AZENIL CAPSULES

PATIENT PACKAGE INSERT IN ACCORDANCE WITH THE

PHARMACISTS’ REGULATIONS (PREPARATIONS) - 1986

The medicine is dispensed with a doctor’s prescription only

AzENIL

®

Capsules

AzENIL

®

200 mg/5 ml Suspension

Each capsule contains:

Azithromycin (as Dihydrate) 250 mg

Each 5 ml of suspension contains:

Azithromycin (as Dihydrate) 200 mg

A list of inactive and allergenic ingredients in the preparation - see

section 6.

Read the leaflet carefully in its entirety before using the medicine.

This leaflet contains concise information about the medicine. If you

have further questions, refer to the doctor or pharmacist.

This medicine has been prescribed for your treatment. Do not pass it

on to others, it may harm them even if it seems to you that their medical

condition is similar to yours.

Azenil

200 mg/5 ml Suspension is intended for children from

6 months of age.

Azenil

Capsules is intended for children weighing more than 45 kg.

1.

WHAT IS THE MEDICINE INTENDED fOR?

For the treatment of infections caused by bacteria susceptible to the

preparation in the respiratory tract (bronchitis, pneumonia, sinusitis,

pharyngitis and tonsillitis), skin and soft tissue, ears, and genital

infections caused by chlamydia trachomatis.

Therapeutic group: Macrolide antibiotic.

2.

BEfORE USING THE MEDICINE

Do not use the medicine if:

x You are sensitive (allergic) to the active ingredient (azithromycin)

or to any of the additional ingredients contained in the medicine

that appear in section 6.

x You have a history of allergic reaction to the preparation or to

erythromycin or to any other antibiotic from the macrolide or

ketolide group.

x You have suffered in the past from jaundice resulting from bile

flow obstruction in the liver (cholestatic jaundice) or from hepatic

dysfunction that happened with the use of azithromycin.

Special warnings regarding use of the medicine

Do not use the medicine without consulting a doctor before starting

treatment if you:

have pneumonia.

have cystic fibrosis.

have known or suspected bacterial infection in the blood.

have liver or kidney function problems.

have an irregular heartbeat, particularly from a problem called ״QT prolongation״.

have a disease which causes muscle weakness (myasthenia

gravis).

have any other medical problems.

are pregnant or breastfeeding, planning to become pregnant or to

breastfeed – see ״Pregnancy and breastfeeding״ section.

If you are taking, or have recently taken, other medicines,

including non-prescription medicines and nutritional

supplements, tell the doctor or pharmacist. In particular, inform

the doctor or pharmacist if you are taking:

nelfinavir (for treatment of AIDS), since the combination may

increase the levels of azithromycin in the blood.

anticoagulants (e.g., warfarin) - you should be monitored for

coagulation indices.

digoxin.

colchicine.

phenytoin.

antacids containing aluminum or magnesium.

Use of the medicine and food

Suspension - can be taken with or without food.

Capsules - take one hour before a meal or two hours after a meal.

Pregnancy and breastfeeding

Do not use the medicine without consulting a doctor before

commencing treatment, if you are pregnant or planning to become

pregnant. It is not known if Azenil

will harm your unborn baby.

Do not use the medicine without consulting a doctor before

commencing treatment, if you are breastfeeding or planning to

breastfeed. Azenil

has been reported to pass into breast milk. Consult

the doctor regarding the best way to feed your baby during the course

of treatment with Azenil

Important information about some of the ingredients of the

medicine

The capsule contains lactose – if you have been told by a doctor that

you have an intolerance to some sugars contact the doctor before

taking the medicine.

The suspension contains sucrose – if you have been told by a doctor

that you have an intolerance to some sugars contact the doctor

before taking the medicine. Exercise caution when using in diabetic

patients.

3.

HOW SHOULD YOU USE THE MEDICINE?

Always use the preparation according to the doctor’s instructions!

Check with the doctor or pharmacist if you are uncertain about the

dosage and treatment regimen of the preparation.

The dosage and treatment regimen will be determined by the doctor

only.

Capsules: Take the capsule whole. Do not open and disperse the

contents of the capsule, as the effect of this mode of administration

has not been assessed.

Do not give the capsule to children weighing less than 45 kg.

Suspension: For children weighing less than 15 kg, the prescribed

dose should be measured as accurately as possible.

Shake the suspension well before each use.

Do not exceed the recommended dose!

If you took an overdose or if a child has accidentally swallowed

the medicine, refer immediately to a doctor or proceed to a hospital

emergency room and bring the package of the medicine with you.

If you forget to take this medicine at the intended time, take a

dose as soon as you remember. However, if it is time for the next dose,

skip the forgotten dose and take the next dose as usual. Never take a

double dose to make up for the forgotten dose!

Adhere to the treatment regimen as recommended by the doctor.

Even if there is an improvement in your health, do not stop treatment

with the medicine without consulting the doctor.

Do not skip a dose of Azenil

or stop taking the medicine, even if you

start to feel better, until the treatment is completed, except in cases in

which you are suffering from a severe allergic reaction or your doctor

has instructed you to stop taking the medicine (see section 4 ״Side effects״). If you skip taking doses or fail to complete the full

Azenil

®

treatment, the treatment may not be adequately effective

and it will be more difficult to treat your infection. Completion of the

full treatment will lower the risk of the bacteria developing resistance

to Azenil

If the bacteria develop resistance to Azenil

, Azenil

and other

antibiotics may not be effective in the future.

Do not take medicines in the dark! Check the label and the dose

each time you take a medicine. Wear glasses if you need them.

If you have further questions regarding use of the medicine, consult

the doctor or pharmacist.

4.

SIDE EffECTS

As with any medicine, use of Azenil

may cause side effects in some

users. Do not be alarmed when reading the list of side effects. You

may not suffer from any of them.

Serious side effects

Stop using and refer to a doctor immediately in the event of:

Serious allergic reactions. Allergic reactions can occur after taking

azithromycin, the active ingredient in Azenil

, even after taking only

one dose. Stop treatment and refer to a doctor immediately if you

experience any of the following symptoms:

- trouble breathing or swallowing

- swelling of the lips, tongue or face

- throat tightness, hoarseness

- rapid heartbeat

- fainting

- skin rash (hives)

- new onset of fever and swollen lymph nodes

Stop using Azenil

with the first sign of a skin rash and refer to a

doctor immediately. A rash may be a sign of a more serious reaction

to Azenil

Liver damage (hepatotoxicity). Stop using the medicine and refer to

a doctor immediately in the event of yellowing of the skin or white

part of the eye, dark-colored urine, nausea or vomiting, abdominal

pain or tenderness, fever, weakness, itching, unusual tiredness,

loss of appetite, change in the color of bowel movements. These

can be signs of a severe reaction to Azenil

(hepatotoxicity).

Refer to a doctor immediately in the event of:

Serious heart rhythm changes (QT prolongation and torsades de

pointes – ventricular heart rate disturbance).

