AZIPROME 500 mg Film-Coated Tablets

MEDICINE NAME
AZIPROME “500 mg film-coated tablets”
Azithromycin dihydrate

PHARMACOTHERAPEUTIC CATEGORY
Antibacterial for systemic use - Macrolides.

THERAPEUTIC INDICATIONS
Treatment of infections caused by germs sensitive to azithromycin.
upper respiratory tract infections (including otitis media, sinusitis, tonsillitis and pharyngitis);
lower respiratory tract infections (including bronchitis and pneumonia);
odontostomatological infections;
skin and soft tissue infections;
non-gonococcal urethritis (from Chlamydia trachomatis);
soft chancre (from Haemophilus ducreyi).

CONTRAINDICATIONS
Hypersensitivity to the active substance or to any of the excipients. Hypersensitivity to erythromycin or to
any of the macrolide or ketolide antibiotics.
Severe hepatic insufficiency.
Azithromycin is generally contraindicated in pregnancy, during breastfeeding and in early
childhood (see "Pregnancy and breastfeeding").

PRECAUTIONS FOR USE
In patients with severe impairment of renal function (GFR < 10 ml/min.), an increase of 33% in systemic
exposure to azithromycin has been observed.
In patients with mild-to-moderate hepatic insufficiency, no evidence of significant changes in serum
azithromycin pharmacokinetics has been demonstrated compared to people with normal hepatic function. In
these patients, azithromycin elimination through the urine appears to increase, probably as compensation
for reduced hepatic clearance. However, since the liver represents the main route of elimination, caution
should be exercised, under medical supervision, in the use of azithromycin in patients with liver disease or
hepatic insufficiency. Cases of fulminant hepatitis that can lead to life-threatening hepatic failure have
been reported with azithromycin. (see “Undesirable effects”). Some patients may have had pre-existing
liver disease and that may have been developed by other hepatotoxic drugs. In case of signs and symptoms
of hepatic dysfunction, such as rapidly developing asthenia associated with jaundice, dark urine,
tendency to bleeding or hepatic encephalopathy, a liver function test or further investigations must be
performed immediately. The administration of azithromycin must be discontinued if hepatic dysfunction
emerges.
If hepatic dysfunction emerges from these tests, the administration of azithromycin must be interrupted.
In patients treated with ergotamine derivatives, the co-administration of macrolide antibiotics has
precipitated ergotism crises. Currently, there is no data available on the possibility of an interaction
between ergot and azithromycin. However, due to the theoretical possibility of ergotism crises, azithromycin
and ergotamine derivatives should not be administered simultaneously..
As with any other antibiotic preparation, particular observation is recommended for the possible occurrence of
superinfections with non-sensitive microorganisms including fungi.
In case of sexually transmitted infections, a concomitant infection with Treponema pallidum must be excluded.

INTERACTIONS
Inform your doctor or pharmacist if you have recently taken any other medicines, even those without a
prescription.

Antacids
In a pharmacokinetic study of the effects of the simultaneous administration of antacids and azithromycin,
no effect on the bioavailability of azithromycin was detected, although a reduction of approximately 25% in
peak serum concentrations was observed.
Therefore, patients taking azithromycin and antacids should not take the two drugs simultaneously.

Cetirizine
In healthy volunteers, the simultaneous administration of a 5-day regimen of azithromycin and cetirizine 20 mg
at steady state did not show pharmacokinetic interactions or significant alterations in the QT interval.

Didanosine (Dideoxyinosine)
The simultaneous administration of daily doses of azithromycin 1200 mg/day and didanosine 400 mg/day in 6
HIV-positive patients had no effect on the pharmacokinetics of didanosine at steady state compared to
placebo.

Digoxin [P-glycoprotein (P-gp) substrates]
The concomitant administration of macrolide antibiotics, including azithromycin, with P-glycoprotein
substrates such as digoxin, has been reported to cause an increase in serum levels of the P-glycoprotein
substrate. Therefore, if azithromycin and P-glycoprotein substrates such as digoxin are administered
concurrently, the possibility of elevated serum levels of the substrate must be considered.
Some macrolide antibiotics may impair the microbial metabolism of digoxin in some patients.

