal heartbeat and can be very dangerous. The chances of this happening are higher in people:- o
- who are elderly
- o
- with a family history of prolonged QT interval
- o
- with low blood potassium
- o
- who take certain medicines to control heart rhythm (antiarrhythmics)
- •
- Worsening of myasthenia gravis (a problem that causes muscle weakness). Certain antibiotics like ZITHROMAX may cause worsening of myasthenia gravis symptoms, including muscle weakness and breathing problems. Call your healthcare provider right away if you have any worsening muscle weakness or breathing problems.
- •
- Diarrhea. Tell your healthcare provider right away if you have watery diarrhea, diarrhea that does not go away, or bloody stools. You may experience cramping and a fever. This could happen after you have finished your ZITHROMAX.
The most common side effects of ZITHROMAX include:- o
- nausea
- o
- stomach pain
- o
- vomiting
These are not all the possible side effects of ZITHROMAX. Tell your healthcare provider about any side effect that bothers you or that does not go away.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store ZITHROMAX?
- •
- Store ZITHROMAX Tablets at 59°F to 86°F (15°C to 30°C).
- •
- Store ZITHROMAX Oral Suspension at 41°F to 86°F (5°C to 30°C).
- •
- Keep ZITHROMAX Oral Suspension in a tightly closed container.
- •
- Safely throw away any medicine that is out of date or no longer needed.
Keep ZITHROMAX and all medicines out of the reach of children.
General information about the safe and effective use of ZITHROMAX.
Medicines are sometimes prescribed for purposes other than those listed in the Patient Information leaflet. Do not use ZITHROMAX for a condition for which it was not prescribed.
Do not give ZITHROMAX to other people, even if they have the same symptoms you have.
It may harm them.
This Patient Information leaflet summarizes the most important information about ZITHROMAX. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about ZITHROMAX that is written for health professionals.
For more information, go to www.zithromax.com or call 1-800-438-1986.
What are the ingredients in ZITHROMAX Tablets and Oral Suspension?
ZITHROMAX Tablets and Oral Suspension
Active ingredient: azithromycin dehydrate
ZITHROMAX Tablets:
Inactive ingredients: dibasic calcium phosphate anhydrous, pregelatinized starch, sodium croscarmellose, magnesium stearate, sodium lauryl sulfate, hypromellose, lactose, titanium dioxide, triacetin, and D&C Red #30 aluminum lake.
ZITHROMAX Oral Suspension:
Inactive ingredients: sucrose; sodium phosphate, tribasic, anhydrous; hydroxypropyl cellulose; xanthan gum; FD&C Red #40; and spray dried artificial cherry, creme de vanilla, and banana flavors.
This Patient Information has been approved by the U.S. Food and Drug Administration.
LAB-0372-7.0
Revised November 2021
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