AZIMAX I.V. Injection (Azithromycin)

Table of Content

Composition

AZIMAX I.V.
Each vial contains:
Azithromycin (anhydrous) ....... 500mg
(as Azithromycin Dihydrate, IP)
As a sterile freeze-dried powder for reconstitution with Sterile Water for Injection, IP.

Each mL of reconstituted injection contains:
Azithromycin (anhydrous) ........ 100mg
(as Azithromycin Dihydrate, IP)

Dosage Form

Powder for I.V. infusion only

Pharmacology

Pharmacodynamics

Azithromycin 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 concentrates in phagocytes and fibroblasts as demonstrated by in vitro incubation techniques. Using such methodology, the ratio of intracellular to extra-cellular concentration was >30 after a 1-hour incubation. In vivo studies suggest that the concentration in phagocytes may contribute to drug distribution to inflamed tissues.

Azithromycin has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections:

Aerobic and Facultative Gram-positive Microorganisms
Staphylococcus aureus
Streptococcus pneumoniae

Note: Azithromycin demonstrates cross-resistance with erythromycin-resistant Gram-positive strains. Most strains of Enterococcus faecalis and methicillin-resistant staphylococci are resistant to azithromycin.

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 activity.

Azithromycin has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections:

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 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. However, the safety and effectiveness of azithromycin 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 activity.

Pharmacokinetics

In patients hospitalized with community-acquired pneumonia and receiving single daily 1-hour I.V. infusions for 2-5 days of 500 mg azithromycin at a concentration of 2 mg/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 I.V. infusion of 500 mg azithromycin at a concentration of 1 mg/mL. Similar pharmacokinetic values were obtained in patients hospitalized with community-acquired pneumonia who received the same 3-hour dosage regimen for 2-5 days.

Plasma concentrations (μg/mL ± S.D.) after the last daily I.V. infusion of 500 mg azithromycin
Infusion
Concentration,Dur
ation
Time after starting the infusion (hour)
 
0.5
 
2
3
4
6
8
 
24
2 mg/mL, 1 hour*
2.98
3.63
0.60
0.40
0.33
0.26
0.27
0.20
0.20
 
±1.1
2
±1.7
3
±0.3
±0.2
3
±0.1
6
±0.1
4
±0.1
5
±0.1
2
±0.1
5
 
0.91
 
 
 
0.32
0.28
0.27
0.22
0.18
 
±0.1
3
±0.1
±0.1
3
±0.1
6
±0.0
5
±0.0
4
±0.0
3
±0.0
2
±0.0
2

"

The average CLt and Vd values were 10.18 mL/min/kg and 33.3 L/kg, respectively, in 18 normal volunteers receiving 1,000-4,000 mg doses given as 1 mg/mL over 2 hours.
Comparison of the plasma pharmacokinetic parameters following the first and fifth daily doses of 500 mg I.V. azithromycin showed only an 8% increase in the Cmax but a 61% increase in the AUC24, reflecting a threefold rise in C24 trough levels.
Following single oral doses of 500 mg azithromycin (two 250 mg 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 I.V. regimen throughout the 24-hour interval. The pharmacokinetic parameters on day 5 of azithromycin 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 250 mg capsules are no longer commercially available. Azithromycin 250 mg tablets are bioequivalent to 250 mg capsules in the fasting state.

Median azithromycin exposure (AUC0-288) in mononuclear (MN) and polymorphonuclear (PMN) leucocytes following 1,500 mg of oral 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) to 12 healthy volunteers, was more than a 1,000-fold and 800-fold greater than in serum, respectively.

Distribution
The serum protein binding of azithromycin 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 I.V. infusions of azithromycin. Selected tissue (or fluid) concentration and tissue (or fluid) to plasma/serum concentration ratios following oral administration of azithromycin are shown in the following table:

Table 1: Azithromycin concentrations following a 500 mg dose (two 250 mg capsules) in adults
Tissue or
Fluid
Time
After
Dose (h)
Tissue or Fluid
Concentration
(μg/g or
μg/mL)*
Corresponding Plasma
or Serum Level
(μg/mL)
Tissue
(Fluid)

Plasma
(Serum)
Ratio*
Skin
72-96
0.4
0.012
35
Lungs
72-96
4.0
0.012
>100
Sputum†
2-4
 
0.64
2
Sputum‡
 
2.9
0.1
30
Tonsil§
9-18
4.5
0.03
>100
Tonsil§
 
0.9
0.006
>100
Cervix¶
 
2.8
0.04
>70

Tissue levels were determined following a single oral dose of 500 mg azithromycin in 7 gynaecological patients. Approximately 17 hours after dosing, azithromycin 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 500 mg on the first day followed by 250 mg 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 have not been performed.

