Prophylaxis of Disseminated Mycobacterium avium complex (MAC) Disease

Azithromycin tablets, taken alone or in combination with rifabutin at its approved dose, are indicated for the prevention of disseminated MAC disease in persons with advanced HIV infection. [see Dosage and Administration (2)]

Treatment of Disseminated MAC Disease

Azithromycin tablets, taken in combination with ethambutol, are indicated for the treatment of disseminated MAC infections in persons with advanced HIV infection .[see Use in Specific Populations (8.4)and Clinical Studies (14.1)]

Prevention of Disseminated MAC Infections

The recommended dose of azithromycin tablets for the prevention of disseminated Mycobacterium aviumcomplex (MAC) disease is: 1,200 mg taken once weekly. This dose of azithromycin tablets may be combined with the approved dosage regimen of rifabutin.

Treatment of Disseminated MAC Infections

Azithromycin 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 vitroactivity against MAC may be added to the regimen of azithromycin plus ethambutol at the discretion of the physician or health care provider.

Multiple-dose regimen

Overall, the most common adverse reactions in adult patients receiving a multiple-dose regimen of azithromycin 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 azithromycin 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 1,200 mg weekly regimen

The nature of adverse reactions seen with the 1200 mg weekly dosing regimen for the prevention of Mycobacterium aviuminfection 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 aviumcomplex 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.

Risk Summary

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 3, 2, and 1 times, respectively, an adult human daily dose of 600 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 3 times an adult human daily dose of 600 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.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Risk Summary

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. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for azithromycin and any potential adverse effects on the breastfed infant from azithromycin or from the underlying maternal condition.

Clinical Considerations

Advise women to monitor the breastfed infant for diarrhea, vomiting, or rash.

Data

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 500 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.

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 to 2,004 days) at doses of < 1 mg/kg/day 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 mg/kg/day to 20 mg/kg/day (oral and/or IV) of azithromycin.

Geriatric Patients with Opportunistic Infections, Including (MAC) Disease:Safety data are available for 30 patients (65 to 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 was 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)]

Cardiac Electrophysiology

QTc interval prolongation was studied in a randomized, placebo-controlled parallel trial in 116 healthy subjects who received either chloroquine (1,000 mg) alone or in combination with oral azithromycin (500 mg, 1,000 mg, and 1,500 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, 1,000 mg and 1,500 mg azithromycin, respectively.

Absorption

The 1 gram single -dose packet is bioequivalent to four 250 mg azithromycin capsule.

When the oral suspension of azithromycin was administered with food, the C maxincreased by 46% and the AUC by 14%.

The absolute bioavailability of two 600 mg tablets was 34% (CV = 56%). Administration of two 600 mg tablets with food increased C maxby 31% (CV = 43%) while the extent of absorption (AUC) was unchanged (mean ratio of AUCs = 1.00; CV = 55%).

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 tissues in humans, 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 importance of these tissue concentration data is unknown.

Azithromycin concentrates in phagocytes and fibroblasts as demonstrated by in vitroincubation techniques. Using such methodology, the ratio of intracellular to extracellular concentration was > 30 after one hr of incubation. In vivostudies suggest that concentration in phagocytes may contribute to drug distribution to inflamed tissues.

Following oral administration of a single 1,200 mg dose (two 600 mg tablets), the mean maximum concentration in peripheral leukocytes was 140 mcg/mL. Concentration remained above 32 mcg/mL, for approximately 60 hr. The mean half-lives for 6 males and 6 females were 34 hr and 57 hr, respectively. Leukocyte-to-plasma C maxratios for males and females were 258 (± 77%) and 175 (± 60%), respectively, and the AUC ratios were 804 (± 31%) and 541 (± 28%), respectively. The clinical relevance of these findings is unknown.

Following oral administration of multiple daily doses of 600 mg (1 tablet/day) to asymptomatic HIV-positive adults, mean maximum concentration in peripheral leukocytes was 252 mcg/mL (± 49%). Trough concentrations in peripheral leukocytes at steady-state averaged 146 mcg/mL (± 33%). The mean leukocyte-to-serum C maxratio was 456 (± 38%) and the mean leukocyte to serum AUC ratio was 816 (± 31%). The clinical relevance of these findings is unknown.

