Aziprome

PACKAGE LEAFLET

NAME OF THE MEDICINAL PRODUCT
AZIPROME “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.
Azithromycin is generally contraindicated during pregnancy, lactation, and in early infancy (see "Pregnancy and lactation").
PRECAUTIONS FOR USE
In patients with severe renal impairment (GFR < 10 ml/min), a 33% increase in systemic exposure to azithromycin has been observed.
In patients with mild to moderate hepatic impairment, no significant changes in serum pharmacokinetics of azithromycin have been demonstrated compared to individuals with normal hepatic function. In these patients, urinary elimination of azithromycin appears to increase, likely as compensation for reduced hepatic clearance. However, since the liver represents the main route of elimination, caution under medical supervision is required when using azithromycin in patients with hepatic disease or hepatic impairment. Cases of fulminant hepatitis that may lead to life-threatening hepatic failure have been reported with azithromycin (see "Undesirable effects"). Some patients may have had pre-existing liver disease or may have been exposed to other hepatotoxic drugs. In case of signs and symptoms of liver dysfunction, such as rapid onset of fatigue associated with jaundice, dark urine, tendency to bleeding, or hepatic encephalopathy, liver function tests or further investigations should be performed immediately. Administration of azithromycin must be discontinued if liver dysfunction occurs.
If such tests reveal liver dysfunction, administration of azithromycin must be stopped.
In patients receiving ergotamine derivatives, concomitant administration of macrolide antibiotics has precipitated ergotism crises. Currently, there are no data available on the possibility of interaction between ergot and azithromycin. However, due to the theoretical risk of ergotism crises, azithromycin and ergot derivatives should not be administered simultaneously.
As with any other antibiotic preparation, particular attention should be paid to the possible emergence of superinfections with non-sensitive microorganisms, including fungi.
In case of sexually transmitted infections, concomitant infection with Treponema pallidum must be ruled out.
INTERACTIONS
Inform your doctor or pharmacist if you have recently taken any other medicines, including those without a prescription.
Antacids
In a pharmacokinetic study evaluating 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 showed no pharmacokinetic interactions or significant changes in QT interval.
Didanosine (Dideoxyinosine)
Concomitant 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 [P-glycoprotein (P-gp) substrates]
Concomitant administration of macrolide antibiotics, including azithromycin, with P-glycoprotein substrates such as digoxin has been reported to cause increased serum levels of the P-glycoprotein substrate. Therefore, if azithromycin and P-glycoprotein substrates such as digoxin are administered concomitantly, the possibility of elevated substrate serum levels should be considered.
Some macrolide antibiotics may impair, in some patients, the microbial metabolism of digoxin at the intestinal level.
Ergotamine
Due to the possible occurrence of ergotism crises, 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 known to undergo significant cytochrome P450-mediated metabolism.
Zidovudine
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, administration of azithromycin resulted in increased concentrations of zidovudine triphosphate, its clinically active metabolite, in peripheral mononuclear cells. The clinical significance of this finding is unclear, but it may represent a benefit for the patient.
Azithromycin does not significantly interact with the hepatic cytochrome P450 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.
Atorvastatin
Concomitant administration of atorvastatin (10 mg/day) and azithromycin (500 mg/day) did not alter the plasma concentration of atorvastatin (based on an assay measuring HMG-CoA reductase inhibitory activity). However, post-marketing cases of rhabdomyolysis have been reported in patients receiving azithromycin and statins.