Elimination

Plasma concentrations of azithromycin following single 500 mg 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 (1 mg/mL), 1-hour I.V.-dosage regimen for 5 days, the amount of administered azithromycin dose excreted in urine in 24 hours was about 11% after the first dose and 14% after the fifth dose. These values are greater than the reported 6% excreted unchanged in urine after oral administration of azithromycin. Biliary excretion is a major route of elimination for unchanged drug, following oral administration.

Special Populations

p>Renal Impairment
Azithromycin pharmacokinetics was investigated in 42 adults (21-85 years of age) with varying degrees of renal impairment. Following the oral administration of a single 1,000 mg dose of azithromycin, 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 with 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 with subjects with normal renal function (GFR >80 mL/min).

Hepatic Impairment
The pharmacokinetics of azithromycin in subjects with hepatic impairment has not been established.

Geriatric Patients
Pharmacokinetic studies with I.V. azithromycin have not been performed in older volunteers. Pharmacokinetics of azithromycin following oral administration in older volunteers (65-85 years old) was similar to those in younger volunteers (18-40 years old) for the 5-day therapeutic regimen.

Paediatric Patients
Pharmacokinetic studies with I.V. azithromycin have not been performed in children.

Drug-Drug Interactions

Drug interaction studies were performed with oral 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 2 and the effects of other drugs on the pharmacokinetics of azithromycin are shown in Table 3.

Co-administration of azithromycin at therapeutic doses had a modest effect on the pharmacokinetics of the drugs listed in Table 2. No dosage adjustment of drugs listed in Table 2 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 3.

Co-administered Drug
Dose of Co-
administered Drug
Dose of
Azithromycin
 
Ratio
(with/without
azithromycin) of
Co-administered
Drug
Pharmacokinetic
Parameters (90%
CI); No Effect =
1.00
 
 
 
 
Mean
Cmax
Mean AUC
Atorvastatin
 

8 days
500 mg/day
PO on days
6-8
 

2
0.83
(0.63 to
1.08)
 

(0.81 to
1.25)
Carbamazepine
200 mg/day ×
2 days, then
200 mg b.i.d.
× 18 days
500 mg/day
PO for days
16-18
7
0.97
(0.88 to
1.06)
0.96
(0.88 to
1.06)
Cetirizine
20 mg/day ×
11 days
500 mg PO on
day 7, then
250 mg/day
on days 8-11
 

4
 

(0.93 to
1.14)
 

(0.92 to
1.13)
Didanosine
200 mg PO
b.i.d. ×
21 days
 

PO on days
8-21
6
 

(0.85 to
2.43)
 

(0.83 to
1.57)
Efavirenz
400 mg/day ×
7 days
600 mg PO on
day 7
 

4
 
0.95*
Fluconazole
200 mg PO
single dose
 

single dose
 

8
 

(0.98 to
1.11)
 

(0.97 to
1.05)
Indinavir
800 mg t.i.d. ×
5 days
 

on day 5
 

8
0.96
(0.86 to
1.08)
0.90
(0.81 to
1.00)
Midazolam
 

day 3
500 mg/day
PO × 3 days
 

2
 

(0.89 to
1.81)
 

(1.01 to
1.56)
Nelfinavir
750 mg t.i.d.
× 11 days
 

on day 9
 

4
0.90
(0.81 to
1.01)
0.85
(0.78 to
0.93)
Rifabutin
300 mg/day ×
10 days
500 mg PO on
day 1, then
250 mg/day
on days 2-10
6
See
footnote
below
NA
Sildenafil
 

days 1 and 4
500 mg/day
PO × 3 days
 

2
 

(0.86 to
1.57)
0.92
(0.75 to
1.12)
Theophylline
4 mg/kg I.V.
on days 1,
11, 25
500 mg PO on
day 7, 250
mg/day on
days 8-11
 

