PACKAGE LEAFLET

NAME OF THE MEDICINAL PRODUCT
AZEPTIN “500 mg film-coated tablets”
Azithromycin dihydrate
PHARMACOTHERAPEUTIC CATEGORY
Systemic antibacterial agents - Macrolides.
THERAPEUTIC INDICATIONS
Treatment of infections caused by microorganisms 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 (caused by Chlamydia trachomatis);
Chancroid (caused by 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 impairment.
WARNINGS AND PRECAUTIONS
Hypersensitivity
As with erythromycin and other macrolides, rare severe allergic reactions have been reported, including angioneurotic
edema and anaphylaxis (rarely fatal), dermatological reactions such as acute generalized exanthematous pustulosis (AGEP),
Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic
symptoms (DRESS). Some of these reactions associated with Azeptin have caused recurrent symptoms and required a prolonged
period of observation and treatment.
If an allergic reaction occurs, administration of the medicinal product must be discontinued and appropriate therapy
initiated. Physicians should be aware that allergic symptoms may reappear after symptomatic treatment has been
discontinued.
Hepatotoxicity
Since the liver is the main route of elimination of azithromycin, caution should be exercised when administering the
drug to patients with significant hepatic disease.
Cases of impaired liver function, hepatitis, cholestatic jaundice, hepatic necrosis and fulminant hepatitis have been
reported with azithromycin, potentially leading to liver failure, some of which have been fatal (see section 4.8). Some
patients may have had pre-existing liver disease or may have taken other hepatotoxic medicinal products. In cases where
signs and symptoms of liver dysfunction occur, such as rapid-onset fatigue associated with jaundice, dark urine,
bleeding tendency or hepatic encephalopathy, liver function tests/diagnostic examinations should be performed immediately.
Discontinue azithromycin treatment immediately if signs of liver dysfunction occur.
Infantile hypertrophic pyloric stenosis (IHPS)
Infantile hypertrophic pyloric stenosis (IHPS) has been reported following the use of azithromycin in neonates (treatment
up to day 42 of life). Parents and healthcare professionals should be advised to contact the physician if vomiting or
irritability occurs after feeding.
Ergotamine derivatives
In patients receiving ergotamine derivatives, co-administration of macrolide antibiotics has precipitated ergotism crises.
Currently, there are 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 concurrently.
As with any other antibiotic preparation, particular attention should be paid to the possible emergence of superinfections
with non-sensitive microorganisms, including fungi.
Clostridium difficile-associated diarrhea
Cases of Clostridium difficile-associated diarrhea (CDAD) have been reported with the use of nearly all antibiotics,
including azithromycin, with severity ranging from mild diarrhea to fatal colitis. Antibiotic treatment alters the normal
colonic flora, leading to overgrowth of C. difficile.
C. difficile produces toxins A and B, which contribute to the development of diarrhea. C. difficile strains producing
excess toxins are associated with increased morbidity and mortality rates, as these infections are often refractory to
antibacterial therapy and frequently require colectomy. C. difficile-associated diarrhea should be considered in all
patients presenting with diarrhea following antibiotic therapy. A careful medical history is also necessary, as cases of
C. difficile-associated diarrhea have been reported more than two months after antibiotic administration.
An increase of 33% in systemic exposure to azithromycin has been observed in patients with severe renal impairment (GFR < 10 ml/min) (see section 5.2).
QT interval prolongation
ECG findings of prolonged cardiac repolarization and QT interval have been observed during treatment with macrolides,
including azithromycin, increasing the risk of developing cardiac arrhythmias and torsade de pointes (see section 4.8).
Therefore, since the following conditions may increase the risk of ventricular arrhythmias (including torsade de pointes),
which may lead to cardiac arrest, azithromycin should be administered with caution in patients with concomitant proarrhythmic conditions (especially in women and elderly patients).
Prescribers should consider the risk of QT interval prolongation, which may be fatal, when evaluating the risk-benefit ratio of azithromycin in high-risk patient groups, such as:

Patients with congenital or documented QT interval prolongation;
Patients receiving other active substances that prolong the QT interval, such as Class IA (quinidine, procainamide) and Class III (dofetilide, amiodarone, sotalol) antiarrhythmics, cisapride and terfenadine, antipsychotics such as pimozide, antidepressants such as citalopram, fluoroquinolones such as moxifloxacin, levofloxacin and chloroquine.