Ergotamine
Due to the possible occurrence of ergotism crises, the concomitant use of azithromycin and ergotamine
derivatives is not recommended (see "Precautions for use").
Pharmacokinetic studies have been conducted between azithromycin and the following compounds that are
known to be subject to significant cytochrome P450-mediated metabolism.

Zidovudine
The administration of single doses of 1000 mg and multiple doses of 1200 mg or 600 mg of azithromycin did
not substantially alter the plasma pharmacokinetics or urinary excretion of zidovudine or its glucuronide
metabolite. However, the administration of azithromycin determined an increase in the concentrations of
phosphorylated zidovudine, its clinically active metabolite, in peripheral mononuclear cells. The clinical
significance of this data is unclear, but may nevertheless constitute a benefit for the patient.
Azithromycin does not interact significantly with the hepatic cytochrome P450 system. It is not believed to be
involved in pharmacokinetic interactions as found with erythromycin and other macrolides. In fact, with
azithromycin, there is no induction or inactivation of hepatic cytochrome P450 through the complex of its
metabolites.

Atorvastatin
The concomitant administration of atorvastatin (10 mg/day) and azithromycin (500 mg/day) did not alter the
plasma concentration of atorvastatin (based on an assay of HMG CoA reductase inhibitory activity). However,
cases of rhabdomyolysis have been reported post-marketing in patients treated with azithromycin and statins.

Carbamazepine
In a pharmacokinetic interaction study conducted on healthy volunteers, no significant effect on plasma levels
of carbamazepine or its active metabolite was observed in patients taking azithromycin simultaneously.

Cimetidine
In a pharmacokinetic study conducted to evaluate the effects of a single dose of cimetidine administered 2 hours
after azithromycin, no alterations in the pharmacokinetics of azithromycin were found.

Cyclosporine
In a pharmacokinetic study conducted on healthy volunteers who were administered an oral dose of 500 mg/day
of azithromycin for 3 days and subsequently a single oral dose of 10 mg/kg of cyclosporine, significant
increases in Cmax and AUC0-5 values of cyclosporine were found. Therefore, the concomitant administration
of the two drugs requires caution. If the co-administration of the two drugs is strictly necessary, the levels of
cyclosporine should be carefully monitored and the dosage of the latter should be modified accordingly.

Efavirenz
The concomitant administration of a single daily dose of azithromycin (600 mg) and efavirenz (400 mg) for 7
days did not produce clinically significant pharmacokinetic interactions.

Fluconazole
The concomitant administration of a single dose of azithromycin (1200 mg) did not alter the pharmacokinetics
of a single dose of fluconazole (800 mg). The total exposure time and the half-life of azithromycin were not
affected by the simultaneous administration of fluconazole, while a decrease in Cmax (18%) clinically
irrelevant was observed. Indinavir
The concomitant administration of a single dose of azithromycin (1200 mg) did not show a statistically
significant effect on the pharmacokinetics of indinavir administered three times a day for 5 days at doses of
800 mg.

Methylprednisolone
A pharmacokinetic study conducted on healthy volunteers showed that azithromycin does not significantly
affect the pharmacokinetics of methylprednisolone.

Midazolam
In healthy volunteers, the concomitant administration of azithromycin 500 mg/day for 3 days did not lead to
clinically significant changes in the pharmacokinetics and pharmacodynamics of a single dose of midazolam 15
mg.

Nelfinavir
The concomitant administration of azithromycin (1200 mg) and nelfinavir at steady state (750 mg three times a
day) produced an increase in the concentrations of azithromycin. Although no clinically significant adverse
reactions were observed and no dosage adjustment is necessary, careful monitoring of the side effects of
azithromycin is recommended.

