INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
ZITHROMAX 500 mg Tablets
ZITHROMAX IV

SCHEDULING STATUS
Schedule 4

Prescription
Required

PROPRIETARY NAME
(and dosage form)

ZITHROMAX 500 mg Tablets
ZITHROMAX IV
(Powder for solution for infusion)

COMPOSITION
Zithromax (azithromycin) is an azalide antibiotic.
Each Zithromax 500 mg tablet contains azithromycin dihydrate equivalent to 500 mg azithromycin base.
Each Zithromax IV vial contains 500 mg of azithromycin (as the dihydrate), providing 100 mg/mL solution following reconstitution.
Inactive excipients:
Zithromax 500 mg tablets contain pregelatinised starch, calcium phosphate dibasic anhydrous, croscarmellose sodium, magnesium stearate/sodium lauryl sulphate blend and are film-coated with white Opadry® which contains hydroxypropyl methylcellulose, triacetin and titanium dioxide.
Zithromax IV contains citric acid and sodium hydroxide.

PHARMACOLOGICAL CLASSIFICATION
A.20.1.1 Broad and medium spectrum antibiotics.

PHARMACOLOGICAL ACTION
Following oral administration in humans, azithromycin is widely distributed throughout the body; bioavailability is approximately 37%. No significant decrease in bio-availability was observed when azithromycin tablets were administered with a meal. The time taken to peak plasma levels is 2-3 hours. Plasma terminal elimination half-life closely reflects the tissue depletion half-life of 2 to 4 days.
In patients hospitalised with community acquired pneumonia receiving single daily one-hour intravenous infusions for 2 to 5 days of 500 mg azithromycin at a concentration of 2 mg/mL, the mean Cmax + S.D. achieved was 3.63 + 1.60 micrograms/mL, while the 24-hour trough level was 0.20 + 0.15 micrograms /mL, and the AUC24 was 9.60 + 4.80 micrograms·h/mL.
The mean Cmax, 24-hour trough and AUC24 values were 1.14 + 0.14 micrograms/mL, 0.18 + 0.02 micrograms/mL, and 8.03 + 0.86 micrograms h/mL, respectively, in normal volunteers receiving a 3-hour intravenous infusion of 500 mg azithromycin at a concentration of 1 mg/mL.
Kinetic studies of variable times ranging from hours to days after oral intake have shown markedly higher azithromycin levels in tissue than in plasma (up to 50 times the maximum observed concentration in plasma) indicating that the drug is highly tissue bound. Concentrations in target tissues such as lung, tonsil and prostate exceed the MIC90 for likely pathogens after a single dose of 500 mg.
In a multiple-dose study in 12 normal volunteers utilizing a 500 mg (1 mg/mL) one-hour intravenous-dosage regimen for five days, the amount of administered azithromycin 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.
In vitro sensitivity does not necessarily imply in vivo efficacy. Azithromycin demonstrates activity in vitro against a wide range of Gram-positive and Gram-negative bacteria including:
Staphylococcus aureus; Streptococcus pneumoniae, Streptococcus pyogenes(Group A) and other Streptococcusspecies; Haemophilus influenzae; Moraxella catarrhalis; Legionella pneumophila, Bordetella pertussis; Borrelia burgdorferi; Haemophilus ducreyi; and Chlamydia trachomatis. Azithromycin also demonstrates in vitroactivity against Mycoplasma pneumoniaeand Treponema pallidum

INDICATIONS
Adults: Zithromax tablets are indicated for mild to moderate infections caused by susceptible organisms; in lower respiratory tract infections including bronchitis due to Haemophilus influenzae, Moraxella catarrhalis, Streptococcus pneumoniae or Staphylococcus aureus and pneumonia due to Streptococcus pneumoniae or Haemophilus influenzae; uncomplicated skin and soft tissue infections; sinusitis due to Haemophilus influenzae, Streptococcus pneumoniae or Staphylococcus aureus; and as an alternative to first line therapy of pharyngitis/tonsillitis.
Zithromax IV is indicated for the treatment of community acquired pneumonia caused by susceptible organisms, including Legionella pneumophila, in patients who require initial intravenous therapy.
In sexually transmitted diseases in men and women, Zithromax tablets are indicated in the treatment of uncomplicated genital infections due to Chlamydia trachomatis.
Children: 1 year and over
Zithromax tablets are indicated for pharyngitis/tonsillitis and otitis media caused by susceptible organisms in children over 45 kg. (Zithromax suspension is recommended in children under 45 kg)
The safety and effectiveness of Zithromax IV for the treatment of infections in children has not been established.

CONTRA-INDICATIONS
Zithromax is contra-indicated in patients with a known hypersensitivity to azithromycin, erythromycin or any of the macrolide antibiotics.
Because of the theoretical possibility of ergotism, Zithromax and ergot derivatives should not be co-administered.
Use in hepatic impairment:
As the liver is the principal route of excretion of Zithromax, it should not be prescribed in patients with hepatic disease.
Use during pregnancy and lactation:
The safety and efficacy of Zithromax in pregnancy and lactation have not been established.
Zithromax IV should only be used in pregnant or lactating women where adequate alternatives are not available.