Refer to a doctor immediately if you have a change in your heartbeat

(rapid or irregular), or if you feel faint and dizzy. Azenil

may cause

a rare heart problem known as prolongation of the QT interval.

This condition can cause an abnormal heartbeat and can be very

dangerous. The risk of this is higher among the elderly, in patients

with a family history of prolonged QT interval, in patients with a low

blood potassium level, in patients taking certain medicines to control

heart rhythm (antiarrhythmics).

Worsening of myasthenia gravis (a disease that causes muscle

weakness).

Antibiotics like Azenil

may worsen myasthenia gravis symptoms,

including muscle weakness and breathing problems.

Watery diarrhea, prolonged diarrhea or bloody stools. You may

experience cramping and fever. These may occur after you have

finished the treatment with Azenil

Common side effects

The most common side effects of Azenil

are:

Loose stools or diarrhea; nausea; abdominal pain; vomiting; vaginal

inflammation; rash; indigestion; headaches.

Additional side effects:

Chest pain, rapid heart beat, flatulence, black stools, jaundice,

inflammation of the kidney, fungal infection, dizziness, vertigo,

somnolence, fatigue, itchiness, photosensitivity, angioedema,

constipation, anorexia, inflammation of the small intestine, gastritis,

anemia, reduced white blood cell (leukocyte) count, agitation,

nervousness, insomnia, fever, facial edema, malaise, pain, cough,

pharyngitis, runny nose, eczema, sweating, inflammation of the eye.

If a side effect occurs, if one of the side effects worsens or if

you are suffering from a side effect not mentioned in the leaflet,

consult with the doctor.

دق ىرخأ ةيويح تاداضمو

لينيزأ نإف ،

لينيزأ ـل ةمواقم ميثارجلا تروط اذإ .لبقتسملا يف ةعجان نوكت لا رادقملا نم دكأتلاو ءاودلا عباط صيخشت بجي !ةمتعلا يف ةيودأ لوانت زوجي لا .كلذ رملأا مزل اذإ ةيبطلا تاراظنلا عض .ءاود اهيف لوانتت ةرم لك يف يئاودلا .يلديصلا وأ بيبطلا رشتسإ ،ءاودلا اذه لامعتسإ لوح ةيفاضإ ةلئسأ كيدل ترفوت اذإ ةيبناجلا ضارعلأا )4 .نيلمعتسملا ضعب دنع ةيبناج

اضارعأ ببسي دق

لينيزأ لامعتسإ نإ ،ءاود لكب امك .اهنم

ايأ يناعت لاأ زئاجلا نم ،ةيبناجلا ضارعلأا ةمئاق نم شهدنت لا ةريطخ ةيبناج ضارعأ :ثودح لاح يف بيبطلا ىلإ

ً

لااح هجوتلاو لامعتسلإا نع فقوتلا بجي ،نيسيمورتيزأ لوانت دعب ةيسسحت لعف دودر ثدحت دق .ةريطخ ةيسسحت لعف دودر فقوت .طقف دحاو يئاود رادقم لوانت دعب ىتح ،

لينيزأ اهيوتحي يتلا ةلاعفلا ةداملا :ةيلاتلا ضارعلأا نم رثكأ وأ دحاوب ترعش اذإ بيبطلا ىلإ

لااح هجوتو جلاعلا نع علبلا يف تابوعص وأ سفنتلا يف تابوعص -

هجولا يف وأ ناسللا يف ،نيتفشلا يف خافتنإ -

ةحب ،ةرجنحلا يف قيضت -

عيرس ضبن -

ءامغإ -

)ىرش( يدلج حفط -

ةيوافميللا ددغلا يف خافتنإو ةنوخسل ديدج روهظ -

هجوتلاو يدلج حفطل ىلولأا ةملاعلا روهظ عم

لينيزأ لامعتسإ نع فقوتلا بجي

لينيزأ ـل ةروطخ رثكأ لعف درل ةملاع نوكي دق حفطلا نإ .بيبطلا ىلإ

لااح يف بيبطلل

لااح هجوتو ءاودلا لامعتسإ نع فقوت .)يدبك ررضت( يدبك ررض ،تاؤيقت وأ نايثغ ،نكاد نولب لوب ،نينيعلا ضايب رارفصإ وأ دلجلا رارفصإ لاح ةيهشلا ةلق ،ذاش قاهرإ ،ةكح ،ماع فعض ،ةنوخس ،نطبلا سمل دنع ةيساسح وأ ملأ

لينيزأ ـل ريطخ لعف درل تاملاع كلت نوكت دق .زاربلا نول يف تاريغت ،ماعطلل .)يدبك ررضت( :ثودح لاح يف بيبطلا ىلإ

ً

لااح هجوتلا بجي بارطضإ ـ تناوپ يد داسروتو

عطقم ةلاطإ( بلقلا مظن يف ةريطخ تاريغت عيرس( ضبنلا يف ريغت كيدل ثدح اذإ بيبطلل

لااح هجوت .)بلقلا مظن يف ينيطب ةردان ةلكشم

لينيزأ ببسي دق .راودبو ماع فعضب ترعش اذإ وأ ،)مظتنم ريغ وأ ةملاس مدع ىلإ ةلاحلا هذه يدؤت دق .

عطقم ةلاطإب فرعت يتلاو بلقلا يف ،نينسملا ىدل كلذ ثودحل ربكأ ةروطخلا نوكت .

ادج ةريطخ نوكت دقو ضبنلا ةبسن مهيدل نيجلاعتم ىدل

عطقم ةلاطلإ ةيلئاع ةقباس مهيدل نيجلاعتم ىدل ةرطيسلل ةنيعم ةيودأ نولوانتي نيجلاعتم ىدل ،مدلا يف مويساتوپلا نم ةضفخنم .)مظنلا تابارطضإ تاداضم( بلقلا مظن ىلع تاداضم مقاف

ت دق .)يلضع فعض ىلإ يدؤي ضرم( ليبولا يلضعلا نهولا مقافت

فعض كلذ يف امب ،ليبولا يلضعلا نهولا ضرم ضارعأ

لينيزأ لثم ةيويح .سفنتلا يف لكاشمو يلضع دق .ةنوخسو تاصلقت نم يساقت دق .زاربلا يف مد وأ رمتسم لاهسإ ،يئام لاهسإ