Sildenafil
In healthy male volunteers, there is no evidence of an effect of azithromycin (500 mg/day for 3 days) on the
AUC and Cmax values of sildenafil or its major circulating metabolites

Rifabutin
The concomitant administration of azithromycin and rifabutin does not alter the serum concentrations of the two
drugs.
Cases of neutropenia have been observed in some patients taking the two drugs simultaneously; although
rifabutin is known to cause neutropenia, it has not been possible to establish a causal relationship between
the aforementioned episodes of neutropenia and the rifabutin-azithromycin association (see "Undesirable
effects").

Theophylline
The simultaneous administration of azithromycin and theophylline to healthy volunteers did not show a
clinically significant interaction between the two drugs.

Terfenadine
Pharmacokinetic studies have not shown interactions between azithromycin and terfenadine. Rare cases of
interaction have occurred in patients who took the two drugs simultaneously, for which a certain correlation
could not be established or excluded.

Triazolam
In 14 healthy volunteers, the concomitant administration of azithromycin 500 mg on day 1 and 250 mg on day 2
and triazolam 0.125 mg on day 2 did not have significant effects on the pharmacokinetic variables of triazolam
compared to triazolam and placebo.

Trimethoprim/Sulfamethoxazole
After concomitant administration for 7 days of trimethoprim/sulfamethoxazole (160 mg/800 mg) and azithromycin
(1200 mg), no significant effect on peak concentrations, exposure time or urinary excretion of either
trimethoprim or sulfamethoxazole was found on day 7. Serum concentrations of azithromycin are similar to
those found in other studies.

Cumarin-type oral anticoagulants
In a pharmacokinetic study conducted on healthy volunteers, it was observed that azithromycin does not alter
the anticoagulant effect of a single dose of warfarin 15 mg.
In post-marketing, cases of potentiation of the anticoagulant action following the concomitant administration of
azithromycin and coumarin-type oral anticoagulants have been reported. Although a causal relationship has
not been established, it is advisable to re-evaluate the frequency with which to monitor prothrombin time when
administering azithromycin to patients receiving coumarin anticoagulants.
Regarding the concomitant use of azithromycin and other drugs that act on coagulation, as no specific
interaction studies have been conducted, careful monitoring of those patients taking the aforementioned drugs in
association is recommended.

SPECIAL WARNINGS
As with erythromycin and other macrolides, serious allergic reactions, including
angioedema and anaphylaxis (rarely fatal), have been rarely reported, which may recur, even in the absence of a new
drug intake, after discontinuation of symptomatic treatment.
Some of these reactions with azithromycin have led to recurring symptoms and require a long
period of observation and treatment.
These reactions require discontinuation of the drug and the initiation of symptomatic treatment
followed by a prolonged observation period.
With the use of almost all antibiotics, including azithromycin, cases of diarrhea associated with
Clostridium difficile (CDAD) have been reported, the severity of which can range from mild diarrhea to fatal colitis. Treatment with
antibiotics alters the normal flora of the colon and leads to an overgrowth of C. difficile.
C. difficile produces toxins A and B that contribute to the development of CDAD. Strains of C. difficile
that produce excess toxins cause an increase in morbidity and mortality rates, as these
infections are generally refractory to antibacterial therapy and often require colectomy.
The possibility of diarrhea associated with C. difficile should be considered in all patients who present
diarrhea following antibiotic treatment. A careful medical history is also necessary, as cases of
diarrhea associated with C. difficile have been reported even more than two months after the administration of
antibiotics.
In treatment with other macrolides, including azithromycin, a prolongation of the
cardiac repolarization and of the QT interval has been found, with the risk of developing cardiac arrhythmia and torsades de
pointes. Therefore, as the following situations can lead to an increase in the risk of ventricular arrhythmias (including torsades de
pointes) that can lead to cardiac arrest, azithromycin must
be used with caution in patients with ongoing proarrhythmic conditions (especially women and elderly patients), such as patients:

• With congenital or documented prolongation of the QT interval
• Currently being treated with other active ingredients known to prolong the QT interval, such as class IA antiarrhythmics (quinidine and procainamide) and class III (amiodarone dofetilide and sotalol), cisapride and terfenadine; antipsychotic agents, such as pimozide; antidepressants such as citalopram; and fluoroquinolones such as moxifloxacin and levofloxacin.
• With an electrolyte disturbance, in particular in cases of hypokalemia and hypomagnesemia.
• With clinically relevant bradycardia, cardiac arrhythmia or severe heart failure

In patients with a higher risk of prolongation of cardiac repolarization, an analogous effect with azithromycin cannot
be completely excluded (see "Undesirable effects").
Exacerbations of symptoms of myasthenia gravis and new onset of myasthenic syndrome have been reported in patients treated with azithromycin
(see "Undesirable effects")
The safety and efficacy of azithromycin in the prevention and treatment of
infection from Mycobacterium Avium Complex in children has not been established

Pregnancy and breastfeeding
The risk of harmful effects on the fetus and/or infant following the intake of azithromycin
cannot be excluded;
Reproduction studies have been conducted in animals using escalating doses up to reaching
maternal toxic concentrations. These studies showed no evidence of hazards to the fetus due to
azithromycin. However, adequate and well-controlled clinical studies on the use of
azithromycin in pregnant women are not available. In animal reproductive toxicity studies, azithromycin has
been shown to cross the placenta, but no teratogenic effects were observed. The safety of azithromycin regarding
the use of the active ingredient in pregnancy has not been confirmed.
Therefore, azithromycin should be used in pregnancy only if the benefit outweighs the risk.
Azithromycin has been reported to be secreted in breast milk, but there are no adequate and
well-controlled clinical studies in breastfeeding women that have characterized the pharmacokinetic excretion of
azithromycin in breast milk.
AZIPROME should therefore be used in women during breastfeeding and in early infancy
only if the potential benefits clearly outweigh the risks and under the control of the physician.
Fertility
In fertility studies conducted on rats, reduced pregnancy rates were noted following
administration of azithromycin. The relevance of these data in humans is unknown.
Ask your doctor or pharmacist for advice before taking any medicine

Effects on the ability to drive and operate machinery
No effects of azithromycin on the ability to drive and operate machinery have been reported.

Important information about some excipients of AZIPROME

Attention the medicine contains lactose:If your doctor has diagnosed you with an intolerance to some
sugars, contact him before taking this medicine.

DOSAGE, METHOD AND DURATION OF ADMINISTRATION

Adults
For the treatment of infections of the upper and lower respiratory tract, skin and soft tissues and
odontostomatological infections: 500 mg per day in a single dose, for three consecutive days.
For the treatment of sexually transmitted diseases, caused by sensitive strains of Chlamydia
trachomatis or Haemophilus ducreyi: 1000 mg, taken once, in a single oral dose.

Elderly
The same dosage regimen as adult patients can be applied to the elderly. Since
elderly patients may be patients with ongoing proarrhythmic conditions, particular caution is recommended due to the risk of developing cardiac arrhythmia and torsades de
pointes (see “Special warnings”)

Children
For children weighing 45 kg or more, the same dosage as adults can be used (500
mg/day for three consecutive days).
The maximum total dose recommended for any pediatric therapy is 1500 mg.
The drug must always be administered in a single daily dose.
AZIPROME can be taken indifferently on an empty stomach or after meals. Eating food
before administering the product may alleviate any gastrointestinal side effects caused by azithromycin.
The tablets must be swallowed whole.

Impaired renal function
No dosage adjustment is required in patients with mild to moderate impairment of renal function (GFR 10 - 80 ml/min.) while caution is advised in those with severe
impairment (GFR < 10 ml/min.) (see "Precautions for use").

Impaired hepatic function
In patients with mild to moderate impairment of hepatic function, the same dosage as patients with normal hepatic function can be used (see "Precautions for use").

