1. Name of medicinal Product

Azithromycin for Injection USP 500mg/vial Taj Pharma

  1. Qualitative and quantitative composition

Azithromycin for Injection USP 500mg/vial Taj Pharma

Azithromycin for Injection USP 500mg/vial Taj Pharma
Each ml contains:
Azithromycin monohydrate USP
Equivalent to Azithromycin 100mg
Citric acid 76.9mg
Sodium HCl for pH Adjustment: Q.S.

  1. Pharmaceutical form

Lyophilized powder for Injection

Indication

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Azithromycin Taj Pharma and other antibacterial drugs, Azithromycin Taj Pharma should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

DESCRIPTION

Azithromycin Taj Pharma for injection contains the active ingredient Azithromycin Taj Pharma, an azalide, a subclass of macrolide antibiotics, for intravenous injection. Azithromycin Taj Pharma has the chemical name (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-αL-ribo-hexopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-1-oxa6 azacyclopentadecan-15-one. Azithromycin Taj Pharma 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 749.00. Azithromycin Taj Pharma has the following structural formula:

structure

Azithromycin Taj Pharma, as the dihydrate, is a white crystalline powder with a molecular formula of C38H72N2O12·2H2O and a molecular weight of 785.0.

Azithromycin Taj Pharma for injection consists of Azithromycin Taj Pharma dihydrate and the following inactive ingredients: citric acid and sodium hydroxide. Azithromycin Taj Pharma for injection is supplied in lyophilized form in a 10-mL vial equivalent to 500mg of Azithromycin Taj Pharma for intravenous administration. Reconstitution,

according to label directions, results in approximately 5mL of Azithromycin Taj Pharma for intravenous injection with each mL containing Azithromycin Taj Pharma dihydrate equivalent to 100mg of Azithromycin Taj Pharma.

CLINICAL PHARMACOLOGY

Pharmacokinetics In patients hospitalized with community-acquired pneumonia receiving single daily one-hour intravenous infusions for 2 to 5 days of 500mg Azithromycin Taj Pharma at a concentration of 2mg/mL, the mean Cmax ± S.D. achieved was 3.63 ± 1.60 µg/mL, while the 24-hour trough level was 0.20 ± 0.15 µg/mL, and the AUC24 was 9.60 ± 4.80 µg·h/mL. The mean Cmax, 24-hour trough and AUC24 values were 1.14 ± 0.14 µg/mL, 0.18 ± 0.02 µg/mL, and 8.03 ± 0.86 µg·h/mL, respectively, in normal volunteers receiving a 3-hour intravenous infusion of 500mg Azithromycin Taj Pharma at a concentration of 1mg/mL. Similar pharmacokinetic values were obtained in patients hospitalized with community-acquired pneumonia that received the same 3-hour dosage regimen for 2–5 days.

Table 1. Plasma Concentrations (µg/mL ± S.D.) After the Last Daily Intravenous Infusion of 500mg Azithromycin Taj Pharma

Infusion Concentration,

Duration

Time after starting the infusion (hr)
 

 

0.51234681224
2mg/mL, 1 hra2.983.630.600.400.330.260.270.200.20
+ 1.12+1.73+0.31+0.23+0.16+0.14+0.15+0.12+0.15
1mg/mL, 3 hrb0.911.021.141.130.320.280.270.220.18
+0.13+0.11+0.13+0.16+0.05+0.04+0.03+0.02+0.02

a = 500mg (2mg/mL) for 2–5 days in community-acquired pneumonia patients

b = 500mg (1mg/mL) for 5 days in healthy subjects

The average CLt and Vd values were 10.18 mL/min/kg and 33.3 L/kg, respectively, in 18 normal volunteers receiving 1000 to 4000-mg doses given as 1mg/mL over 2 hours. Comparison of the plasma pharmacokinetic parameters following the 1st and 5th daily doses of 500mg intravenous Azithromycin Taj Pharma showed only an 8% increase in Cmax but a 61% increase in AUC24 reflecting a threefold rise in C24 trough levels. Following single oral doses of 500mg Azithromycin Taj Pharma (two 250mg capsules) to 12 healthy volunteers, Cmax, trough level, and AUC24 were reported to be 0.41 µg/mL, 0.05 µg/mL, and 2.6 µg·h/mL, respectively. These oral values are approximately 38%, 83%, and 52% of the values observed following a single 500-mg I.V. 3-hour infusion (Cmax: 1.08 µg/mL, trough: 0.06 µg/mL, and AUC24: 5.0 µg·h/mL). Thus, plasma concentrations are higher following the intravenous regimen throughout the 24-hour interval. The pharmacokinetic parameters on day 5 of Azithromycin Taj Pharma 250-mg capsules following a 500-mg oral loading dose to healthy young adults (age 18–40 years old) were as follows: Cmax: 0.24 µg/mL, AUC24: 2.1 µg·h/mL. Azithromycin Taj Pharma 250mg capsules are no longer commercially available. Azithromycin Taj Pharma 250mg tablets are bioequivalent to 250mg capsules in the fasting state.