لينيزأ ـب جلاعلا نم كئاهتنإ دعب كلت رهظت ةعئاش ةيبناج ضارعأ :يه

لينيزأ ـل

اعويش رثكلأا ةيبناجلا ضارعلأا تابوعص ؛حفط ؛لبهملا يف باهتلإ ؛تاؤيقت ؛نطبلا يف ملاآ ؛نايثغ ؛لاهسإ وأ نيل زارب .عادص ؛ةيمضه :ةيفاضإ ةيبناج ضارعأ ثولت ،ىلكلا يف باهتلإ ،ناقري ،دوسأ زارب ،ةخفن ،ةعيرس بلق تابرض ،ردصلا يف ملأ ،دلجلا تحت خافتنإ ،ءوضلل ةيساسح ،ةكح ،قاهرإ ،مونلل ليم ،وغيتريڤ ،راود ،يرطف ايلاخ ددع يف ضافخنإ ،مد رقف ،ةدعملا يف باهتلإ ،ةقيقدلا ءاعملأا باهتلإ ،مهق ،كاسمإ روعشلا ،هجولا يف ةمذو ،ةنوخس ،قرأ ،ةيبصع ،ءوده ةلق ،)

leukocyte

( ءاضيبلا مدلا .نيعلا يف باهتلإ ،قرعت ،اميزكإ ،حشر ،ةرجنحلا باهتلإ ،لاعس ،ملأ ،ةماع ةكعوب يناعت امدنع وأ ةيبناجلا ضارعلأا ىدحإ تمقافت اذإ ،يبناج ضرع رهظ اذإ .بيبطلا ةراشتسإ كيلع ،ةرشنلا هذه يف ركذي مل يبناج ضرع نم طبارلا ىلع طغضلا ةطساوب ةحصلا ةرازول ةيبناج ضارعأ نع غيلبتلا ناكملإاب عقومل ةيسيئرلا ةحفصلا ىلع دوجوملا »يئاود جلاع بقع ةيبناج ضارعأ نع غيلبت« غيلبتلل رشابملا جذومنلا ىلإ كهجوي يذلا )

www.health.gov.il

( ةحصلا ةرازو :طبارلا حفصت قيرط نع وأ ،ةيبناج ضارعأ نع

https://forms.gov.il/globaldata/getsequence/getsequence.

aspx?formType=AdversEffectMedic@moh.gov.il

؟ءاودلا نيزخت ةيفيك )5 .ةيوئم ةجرد 25 نود ةرارح ةجردب )طلخلا لبق قوحسم( قلعملاو تلاوسبكلا ظفح بجي هلامعتسإو ةيوئم ةجرد 25 نود ةرارح ةجردب )طلخلا دعب( زهاجلا قلعملا ظفح بجي .مايأ 5 للاخ لوانتم نع

اديعب قلغم ناكم يف رخآ ءاود لكو ءاودلا اذه ظفح بجي !ممستلا بنجت ببست لا .ممستلاب مهتباصإ يدافتل كلذو ،عضرلا وأ/و لافطلأا ةيؤر لاجمو يديأ .بيبطلا نم ةحيرص تاميلعت نودب ؤيقتلا ىلع رهظي يذلا )

exp. date

( ةيحلاصلا خيرات ءاضقنإ دعب ءاودلا لامعتسإ زوجي لا .رهشلا سفن نم ريخلأا مويلا ىلإ ةيحلاصلا خيرات ريشي .ةبلعلا رهظ ةيفاضإ تامولعم )6

اضيأ ةلاعفلا ةداملل ةفاضلإاب ءاودلا يوتحي :تلاوسبك

Anhydrous Lactose, Maize Starch, Magnesium Stearate, Sodium

Lauryl Sulphate, Gelatin, Titanium dioxide.

:قلعم

Sucrose, Sodium Phosphate Tribasic Anhydrous, Hydroxypropyl

Cellulose, Xanthan Gum, Artificial Flavors: Cherry, Crème de

Vanilla and Banana.

:زوتكل ىلع تلاوسبك

™

لينيزأ يوتحي .زوتكل غلم 151٫55 ىلع ةلوسبك لك يوتحت :زوركس ىلع قلعم

™

لينيزأ يوتحي .زوركس مارغ 3٫87 ىلع يوتحت قلعملا نم للم 5 لك .مويدوص ىلع نايوتحي قلعم

™

لينيزأ و تلاوسبك

™

لينيزأ :ةبلعلا ىوتحم وه امو ءاودلا ودبي فيك

ZTM 250

« ـو »

PFIZER

« تاملكلا عم ضيبأ نولب ةلوسبك :تلاوسبك

لينيزأ .دوسلأا ربحلاب ةعوبطم سايق ةنقحم ىلع ةبلع لك يوتحت .تياو فوأ ـ ضيبأ نولب قوحسم :قلعم

لينيزأ .ةريغص سأكو للم 5 مجحب ةريغص ةقعلم ،للم 10 مجحب :اهيلع قداصملا بلعلا ماجحأ تلاوسبك 6 :تلاوسبك

لينيزأ قوحسم ىلع يوتحت ةوبع :تاوبعلا نم نيمجح رفوتي :قلعم للم 5/غلم 200

لينيزأ )غلم 900( قوحسم ىلع يوتحت ةوبع ،للم 15 مجحب قلعم ريضحتل )غلم 600( .للم 22٫5 مجحب قلعم ريضحتل .بلعلا ماجحأ ةفاك قوست لاأ زئاجلا نم ،9 ركنش عراش ،.ض.م ليئارسإ اكيتپسامراف يإ فإ يپ رزياف :زايتملإا بحاص 46725 حاووتيپ ايلستره .ايلاطيإ ،

S.r.l.

انيتلا امراف تفوه :جتنملا مسإ :ةحصلا ةرازو يف يموكحلا ةيودلأا لجس يف ءاودلا لجس مقر 117-66-29827 :تلاوسبك

لينيزأ 118-26-29828 :قلعم

لينيزأ مغرلا ىلع .ركذملا ةغيصب ةرشنلا هذه ةغايص تمت ،ةءارقلا نيوهتو ةلوهس لجأ نم .نيسنجلا لاكل صصخم ءاودلا نإف ،كلذ نم 2018 بآ خيراتب صخ

رو صح

ف اهاوتحمو ةرشنلا هذه ةغيص ةحصلا ةرازو ترقأ 2019 ناريزح خيراتب ةحصلا ةرازو تاميلعت بجومب اهثيدحت متو

Side effects can be reported to the Ministry of Health by clicking on

the link ״Report side effects of drug treatment״ found on the Ministry

of Health homepage (www.health.gov.il), that directs you to the online

form for reporting side effects, or by entering the link:

https://forms.gov.il/globaldata/getsequence/getsequence.aspx?form

Type=AdversEffectMedic@moh.gov.il

5.

HOW SHOULD THE MEDICINE BE STORED?

Store the capsules and the suspension (powder before reconstitution)

at a temperature below 25°C.

Store the prepared suspension (after reconstitution) at a temperature

below 25°C and use within 5 days.

Avoid poisoning! This medicine and any other medicine must be kept

in a safe place out of the reach and sight of children and/or infants

in order to avoid poisoning. Do not induce vomiting unless explicitly

instructed to do so by the doctor.

Do not use the medicine after the expiry date (exp. date) that appears

on the package. The expiry date refers to the last day of that month.

6.

fURTHER INfORMATION

In addition to the active ingredient, the medicine also contains:

Capsules:

Anhydrous Lactose, Maize Starch, Magnesium Stearate, Sodium

Lauryl Sulphate, Gelatin, Titanium dioxide.