Patients with electrolyte imbalances, especially hypokalemia and hypomagnesemia;
Patients with clinically significant bradycardia, cardiac arrhythmia or severe heart failure;
Women and elderly patients who may show greater sensitivity to drug-related effects on QT interval alteration.

Exacerbation of symptoms of myasthenia gravis and initial onset of myasthenic syndrome have been reported in patients receiving azithromycin (see section 4.8).
INTERACTIONS
Inform your doctor or pharmacist if you have recently taken any other medicinal products, including those without a prescription.
Antacids
In a pharmacokinetic study assessing the effects of concomitant administration of antacids and azithromycin, no effect on azithromycin bioavailability was observed, although a reduction of approximately 25% in peak serum concentrations was noted. Therefore, patients receiving azithromycin and antacids should not take the two drugs simultaneously.
Cetirizine
In healthy volunteers, concomitant administration of a 5-day regimen of azithromycin and cetirizine 20 mg at steady state did not reveal any pharmacokinetic interactions or significant changes in QT interval.
Didanosine
Concomitant administration of daily doses of azithromycin 1200 mg/day and didanosine 400 mg/day in 6 HIV-positive patients was observed to have no effect on the steady-state pharmacokinetics of didanosine compared to placebo.
Digoxin
Some macrolide antibiotics may impair the microbial metabolism of digoxin in the intestinal tract in some patients. Patients taking azithromycin and digoxin concurrently should be aware of the potential for increased digoxin levels.
Colchicine (used for gout and familial Mediterranean fever)
Ergotamine
Due to the possible occurrence of ergotism crises, concomitant use of azithromycin and ergotamine derivatives is not recommended (see "Precautions for use").
Zidovudine
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, administration of azithromycin resulted in increased concentrations of zidovudine monophosphate, its clinically active metabolite, in peripheral mononuclear cells. The clinical significance of this finding is unclear, but it may represent a potential benefit for the patient.
Azithromycin does not significantly interact with the hepatic cytochrome P450 enzyme system. It is not considered to be involved in pharmacokinetic interactions as observed with erythromycin and other macrolides. Indeed, azithromycin does not induce or inactivate hepatic cytochrome P450 via its metabolite complex.
Pharmacokinetic studies have been conducted between azithromycin and the following drugs, which are known to have significant metabolism mediated by cytochrome P450.
Atorvastatin
Concomitant administration of atorvastatin (10 mg/day) and azithromycin (500 mg/day) did not cause alterations in HMG-CoA reductase activity.
Carbamazepine
In an interaction study conducted in healthy volunteers, no significant effect on plasma levels of carbamazepine or its active metabolite was observed in patients taking azithromycin concomitantly.
Cimetidine
In a pharmacokinetic study assessing the effects of a single dose of cimetidine administered 2 hours apart from azithromycin, no alterations in azithromycin pharmacokinetics were observed.
Cyclosporine
In a pharmacokinetic study conducted in healthy volunteers who received an oral dose of 500 mg/day of azithromycin for 3 days followed by a single oral dose of 10 mg/kg of cyclosporine, significant increases in cyclosporine Cmax and AUC 0-5 values were observed. Therefore, caution is required if the two drugs are administered concomitantly. If co-administration is strictly necessary, cyclosporine levels should be closely monitored and its dosage adjusted accordingly.
Efavirenz
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.
No dosage adjustment is necessary when azithromycin is administered in combination with efavirenz.
Fluconazole
Concomitant administration of a single dose of azithromycin (1200 mg) did not alter the pharmacokinetics of a single dose of fluconazole (800 mg). Total exposure time and half-life of azithromycin were not influenced by concomitant administration of fluconazole, while a clinically irrelevant decrease in Cmax (18%) was observed. No dosage adjustment is necessary when azithromycin is administered in combination with fluconazole.
Indinavir
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 daily for 5 days at a dose of 800 mg. No dosage adjustment is necessary when azithromycin is administered in combination with indinavir.
Methylprednisolone
A pharmacokinetic study conducted in healthy volunteers showed that azithromycin does not significantly affect the pharmacokinetics of methylprednisolone.
Midazolam
In healthy volunteers, concomitant administration of azithromycin 500 mg/day for 3 days did not result in clinically significant changes in the pharmacokinetics and pharmacodynamics of a single dose of midazolam 15 mg.