Median Azithromycin Taj Pharma exposure (AUC0–288) in mononuclear (MN) and polymorphonuclear (PMN) leukocytes following 1,500mg of oral Azithromycin Taj Pharma, administered in single daily doses over either 5 days (two 250mg tablets on day 1, followed by one 250mg tablet on days 2–5) or 3 days (500mg per day for days 1–3) to 12 healthy volunteers, was more than a 1000-fold and 800-fold greater than in serum, respectively. Distribution The serum protein binding of Azithromycin Taj Pharma is variable in the concentration range approximating human exposure, decreasing from 51% at 0.02 µg/mL to 7% at 2 µg/mL. Tissue concentrations have not been obtained following intravenous infusions of Azithromycin Taj Pharma. Selected tissue (or fluid) concentration and tissue (or fluid) to plasma/serum concentration ratios following oral administration of Azithromycin Taj Pharma are shown in the following table:

Table 2. Azithromycin Taj Pharma Concentrations Following a 500mg Dose (Two 250mg Capsules) in Adults

Tissue or FluidTime After Dose (hr)Tissue or Fluid

Concentration (µg/g

or µg/ml)

Corresponding

Plasma or Serum

Level (µg/ml)

Tissue (Fluid)

Plasma (Serum)

Ratio1

Skin72-760.40.01235
Lung72-764.00.012>100
Sputum*2-41.00.642
Sputum*10-122.90.130
Tonsil***9-184.50.03>100
Tonsil***1800.90.006>100
Cervix****192.80.0470

High tissue concentrations should not be interpreted to be quantitatively related to clinical efficacy. The antimicrobial activity of Azithromycin Taj Pharma 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. * Sample was obtained 2–4 hours after the first dose. ** Sample was obtained 10–12 hours after the first dose. *** Dosing regimen of 2 doses of 250mg each, separated by 12 hours. **** Sample was obtained 19 hours after a single 500mg dose. Tissue levels were determined following a single oral dose of 500mg Azithromycin Taj Pharma in 7 gynecological patients. Approximately 17 hours after dosing, Azithromycin Taj Pharma concentrations were 2.7 µg/g in ovarian tissue, 3.5 µg/g in uterine tissue, and 3.3 µg/g in salpinx. Following a regimen of 500mg on the first day followed by 250mg daily for 4 days, concentrations in the cerebrospinal fluid were less than 0.01 µg/mL in the presence of non-inflamed meninges.

Metabolism

In vitro and in vivo studies to assess the metabolism of Azithromycin Taj Pharma have not been performed.

Elimination

Plasma concentrations of Azithromycin Taj Pharma following single 500mg oral and I.V. doses declined in a polyphasic pattern with a mean apparent plasma clearance of 630 mL/min and terminal elimination half-life of 68 hours. The prolonged terminal half-life is thought to be due to extensive uptake and subsequent release of drug from tissues.

In a multiple-dose study in 12 normal volunteers utilizing a 500-mg (1mg/mL) one-hour intravenousdosage regimen for five days, the amount of administered Azithromycin Taj Pharma dose excreted in urine in 24 hours was about 11% after the 1st dose and 14% after the 5th dose. These values are greater than the reported 6% excreted unchanged in urine after oral administration of Azithromycin Taj Pharma. Biliary excretion is a major route of elimination for unchanged drug, following oral administration.

Special Populations

Renal Insufficiency

Azithromycin Taj Pharma pharmacokinetics were investigated in 42 adults (21 to 85 years of age) with varying degrees of renal impairment. Following the oral administration of a single 1,000mg dose of Azithromycin Taj Pharma, 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). (See DOSAGE AND ADMINISTRATION.)

Hepatic Insufficiency

The pharmacokinetics of Azithromycin Taj Pharma in subjects with hepatic impairment have not been established.

Gender

There are no significant differences in the disposition of Azithromycin Taj Pharma between male and female subjects. No dosage adjustment is recommended based on gender.

Geriatric Patients

Pharmacokinetic studies with intravenous Azithromycin Taj Pharma have not been performed in older volunteers.

Pharmacokinetics of Azithromycin Taj Pharma following oral administration in older volunteers (65–85 years old) were similar to those in younger volunteers (18–40 years old) for the 5-day therapeutic regimen.

Pediatric Patients

Pharmacokinetic studies with intravenous Azithromycin Taj Pharma have not been performed in children.

Drug-Drug Interactions

Drug interaction studies were performed with oral Azithromycin Taj Pharma and other drugs likely to be coadministered. The effects of co-administration of Azithromycin Taj Pharma on the pharmacokinetics of other drugs are shown in Table 3 and the effect of other drugs on the pharmacokinetics of Azithromycin Taj Pharma are shown in Table 4.

Co-administration of Azithromycin Taj Pharma at therapeutic doses had a modest effect on the pharmacokinetics of the drugs listed in Table 3. No dosage adjustment of drugs listed in Table 3 is recommended when coadministered with Azithromycin Taj Pharma.

Co-administration of Azithromycin Taj Pharma with efavirenz or fluconazole had a modest effect on the pharmacokinetics of Azithromycin Taj Pharma. Nelfinavir significantly increased the Cmax and AUC of Azithromycin Taj Pharma. No dosage adjustment of Azithromycin Taj Pharma is recommended when administered with drugs listed in Table 4. (See PRECAUTIONS – Drug Interactions.)