Metabolism

In vitroand in vivostudies 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 an average terminal half-life of 68 hr. 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

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 C maxand AUC of azithromycin. No dosage adjustment of azithromycin is recommended when administered with drugs listed in Table 2. [see Drug Interactions (7.3)]

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

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). The mechanism of acquired mutational resistance in isolates of Mycobacterium aviumcomplex (i.e., 23S rRNA genemutation) is the same for both clarithromycin and azithromycin.

Antimicrobial Activity

Azithromycin has been shown to be active against the following microorganisms, both in vitroand in clinical infections. [see Indications and Usage (1)]

Mycobacteria

• Mycobacterium aviumcomplex (MAC) consisting of:
•    Mycobacterium avium
•    Mycobacterium intracellulare

Other Microorganisms

• Chlamydia trachomatis

Susceptibility Testing

For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for azithromycin tablets, please see: https://www.fda.gov/STIC.

Prevention of Disseminated MAC Disease

Two randomized, double-blind clinical trials were performed in patients with CD4 counts < 100 cells/mcL. The first trial (Study 155) compared azithromycin (1,200 mg once weekly) to placebo and enrolled 182 patients with a mean CD4 count of 35 cells/mcL. The second trial (Study 174) randomized 723 patients to either azithromycin (1,200 mg once weekly), rifabutin (300 mg daily), or the combination of both. The mean CD4 count was 51 cells/mcL. The primary endpoint in these trials was disseminated MAC disease. Other endpoints included the incidence of clinically significant MAC disease and discontinuations from therapy for drug-related side effects.

MAC bacteremia

In Study 155, 85 patients randomized to receive azithromycin and 89 patients randomized to receive placebo met the entrance criteria. Cumulative incidences at 6, 12, and 18 months of the possible outcomes are in the following table:

The difference in the one -year cumulative incidence rates of disseminated MAC disease (placebo – azithromycin) is 10.9%. This difference is statistically significant (p = 0.037) with a 95% confidence interval for this difference of 0.8%, 20.9%. The comparable number of patients experiencing adverse events and the fewer number of patients lost to follow-up on azithromycin should be taken into account when interpreting the significance of this difference.

In Study 174, 223 patients randomized to receive rifabutin, 223 patients randomized to receive azithromycin, and 218 patients randomized to receive both rifabutin and azithromycin met the entrance criteria. Cumulative incidences at 6, 12, and 18 months of the possible outcomes are recorded in the following table:

Comparing the cumulative one -year incidence rates, azithromycin monotherapy is at least as effective as rifabutin monotherapy. The difference (rifabutin – azithromycin) in the one -year rates (7.6%) is statistically significant (p = 0.022) with an adjusted 95% confidence interval (0.9%, 14.3%). Additionally, azithromycin/rifabutin combination therapy is more effective than rifabutin alone. The difference (rifabutin – azithromycin/rifabutin) in the cumulative one -year incidence rates (12.5%) is statistically significant (p < 0.001) with an adjusted 95% confidence interval of 6.6%, 18.4%. The comparable number of patients experiencing adverse events and the fewer number of patients lost to follow-up on rifabutin should be taken into account when interpreting the significance of this difference.

In Study 174, sensitivity testing 1was performed on all available MAC isolates from subjects randomized to either azithromycin, rifabutin, or the combination. The distribution of MIC values for azithromycin from susceptibility testing of the breakthrough isolates was similar between trial arms. As the efficacy of azithromycin in the treatment of disseminated MAC has not been established, the clinical relevance of these in vitroMICs as an indicator of susceptibility or resistance is not known.

Clinically Significant Disseminated MAC Disease

In association with the decreased incidence of bacteremia, patients in the groups randomized to either azithromycin alone or azithromycin in combination with rifabutin showed reductions in the signs and symptoms of disseminated MAC disease, including fever or night sweats, weight loss, and anemia.