Carbamazepine
In a pharmacokinetic 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 evaluating 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 500 mg/day oral azithromycin for 3 days followed by a single oral dose of 10 mg/kg cyclosporine, significant increases in C_max and AUC_0-5 of cyclosporine were observed. Therefore, concomitant administration of the two drugs requires caution. If coadministration 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.
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 affected by concomitant administration of fluconazole, while a clinically irrelevant decrease in C_max (18%) was observed.
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 800 mg.
Metilprednisolone
A pharmacokinetic study 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 15 mg dose of midazolam.
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 required, careful monitoring for azithromycin side effects is advised.
Sildenafil
In healthy male volunteers, there was no evidence of an effect of azithromycin (500 mg/day for 3 days) on AUC and C_max of sildenafil or its main circulating metabolites.
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 concomitantly; although neutropenia is known to occur with rifabutin, a causal relationship between these neutropenia episodes 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 simultaneously, but a definite correlation could not be established or ruled out.
Triazolam
In 14 healthy volunteers, concomitant administration of azithromycin 500 mg on Day 1 and 250 mg on Day 2, together with triazolam 0.125 mg on Day 2, had no significant effects on triazolam pharmacokinetic variables 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 Day 7 on peak concentrations, exposure time, or urinary excretion of either trimethoprim or sulfamethoxazole. Azithromycin serum concentrations were similar to those observed in other studies.
Oral anticoagulants of the coumarin type
In a pharmacokinetic study in healthy volunteers, azithromycin did not alter the anticoagulant effect of a single 15 mg dose of warfarin.
In the post-marketing phase, cases of enhanced anticoagulant effect following concomitant administration of azithromycin and oral coumarin-type anticoagulants have been reported. Although a causal relationship has not been established, it is advisable to reassess the frequency of monitoring prothrombin time when azithromycin is administered to patients receiving coumarin-type anticoagulants.
Regarding concomitant use of azithromycin and other drugs affecting coagulation, since specific interaction studies have not been conducted, careful monitoring of patients taking these drugs in combination is recommended.
SPECIAL WARNINGS
As with erythromycin and other macrolides, severe allergic reactions, including angioedema and anaphylaxis (rarely fatal), have been rarely reported. These reactions may recur, even in the absence of re-exposure to the drug, after discontinuation of symptomatic treatment.
Some of these reactions with azithromycin have led to recurrent symptoms and require a prolonged period of observation and treatment.
These reactions require discontinuation of the drug and initiation of symptomatic treatment followed by a prolonged observation period.
With the use of nearly all antibiotics, including azithromycin, cases of Clostridium difficile-associated diarrhea (CDAD) have been reported, 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 CDAD. Strains of C. difficile 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.
With treatment using other macrolides, including azithromycin, prolongation of cardiac repolarization and QT interval has been observed, with risk of developing cardiac arrhythmia and torsades de pointes. Therefore, as the following conditions may increase the risk of ventricular arrhythmias (including torsades de pointes), which may lead to cardiac arrest, azithromycin should be used with caution in patients with ongoing proarrhythmic conditions (especially women and elderly patients), such as:

• Congenital or documented QT interval prolongation
• Currently receiving other active substances known to prolong the QT interval, such as class IA antiarrhythmics (quinidine, procainamide) and class III (amiodarone, dofetilide, sotalol), cisapride, and terfenadine; antipsychotic agents such as pimozide; antidepressants such as citalopram; and fluoroquinolones such as moxifloxacin and levofloxacin.
• Electrolyte disturbances, particularly hypokalemia and hypomagnesemia.
• Clinically significant bradycardia, cardiac arrhythmia, or severe heart failure.

In patients with a higher risk of cardiac repolarization prolongation, a similar effect with azithromycin cannot be entirely ruled out (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 for prevention and treatment of Mycobacterium avium complex infection in children have not been established.
Pregnancy and lactation
The risk of harmful effects on the fetus and/or child following azithromycin intake is not excluded.
Animal reproduction studies have been conducted using escalating doses up to toxic maternal concentrations. These studies showed no evidence of fetal risk 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 was shown to cross the placenta, but no teratogenic effects were observed. The safety of azithromycin regarding its use during pregnancy has not been confirmed.
Therefore, azithromycin should be used during pregnancy only if the benefit outweighs the risk.
It has been reported that azithromycin is excreted in human milk, but there are no adequate and well-controlled clinical studies in lactating women characterizing the pharmacokinetics of azithromycin excretion in breast milk.
AZIPROME should therefore be used in women during lactation and in early infancy only when potential benefits clearly outweigh the risks and under medical supervision.
Fertility
In fertility studies conducted in rats, reduced pregnancy rates were observed following administration of azithromycin. The relevance of these findings to humans is unknown.
Consult your doctor or pharmacist before taking any medicine.
Effects on ability to drive vehicles and use machinery
No effects of azithromycin on the ability to drive vehicles and use machinery have been reported.
Important information about some excipients of AZIPROME
Caution: the medicine contains lactose: If your doctor has diagnosed you with an intolerance to certain sugars, contact him before taking this medicine.
DOSAGE, METHOD, AND DURATION OF ADMINISTRATION
Adults
For 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 treatment of sexually transmitted diseases caused by susceptible strains of Chlamydia trachomatis or Haemophilus ducreyi: 1000 mg as a single oral dose.
Elderly
The same dosing regimen as for adult patients may be applied to elderly patients. Since elderly patients may have 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 for adults may be used (500 mg/day for three consecutive days).
The maximum recommended total dose for any pediatric therapy is 1500 mg.
The drug should always be administered as a single daily dose.
AZIPROME may be taken either on an empty stomach or after meals. Taking food before administration of the product may reduce potential gastrointestinal adverse effects caused by azithromycin.
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). However, caution is advised in patients with severe renal impairment (GFR < 10 ml/min) (see "Precautions for use").
Hepatic impairment
In patients with mild to moderate hepatic impairment, the same dosage as for patients with normal hepatic function may be used (see "Precautions for use").
OVERDOSE
Adverse events occurring with doses higher than recommended have been 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 AZIPROME, contact your doctor immediately or go to the nearest hospital.
EFFECTS DUE TO TREATMENT INTERRUPTION
If you have any doubts about the use of AZIPROME, consult your doctor or pharmacist.
UNDESIRABLE EFFECTS
Like all medicines, AZIPROME can cause undesirable effects, although not everyone experiences them.
The following table lists adverse reactions identified through clinical studies and post-marketing surveillance, classified by system organ class 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 (frequency cannot be estimated from available data). Within each frequency category, undesirable effects are listed in decreasing order of severity.
Adverse reactions possibly or probably related to azithromycin based on clinical trial and post-marketing surveillance experience

mouth
Salivary
hypersecretion
Hepatobiliary Liver function abnormal liver
disorders Jaundice cholestatic rarely
hepatic insufficiency (which has
caused death) (see
Special
warnings and
precautions for
use)
Fulminant hepatitis
Hepatic necrosis
Skin and
subcutaneous
tissue disorders
Skin rash Photosensitivity Reactions Stevens-Johnson
Pruritus syndrome
Urticaria Erythema
Dermatitis multiforme
Skin dryness
Hyperhidrosis Toxic epidermal
necrolysis
Musculoskeletal Osteoarthritis Arthralgia
and connective Myalgia
tissue disorders Back pain
Neck pain
Renal and Disuria Acute renal
urinary disorders Renal pain failure
Interstitial nephritis
Reproductive
system and
breast disorders
Metrorrhagia
Testicular disorders
Systemic Injection site Pain at injection
disorders and reactions* site*
administration- Inflammation at Astenia
related injection site* Malaise
conditions Fatigue
Facial swelling
Chest pain
Pyrexia
Pain
Peripheral edema
Investigations Decrease in Increased aspartate
lymphocyte count aminotransferase
Increase in Increased alanine
eosinophil count aminotransferase
Decrease in

* for infusion solution powder only
Adverse reactions possibly or probably related to prophylaxis and treatment of infections
due to Mycobacterium Avium Complex based on clinical trial and post-marketing surveillance experience.
The following adverse reactions differ from those listed above for immediate-release or extended-release formulations,
based on type or frequency.

Following the instructions in this leaflet reduces the risk of adverse effects.
Reporting of adverse reactions
If you experience any adverse reaction, including those not listed in this leaflet, consult your doctor or pharmacist.
Adverse reactions can also be reported directly via the national reporting system at the website www.agenziafarmaco.gov.it/it/responsabili. Reporting adverse reactions helps provide more information on the safety of this medicine.
EXPIRY DATE AND STORAGE
Expiry date: see the date printed on the packaging.
Warning: Do not use AZIPROME after the expiry date stated on the label.
The expiry date refers to the product stored in its original, unopened packaging under appropriate storage conditions.
KEEP AZIPROME OUT OF THE SIGHT AND REACH OF CHILDREN
Medicines must not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer in 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
PROGE FARM S.r.l.
Largo Donegani 4/A
28100 Novara
MANUFACTURER
Bluepharma – Industria Farmacêutica S.A.
S. Martinho do Bispo – Coimbra
Portugal