Table 3. Drug Interactions: Pharmacokinetic Parameters for Co-administered Drugs in the Presence of Azithromycin Taj Pharma

Co-administered DrugDose of Coadministered DrugDose of Azithromycin Taj PharmanRatio (with/without Azithromycin Taj Pharma) of Co-administered Drug Pharmacokinetic Parameters (90% CI); No Effect = 1.00
Atorvastatin10mg/day × 8 days500mg/day PO on days 6–8120.83 (0.63 to 1.08)1.01 (0.81 to 1.25)
Carbamazepine200mg/day × 2 days, then 200mg BID × 18 days500mg/day PO for days 16–1870.97 (0.88 to 1.06)0.96 (0.88 to 1.06)
Cetirizine20mg/day × 11 days500mg PO on day 7, then 250mg/day on days 8–11141.03 (0.93 to 1.14)1.02 (0.92 to 1.13)
Didanosine200mg PO BID × 21 days1,200mg/day PO on days 8–2161.44 (0.85 to 2.43)1.14 (0.83 to 1.57)
Efavirenz400mg/day × 7 days600mg PO on day 7141.04*0.95*
Fluconazole200mg PO single dose1,200mg PO single dose181.04 (0.98 to 1.11)1.01 (0.97 to 1.05)
Indinavir800mg TID × 5 days1,200mg PO on day 5180.96 (0.86 to 1.08)0.90 (0.81 to 1.00)
Midazolam15mg PO on day 3500mg/day PO × 3 days121.27 (0.89 to 1.81)1.26 (1.01 to 1.56)
Nelfinavir750mg TID × 11 days1,200mg PO on day 9140.90 (0.81 to 1.01)0.85 (0.78 to 0.93)
Rifabutin300mg/day × 10 days500mg PO on day 1, then 250mg/day on days 2–106See footnote belowNA
Sildenafil100mg on days 1 and 4500mg/day PO × 3 days121.16 (0.86 to 1.57)0.92 (0.75 to 1.12)
Theophylline4mg/kg IV on days 1, 11, 25500mg PO on day 7, 250mg/day on days 8–11101.19 (1.02 to 1.40)1.02 (0.86 to 1.22)
Theophylline300mg PO BID × 15 days500mg PO on day 6, then 250mg/day on days 7–1081.09 (0.92 to 1.29)1.08 (0.89 to 1.31)
Triazolam0.125mg on day 2500mg PO on day 1, then 250mg/day on day 2121.06*1.02*
Trimethoprim/ Sulfamethoxazole160mg/800mg/day PO × 7 days1,200mg PO on day 7120.85 (0.75 to 0.97)/ 0.90 (0.78 to 1.03)0.87 (0.80 to 0.95)/ 0.96 (0.88 to 1.03)
Zidovudine500mg/day PO × 21 days600mg/day PO × 14 days51.12 (0.42 to 3.02)0.94 (0.52 to 1.70)
Zidovudine500mg/day PO × 21 days1,200mg/day PO × 14 days41.31 (0.43 to 3.97)1.30 (0.69 to 2.43)

 

Table 4. Drug Interactions: Pharmacokinetic Parameters for Azithromycin Taj Pharma in the Presence of Co-administered Drugs (See PRECAUTIONS – Drug Interactions.)

Co-administered DrugDose of Coadministered DrugDose of Azithromycin Taj PharmanRatio (with/without co-administered drug) of Azithromycin Taj Pharma Pharmacokinetic Parameters (90% CI); No Effect = 1.00
Mean CmaxMean AUC
Efavirenz400mg/day × 7 days600mg PO on day 7141.22 (1.04 to 1.42)0.92*
Fluconazole200mg PO single dose1,200mg PO single dose180.82 (0.66 to 1.02)1.07 (0.94 to 1.22)
Nelfinavir750mg TID × 11 days1,200mg PO on day 9142.36 (1.77 to 3.15)2.12 (1.80 to 2.50)
Rifabutin300mg/day × 10 days500mg PO on day 1, then 250mg/day on days 2–106See footnote belowNA

 

NA = not available

* 90% confidence interval not reported

Mean Azithromycin Taj Pharma concentrations one day after the last dose were 53 ng/mL when coadministered with 300mg daily rifabutin and 49 ng/mL when coadministered with placebo.

Microbiology

Azithromycin Taj Pharma acts by binding to the 50S ribosomal subunit of susceptible microorganisms and, thus, interfering with microbial protein synthesis. Nucleic acid synthesis is not affected.

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

Azithromycin Taj Pharma has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section of the package insert for Azithromycin Taj Pharma for injection.

Aerobic and facultative Gram-positive microorganisms

Staphylococcus aureus

Streptococcus pneumoniae

NOTE: Azithromycin Taj Pharma demonstrates cross-resistance with erythromycin-resistant gram-positive strains.

Most strains of Enterococcus faecalis and methicillin-resistant staphylococci are resistant to Azithromycin Taj Pharma.

Aerobic and facultative Gram-negative microorganisms

Haemophilus influenzae

Moraxella catarrhalis

Neisseria gonorrhoeae

 “Other” microorganisms

Chlamydia pneumoniae

Chlamydia trachomatis

Legionella pneumophila

Mycoplasma hominis

Mycoplasma pneumoniae

Beta-lactamase production should have no effect on Azithromycin Taj Pharma activity.

Azithromycin Taj Pharma has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section of the package insert for Azithromycin Taj Pharma tablets and Azithromycin Taj Pharma for oral suspension.

Aerobic and facultative Gram-positive microorganisms

Staphylococcus aureus

Streptococcus agalactiae

Streptococcus pneumoniae

Streptococcus pyogenes

Aerobic and facultative Gram-negative microorganisms

Haemophilus ducreyi

Haemophilus influenzae

Moraxella catarrhalis

Neisseria gonorrhoeae

“Other” microorganisms

Chlamydia pneumoniae

Chlamydia trachomatis

Mycoplasma pneumoniae

Beta-lactamase production should have no effect on Azithromycin Taj Pharma activity.