Suspension:

Sucrose, Sodium Phosphate Tribasic Anhydrous, Hydroxypropyl

Cellulose, Xanthan Gum, Artificial Flavors: Cherry, Crème de Vanilla

and Banana.

Azenil

®

Capsules contain lactose:

Each capsule contains 151.55 mg lactose.

Azenil

®

Suspension contains sucrose:

Each 5 ml of suspension contains 3.87 g sucrose.

Azenil

®

Capsules and Azenil

®

Suspension contain sodium.

What the medicine looks like and the contents of the package:

Azenil

Capsules: White-colored capsule with ״PFIZER״ and ״ZTM 250״ printed in black ink.

Azenil

Suspension: White to off-white-colored powder. Each package

contains a 10-ml measuring syringe, a 5-ml teaspoon and a cup.

Approved package sizes:

Azenil

Capsules: 6 capsules

Azenil

200 mg/5 ml suspension:

There are two package sizes: A package containing powder (600 mg)

to prepare a 15 ml suspension, a package containing powder (900 mg)

to prepare a 22.5 ml suspension.

Not all package sizes may be marketed.

Registration holder: Pfizer PFE Pharmaceuticals Israel Ltd.,

9 Shenkar Street, Herzeliya Pituach 46725.

Manufacturer: Haupt Pharma Latina S.r.l., Italy.

Registration number of the medicine in the National Drug Registry of

the Ministry of Health:

Azenil

Capsules:

117.66.29827

Azenil

Suspension:

118.26.29828

This leaflet was checked and approved by the Ministry of Health in

August 2018 and was updated in accordance with the Ministry of

Health guidelines in June 2019.

Zithromax I.V LPD CC 100619

0037094

2018

0038280

2018

ZITHROMAX

®

I.V.

FULL PRESCRIBING INFORMATION

NAME OF THE MEDICINAL PRODUCT

ZITHROMAX

I.V.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vail contains Azithromycin dihydrate 524.1 mg equivalent to 500 mg azithromycin base.

Excipients with known effect:

Sodium hydroxide 198.3 mg/vial

For the full list of excipients, see section Description (11) in this leaflet.

PHARMACEUTICAL FORM

Powder for solution for infusion

1

INDICATIONS AND USAGE

Treatment of infections caused by susceptible strains of the designated microorganisms in the following conditions:

community-acquired pneumonia (CAP) and pelvic inflammatory disease (PID).

2

DOSAGE AND ADMINISTRATION

For the treatment of adult patients with CAP due to the indicated organisms, the recommended dose of intravenous

azithromycin is 500 mg as a single daily dose by the IV route for at least two days. Intravenous therapy should be followed

by oral azithromycin at 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.

For the treatment of adult patients with PID due to the indicated organisms, the recommended dose of intravenous

azithromycin is 500 mg as a single dose by the IV route for one or two days. Intravenous 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

conversion 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 anaerobic agent may be

administered in combination with azithromycin.

After reconstitution and dilution, the recommended route of administration for intravenous azithromycin is by IV infusion

only. Do not administer as an intravenous bolus or an intramuscular injection.

The infusate concentration and rate of infusion for azithromycin intravenous (IV) should be either 1 mg/ml over 3 hours or

2 mg/ml over 1 hour. An intravenous dose of 500 mg azithromycin should be infused for a minimum duration of one (1)

hour.

In Children:

The safety and efficacy of intravenous azithromycin for the treatment of infections in children has not been established.

SPECIAL POPULATIONS:

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In the Elderly: The same dosage as in adult patients is used in the elderly. Elderly patients may be more susceptible to

development of torsades de pointes arrhythmia than younger patients (see 5 Warnings and Precautions [5.4]).

In Patients with Renal Impairment: No dose adjustment is necessary in patients with mild to moderate renal

impairment (GFR 10 - 80 ml/min). Caution should be exercised when azithromycin is administered to patients with

severe renal impairment (GFR < 10 ml/min) (see 12 Clinical Pharmacology (12.3)].

In Patients with Hepatic Impairment: The same dosage as in patients with normal hepatic function may be used in patients

with mild to moderate hepatic impairment. Since azithromycin is metabolised in the liver and excreted in the bile, the drug

should not be given to patients suffering from severe liver disease. No studies have been conducted regarding treatment

of such patients with azithromycin (see Contraindications [4.2, 5.2]).

2.1 Preparation of the Solution for Intravenous Administration

Reconstitution: Prepare the initial IV solution for infusion by adding 4.8 ml of sterilized Water for Injection to the 500 mg

vial and shaking the vial until all of the drug is dissolved. Since azithromycin IV 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

sterilized Water for Injection is dispensed. Each ml of reconstituted solution contains 100 mg azithromycin.

Chemical and physical in-use stability of the reconstituted product has been demonstrated for 24 hours below 30

C. When

diluted according to the instructions, the diluted solution is chemically and physically stable for 24 hours at or below 30

or for 7 days if stored under refrigeration 2

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage

times and conditions prior to use are the responsibility of the user and would normally be no longer than 24 hours at 2 to

C, unless reconstitution and dilution have taken place in controlled and validated aseptic conditions.

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)

½ Normal Saline (0.45% sodium chloride)

5% Dextrose in Water

Lactated Ringer’s Solution

5% Dextrose in ½ 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 ½ Normal Saline (0.45% sodium chloride)

Normosol®-M in 5% Dextrose

Normosol®-R in 5% Dextrose

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.

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3

DOSAGE FORMS AND STRENGTHS

Azithromycin dihydrate 524.1 mg equivalent to 500 mg azithromycin base.

Zitromax IV is supplied in lyophilized form in a 10 ml vial equivalent to 500 mg azithromycin for intravenous administration.

Upon reconstitution, azithromycin powder yields a solution containing the equivalent of

100 mg azithromycin per 1 ml

4

CONTRAINDICATIONS

4.1

Hypersensitivity

ZITHROMAX

I.V. is contraindicated in patients with known hypersensitivity to azithromycin, erythromycin, any macrolide

or ketolide drugs.

4.2

Hepatic Dysfunction

ZITHROMAX

I.V. is contraindicated in patients with a history of cholestatic jaundice/hepatic dysfunction associated with

prior use of azithromycin.

5

WARNINGS AND PRECAUTIONS

5.1

Hypersensitivity

Serious allergic reactions, including angioedema, anaphylaxis, and dermatologic reactions including Acute Generalized

Exanthematous Pustulosis (AGEP), Stevens-Johnson Syndrome, and toxic epidermal necrolysis have been reported in

patients on azithromycin therapy. [see Contraindications (4.1)]

Fatalities have been reported. Cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) have also

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 the allergic symptoms may reappear after symptomatic therapy has been discontinued.

5.2

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.

5.3

Infantile hypertrophic pyloric stenosis (IHPS)

Following the use of azithromycin in neonates (treatment up to 42 days of life), IHPS has been reported. Direct parents

and caregivers to contact their physician if vomiting or irritability with feeding occurs.