Discontinuations from Therapy for Drug-Related Side Effects

In Study 155, discontinuations for drug-related toxicity occurred in 8.2% of subjects treated with azithromycin and 2.3% of those given placebo (p = 0.121). In Study 174, more subjects discontinued from the combination of azithromycin and rifabutin (22.7%) than from azithromycin alone (13.5%; p = 0.026) or rifabutin alone (15.9%; p = 0.209).

Safety

As these patients with advanced HIV disease were taking multiple concomitant medications and experienced a variety of intercurrent illnesses, it was often difficult to attribute adverse reactions to study medication. Overall, the nature of adverse reactions seen on the weekly dosage regimen of azithromycin over a period of approximately one year in patients with advanced HIV disease were similar to that previously reported for shorter course therapies.

Adverse reactions related to the gastrointestinal tract were seen more frequently in patients receiving azithromycin than in those receiving placebo or rifabutin. In Study 174, 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.

Changes in Laboratory Values

In these immunocompromised patients with advanced HIV infection, it was necessary to assess laboratory abnormalities developing on trial with additional criteria if baseline values were outside the relevant normal range.

Treatment of Disseminated MAC Disease

One randomized, double -blind clinical trial (Study 189) was performed in patients with disseminated MAC. In this trial, 246 HIV -infected patients with disseminated MAC received either azithromycin 250 mg daily (N = 65), azithromycin 600 mg daily (N = 91), or clarithromycin 500 mg twice a day (N = 90), each administered with ethambutol 15 mg/kg daily, for 24 weeks. Blood cultures and clinical assessments were performed every 3 weeks through week 12 and monthly thereafter through week 24. After week 24, patients were switched to any open -label therapy at the discretion of the investigator and followed every 3 months through the last follow -up visit of the trial. Patients were followed from the baseline visit for a period of up to 3.7 years (median: 9 months). MAC isolates recovered during treatment or post-treatment were obtained whenever possible.

The primary endpoint was sterilization by week 24. Sterilization was based on data from the central laboratory, and was defined as two consecutive observed negative blood cultures for MAC, independent of missing culture data between the two negative observations. Analyses were performed on all randomized patients who had a positive baseline culture for MAC.

The azithromycin 250 mg arm was discontinued after an interim analysis at 12 weeks showed a significantly lower clearance of bacteremia compared to clarithromycin 500 mg twice a day. Efficacy results for the azithromycin 600 mg daily and clarithromycin 500 mg twice a day treatment regimens are described in the following table:

The primary endpoint, rate of sterilization of blood cultures (two consecutive negative cultures) at 24 weeks, was lower in the azithromycin 600 mg daily group than in the clarithromycin 500 mg twice a day group.

Sterilization by Baseline Colony Count

Within both treatment groups, the sterilization rates at week 24 decreased as the range of MAC cfu/mL increased.

Susceptibility Pattern of MAC Isolates

Susceptibility testing was performed on MAC isolates recovered at baseline, at the time of breakthrough on therapy or during post-therapy follow-up. The T100 radiometric broth method was employed to determine azithromycin and clarithromycin MIC values. Azithromycin MIC values ranged from < 4 mcg/mL to > 256 mcg/mL and clarithromycin MICs ranged from < 1 mcg/mL to > 32 mcg/mL. The individual MAC susceptibility results demonstrated that azithromycin MIC values could be 4 to 32 -fold higher than clarithromycin MIC values.

During treatment and post-treatment follow -up for up to 3.7 years (median: 9 months) in Study 189, a total of 6/68 (9%) and 6/57 (11%) of the patients randomized to azithromycin 600 mg daily and clarithromycin 500 mg twice a day respectively, developed MAC blood culture isolates that had a sharp increase in MIC values. All twelve MAC isolates had azithromycin MICs ≥ 256 mcg/mL and clarithromycin MICs > 32 mcg/mL. These high MIC values suggest development of drug resistance. However, at this time, specific breakpoints for separating susceptible and resistant MAC isolates have not been established for either macrolide.