WARNINGS
Rare serious allergic reactions, including angioedema and anaphylaxis (rarely fatal), have been reported. Some of these reactions with azithromycin have resulted in recurrent symptoms and required a longer period of observation and treatment.
Pseudomembranous colitis has been reported and may range in severity from mild to life- threatening. Therefore it is important to consider this diagnosis in patients with diarrhoea subsequent to administration of Zithromax.
Observation for signs of superinfection with non-susceptible organisms, including fungi, is recommended.
Use in renal impairment:
There are no data regarding Zithromax usage in patients with renal impairment, thus caution should be exercised when prescribing Zithromax in these patients.
Use in children under 1 year of age:
The safety and efficacy of oral Zithromax preparations in children less than 1 year have not been established.
The safety and effectiveness of Zithromax IV for the treatment of infections in children has not been established.
Azithromycin powder for solution for infusion should be reconstituted and diluted as directed and administered as an intravenous infusion over not less than 60 minutes.
All volunteers who received infusate concentrations above 2.0 mg/mL experienced local infusion site reactions and therefore, higher concentrations should be avoided.

DOSAGE AND DIRECTIONS FOR USE
ZITHROMAX TABLETS
Zithromax should be administered as a single daily dose with or without food.
Zithromax tablets should be taken whole.
Adults:
For all indications other than sexually transmitted diseases, the total dose is 1,5 g which should be given as 500 mg daily for 3 days
For sexually transmitted diseases caused by Chlamydia trachomatis the dose is 1 g given as a single dose.
Use in the elderly:
Normal adult dosage is recommended.
Use in children:
Children over 45 kg - dose as per adults.
This formulation is not suitable for children under 45 kg.

ZITHROMAX IV
For more severe infections, the recommended dose of Zithromax IV for the treatment of adult patients with community acquired pneumonia requiring hospitilisation due to the indicated organisms is 500 mg as a single daily dose by the intravenous route for at least two days. Intravenous therapy should be followed by azithromycin by the oral route as a single daily dose of 500 mg to complete a 7 to 10 day course of therapy. The timing of the conversion to oral therapy should be done at the discretion of the physician and in accordance with clinical response.
Use in elderly
No dosage adjustment is necessary in elderly patients requiring azithromycin therapy.
Use in children
The safety and effectiveness of Zithromax IV for the treatment of infections in children has not been established.
Administration
ZithromaxIV after reconstitution and dilution is for administration by intravenous infusion. Zithromax IV should not be given as a bolus or as an intramuscular injection.
The infusate concentration and rate of infusion for azithromycin powder for solution for infusion should be either 1 mg/mL over 3 hours or 2 mg/mL over 1 hour.
Preparation of the solution for intravenous administration is as follows:
Reconstitution:
Prepare the initial solution of azithromycin powder for solution for infusion by adding 4.8 mL of sterilised Water For Injections to the 500 mg vial and shaking the vial until all of the drug is dissolved. It is recommended that a standard 5 mL (non-automated) syringe be used to ensure that the exact amount of 4.8 mL of sterilised Water for Injections is dispensed. Each mL of reconstituted solution contains 100 mg azithromycin.
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 over a concentration range of 1.0-2.0 mg/mL, transfer 5 mL of the 100 mg/mL azithromycin solution into the appropriate amount of any of the diluents listed below.

Final Infusion Solution Concentration (mg/mL)	Amount of Diluent (mL)
1.0 mg/mL	500 mL
2.0 mg/mL	250 mL

The reconstituted solution can be diluted with:
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)
It is recommended that a 500 mg dose of azithromycin powder for solution for infusion, diluted as above, be infused over a period of not less than 60 minutes.
Zithromax IV reconstituted solution may be diluted using the instructions and compatible infusion solutions provided above. Other intravenous substances, additives or medications should not be added to Zithromax IV, or infused simultaneously through the same intravenous line.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
The majority of side-effects are gastrointestinal in origin with anorexia, nausea, abdominal discomfort (pain/cramps), flatulence, vomiting and diarrhoea less frequently resulting in dehydration, dyspepsia, constipation and loose stools.
Local inflammation/pain at the infusion site has been reported with intravenous 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 250 mL infusion) or over 3 hours (1 mg/mL as 500 mL infusion).
There have been reports of hearing impairment including hearing loss, deafness and or tinnitus in some patients receiving Zithromax.
Interstitial nephritis and acute renal failure have been reported.
Cases of abnormal liver function including hepatitis and cholestatic jaundice have been reported.
Reductions in neutrophil counts have occasionally been observed.
The following side-effects have occurred: Chest pain, malaena, nephritis, vaginitis, headache, vertigo, dizziness, convulsions, somnolence and fatigue.
There have been rare reports of taste disturbances.
Palpitations and arrythmias including ventricular tachycardia have been reported although a causal relationship to Zithromax has not been established.
Asthenia and paraesthesiae have been reported although a causal relationship may not have been established.
Allergic reactions including arthralgia, oedema, urticaria, rash, photosensitivity, angioedema and anaphylaxis (less frequently fatal) have occurred - see "Warnings". Less frequently, serious skin reactions including erythema multiforme, Stevens Johnson syndrome and toxic epidermal necrolysis, have occurred.