OVERDOSE
Adverse events occurring with doses higher than those recommended have been similar to those recorded with
normal doses. In case of overdose, appropriate general symptomatic and supportive measures are indicated.
In case of accidental ingestion/intake of an excessive dose of AZIPROME, immediately warn
the doctor or go to the nearest hospital

EFFECTS DUE TO DISCONTINUATION OF TREATMENT
If you have any doubts about the use of AZIPROME, consult your doctor or pharmacist

UNDESIRABLE EFFECTS
Like all medicines, AZIPROME can cause side effects, although not everyone will
experience them
The following table lists the adverse reactions identified through clinical studies and post-
marketing surveillance with classification by systems and organs and frequency. Adverse reactions emerging from post-marketing
experience are reported in italics. The frequency group is defined using the following
convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100),
rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); and not known (the frequency cannot be defined
based on available data). Within each frequency class, adverse effects are
reported in decreasing order of severity.

Adverse reactions possibly or probably related to azithromycin based on the experience
of clinical studies and post-marketing surveillance

Mouth
Increased salivation

Hepato-biliary disorders
Hepatic insufficiency (which has rarely caused death) (see Special warnings and precautions for use)
Fulminant hepatitis
Necrotic hepatitis

Skin and subcutaneous tissue disorders
Abnormal liver function Cholestatic jaundice Skin rash Pruritus Urticaria Dermatitis Dry skin Hyperhidrosis Photosensitivity reactions Stevens-Johnson syndrome Toxic epidermal necrosis, multiforme erythema

Musculoskeletal and connective tissue disorders
Osteoarthritis Myalgia Back pain Neck pain Arthralgia

Renal and urinary disorders
Acute renal insufficiency Interstitial nephritis

Reproductive system and breast disorders
Dysuria Renal pain Metrorrhagia Testicular disorders

Systemic disorders and conditions related to the site of administration
Pain at the injection site *, inflammation at the injection site* Edema Asthenia Malaise Fatigue Facial edema Chest pain Fever Pain Peripheral edema

Laboratory testsDecrease in lymphocyte count Increase in eosinophil count Decrease Increase in aspartate aminotransferase Increase in alanine aminotransferase Increase in bilirubin in blood Increase in creatinine in blood Increase in blood urea Abnormal concentration of potassium in blood Increase in alkaline phosphatase Increase in chloride concentration in blood Increase in glucose concentration in blood Increase in platelets Increase in hematocrit Increase in bicarbonate concentration in blood Abnormal concentration of sodium in blood

* only for powder for solution for infusion

Adverse reactions possibly or probably related to the prophylaxis and treatment of infections
caused by Mycobacterium Avium Complex based on the experience of clinical studies and post-
marketing surveillance.
The following adverse reactions differ from those reported above with immediate or prolonged release
formulations, based on the type or frequency

Reporting of adverse reactions
If you experience any side effects, including those not listed in this leaflet, tell your
doctor or pharmacist. Adverse reactions can also be reported directly through
the national reporting system at www.agenziafarmaco.gov.it/it/responsabili”. The
reporting of adverse reactions helps to provide more information on the safety of
this medicine.”

EXPIRY DATE AND STORAGE
Expiry date: see the expiry date printed on the packaging.
Caution: Do not use AZIPROME after the expiry date that is reported on the label.
The expiry date refers to the product in intact packaging, correctly stored.
KEEP AZIPROME OUT OF THE REACH AND SIGHT OF CHILDREN
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist
how to dispose of medicines you no longer use. This will help protect the environment.

COMPOSITION
Each film-coated tablet contains:
Active ingredient :azithromycin dihydrate 524.1 mg equivalent to azithromycin 500 mg.
Excipients: Anhydrous calcium hydrogen phosphate, pregelatinized starch, sodium lauryl sulfate, crospovidone,
magnesium stearate.
Coating: hypromellose, titanium dioxide, triacetin, lactose monohydrate.

PHARMACEUTICAL FORM AND CONTENT
Film-coated tablets.
Blister containing 3 tablets of 500 mg.

MARKETING AUTHORISATION HOLDER
PROGE FARM S.r.l.
Largo Donegani 4/A
28100 Novara

MANUFACTURER
Bluepharma – Industria Farmaceutica S.A.

• S. Martinho do Bispo – Coimbra Portugal