5.4 QT Prolongation

Prolonged cardiac repolarization and QT interval, imparting a risk of developing cardiac arrhythmia and torsades de

pointes, have been seen with 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

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patients with ongoing proarrhythmic conditions such as uncorrected hypokalemia or hypomagnesemia,

clinically significant bradycardia, and in patients receiving Class IA (quinidine, procainamide) or Class III

(dofetilide, amiodarone, sotalol) antiarrhythmic agents.

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

5.5 Clostridium difficile-Associated Diarrhea

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

ZITHROMAX

I.V., 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.

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 antibacterial therapy and may

require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial 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 antibacterial use not directed against C. difficile may need to be discontinued.

Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical

evaluation should be instituted as clinically indicated.

5.6 Exacerbation of Myasthenia Gravis

Exacerbations of symptoms of myasthenia gravis and new onset of myasthenic syndrome have been reported in patients

receiving azithromycin therapy.

5.7 Infusion Site Reactions

ZITHROMAX

I.V. 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 (2)]

Local IV site reactions have been reported with the 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 hr (1 mg/mL as 500 mL infusion) [see Adverse Reactions (6)]. All volunteers who received infusate concentrations

above 2.0 mg/mL experienced local IV site reactions and, therefore, higher concentrations should be avoided.

5.8 Development of Drug-Resistant Bacteria

Prescribing ZITHROMAX

I.V. in the absence of a proven or strongly suspected bacterial infection is unlikely to provide

benefit to the patient and increases the risk of the development of drug-resistant bacteria.

6

ADVERSE REACTIONS

6.1

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials

of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed

in practice.

In clinical trials of intravenous azithromycin for community-acquired pneumonia, in which 2 to 5 IV doses were given, the

reported adverse reactions 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 intravenous ZITHROMAX

I.V. therapy, and a total of 2.4% discontinued

azithromycin 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 to 2 IV 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.

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Clinical adverse reactions leading to discontinuations from these studies were gastrointestinal (abdominal pain, nausea,

vomiting, diarrhea), and rashes; laboratory side effects leading to discontinuation were increases in transaminase levels

and/or alkaline phosphatase levels.

Overall, the most common adverse reactions associated with treatment in adult patients who received ZITHROMAX

I.V.

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 adverse reactions associated with treatment in adult women who received ZITHROMAX

I.V. in trials

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 was co-administered with metronidazole in these trials, a higher proportion of women experienced adverse

reactions of nausea (10.3%), abdominal pain (3.7%), vomiting (2.8%), infusion site reaction, stomatitis, dizziness, or

dyspnea (all at 1.9%).

Adverse reactions 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.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued

monitoring of the benefit/risk balance of the medicinal product.

Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using

an online form

http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@moh.gov.il

6.2

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of azithromycin. Because these reactions

are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or

establish a causal relationship to drug exposure.

Adverse reactions reported with azithromycin 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 reports of QT

prolongation and torsade's de pointes.

Gastrointestinal: Anorexia, constipation, dyspepsia, flatulence, vomiting/diarrhea, pseudomembranous colitis, pancreatitis,

oral candidiasis, pyloric stenosis, and reports of tongue discoloration.

General: Asthenia, paresthesia, fatigue, malaise and anaphylaxis (including fatalities).

Genitourinary: Interstitial nephritis and acute renal failure and vaginitis.

Hematopoietic: Thrombocytopenia.

Liver/biliary: Abnormal liver function, hepatitis, cholestatic jaundice, hepatic necrosis, and hepatic failure. [see Warnings

and Precautions (5.2)]

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

syncope.

Psychiatric: Aggressive reaction and anxiety.

Skin/appendages: Pruritus, serious skin reactions including, erythema multiforme, AGEP, Stevens-Johnson syndrome,

toxic epidermal necrolysis, and DRESS.

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

perversion and/or loss.

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6.3

Laboratory Abnormalities

Significant abnormalities (irrespective of drug relationship) occurring during the clinical trials were reported as follows:

elevated ALT (SGPT), AST (SGOT), creatinine (4 to 6%)

elevated LDH, bilirubin (1 to 3%)

leukopenia, neutropenia, decreased platelet count, and elevated serum alkaline phosphatase (less than 1%)

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 ZITHROMAX

I.V., less than 2% of patients

discontinued azithromycin therapy because of treatment-related liver enzyme abnormalities.

7

DRUG INTERACTIONS

7.1

Nelfinavir

Co-administration of nelfinavir at 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 adverse reactions of azithromycin, such as liver enzyme

abnormalities and hearing impairment, is warranted. [see Adverse Reactions (6)]

7.2

Warfarin

Spontaneous post-marketing reports suggest that concomitant administration of azithromycin may potentiate the effects of

oral anticoagulants such as warfarin, although the prothrombin time was not affected in the dedicated drug interaction

study with azithromycin and warfarin. Prothrombin times should be carefully monitored while patients are receiving

azithromycin and oral anticoagulants concomitantly.

7.3

Potential Drug-Drug Interaction with Macrolides

Interactions with digoxin, colchicine or phenytoin have not been reported in clinical trials with azithromycin .No specific

drug interaction studies have been performed to evaluate potential drug-drug interaction. However, drug interactions have

been observed with other macrolide products. Until further data are developed regarding drug interactions when digoxin,

colchicine or phenytoin are used with azithromycin careful monitoring of patients is advised.

8

USE IN SPECIFIC POPULATIONS

8.1

Pregnancy

Risk Summary

Available data from published literature and postmarketing experience over several decades with azithromycin use in

pregnant women have not identified any drug-associated risks for major birth defects, miscarriage, or adverse maternal or

fetal outcomes (see Data).

Developmental toxicity studies with azithromycin in rats, mice, and rabbits showed no drug-induced fetal malformations at

doses up to 4, 2, and 2 times, respectively, an adult human daily dose of 500 mg based on body surface area. Decreased

viability and delayed development were observed in the offspring of pregnant rats administered azithromycin from day 6 of

pregnancy through weaning at a dose equivalent to 4 times an adult human daily dose of 500 mg based on body surface

area (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All

pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the

estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to

20%, respectively.

Data

Human Data

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Available data from published observational studies, case series, and case reports over several decades do not suggest

an increased risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes with azithromycin use in

pregnant women. Limitations of these data include the lack of randomization and inability to control for confounders such

as underlying maternal disease and maternal use of concomitant medications.

Animal Data

Reproductive and developmental toxicology studies have not been conducted using IV administration of azithromycin to

animals. Azithromycin administered during the period of organogenesis did not cause fetal malformations in rats and mice

at oral doses up to 200 mg/kg/day (moderately maternally toxic). Based on body surface area, this dose is approximately

4 (rats) and 2 (mice) times an adult human daily dose of 500 mg. In rabbits administered azithromycin at oral doses of 10,

20, and 40 mg/kg/day during organogenesis, reduced maternal body weight and food consumption were observed in all

groups; no evidence of fetotoxicity or teratogenicity was observed at these doses, the highest of which is estimated to be

2 times an adult human daily dose of 500 mg based on body surface area.

