ZITROGRAM 500 mg Tabletki Powlekane

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1. ZITROGRAM “500 mg film-coated tablets”

ZITROGRAM “500 mg film-coated tablets”

Azithromycin dihydrate
PHARMACOTHERAPEUTIC CATEGORY
Systemic antibiotics - 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 (due to Chlamydia trachomatis);
soft chancre (due to Haemophilus ducreyi).

CONTRAINDICATIONS
The use of the product is contraindicated in patients with hypersensitivity to azithromycin, erythromycin, any
macrolide or ketolide antibiotic, or any of the excipients.

PRECAUTIONS FOR USE
In patients with severe renal impairment (GFR < 10 ml/min.), a 33% increase in systemic exposure to
azithromycin has been observed.
No dosage adjustment is required in patients with mild to moderate renal impairment (GFR 10 – 80 ml/min.)
while caution is advised in those with severe impairment (GFR < 10 ml/min.).
Since the liver is the main route of elimination of azithromycin, its use in patients with significant liver
disease must be undertaken with caution by the doctor.
Cases of fulminant hepatitis, potentially causing liver failure constituting a life-threatening risk (see “Undesirable
Effects”) have been reported with azithromycin.
Some patients may have had pre-existing liver disease or may have been taking other hepatotoxic
medicines.
In cases where signs and symptoms of liver dysfunction develop, such as rapid-onset asthenia associated
with jaundice, dark urine, a tendency to bleed or hepatic encephalopathy, immediate analysis/diagnostic
tests for liver function should be performed.
The administration of azithromycin should be discontinued in case of liver dysfunction.
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 ergotamine
and azithromycin. However, due to the theoretical possibility of ergotism, azithromycin and ergotamine
should not be administered simultaneously.
As with any other antibiotic preparation, particular observation is recommended for the possible onset of
superinfections with non-sensitive microorganisms including fungi.
In the case of sexually transmitted infections, a concomitant infection with Treponema pallidum must be
excluded.

INTERACTIONS
Inform your doctor or pharmacist if you are taking, have recently taken or may take any other medicine,
including those without a prescription:
Azithromycin should be used with caution in patients taking medicines known to prolong the QT interval with
the potential to induce cardiac arrhythmia, such as hydroxychloroquine.

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 undergoing therapy with azithromycin and
antacids should not take the two medicines 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
It has been observed that 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 steady-state pharmacokinetics of
didanosine compared to placebo.

Digoxin (used for the treatment of heart failure)
It has been reported that the simultaneous administration of macrolide antibiotics, including azithromycin, with
P-glycoprotein substrates, such as digoxin, causes an increase in the levels of P-glycoprotein substrates in
serum.
Therefore, if azithromycin and P-glycoprotein substrates such as digoxin are administered simultaneously,
the possibility of an increase in the serum concentration of P-glycoprotein substrates should be considered.
Colchicine (used for gout and familial Mediterranean fever)

Zidovudine
The administration of single doses of 1000 mg and multiple doses of 1200 mg or 600 mg of azithromycin has
a minimal effect on the plasma pharmacokinetics or urinary excretion of zidovudine or its glucuronide
metabolite. However, the administration of azithromycin has determined an increase in the concentrations of
phosphorylated zidovudine, the clinically active metabolite of zidovudine, in peripheral mononuclear cells.
The clinical significance of this data is unclear, but it 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.

Ergotamine
Due to the possible onset of ergotism crises, the concomitant use of azithromycin and ergotamine derivatives is
not recommended (see section "Precautions for use").
Pharmacokinetic studies have been conducted between azithromycin and the following drugs, for which a
significant metabolic activity mediated by cytochrome P450 is known.

Statins
The concomitant administration of atorvastatin (10 mg/day) and azithromycin (500 mg/day) did not modify
the plasma concentration of atorvastatin (measured by testing for inhibition of HMG CoA reductase activity).
However, cases of rhabdomyolysis have been reported post-marketing in patients who have taken azithromycin in
association with statins.