The following in vitro data are available, but their clinical significance is unknown.

At least 90% of the following microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoints for Azithromycin Taj Pharma. However, the safety and effectiveness of Azithromycin Taj Pharma in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

Aerobic and facultative Gram-positive microorganisms

Streptococci (Groups C, F, G)

Viridans group streptococci

Aerobic and facultative Gram-negative microorganisms

Bordetella pertussis

Anaerobic microorganisms

Peptostreptococcus species

Prevotella bivia

“Other” microorganisms

Ureaplasma urealyticum

Beta-lactamase production should have no effect on Azithromycin Taj Pharma activity.

Susceptibility Testing Methods

When available, the results of in vitro susceptibility test results for antimicrobial drugs used in resident hospitals should be provided to the physician as periodic reports which describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports may differ from susceptibility data obtained from outpatient use, but could aid the physician in selecting the most effective antimicrobial.

Dilution techniques

Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs).

These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method1,3 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of Azithromycin Taj Pharma powder. The MIC values should be interpreted according to criteria provided in Table 5.

Diffusion techniques

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure2,3 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 15-µg Azithromycin Taj Pharma to test the susceptibility of microorganisms to Azithromycin Taj Pharma. The disk diffusion interpretive criteria are provided in Table 5.

TABLE 5. SUSCEPTIBILITY INTERPRETIVE CRITERIA FOR AZITHROMYCIN, SUSCEPTIBILITY TEST RESULT INTERPRETIVE CRITERIA

Minimum Inhibitory Concentrations (µg/mL)
PathogenSIRaSIRa
Haemophilus spp.< 4> 12
Staphylococcus aureus< 24> 8> 1814-17< 13
Streptococci including S. pneumoniaeb<   0.51> 2> 1814-17< 13

 

a The current absence of data on resistant strains precludes defining any category other than “susceptible”. If strains yield MIC results other than susceptible, they should be submitted to a reference laboratory for further testing.

b Susceptibility of streptococci including S. pneumoniae to Azithromycin Taj Pharma and other macrolides can be predicted by testing erythromycin. No interpretive criteria have been established for testing Neisseria gonorrhoeae. This species is not usually tested.

A report of “susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound reaches the concentrations usually achievable. A report of “intermediate” indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “resistant” indicates that the pathogen is not likely to be inhibited if the antimicrobial compound reaches the concentrations usually achievable; other therapy should be selected.

QUALITY CONTROL

Standardized susceptibility test procedures require the use of quality control microorganisms to control the technical aspects of the test procedures. Standard Azithromycin Taj Pharma powder should provide the following range of values noted in Table 6. Quality control microorganisms are specific strains of organisms with intrinsic biological properties. QC strains are very stable strains which will give a standard and repeatable susceptibility pattern. The specific strains used for microbiological quality control are not clinically significant.

Table 6. Acceptable Quality Control Ranges for Azithromycin Taj Pharma

QC StrainMinimum Inhibitory Concentrations (µg/mL)Disk Diffusion (zone diameters in mm)
Haemophilus influenzae ATCC 492471.0–4.013–21
Staphylococcus aureus ATCC 292130.5–2.0
Staphylococcus aureus ATCC 2592321–26
Streptococcus pneumoniae ATCC 496190.06–0.2519–25

 

INDICATIONS AND USAGE

Azithromycin Taj Pharma for injection is indicated for the treatment of patients with infections caused by susceptible strains of the designated microorganisms in the conditions listed below. As recommended dosages, durations of therapy, and applicable patient populations vary among these infections, please see DOSAGE AND ADMINISTRATION for dosing recommendations.

Community-acquired pneumonia due to Chlamydia pneumoniae, Haemophilus influenzae, Legionella pneumophila, Moraxella catarrhalis, Mycoplasma pneumoniae, Staphylococcus aureus, or Streptococcus pneumoniae in patients who require initial intravenous therapy.

Pelvic inflammatory disease due to Chlamydia trachomatis, Neisseria gonorrhoeae, or Mycoplasma hominis in patients who require initial intravenous therapy. If anaerobic microorganisms are suspected of contributing to the infection, an antimicrobial agent with anaerobic activity should be administered in combination with Azithromycin Taj Pharma.

Azithromycin Taj Pharma for injection should be followed by Azithromycin Taj Pharma by the oral route as required. (See DOSAGE AND ADMINISTRATION.)

Appropriate culture and susceptibility tests should be performed before treatment to determine the causative microorganism and its susceptibility to Azithromycin Taj Pharma. Therapy with Azithromycin Taj Pharma may be initiated before results of these tests are known; once the results become available, antimicrobial therapy should be adjusted accordingly.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Azithromycin Taj Pharma and other antibacterial drugs, Azithromycin Taj Pharma should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

 CONTRAINDICATIONS

Azithromycin Taj Pharma is contraindicated in patients with known hypersensitivity to Azithromycin Taj Pharma, erythromycin, any macrolide or ketolide antibiotic.

WARNINGS

Serious allergic reactions, including angioedema, anaphylaxis, and dermatologic reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported rarely in patients on Azithromycin Taj Pharma therapy. Although rare, fatalities have been reported. (See CONTRAINDICATIONS.)

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 Taj Pharma exposure. These patients required prolonged periods of observation and symptomatic treatment. The relationship of these episodes to the long tissue half-life of Azithromycin Taj Pharma and subsequent prolonged exposure to antigen is unknown at present.