0
 

(1.02 to
1.40)
 

(0.86 to
1.22)
Theophylline
300 mg PO b.i.d. ×
15 days
500 mg PO on
day 6, then
250 mg/day
on days 7-10
8
 

(0.92 to
1.29)
 

(0.89 to
1.31)
Triazolam
0.125 mg on
day 2
500 mg PO on
day 1, then
250 mg/day
on day 2
 

2
 
 
Trimethoprim/Sulphamethoxazole
 

mg/day PO ×
7 days
 

on day 7
 

2
0.85
(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)
Zidovudine
500 mg/day
PO × 21 days
600 mg/day
PO × 14 days
5
 

(0.42 to
3.02)
0.94
(0.52 to
1.70)
Zidovudine
500 mg/day
PO × 21 days
 

PO × 14 days
4
 

(0.43 to
3.97)
 

(0.69 to
2.43)
Table 3: Drug Interactions: Pharmacokinetic Parameters for Azithromycin in the Presence of Co-administered Drugs
Table 2: Drug Interactions: Pharmacokinetic Parameters for Co-administered Drugs in the Presence of Azithromycin

Table>

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 ×
7 days
600 mg PO on
day 7
 
 

(1.04 to
1.42)
0.92*
Fluconazole
200 mg PO
single dose
 

single dose
 
0.82
(0.66 to
1.02)
 

(0.94 to
1.22)
Nelfinavir
750 mg t.i.d. ×
11 days
 

day 9
 
2.36
(1.77 to
3.15)
2.12
(1.80 to
2.50)
Rifabutin
300 mg/day ×
10 days
500 mg PO on
day 1, then 250
mg/day on days
2-10
6
See footnote
below
NA

Indications

Azithromycin for injection is indicated for the treatment of patients with infections caused by susceptible strains of the designated microorganisms in the conditions listed below:

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 I.V. Therapy.

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

Azithromycin for injection should be followed by azithromycin by the oral route as required.

Appropriate culture and susceptibility tests should be performed before treatment to determine the causative microorganism and its susceptibility to azithromycin. Therapy with azithromycin 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 and other antibacterial drugs, azithromycin 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.

Dosage and Administration

The recommended dose of azithromycin for injection for the treatment of adult patients with community-acquired pneumonia due to the indicated organisms is 500 mg as a single daily dose by the I.V. route for at least 2 days. I.V. therapy should be followed by azithromycin by the oral route at a single, daily dose of 500 mg, administered as two 250 mg 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 for injection for the treatment of adult patients with pelvic inflammatory disease due to the indicated organisms is 500 mg as a single daily dose by the I.V. route for 1 or 2 days. I.V. therapy should be followed by azithromycin by the oral route at a single, daily dose of 250 mg 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.

Renal Impairment

No dosage adjustment is recommended for subjects with renal impairment (GFR ≤80 mL/min). The mean AUC0-120 was similar in subjects with a GFR of 10-80 mL/min compared with subjects with normal renal function, whereas it increased by 35% in subjects with GFR <10 mL/min compared with subjects with normal renal function. Caution should be exercised when azithromycin is administered to subjects with severe renal impairment.

Hepatic Impairment

The pharmacokinetics of azithromycin in subjects with hepatic impairment has not been established. No dose adjustment recommendations can be made in patients with impaired hepatic function.

No dosage adjustment is recommended based on age or gender.

Reconstitution

  1. Prepare the initial solution of azithromycin Injection by adding 5 mL of Sterile Water for Injection to the 500 mg vial.
  2. Shake the vial until the entire drug is dissolved.
  3. Transfer the entire 5 mL of the above into either 500 ml/ 250 ml of the diluents (listed in the pack insert)
  • For concentration of 1mg/ ml, add 500 ml of the diluent to 5ml of azithromycin solution.
  • For concentration of 2mg/ ml ,add 250ml of the diluent to 5ml of the azithromycin solution.
 
Azithromycin solution
Amount of diluent
Infusion period
 
5 ml
500ml
Over 3 hrs
2mg/ ml
5 ml
250ml
Over 1 hr

The infusate concentration and rate of infusion for azithromycin for injection should be either 1 mg/mL over 3 hours or 2 mg/mL over 1 hour..