Carbamazepine
In an 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 before azithromycin, no changes in the pharmacokinetics of azithromycin were found.

Cumarin-type oral anticoagulants
In an interaction pharmacokinetic study conducted on healthy volunteers, it was observed that azithromycin does
not modify the anticoagulant effect of a single dose of warfarin 15 mg.
In the post-marketing phase, 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-type 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.

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 the C and AUC values of cyclosporine were found.
Therefore, the possible concomitant administration of the two drugs requires caution. If the co-administration
of the two drugs is strictly necessary, the levels of cyclosporine and the dosage of the latter must be carefully
monitored and 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 C (18%) of azithromycin
clinically irrelevant was observed.

Indinavir
The concomitant administration of azithromycin (1200 mg) and indinavir at steady state (750 mg three times a
day) produced an increase in the concentrations of azithromycin.
No clinically significant adverse reactions were observed and no dosage adjustment is necessary.

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

Sildenafil
In healthy male volunteers, no effects of azithromycin (500 mg/day for 3 days) on the AUC and C of sildenafil
or its main circulating metabolite were found.

Terfenadine
Pharmacokinetic studies have not shown interactions between azithromycin and terfenadine.
Some rare cases have been reported in which the possibility of such an interaction could not be completely
excluded; however, there is no scientific evidence that the interaction has occurred.

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

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 and pharmacodynamic
variables of a single dose of triazolam.

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

SPECIAL WARNINGS
Hypersensitivity and anaphylactic reactions
As with erythromycin and other macrolides, serious allergic reactions, including
angioedema and anaphylaxis (rarely fatal), dermatological reactions including Stevens Johnson
syndrome (SJS), toxic epidermal necrolysis (TEN) (rarely fatal) and drug eruption with eosinophilia and systemic
symptoms (DRESS) have been rarely observed.
Some of these reactions associated with the administration of azithromycin have involved recurrences and
therefore require a prolonged period of observation and treatment. In case of an allergic reaction, the
drug must be discontinued and appropriate therapy must be instituted. Doctors must be
aware that the recurrence of allergic symptoms may occur once symptomatic therapy is stopped.
Diarrhea associated with Clostridium difficile
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 colon flora and leads to an overgrowth of C. difficile.
C. difficileproduces toxins A and B that contribute to the development of diarrhea associated with Clostridium
difficile (CDAD). Strains of C. difficilethat produce excess toxins cause an increase in rates of
morbidity and mortality, as these infections are generally refractory to antibacterial therapy and
often require colectomy. The possibility of CDAD should be considered in all patients who
present with diarrhea following antibiotic treatment. A careful medical history is also necessary as
cases of CDAD have been reported even more than two months after the administration of antibiotics.
Prolongation of the QT interval
In treatment with other macrolides, including azithromycin, a prolongation of
cardiac repolarization and the QT interval has been found, with the risk of developing cardiac arrhythmia and torsades de pointes
(see section Undesirable effects).
Therefore, since these conditions can determine a higher risk of ventricular arrhythmia
(including torsades de pointes) that can lead to cardiac arrest, azithromycin should be used with
caution in patients who present with pro-arrhythmic conditions in progress (especially women and the elderly) such as in
patients:

• with congenital or documented prolongation of the QT interval;
• undergoing treatment with other active ingredients that prolong the QT interval, such as class IA (quinidine and procainamide) and class III (dofetilide amiodarone and sotalol) antiarrhythmics, cisapride and terfenadine; antipsychotic agents such as pimozide; antidepressants such as citalopram and fluoroquinolones such as moxifloxacin, levofloxacin, chloroquine.
• with electrolyte alterations, especially in cases of hypokalemia and hypomagnesemia
• with clinically significant bradycardia, cardiac arrhythmia or severe heart failure.

Myasthenia Gravis
Exacerbation of symptoms of myasthenia gravis and the initial onset of myasthenic syndrome have been reported in patients treated with azithromycin.
The safety and efficacy for the prevention or treatment of infections caused by Mycobacterium Avium

Complexin children has not been demonstrated.