If an allergic reaction occurs, the drug should be discontinued and appropriate therapy should be instituted. Physicians should be aware that reappearance of the allergic symptoms may occur when symptomatic therapy is discontinued.

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Azithromycin Taj Pharma, 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. difficile.

  1. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. 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.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

PRECAUTIONS

General

Because Azithromycin Taj Pharma is principally eliminated via the liver, caution should be exercised when Azithromycin Taj Pharma is administered to patients with impaired hepatic function. Due to the limited data in subjects with GFR <10 mL/min, caution should be exercised when prescribing Azithromycin Taj Pharma in these patients. (See CLINICAL PHARMACOLOGY, Special Populations, Renal Insufficiency.)

Azithromycin Taj Pharma for injection should be reconstituted and diluted as directed and administered as an intravenous infusion over not less than 60 minutes. (See DOSAGE AND ADMINISTRATION.)

Local I.V. site reactions have been reported with the intravenous administration of Azithromycin Taj Pharma. The incidence and severity of these reactions were the same when 500mg Azithromycin Taj Pharma were given over 1 hour (2mg/mL as 250 mL infusion) or over 3 hours (1mg/mL as 500 mL infusion). (See ADVERSE REACTIONS.) All volunteers who received infusate concentrations above 2.0mg/mL experienced local I.V. site reactions and, therefore, higher concentrations should be avoided.

Prolonged cardiac repolarization and QT interval, imparting a risk of developing cardiac arrhythmia and torsades de pointes, have been seen in treatment with other macrolides. A similar effect with Azithromycin Taj Pharma cannot be completely ruled out in patients at increased risk for prolonged cardiac repolarization.

Prescribing Azithromycin Taj Pharma in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Information for Patients

Patients should be directed to discontinue Azithromycin Taj Pharma and contact a physician if any signs of an allergic reaction occur.

Patients should be counseled that antibacterial drugs including Azithromycin Taj Pharma should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Azithromycin Taj Pharma is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of the therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Azithromycin Taj Pharma or other antibacterial drugs in the future.

Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.

Drug Interactions

Co-administration of nelfinavir at steady-state with a single oral dose of Azithromycin Taj Pharma resulted in increased Azithromycin Taj Pharma serum concentrations. Although a dose adjustment of Azithromycin Taj Pharma is not recommended when administered in combination with nelfinavir, close monitoring for known side effects of Azithromycin Taj Pharma, such as liver enzyme abnormalities and hearing impairment, is warranted. (See ADVERSE REACTIONS.)

Azithromycin Taj Pharma given by the oral route did not affect the prothrombin time response to a single dose of warfarin. However, prudent medical practice dictates careful monitoring of prothrombin time in all patients treated with Azithromycin Taj Pharma and warfarin concomitantly. Concurrent use of macrolides and warfarin in clinical practice has been associated with increased anticoagulant effects.

Drug interaction studies were performed with Azithromycin Taj Pharma and other drugs likely to be coadministered. (See CLINICAL PHARMACOLOGY, Drug-Drug Interactions.) When used in therapeutic doses, Azithromycin Taj Pharma had a modest effect on the pharmacokinetics of atorvastatin, carbamazepine, cetirizine, didanosine, efavirenz, fluconazole, indinavir, midazolam, rifabutin, sildenafil, theophylline (intravenous and oral), triazolam, trimethoprim/sulfamethoxazole or zidovudine. Co-administration with efavirenz or fluconazole had a modest effect on the pharmacokinetics of Azithromycin Taj Pharma. No dosage adjustment of either drug is recommended when Azithromycin Taj Pharma is coadministered with any of these agents.

Interactions with the drugs listed below have not been reported in clinical trials with Azithromycin Taj Pharma; however, no specific drug interaction studies have been performed to evaluate potential drug-drug interaction. Nonetheless, they have been observed with macrolide products. Until further data are developed regarding drug interactions when Azithromycin Taj Pharma and these drugs are used concomitantly, careful monitoring of patients is advised:

Digoxin – elevated digoxin concentrations.

Ergotamine or dihydroergotamine – acute ergot toxicity characterized by severe peripheral

vasospasm and dysesthesia.

Terfenadine, cyclosporine, hexobarbital and phenytoin – elevated concentrations.

Laboratory Test Interactions

There are no reported laboratory test interactions.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been performed to evaluate carcinogenic potential.

Azithromycin Taj Pharma has shown no mutagenic potential in standard laboratory tests: mouse lymphoma assay, human lymphocyte clastogenic assay, and mouse bone marrow clastogenic assay. No evidence of impaired fertility due to Azithromycin Taj Pharma was found.

Pregnancy

Teratogenic Effects. Pregnancy Category B: Reproduction studies have been performed in rats and mice at doses up to moderately maternally toxic dose concentrations (i.e., 200mg/kg/day by the oral route). These doses, based on amg/m2 basis, are estimated to be 4 and 2 times, respectively, the human daily dose of 500mg by the oral route. In the animal studies, no evidence of harm to the fetus due to Azithromycin Taj Pharma was found. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Azithromycin Taj Pharma should be used during pregnancy only if clearly needed.

Nursing Mothers

It is not known whether Azithromycin Taj Pharma is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Azithromycin Taj Pharma is administered to a nursing woman.