In a pre- and postnatal development study, azithromycin was administered orally to pregnant rats from day 6 of pregnancy

until weaning at doses of 50 or 200 mg/kg/day. Maternal toxicity (reduced food consumption and body weight gain;

increased stress at parturition) was observed at the higher dose. Effects in the offspring were noted at 200 mg/kg/day

during the postnatal development period (decreased viability, delayed developmental landmarks). These effects were not

observed in a pre- and postnatal rat study when up to 200 mg/kg/day of azithromycin was given orally beginning on day

15 of pregnancy until weaning.

8.2

Lactation

Risk Summary

Azithromycin is present in human milk (see Data). Non-serious adverse reactions have been reported in breastfed infants

after maternal administration of azithromycin (see Clinical Considerations). There are no available data on the effects of

azithromycin on milk production. The developmental and health benefits of breastfeeding should be considered along with

the mother’s clinical need for ZITHROMAX and any potential adverse effects on the breastfed infant from ZITHROMAX or

from the underlying maternal condition.

Clinical Considerations

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

Data

Azithromycin breastmilk concentrations were measured in 20 women after receiving a single 2 g oral dose of azithromycin

during labor. Breastmilk samples collected on days 3 and 6 postpartum as well

as 2 and 4 weeks postpartum revealed the

presence of azithromycin in breastmilk up to 4 weeks after dosing. In another study, a single dose of azithromycin 500 mg

was administered intravenously to 8 women prior to incision for cesarean section. Breastmilk (colostrum) samples

obtained between 12 and 48 hours after dosing revealed that azithromycin persisted in breastmilk up to 48 hours.

8.3

Pediatric Use

Safety and effectiveness of azithromycin for injection in children or adolescents have not been established. In controlled

clinical studies, azithromycin has been administered to pediatric patients (age 6 months to 16 years) by the oral route. For

information regarding the use of azithromycin for oral suspension in the treatment of pediatric patients, see Indications

and Usage (1), and Dosage and Administration (2) of the prescribing information for Azenil 200mg/ 5mL Suspension

(azithromycin for oral suspension).

8.4

Geriatric Use

Pharmacokinetic studies with intravenous azithromycin have not been performed in older volunteers. Pharmacokinetics of

azithromycin 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 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 reactions,

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laboratory abnormalities, and discontinuations. Similar decreases in clinical response were noted in azithromycin- and

comparator-treated patients with increasing age.

ZITHROMAX

I.V. contains 114 mg (4.96 mEq) of sodium per vial. At the usual recommended doses, patients would

receive 114 mg (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.

Elderly patients may be more susceptible to development of torsades de pointes arrhythmias than younger patients. [see

Warnings and Precautions (5.4 )]

10

OVERDOSAGE

Adverse reactions experienced in higher than recommended doses were similar to those seen at normal doses

particularly nausea, diarrhea, and vomiting. In the event of overdosage, general symptomatic and supportive measures

are indicated as required.

11

DESCRIPTION

ZITHROMAX

I.V. contains the active ingredient azithromycin, an azalide, a subclass of macrolide antibacterial drug, for

intravenous injection. Azithromycin has the chemical name (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-

[(2,6-dideoxy-3-C-methyl-3-O -methyl-

-L-ribo-hexopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-hepta-

methyl- 11- [[3,4,6-trideoxy-3-(dimethylamino)-

-D-xylo-hexopyranosyl]oxy]-1-oxa- 6-azacyclopentadecan-15-one.

Azithromycin 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 C

, and its molecular weight is

749.00. Azithromycin has the following structural formula:

Azithromycin, as the dihydrate, is a white crystalline powder with a molecular formula of C

· 2H

O and a

molecular weight of 785.0.

ZITHROMAX

I.V. consists of azithromycin dihydrate and the following inactive ingredients: citric acid and sodium

hydroxide. ZITHROMAX

I.V. is supplied in lyophilized form in a 10 mL vial equivalent to 500 mg of azithromycin for

intravenous administration. Reconstitution, according to label directions, results in approximately 5 mL of ZITHROMAX

I.V. with each mL containing azithromycin dihydrate equivalent to 100 mg of azithromycin.

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12

CLINICAL PHARMACOLOGY

12.1

Mechanism of Action

Azithromycin is a macrolide antibacterial drug [ see Microbiology (12.4)].

12.2

Pharmacodynamics

Based on animal models of infection, the antibacterial activity of azithromycin appears to correlate with the ratio of area

under the concentration-time curve to minimum inhibitory concentration (AUC/MIC) for certain pathogens (S. pneumoniae

and S. aureus). The principal pharmacokinetic/pharmacodynamic parameter best associated with clinical and

microbiological cure has not been elucidated in clinical trials with azithromycin.

Cardiac Electrophysiology

QTc interval prolongation was studied in a randomized, placebo-controlled parallel

trial in

116 healthy subjects who

received either chloroquine (1000 mg) alone or in combination with oral azithromycin (500 mg, 1000 mg, and 1500 mg

once daily). Co- administration of azithromycin increased the QTc interval in a dose- and concentration- dependent

manner. In comparison to chloroquine alone, the maximum mean (95% upper confidence bound) increases in QTcF were 5

(10) ms, 7 (12) ms and 9 (14) ms with the co-administration of 500 mg, 1000 mg and 1500 mg azithromycin, respectively.

Since the mean C

of azithromycin following a 500 mg IV dose given over 1 hr is higher than the mean C

azithromycin following the administration of a 1500 mg oral dose, it is possible that QTc may be prolonged to a greater

extent with IV azithromycin at close proximity to a one hour infusion of 500 mg.

12.3

Pharmacokinetics

In patients hospitalized 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 C

± S.D. achieved was 3.63 ± 1.60 mcg/mL,

while the 24-hour trough level was 0.20 ± 0.15 mcg/mL, and the AUC

was 9.60 ± 4.80 mcg·hr/mL.

The mean C

, 24-hour trough and AUC

values were 1.14 ± 0.14 mcg/mL, 0.18 ± 0.02 mcg/mL, and 8.03

±0.86 mcg·hr/mL, respectively, in normal volunteers receiving a 3-hour intravenous 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.

Infusion

Concentration,

Duration

Time after starting the infusion (hr)

0.5

1

2

3

4

6

8

12

24

2 mg/mL, 1 hr

a

2.98

±1.12

3.63

±1.73

0.60

±0.31

0.40

±0.23

0.33

±0.16

0.26

±0.14

0.27±0.15

0.20

±0.12

0.20

±0.15

1 mg/mL, 3 hr

b

0.91

±0.13

1.02

±0.11

1.14

±0.13

1.13

±0.16

0.32

±0.05

0.28

±0.04

0.27±0.03

0.22

±0.02

0.18

±0.02

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

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

Comparison of the plasma pharmacokinetic parameters following the 1st and 5th daily doses of 500 mg intravenous

azithromycin showed only an 8% increase in C

but a 61% increase in AUC

reflecting a threefold rise in C

trough

levels.