Nelfinavir
Concomitant administration of azithromycin (1200 mg) and nelfinavir at steady state (750 mg three times daily) resulted in increased azithromycin concentrations. Although no clinically significant adverse reactions were observed and no dosage adjustment is necessary, careful monitoring of azithromycin side effects is advised.
Rifabutin
Concomitant administration of azithromycin and rifabutin does not alter serum concentrations of either drug.
Cases of neutropenia have been observed in some patients taking both drugs concurrently; although rifabutin is known to cause neutropenia, a causal relationship between these episodes of neutropenia and the rifabutin-azithromycin combination could not be established (see "Undesirable effects").
Theophylline
Concomitant administration of azithromycin and theophylline in 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 taking both drugs concomitantly, but a definite correlation could not be established or excluded.
Triazolam
In 12 healthy volunteers, concomitant administration of azithromycin 500 mg on day 1 and 250 mg on day 2 and triazolam 0.125 mg on day 2 had no significant effects on the pharmacokinetic variables of triazolam compared to triazolam and placebo.
Trimethoprim/Sulfamethoxazole
After 7 days of concomitant administration of trimethoprim/sulfamethoxazole (160 mg/800 mg) and azithromycin (1200 mg), no significant effect was observed on peak concentrations, exposure time or urinary excretion of either trimethoprim or sulfamethoxazole on day 7. Serum concentrations of azithromycin were similar to those observed in other studies. No dosage adjustment is necessary when azithromycin is administered in combination with trimethoprim/sulfamethoxazole.
Oral anticoagulants of the coumarin type
In a pharmacokinetic study conducted in healthy volunteers, azithromycin was observed not to alter the anticoagulant effect of a single 15 mg dose of warfarin.
In the post-marketing phase, cases of enhanced anticoagulant action have been reported following concomitant administration of azithromycin and oral coumarin-type anticoagulants. Although a causal relationship has not been established, it is advisable to reassess the frequency of monitoring prothrombin time when administering azithromycin to patients receiving coumarin-type anticoagulants.
Regarding the concomitant use of azithromycin and other drugs affecting coagulation, since no specific interaction studies have been conducted, careful monitoring is advised for patients taking these drugs in combination.
Pregnancy
Animal reproduction studies were conducted using escalating doses up to moderately maternally toxic concentrations. These studies showed no evidence of fetal risk due to azithromycin. In reproductive toxicity studies in animals, azithromycin was shown to cross the placenta, but no teratogenic effects were observed. However, adequate and well-controlled studies in pregnant women are not available. Since animal reproduction studies are not always predictive of human response, azithromycin should be used during pregnancy only if clearly needed.
Breastfeeding
Limited information available from published literature indicates that azithromycin is present in human milk at an estimated median daily dose between 0.1 and 0.7 mg/kg/day. No adverse effects have been observed in breastfed infants.
A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from azithromycin therapy, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the mother.
Fertility
In fertility studies conducted in rats, a reduction in the number of pregnancies was observed following administration of azithromycin. The relevance of these observations in humans is unknown.
Consult your doctor or pharmacist before taking any medicinal product.
Effects on ability to drive and use machines
There are no data demonstrating that azithromycin may affect patients' ability to drive vehicles or operate machinery.
Important information about certain excipients in AZEPTIN
Attention: The medicinal product contains lactose: If your doctor has diagnosed you with an intolerance to certain sugars, contact him/her before taking this medicinal product.
DOSAGE, METHOD AND DURATION OF ADMINISTRATION
Adults
For the treatment of upper and lower respiratory tract infections, skin and soft tissue infections, and odontostomatological infections: 500 mg once daily 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 as a single oral dose.
Elderly
The same dosing regimen may be applied to elderly patients.
Children
For children weighing 45 kg or more, the same adult dosage may be used (500 mg/day for three consecutive days).
The maximum total recommended dose for any pediatric therapy is 1500 mg.
The drug should always be administered as a single daily dose.
AZEPTIN may be taken with or without food. Taking food before administration of the product may reduce any gastrointestinal adverse effects caused by azithromycin.
The tablets should be swallowed whole.
Renal impairment
Dosage adjustment is not required in patients with mild to moderate renal impairment (GFR 10 - 80 ml/min). Caution is advised in patients with severe renal impairment (GFR < 10 ml/min) (see "Precautions for use").
Hepatic impairment
The same dosage as in patients with normal hepatic function may be used in patients with mild to moderate hepatic impairment (see "Precautions for use").