Pediatric Use

Safety and effectiveness of Azithromycin Taj Pharma for injection in children or adolescents under 16 years have not been established. In controlled clinical studies, Azithromycin Taj Pharma has been administered to pediatric patients (age 6 months to 16 years) by the oral route. For information regarding the use of Azithromycin Taj Pharma for oral suspension in the treatment of pediatric patients, refer to the INDICATIONS

AND USAGE and DOSAGE AND ADMINISTRATION sections of the prescribing information for Azithromycin Taj Pharma for oral suspension 100mg/5 mL and 200mg/5 mL bottles.

Geriatric Use

Pharmacokinetic studies with intravenous Azithromycin Taj Pharma have not been performed in older volunteers. Pharmacokinetics of Azithromycin Taj Pharma following oral administration in older volunteers (65–85 years old) were similar to those in younger volunteers (18–40 years old) for the 5-day therapeutic regimen.

In multiple-dose clinical trials of intravenous Azithromycin Taj Pharma in the treatment of community-acquired pneumonia, 45% of patients (188/414) were at least 65 years of age and 22% of patients (91/414) were at least 75 years of age. No overall differences in safety were observed between these subjects and younger subjects in terms of adverse events, laboratory abnormalities, and discontinuations. Similar decreases in clinical response were noted in Azithromycin Taj Pharma- and comparator-treated patients with increasing age.

Azithromycin Taj Pharma for injection contains 114mg (4.96 mEq) of sodium per vial. At the usual recommended doses, patients would receive 114mg (4.96 mEq) of sodium. The geriatric population may respond with a blunted natriuresis to salt loading. The total sodium content from dietary and non-dietary sources may be clinically important with regard to such diseases as congestive heart failure.

ADVERSE REACTIONS

In clinical trials of intravenous Azithromycin Taj Pharma for community-acquired pneumonia, in which 2–5 I.V. doses were given, most of the reported side effects were mild to moderate in severity and were reversible upon discontinuation of the drug. The majority of patients in these trials had one or more comorbid diseases and were receiving concomitant medications. Approximately 1.2% of the patients discontinued intravenous Azithromycin Taj Pharma therapy, and a total of 2.4% discontinued Azithromycin Taj Pharma therapy by either the intravenous or oral route because of clinical or laboratory side effects.

In clinical trials conducted in patients with pelvic inflammatory disease, in which 1–2 I.V. doses were given, 2% of women who received monotherapy with Azithromycin Taj Pharma and 4% who received Azithromycin Taj Pharma plus metronidazole discontinued therapy due to clinical side effects.

Clinical side effects leading to discontinuations from these studies were most commonly gastrointestinal (abdominal pain, nausea, vomiting, diarrhea), and rashes; laboratory side effects leading to discontinuation were increases in transaminase levels and/or alkaline phosphatase levels.

Clinical

Overall, the most common side effects associated with treatment in adult patients who received I.V./P.O. Azithromycin Taj Pharma in studies of community-acquired pneumonia were related to the gastrointestinal system with diarrhea/loose stools (4.3%), nausea (3.9%), abdominal pain (2.7%), and vomiting (1.4%) being the most frequently reported. Approximately 12% of patients experienced a side effect related to the intravenous infusion; most common were pain at the injection site (6.5%) and local inflammation (3.1%).

The most common side effects associated with treatment in adult women who received I.V./P.O. Azithromycin Taj Pharma in studies of pelvic inflammatory disease were related to the gastrointestinal system. Diarrhea (8.5%) and nausea (6.6%) were most commonly reported, followed by vaginitis (2.8%), abdominal pain (1.9%), anorexia (1.9%), rash and pruritus (1.9%). When Azithromycin Taj Pharma was coadministered with metronidazole in these studies, a higher proportion of women experienced side effects of nausea (10.3%), abdominal pain (3.7%), vomiting (2.8%), application site reaction, stomatitis, dizziness, or dyspnea (all at 1.9%).

No other side effects occurred in patients on the multiple dose I.V./P.O. regimen of Azithromycin Taj Pharma in these studies with a frequency greater than 1%.

Side effects that occurred with a frequency of 1% or less included the following:

Gastrointestinal: dyspepsia, flatulence, mucositis, oral moniliasis, and gastritis

Nervous System: headache, somnolence

Allergic: bronchospasm

Special Senses: taste perversion

Post-Marketing Experience

Adverse events reported with Azithromycin Taj Pharma during the post-marketing period in adult and/or pediatric patients for which a causal relationship may not be established include:

Allergic: Arthralgia, edema, urticaria and angioedema

Cardiovascular: Arrhythmias including ventricular tachycardia and hypotension

There have been rare reports of QT prolongation and torsades de pointes.

Gastrointestinal: Anorexia, constipation, dyspepsia, flatulence, vomiting/diarrhea rarely resulting in dehydration, pseudomembranous colitis, pancreatitis, oral candidiasis and rare reports of tongue discoloration

General: Asthenia, paresthesia, fatigue, malaise and anaphylaxis (rarely fatal).

Genitourinary: Interstitial nephritis and acute renal failure and vaginitis

Hematopoietic: Thrombocytopenia

Liver/Biliary: Abnormal liver function including hepatitis and cholestatic jaundice, as well as rare

cases of hepatic necrosis and hepatic failure, some of which have resulted in death

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

Psychiatric: Aggressive reaction and anxiety

Skin/Appendages: Pruritus, rarely serious skin reactions including erythema multiforme, StevensJohnson syndrome and toxic epidermal necrolysis

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

Laboratory Abnormalities

Significant abnormalities (irrespective of drug relationship) occurring during the clinical trials were reported as follows: with an incidence of 4–6%, elevated ALT (SGPT), AST (SGOT), creatinine with an incidence of 1–3%, elevated LDH, bilirubin with an incidence of less than 1%, leukopenia, neutropenia, decreased platelet count, and elevated serum alkaline phosphatase

When follow-up was provided, changes in laboratory tests appeared to be reversible.