Following single-oral doses of 500 mg azithromycin (two 250 mg capsules) to 12 healthy volunteers, C

, trough level,

and AUC

were reported to be 0.41 mcg/mL, 0.05 mcg/mL, and 2.6 mcg·hr/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 (C

1.08 mcg/mL, trough: 0.06 mcg/mL, and AUC

: 5.0 mcg·hr/mL). Thus, plasma concentrations are higher following the

intravenous regimen throughout the 24-hour interval.

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Distribution

The serum protein binding of azithromycin is variable in the concentration range approximating human exposure,

decreasing from 51% at 0.02 mcg/mL to 7% at 2 mcg/mL.

Tissue concentrations have not been obtained following intravenous infusions of azithromycin, but following oral

administration in humans azithromycin has been shown to penetrate into tissues, including skin, lung, tonsil, and cervix.

Tissue levels were determined following a single oral dose of 500 mg azithromycin in 7 gynecological patients.

Approximately 17 hr after dosing, azithromycin concentrations were 2.7 mcg/g in ovarian tissue, 3.5 mcg/g in uterine

tissue, and 3.3 mcg/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 mcg/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 IV doses declined in a polyphasic pattern with a

mean apparent plasma clearance of 630 mL/min and terminal elimination half-life of 68 hr. The prolonged terminal half-life

is thought to be due to extensive uptake and subsequent release of drug from tissues.

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 hr 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. Biliary excretion is a major route of elimination for unchanged drug, following oral

administration.

Specific Populations

Patients with Renal Impairment

Azithromycin 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 1,000 mg dose of azithromycin, mean C

and AUC

0-120

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 C

and AUC

0-120

increased 61% and

35%, respectively in subjects with severe renal impairment (GFR <10 mL/min) compared to subjects with normal renal

function (GFR >80 mL/min).

Patients with Hepatic Impairment

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

Male and Female Patients

There are no significant differences in the disposition of azithromycin between male and female subjects. No dosage

adjustment is recommended based on gender.

Geriatric Patients

Pharmacokinetic studies with intravenous azithromycin have not been performed in older volunteers. Pharmacokinetics of

azithromycin 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. [see Geriatric Use 8.4 )].

Pediatric Patients

Pharmacokinetic studies with intravenous azithromycin have not been performed in children.

Drug Interaction Studies

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 1 and the effects of other

drugs on the pharmacokinetics of azithromycin are shown in Table 2.

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Co-administration of azithromycin at therapeutic doses had a modest effect on the pharmacokinetics of the drugs listed in

Table 1. No dosage adjustment of drugs listed in Table 1 is recommended when co-administered with azithromycin.

Co-administration of azithromycin with efavirenz or fluconazole had a modest effect on the pharmacokinetics of

azithromycin. Nelfinavir significantly increased the C

and AUC of azithromycin. No dosage adjustment of azithromycin

is recommended when administered with drugs listed in Table 2 [see Drug Interactions (7.3)].

Table 1. Drug Interactions: Pharmacokinetic Parameters for Co-administered Drugs in the Presence of

Azithromycin

Co-

administered

Drug

Dose of Co-administered

Drug

Dose of Azithromycin

n

Ratio (with/without

azithromycin) of Co-

administered Drug

Pharmacokinetic Parameters

(90% CI); No Effect = 1.00

Mean C

max

Mean AUC

Atorvastatin

10 mg/day for 8 days

500 mg/day orally on days 6-8

0.83

(0.63 to 1.08)

1.01

(0.81 to 1.25)

Carbamazepine

200 mg/day for 2 days,

then 200 mg twice a day

for 18 days

500 mg/day orally for days 16-

0.97

(0.88 to 1.06)

0.96

(0.88 to 1.06)

Cetirizine

20 mg/day for 11 days

500 mg orally on day 7, then

250 mg/day on days 8-11

1.03

(0.93 to 1.14)

1.02

(0.92 to 1.13)

Didanosine

200 mg orally twice a day

for 21 days

1,200 mg/day orally on days 8-

1.44

(0.85 to 2.43)

1.14

(0.83 to 1.57)

Efavirenz

400 mg/day for 7 days

600 mg orally on day 7

1.04*

0.95*

Fluconazole

200 mg orally single dose

1,200 mg orally single dose

1.04

(0.98 to 1.11)

1.01

(0.97 to 1.05)

Indinavir

800 mg three times a day

for 5 days

1,200 mg orally on day 5

0.96

(0.86 to 1.08)

0.90

(0.81 to 1.00)

Midazolam

15 mg orally on day 3

500 mg/day orally for 3 days

1.27

(0.89 to 1.81)

1.26

(1.01 to 1.56)

Nelfinavir

750 mg three times a day

for 11 days

1,200 mg orally on day 9

0.90

(0.81 to 1.01)

0.85

(0.78 to 0.93)

Sildenafil

100 mg on days 1 and 4

500 mg/day orally for 3 days

1.16

(0.86 to 1.57)

0.92

(0.75 to 1.12)

Theophylline

4 mg/kg IV on days 1, 11,

500 mg orally on day 7, 250

mg/day on days 8-11

1.19

(1.02 to 1.40)

1.02

(0.86 to 1.22)

Theophylline

300 mg orally BID

days

500 mg orally on day 6, then

250 mg/day on days 7-10

1.09

(0.92 to 1.29)

1.08

(0.89 to 1.31)

Triazolam

0.125 mg on day 2

500 mg orally on day 1, then

250 mg/day on day 2

1.06*

1.02*

Trimethoprim/

Sulfamethoxazol

160 mg/800 mg/day orally

for 7 days

1,200 mg orally on day 7

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 orally for 21

days

600 mg/day orally for 14 days

1.12

(0.42 to 3.02)

0.94

(0.52 to 1.70)

Zidovudine

500 mg/day orally for 21

days

1,200 mg/day orally for 14 days

1.31

(0.43 to 3.97)

1.30

(0.69 to 2.43)

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* - 90% Confidence interval not reported

Table 2. Drug Interactions: Pharmacokinetic Parameters for Azithromycin in the Presence of Co-administered

Drugs [see Drug Interactions (7.3)].

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 C

max

Mean AUC

Efavirenz

400 mg/day for 7 days

600 mg orally on day

1.22

(1.04 to 1.42)

0.92*

Fluconazole

200 mg orally single

dose

1,200 mg orally single

dose

0.82

(0.66 to 1.02)

1.07

(0.94 to 1.22)

Nelfinavir

750 mg three times a

day for 11 days

1,200 mg orally on

day 9

2.36

(1.77 to 3.15)

2.12

(1.80 to 2.50)

* - 90% Confidence interval not reported

12.4

Microbiology

Mechanism of Action

Azithromycin acts by binding to the 23S rRNA of the 50S ribosomal subunit of susceptible microorganisms inhibiting

bacterial protein synthesis and impeding the assembly of the 50S ribosomal subunit.