Note:

  • 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.
  • Diluent which can be used are listed below :
    • Normal Saline (0.9% sodium chloride)
    • Half of Normal Saline (0.45% sodium chloride)
    • 5% Dextrose in Water
    • Lactated Ringer's Solution
    • 5% Dextrose in half of Normal Saline (0.45% sodium chloride) with 20 mEq KCl
    • 5% Dextrose in Lactated Ringer's Solution
    • 5% Dextrose in one-third of Normal Saline (0.3% sodium chloride)
    • 5% Dextrose in half of Normal Saline (0.45% sodium chloride)
  • It is recommended that a 500 mg dose of azithromycin for injection, diluted as above, be infused over a period of not less than 60 minutes.
  • Azithromycin for injection should not be given as a bolus or as an intramuscular injection.
  • Other I.V. substances, additives, or medications should not be added to azithromycin for injection, or infused simultaneously through the same I.V. line.

Contraindications

Azithromycin is contraindicated in patients with a known hypersensitivity to azithromycin, erythromycin, any macrolide or ketolide antibiotic. Azithromycin is contraindicated in patients with a history of cholestatic jaundice/hepatic dysfunction associated with prior use of azithromycin.

Warnings and Precautions

Hypersensitivity

Serious allergic reactions, including angio-oedema, anaphylaxis, and dermatologic reactions, including Stevens-Johnson Syndrome and toxic epidermal necrolysis, have been reported rarely in patients on azithromycin therapy (although rare, fatalities have been reported). 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 exposure. These patients required prolonged periods of observation and symptomatic treatment. The relationship of these episodes to the long tissue half-life of azithromycin 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.

Hepatotoxicity

Abnormal liver function, hepatitis, cholestatic jaundice, hepatic necrosis, and hepatic failure have been reported, some of which have resulted in death. Discontinue azithromycin immediately if signs and symptoms of hepatitis occur.

Clostridium difficile-associated diarrhoea
Clostridium difficile-associated diarrhoea (CDAD) has been reported with use of nearly all antibacterial agents, including azithromycin for injection, and may range in severity from mild diarrhoea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon, leading to overgrowth of C. Difficile.

C. 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 a colectomy. CDAD must be considered in all patients who present with diarrhoea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over 2 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.

QT Prolongation

Prolonged cardiac repolarization and QT interval, imparting a risk of developing cardiac arrhythmia and torsades de pointes, have been seen in treatment with macrolides, including azithromycin. Cases of torsades de pointes have been spontaneously reported during postmarketing surveillance in patients receiving azithromycin. Providers should consider the risk of QT prolongation, which can be fatal, when weighing the risks and benefits of azithromycin for at-risk groups, including

  • patients with known prolongation of the QT interval, a history of torsades de pointes, congenital long QT syndrome, bradyarrhythmias or uncompensated heart failure;
  • patients on drugs known to prolong the QT interval; and,
  • patients with ongoing pro-arrhythmic conditions such as uncorrected hypokalaemia or hypomagnesaemia, clinically significant bradycardia, and in patients receiving Class IA (quinidine, procainamide) or Class III (dofetilide, aminodarone, sotalol) anti-arrhythmic agents.

Elderly patients may be more susceptible to drug-associated effects on the QT interval.

General

Because azithromycin is principally eliminated via the liver, caution should be exercised when azithromycin 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 in these patients.

Azithromycin for injection should be reconstituted and diluted as directed and administered as an I.V. infusion over not less than 60 minutes.

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

Exacerbation of symptoms of myasthenia gravis and new onset of myasthenic syndrome have been reported in patients receiving azithromycin therapy. Prescribing azithromycin 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.

Drug Interactions

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

Although, in a study of 22 healthy men, a 5-day course of azithromycin did not affect the prothrombin time from a subsequently administered dose of warfarin, spontaneous postmarketing reports suggest that concomitant administration of azithromycin may potentiate the effects of oral anticoagulants. Prothrombin times should be carefully monitored while patients are receiving azithromycin and oral anticoagulants concomitantly.