In multiple-dose clinical trials involving more than 750 patients treated with Azithromycin Taj Pharma (I.V./P.O.), less than 2% of patients discontinued Azithromycin Taj Pharma therapy because of treatment-related liver enzyme abnormalities.

DOSAGE AND ADMINISTRATION

(See INDICATIONS AND USAGE and CLINICAL PHARMACOLOGY.)

The recommended dose of Azithromycin Taj Pharma for injection for the treatment of adult patients with community-acquired pneumonia due to the indicated organisms is: 500mg as a single daily dose by the intravenous route for at least two days. Intravenous therapy should be followed by Azithromycin Taj Pharma by the oral route at a single, daily dose of 500mg, administered as two 250mg tablets to complete a 7- to 10-day course of therapy. The timing of the switch to oral therapy should be done at the discretion of the physician and in accordance with clinical response.

The recommended dose of Azithromycin Taj Pharma for the treatment of adult patients with pelvic inflammatory disease due to the indicated organisms is: 500mg as a single daily dose by the intravenous route for one or two days. Intravenous therapy should be followed by Azithromycin Taj Pharma by the oral route at a single, daily dose of 250mg to complete a 7-day course of therapy. The timing of the switch to oral therapy should be done at the discretion of the physician and in accordance with clinical response. If anaerobic microorganisms are suspected of contributing to the infection, an antimicrobial agent with anaerobic activity should be administered in combination with Azithromycin Taj Pharma.

Renal Insufficiency

No dosage adjustment is recommended for subjects with renal impairment (GFR ≤80 mL/min). The mean AUC0–120 was similar in subjects with GFR 10–80 mL/min compared to subjects with normal renal function, whereas it increased 35% in subjects with GFR <10 mL/min compared to subjects with normal renal function. Caution should be exercised when Azithromycin Taj Pharma is administered to subjects with severe renal impairment. (See CLINICAL PHARMACOLOGY, Special Populations, Renal Insufficiency.)

Hepatic Insufficiency

The pharmacokinetics of Azithromycin Taj Pharma in subjects with hepatic impairment have not been established. no dose adjustment recommendations can be made in patients with impaired hepatic function. (see clinical pharmacology, special populations, hepatic insufficiency.)

No dosage adjustment is recommended based on age or gender. (See CLINICAL PHARMACOLOGY, Special Populations.)

The infusate concentration and rate of infusion for Azithromycin Taj Pharma for injection should be either 1mg/mL over 3 hours or 2mg/mL over 1 hour. Azithromycin Taj Pharma for injection should not be given as a bolus or as an intramuscular injection.

Preparation of the solution for intravenous administration is as follows:

Reconstitution

Prepare the initial solution of Azithromycin Taj Pharma for injection by adding 4.8 mL of Sterile Water For Injection to the 500mg vial and shaking the vial until all of the drug is dissolved. Since Azithromycin Taj Pharma for injection is supplied under vacuum, it is recommended that a standard 5 mL (non-automated) syringe be used to ensure that the exact amount of 4.8 mL of Sterile Water is dispensed. Each mL of reconstituted solution contains 100mg Azithromycin Taj Pharma. Reconstituted solution is stable for 24 hours when stored below 30°C or 86°F.

Parenteral drug products should be inspected visually for particulate matter prior to administration. If particulate matter is evident in reconstituted fluids, the drug solution should be discarded.

Dilute this solution further prior to administration as instructed below.

Dilution

To provide Azithromycin Taj Pharma over a concentration range of 1.0–2.0mg/mL, transfer 5 mL of the 100mg/mL Azithromycin Taj Pharma solution into the appropriate amount of any of the diluents listed below:

Normal Saline (0.9% sodium chloride)

1/2 Normal Saline (0.45% sodium chloride)

5% Dextrose in Water

Lactated Ringer’s Solution

5% Dextrose in 1/2 Normal Saline (0.45% sodium chloride) with 20 mEq KCl

5% Dextrose in Lactated Ringer’s Solution

5% Dextrose in 1/3 Normal Saline (0.3% sodium chloride)

5% Dextrose in 1/2 Normal Saline (0.45% sodium chloride)

Final Infusion Solution Concentration (mg/mL) Amount of Diluent (mL)

1.0mg/mL 500 mL

2.0mg/mL 250 mL

It is recommended that a 500-mg dose of Azithromycin Taj Pharma for injection, diluted as above, be infused over a period of not less than 60 minutes.

Azithromycin Taj Pharma for injection should not be given as a bolus or as an intramuscular injection.

Other intravenous substances, additives, or medications should not be added to Azithromycin Taj Pharma for injection, or infused simultaneously through the same intravenous line.

Storage

When diluted according to the instructions (1.0mg/mL to 2.0mg/mL), Azithromycin Taj Pharma for injection is stable for 24 hours at or below room temperature (30°C or 86°F), or for 7 days if stored under refrigeration (5°C or 41°F).