Resistance

Azithromycin demonstrates cross-resistance with erythromycin. The most frequently encountered mechanism of

resistance to azithromycin is modification of the 23S rRNA target, most often by methylation. Ribosomal modifications can

determine cross resistance to other macrolides, lincosamides and streptogramin B (MLSB phenotype).

Antimicrobial Activity

Azithromycin has been shown to be active against the following microorganisms, both in vitro and in clinical infections.

[see Indications and Usage (1)]

Gram-positive Bacteria

Staphylococcus aureus

Streptococcus pneumoniae

Gram-negative Bacteria

Haemophilus influenzae

Moraxella catarrhalis

Neisseria gonorrhoeae

Legionella pneumophila

Other Bacteria

Chlamydophila pneumoniae

Chlamydia trachomatis

Mycoplasma hominis

Mycoplasma pneumoniae

The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following

bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for

azithromycin against isolates of similar genus or organism group. However, the efficacy of azithromycin in treating clinical

infections caused by these bacteria has not been established in adequate and well controlled clinical trials.

Aerobic Gram Positive Bacteria

Streptococci (Groups C, F, G)

Viridans group streptococci

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Gram Negative Bacteria

Bordetella pertussis

Anaerobic Bacteria

Peptostreptococcus species

Prevotella bivia

Other Bacteria

Ureaplasma urealyticum

Susceptibility Testing

For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control

standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

13

NONCLINICAL TOXICOLOGY

13.1

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been performed to evaluate carcinogenic potential. Azithromycin has shown no

mutagenic potential in standard laboratory tests: mouse lymphoma assay, human lymphocyte clastogenic assay, and

mouse bone marrow clastogenic assay.). In fertility studies conducted in male and female rats, oral administration of

azithromycin for 64 to 66 days (males) or 15 days (females) prior to and during cohabitation resulted in decreased

pregnancy rate at 20 and 30 mg/kg/day when both males and females were treated with azithromycin. This minimal effect

on pregnancy rate (approximately 12% reduction compared to concurrent controls) did not become more pronounced

when the dose was increased from 20 to 30 mg/kg/day (approximately 0.4 to 0.6 times the adult daily dose of 500 mg

based on body surface area) and it was not observed when only one animal in the mated pair was treated. There were no

effects on any other reproductive parameters, and there were no effects on fertility at 10 mg/kg/day. The relevance of

these findings to patients being treated with azithromycin at the doses and durations recommended in the prescribing

information is uncertain.

13.2

Animal Toxicology and/or Pharmacology

Phospholipidosis (intracellular phospholipid accumulation) has been observed in some tissues of mice, rats, and dogs

given multiple oral doses of azithromycin. It has been demonstrated in numerous organ systems (e.g., eye, dorsal root

ganglia, liver, gallbladder, kidney, spleen, and/or pancreas) in dogs and rats treated with azithromycin at doses which,

expressed on the basis of body surface area, are similar to or less than the highest recommended adult human dose. This

effect has been shown to be reversible after cessation of azithromycin treatment. Based on the pharmacokinetic data,

phospholipidosis has been seen in the rat (50 mg/kg/day dose) at the observed maximal plasma concentration of

1.3 mcg/mL (1.6 times the observed C

of 0.821 mcg /mL at the adult dose of 2 g.) Similarly, it has been shown in the

dog (10 mg/kg/day dose) at the observed maximal serum concentration of 1 mcg /mL (1.2 times the observed C

0.821 mcg /mL at the adult dose of 2 g).

Phospholipidosis was also observed in neonatal rats dosed for 18 days at 30 mg/kg/day, which is less than the pediatric

dose of 60 mg/kg based on body surface area. It was not observed in neonatal rats treated for 10 days at 40 mg/kg/day

with mean maximal serum concentrations of 1.86 mcg /ml, approximately 1.5 times the C

of 1.27 mcg/ml at the

pediatric dose. Phospholipidosis has been observed in neonatal dogs (10 mg/kg/day) at maximum mean whole blood

concentrations of 3.54 mcg /ml, approximately 3 times the pediatric dose C

. The significance of the findings for animals

and for humans is unknown.

14

CLINICAL STUDIES

14.1

Community-Acquired Pneumonia

In a controlled trial of community-acquired pneumonia performed in the U.S., azithromycin (500 mg as a single daily dose

by the intravenous route for 2 to 5 days, followed by 500 mg/day by the oral route to complete 7 to 10 days therapy) was

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compared to cefuroxime (2250 mg/day in three divided doses by the intravenous route for 2 to 5 days followed by

1000 mg/day in two divided doses by the oral route to complete 7 to 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 to 14 days post-therapy were as follows:

Clinical Outcome

Azithromycin

Comparator

Cure

Improved

Success (Cure + Improved)

In a separate, uncontrolled clinical and microbiological trial performed in the U.S., 94 patients with community-acquired

pneumonia who received azithromycin 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 to 14 days post-therapy were

as follows:

Clinical Outcome

Azithromycin

Cure

Improved

Success (Cure + Improved)

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:

(at last completed visit)

Azithromycin

S. pneumoniae

64/67 (96%)

H. influenzae

41/43 (95%)

M. catarrhalis

9/10 (90%)

S. aureus

9/10 (90%)

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 to 14 days post-therapy for patients treated with azithromycin with evidence

(serology and/or culture) of atypical pathogens for both trials were as follows:

Evidence of Infection

Total

Cure

Improved

Cure + Improved

Mycoplasma

pneumoniae

11 (61%)

5 (28%)

16 (89%)

Chlamydia

pneumoniae

15 (44%)

13 (38%)

28 (82%)

Legionella

pneumophila

5 (31%)

8 (50%)

13 (81%)

15

HOW SUPPLIED/STORAGE AND HANDLING

ZITHROMAX

I.V. is packaged in 10 ml type I flint tubular glass vial and closed with gray bromobutyl rubber stopper and

flip-off aluminum seal.

List of excipients

citric acid (anhydrous) 384.6 mg/vial, sodium hydroxide 198.3 mg/vial and water for injection.

Incompatibilities

Other intravenous substances, additives or medications should not be added to intravenous azithromycin, or infused

simultaneously through the same intravenous line.

Shelf-Life

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The expiry date of the product is indicated on the packaging materials.

For storage and shelf life information after reconstitution, see Special Precautions for Storage

Special Precautions for Storage

Store the vial below 30

After reconstitution:

When diluted according to the instructions, the diluted solution is chemically and physically stable for 24 hours at or below

C or for 7 days if stored under refrigeration 2 ºC - 8ºC,

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 -

8ºC, unless reconstitution and dilution has taken place in controlled and validated aseptic conditions.

16 MANUFACTURER:

Fareva Amboise, Poce-Sur-Cisse, France.

17 LICENSE HOLDER: Pfizer PFE Pharmaceuticals Israel Ltd., 9 Shenkar St., Herzliya Pituach 46725.

18 LICENSE NUMBER: 124-14-30374

The content of this leaflet was approved by the Ministry of Health in March 2016 and updated according to the guidelines

of the Ministry of Health in June 2019