OVERDOSE
Adverse events occurring with doses higher than recommended were similar to those observed with normal doses. In case of overdose, appropriate general symptomatic and supportive measures are indicated.
In case of accidental ingestion/overdose of AZEPTIN, contact your doctor immediately or go to the nearest hospital.
EFFECTS DUE TO TREATMENT DISCONTINUATION
If you have any doubts about the use of AZEPTIN, consult your doctor or pharmacist.
UNDESIRABLE EFFECTS
Like all medicinal products, AZEPTIN can cause undesirable effects, although not everyone experiences them.
The following undesirable effects were reported in clinical trials:
Blood and lymphatic system: Transient episodes of mild neutropenia were observed in clinical trials, although a causal relationship with azithromycin was not established.
Ear and vestibular system: Following azithromycin administration, some episodes of altered auditory function, including hearing loss, deafness and/or tinnitus, have been observed, mostly in experimental studies using higher doses and longer durations than normally recommended. When patient follow-up information was available, these events were mostly reversible.
Gastrointestinal system: Nausea, vomiting, diarrhea, loose stools, abdominal discomfort (pain/cramps) and flatulence.
Hepatobiliary system: Altered liver function.
Skin and subcutaneous tissue: Allergic reactions including rash and angioedema have been reported.
In post-marketing experience, the following undesirable effects have been reported:
Infections: Moniliasis and vaginitis.
Blood and lymphatic system: Thrombocytopenia.
Immune system: Anaphylaxis (rarely fatal) (see "Precautions for use").
Metabolism and nutrition: Anorexia.
Psychiatric disorders: Aggressive behavior, irritability, agitation and anxiety.
Nervous system: Dizziness/mild vertigo, seizures (as observed with other macrolides), headache, somnolence, paresthesia, hyperactivity and syncope. Rare cases of altered and/or loss of taste and smell have occurred; however, a causal relationship has not been established.
Ear and vestibular system: Vertigo.
Cardiac disorders: As with other macrolides, some cases of palpitations and arrhythmias, including ventricular tachycardia, have been reported. Rare cases of QT interval prolongation and torsade de pointes have been reported. A causal relationship between azithromycin and these effects has not been established (see "Precautions for use").
Vascular system: Hypotension.
Gastrointestinal system: Vomiting/diarrhea (rarely dehydration), dyspepsia, constipation, pseudomembranous colitis, pancreatitis and rarely tongue discoloration.
Hepatobiliary system: Hepatitis and cholestatic jaundice have been reported. Rare cases of hepatic necrosis and liver failure, rarely resulting in patient death, have also been reported. A causal relationship has not been established.
Skin and subcutaneous tissue: Allergic reactions including pruritus, rash, photosensitivity, edema, urticaria and angioedema have been reported. Rare cases of severe skin reactions such as erythema multiforme, red scaly rash with pustule and blister formation (exanthematous pustulosis), drug rash with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported.
Musculoskeletal and connective tissue disorders: Arthralgia.
Renal and urinary system: Interstitial nephritis and acute renal failure have been reported.
General disorders: Cases of asthenia have been reported, although a causal relationship with azithromycin has not been established; fatigue and malaise.
If you experience any undesirable effect, including those not listed in this leaflet, contact your doctor or pharmacist. Undesirable effects can also be reported directly via the national reporting system at
http://www.agenziafarmaco.gov.it/content/come-segnalare-una-sospetta-reazione-avversa . Reporting of adverse effects helps provide more information on the safety of this medicinal product.
EXPIRY DATE AND STORAGE
Expiry date: see the date on the packaging.
Caution: Do not use AZEPTIN after the expiry date stated on the label.
The expiry date refers to the product in intact packaging, correctly stored.
KEEP AZEPTIN OUT OF THE SIGHT AND REACH OF CHILDREN
Medicinal products must not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicinal products you no longer use. This will help protect the environment.
COMPOSITION
Each film-coated tablet contains:
Active substance: 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, monohydrate lactose.
PHARMACEUTICAL FORM AND CONTENT
Film-coated tablets.
Blister pack containing 3 tablets of 500 mg.
MARKETING AUTHORISATION HOLDER
DYMALIFE PHARMACEUTICAL S.R.L. Via Bagnulo, 95 80063 Piano di Sorrento (Na)
MANUFACTURER
Bluepharma – Industria Farmaceutica S.A.
S. Martinho do Bispo – Coimbra
Portugal