HOW SUPPLIED

Azithromycin Taj Pharma for injection is supplied in lyophilized form under a vacuum in a 10-mL vial equivalent to 500mg of Azithromycin Taj Pharma for intravenous administration. Each vial also contains sodium hydroxide and 413.6mg citric acid.

These are packaged as follows:

10 vials of 500mg

CLINICAL STUDIES

Community-Acquired Pneumonia

In a controlled study of community-acquired pneumonia performed in the U.S., Azithromycin Taj Pharma (500mg as a single daily dose by the intravenous route for 2–5 days, followed by 500mg/day by the oral route to complete 7–10 days therapy) was compared to cefuroxime (2250mg/day in three divided doses by the intravenous route for 2–5 days followed by 1000mg/day in two divided doses by the oral route to complete 7–10 days therapy), with or without erythromycin. For the 291 patients who were evaluable for clinical efficacy, the clinical outcome rates, i.e., cure, improved, and success (cure + improved) among the 277 patients seen at 10–14 days post-therapy were as follows:

Clinical OutcomeAzithromycin Taj PharmaComparator
Cure46%44%
Improved32%30%
Success (Cure + Improved)78%74%

In a separate, uncontrolled clinical and microbiological trial performed in the U.S., 94 patients with community-acquired pneumonia who received Azithromycin Taj Pharma in the same regimen were evaluable for clinical efficacy. The clinical outcome rates, i.e., cure, improved, and success (cure + improved) among the 84 patients seen at 10–14 days post-therapy were as follows:

Clinical OutcomeAzithromycin Taj Pharma
Cure60%
Improved29%
Success (Cure + Improved)89%

Microbiological determinations in both trials were made at the pre-treatment visit and, where applicable, were reassessed at later visits. Serological testing was done on baseline and final visit specimens. The following combined presumptive bacteriological eradication rates were obtained from the evaluable groups:

Combined Bacteriological Eradication Rates for Azithromycin Taj Pharma:
(at last completed visit) Azithromycin Taj PharmaAzithromycin Taj Pharma
S. pneumoniae64/67
H. influenzae41/43
M. catarrhalis9/10
S. aureus9/10

a Nineteen of twenty-four patients (79%) with positive blood cultures for S. pneumoniae were cured (intent to treat analysis) with eradication of the pathogen.

The presumed bacteriological outcomes at 10–14 days post-therapy for patients treated with Azithromycin Taj Pharma with evidence (serology and/or culture) of atypical pathogens for both trials were as follows:

Evidence of InfectionTotalCureImprovedCure + Improved
Mycoplasma pneumoniae1811 (61%)5 (28%)16 (89%)
Chlamydia pneumoniae3415 (44%)13 (38%)28 (82%)
Legionella pneumophila165 (31%)8 (50%)13 (81%)

 

ANIMAL TOXICOLOGY

Phospholipidosis (intracellular phospholipid accumulation) has been observed in some tissues of mice, rats, and dogs given multiple doses of Azithromycin Taj Pharma. It has been demonstrated in numerous organ systems (e.g., eye, dorsal root ganglia, liver, gallbladder, kidney, spleen, and pancreas) in dogs treated with Azithromycin Taj Pharma at doses which, expressed on the basis ofmg/m2, are approximately equal to the recommended adult human dose, and in rats treated at doses approximately one-sixth of the recommended adult human dose. This effect has been shown to be reversible after cessation of Azithromycin Taj Pharma treatment. Phospholipidosis has been observed to a similar extent in the tissues of neonatal rats and dogs given daily doses of Azithromycin Taj Pharma ranging from 10 days to 30 days. Based on the pharmacokinetic data, phospholipidosis has been seen in the rat (30mg/kg dose) at observed Cmax value of 1.3 µg/mL (six times greater than the observed Cmax of 0.216 µg/mL at the pediatric dose of 10mg/kg). Similarly, it has been shown in the dog (10mg/kg dose) at observed Cmax value of 1.5 µg/mL (seven times greater than the observed same Cmax and drug dose in the studied pediatric population). On amg/m2 basis, 30mg/kg dose in the neonatal rat (135mg/m2) and 10mg/kg dose in the neonatal dog (79mg/m2) are approximately 0.45 and 0.3 times, respectively, the recommended  dose in the pediatric patients with an average body weight of 25 kg. Phospholipidosis, similar to that seen in the adult animals, is reversible after cessation of Azithromycin Taj Pharma treatment. The significance of these findings for animals and for humans is unknown.

REFERENCES

  1. National Committee for Clinical Laboratory Standards, Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically – Fifth Edition. Approved Standard NCCLS Document M7-A5, Vol. 20, No.
  2. (ISBN 1-56238-394-9). NCCLS, 940 West Valley Road, Suite 1400, Wayne, PA 19087-1898, January, 2000. 2. National Committee for Clinical Laboratory Standards, Performance Standards for Antimicrobial Disk Susceptibility Tests – Seventh Edition. Approved Standard NCCLS Document M2-A7, Vol. 20, No. 1 (ISBN 1-56238-393-0). NCCLS, 940 West Valley Road, Suite 1400, Wayne, PA 19087- 1898, January, 2000.
  3. National Committee for Clinical Laboratory Standards, Performance Standards for Antimicrobial Susceptibility Testing – Eleventh Informational Supplement. NCCLS Document M100-S11, Vol. 21, No. 1 (ISBN 1-56238-426-0). NCCLS, 940 West Valley Road, Suite 1400, Wayne, PA 19087- 1898, January, 2001.

Manufactured in India by:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com