Drug interaction studies were performed with azithromycin and other drugs likely to be co-administered. When used in therapeutic doses, azithromycin had a modest effect on the pharmacokinetics of atorvastatin, carbamazepine, cetirizine, didanosine, efavirenz, fluconazole, indinavir, midazolam, rifabutin, sildenafil, theophylline (I.V. and oral), triazolam, trimethoprim/sulphamethoxazole or zidovudine. Co-administration with efavirenz or fluconazole had a modest effect on the pharmacokinetics of azithromycin. No dosage adjustment of either drug is recommended when azithromycin is co-administered with any of these agents.
Interactions with the drugs listed below have not been reported in clinical trials with azithromycin; 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 and these drugs are used concomitantly, careful monitoring of patients is advised.

Digoxin: Causes elevated digoxin concentrations.

Ergotamine or Dihydroergotamine: Causes acute ergot toxicity characterized by severe peripheral vasospasm and dysaesthesia.

Terfenadine, Cyclosporine, Hexital and Phenytoin: Results in elevated concentrations.

Laboratory Test Interactions
There no reported laboratory test actions.

Pregnancy

There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, azithromycin should be used during pregnancy only if clearly needed.

Lactation

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

Paediatric Use

Safety and effectiveness of azithromycin for injection in children or adolescents below 16 years of age have not been established.

Geriatric Use

Pharmacokinetic studies with I.V. azithromycin have not been performed in older volunteers. Pharmacokinetics of azithromycin following oral administration in older volunteers (65-85 years old) was similar to those in younger volunteers (18-40 years old) for the 5-day therapeutic regimen.

In multiple-dose clinical trials of I.V. azithromycin 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- and comparator-treated patients with increasing age.

Elderly patients may be more susceptible to development of torsades de pointes arrhythmia than younger patients.

Undesirable Effects

In clinical trials of I.V. azithromycin for community-acquired pneumonia, in which two to five 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 co-morbid diseases and were receiving concomitant medications. Approximately 1.2% of the patients discontinued I.V. azithromycin therapy, and a total of 2.4% discontinued azithromycin therapy by either the I.V. or oral route because of clinical or laboratory side effects.

In clinical trials conducted in patients with pelvic inflammatory disease, in which one to two I.V. doses were given, 2% of women who received monotherapy with azithromycin and 4% who received azithromycin 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, diarrhoea), 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./PO azithromycin. Azithromycin in studies of community-acquired pneumonia were related to the gastrointestinal system with diarrhoea/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 I.V. 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./PO. Azithromycin in studies of pelvic inflammatory disease were related to the gastrointestinal system. Diarrhoea (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 was co-administered with metronidazole in these studies, a higher proportion of women experienced side effects of nausea (10.3%), abdominal pain (3.7%), vomiting (2.8%), application site reaction, stomatitis, dizziness, or dyspnoea (all at 1.9%).

No other side effects occurred in patients on the multiple dose I.V./PO regimen of azithromycin 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.

Postmarketing Experience

Adverse events reported with azithromycin during the postmarketing period in adult and/or paediatric patients for which a causal relationship may not be established included the following:
Allergic: Arthralgia, oedema, urticaria and angio-oedema.
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/diarrhoea rarely resulting in dehydration, pseudomembranous colitis, pancreatitis, oral candidiasis, pyloric stenosis, and rare reports of tongue discolouration.
General: Asthenia, paraesthesia, fatigue, malaise and anaphylaxis (rarely fatal).
Genitourinary: Interstitial nephritis and acute renal failure and vaginitis.
Haematopoietic: Thrombocytopenia.
Liver/Biliary: Adverse reactions related to hepatic dysfunction have been reported in postmarketing experience with azithromycin.
Nervous System: Convulsions, dizziness/vertigo, headache, somnolence, hyperactivity, nervousness, agitation and syncope.
Psychiatric: Aggressive reaction and anxiety.
Skin/Appendages: Pruritus; rarely, serious skin reactions, including erythema multiforme, Stevens-Johnson 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 <1%: Leucopenia, 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 (I.V./PO), less than 2% of patients discontinued azithromycin therapy because of treatment-related liver enzyme abnormalities.

Overdosage

Seek medical emergency in case of overdosage.

Storage and Handling Instructions

Reconstituted solution is stable for 24 hours when stored below 30°C (86°F).

Packaging Information

AZIMAX I.V: Available in a Vial of 10 ml.