INTERACTIONS:
The following information on drug interactions refers to oral azithromycin.
Ergot derivatives:
Because of the theoretical possibility of ergotism, Zithromax and ergot derivatives should not be co-administered.
Special administration advised with the following:
Antacids:
In patients receiving Zithromax tablets and antacids, Zithromax tablets should be taken at least 1 hour before or 2 hours after the antacid. Administration of oral antacids is not expected to affect the disposition of azithromycin given intravenously.
Cimetidine:
A single dose of cimetidine administered 2 hours before Zithromax had no effect on the pharmacokinetics of azithromycin.
No interactions reported with the following:
Carbamazepine:
In a pharmacokinetic interaction study in healthy volunteers, no significant effect was observed on the plasma levels of carbamazepine or its active metabolite.
Methylprednisolone:
In a pharmacokinetic interaction study in healthy volunteers, Zithromax had no significant effect on the pharmacokinetics of methylprednisolone.
Theophylline:
There is no evidence of any pharmacokinetic interaction when Zithromax and theophylline are co-administered to healthy volunteers.
Zidovudine:
In a preliminary pharmacokinetic study of Zithromax in HIV-positive patients treated with zidovudine, no significant effect on the pharmacokinetic parameters of zidovudine and its glucuronide metabolite was found. The only significant difference in azithromycin kinetics was a shortening of the time to reach maximal concentration when the first and last day levels were compared.
Special precautionary monitoring is advised with the following:
Cyclosporin:
Some of the related macrolide antibiotics interfere with the metabolism of cyclosporin. In the absence of pharmacokinetic studies or clinical data investigating potential interaction between Zithromax and cyclosporin, caution should be exercised before co-administration of these two drugs. If co-administration is necessary, cyclosporin levels should be monitored and the dose adjusted accordingly.
Digoxin:
Some of the macrolide antibiotics have been reported to impair the metabolism of digoxin (in the gut) in some patients. Therefore, in patients receiving concomitant Zithromax, a related azalide antibiotic, and digoxin the possibility of raised digoxin levels should be borne in mind.
Warfarin:
In a pharmacokinetic interaction study, Zithromax did not alter the anticoagulant effect of a single 15 mg dose of warfarin administered to healthy volunteers. Zithromax and warfarin may be co-administered, but monitoring of the prothrombin time should be continued as routinely performed.
Terfenadine:
There have been less frequent reports of an interaction in patients receiving Zithromax and terfenadine where the possibility of such an interaction could not entirely be excluded

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
There are no data on overdosage with Zithromax. Typical symptoms of overdosage with macrolide antibiotics include hearing loss, severe nausea, vomiting and diarrhoea. Gastric lavage and general supportive measures are indicated.

IDENTIFICATION
Zithromax 500 mg tablets are oval, white scored film-coated tablets engraved “ZTM 500”on one side and “PFIZER”on the other side.
Zithromax IV (Powder for solution for infusion) is a white to off-white cake powder. The reconstituted solution is clear and colourless, visually free of undissolved matter and essentially free from particles of foreign matter.

PRESENTATION
Zithromax 500 mg tablets:        PVC blister packs of 2 or 3 tablets in an outer cardboard carton.
Zithromax IV (azithromycin powder for solution for infusion) is packaged in single use 10 mL clear and colourless glass vial and closed with a rubber stopper and aluminium over-seal.

STORAGE INSTRUCTIONS
Zithromax Tablets
Store below 30°C. Keep out of reach of children.
Zithromax IV
Store below 25°C. Keep out of reach of children. Keep vial in original packaging until use
Chemical and physical in-use stability of the reconstituted product has been demonstrated for 24 hours at 30°C. When diluted according to the instructions the diluted solution is chemically and physically stable for 24 hours at or below 30°C or for 7 days if stored under refrigeration (5°C). However, from a microbiological point of view, the product should be used immediately. If not used immediately, the in-use storage times and conditions are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless reconstitution and dilution has taken place in controlled and validated aseptic conditions.

REGISTRATION NUMBER

Zithromax Tablets:	31/20.1.1/45
Zithromax IV:	36/20.1.1/0190

NAME AND BUSINESS ADDRESS OF APPLICANT
Pfizer Laboratories (Pty) Ltd
102 Rivonia Road
Sandton 2196
South Africa

Licensed from: Pliva, Zagreb, Croatia

DATE OF PUBLICATION OF THIS PACKAGE INSERT
30 April 2003

ZIMBABWE DETAILS Zithromax 500 mg tablets: 7.2.5 Anti-infective drugs (others) 2001/7.2.5/3954        PP

Updated on this site: February 2005
Source: Pharmaceutical Industry
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