The tablets contain lactose.
If your doctor has diagnosed you with intolerance to some sugars, contact him before taking this
medicine.
The tablets contain lactose. Patients with rare hereditary galactose intolerance,
Lapp lactase deficiency, or glucose-galactose malabsorption should not take this
medicine.
Fertility, pregnancy and breastfeeding
Pregnancy
There is insufficient information on the safety of azithromycin taken during pregnancy. Therefore,
during pregnancy, your doctor will prescribe this medicine only if strictly necessary.
Breastfeeding
Azithromycin passes into breast milk. Therefore, in breastfeeding women, your doctor will prescribe this
medicine only if strictly necessary.
Fertility
In fertility studies conducted on rats, a reduction in fertility rate was noted following
administration of azithromycin. The relevance of this data is unknown for humans.

Effects on the ability to drive and operate machinery
There is no evidence that azithromycin could impair the ability to drive and operate
machinery.

DOSAGE, ADMINISTRATION AND DURATION OF TREATMENT

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 used in adult patients can be applied to the elderly patient.
Since elderly patients may be patients with pro-arrhythmic conditions in progress, particular
caution is recommended due to the risk of developing cardiac arrhythmia and torsades de pointes.

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.
ZITROGRAM can be taken indifferently on an empty stomach or after meals. Taking food
before administering the product may attenuate any gastrointestinal side effects caused by azithromycin.
The tablets must be swallowed whole.

OVERDOSAGE
Adverse events occurring with doses higher than those recommended have been similar to those recorded with
normal doses.
In case of accidental ingestion/intake of an excessive dose of ZITROGRAM, immediately
inform your doctor or go to the nearest hospital
If you have any doubts about the use of ZITROGRAM, consult your doctor or pharmacist

UNDESIRABLE EFFECTS
Like all medicines, ZITROGRAM can cause side effects, although not everyone
will experience them
The following table lists the adverse reactions identified during the conduct of
clinical studies and in post-marketing experience, divided by system and organ class and
frequency according to MedDRA (MedDRA SOCs). Frequency is defined using the following parameters:
very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to <
1/1000); very rare (<1/10000) and not known (frequency cannot be defined based on
available data). Within each frequency class, adverse effects are listed in order of
decreasing severity.

Adverse reactions with possible or probable correlation to azithromycin based on the results of
clinical studies and post-marketing experience.

Adverse reactions possibly or probably correlated to prophylaxis and treatment of
Mycobacterium Avium Complexbased on the results of clinical studies and post-marketing experience.

These adverse reactions differ from those reported by immediate or prolonged release formulations, both in type and frequency.

Reporting of suspected adverse reactions

If you experience any side effects, including those not listed in this leaflet, please inform your

doctor or pharmacist. Adverse reactions can also be reported directly through the

national reporting system at the addresswww.aifa.gov.it/content/segnalazioni-reazioni-avverse ”.

Reporting of suspected adverse reactions contributes to providing 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 ZITROGRAM after the expiry date stated on the label.
The expiry date refers to the product in intact packaging, correctly stored.
DO NOT USE IF THERE ARE OBVIOUS SIGNS OF DETERIORATION
No special storage conditions
KEEP ZITROGRAM OUT OF THE SIGHT AND REACH 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 base 500 mg.
Excipients: Anhydrous calcium hydrogen phosphate, pregelatinized starch, sodium lauryl sulfate, croscarmellose sodium,
sodium carboxymethyl cellulose, magnesium stearate.
Coating: hypromellose (E464), titanium dioxide (E171), triacetin (E1518), lactose monohydrate.

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

MARKETING AUTHORISATION HOLDER
Aesculapius Farmaceutici S.r.l.- Via Cefalonia, 70 - 25124 Brescia

MANUFACTURER
Special Product’s Line S.P.A.- Via Fratta Rotonda Vado Largo, 1 – 03012 ANAGNI (FR)
October 2023