Active ingredients: Azithromycin
AZITHROMYCIN DOC Generici 500 mg film-coated tablets
Why is Azithromycin - Generic Drug used? What is it for?
PHARMACOTHERAPEUTIC CATEGORY
Antibacterials for systemic use - Macrolides.
THERAPEUTIC INDICATIONS
- Treatment of infections caused by azithromycin-sensitive germs.
- 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 ulcer (from Haemophilus ducreyi).
Contraindications When Azithromycin - Generic Drug should not be used
The use of this product is contraindicated in patients with hypersensitivity to azithromycin, erythromycin, to any of the macrolide or ketolide antibiotics, or to any of the excipients.
Precautions for use What you need to know before taking Azithromycin - Generic Drug
In patients with severe renal impairment (GFR <10 ml / min), a 33% increase in systemic exposure to azithromycin was observed.
No dosage adjustment is required in patients with mild to moderate renal impairment (GFR 10 - 80 mL / min) while caution should be exercised in those with severe impairment (GFR <10 mL / min).
Since the liver is the major route of elimination of azithromycin, its use in patients with significant liver disease should be undertaken with caution by the physician.
Cases of fulminant hepatitis potentially leading to life-threatening liver failure have been reported with azithromycin (see "Side Effects"). Some of these patients may have suffered from pre-existing liver disease or may have taken other hepatotoxic medicines.
In cases where signs and symptoms of impaired liver function develop, such as rapid onset asthenia associated with jaundice, dark urine, bleeding tendency or hepatic encephalopathy, liver function tests / diagnostics should be performed immediately.
Administration of azithromycin should be discontinued if hepatic dysfunction emerges. In patients receiving ergotamine derivatives, co-administration of macrolide antibiotics has aggravated ergotism. 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 derivatives should not be administered simultaneously.
As with any other antibiotic preparation, particular attention is recommended to the signs relating to the onset of superinfections with non-sensitive microorganisms, including fungi.
In case of sexually transmitted infections it is necessary to exclude a concomitant infection with Treponema pallidum.Interactions Which drugs or foods can modify the effect of Azithromycin - Generic Drug
Tell 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 concomitant administration of antacids and azithromycin, no effect on the bioavailability of azithromycin was observed, although an approximately 25% reduction in maximum serum concentrations was observed. with azithromycin and antacids you should not take the two drugs at the same time.
Cetirizine
In healthy volunteers, co-administration of a 5-day regimen of azithromycin and 20 mg cetirizine at steady state did not reveal any pharmacokinetic interactions or significant alterations in the QT interval.
Didanosine (Dideoxinosine)
Co-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 (substrates of P-gp)
Concomitant administration of macrolide antibiotics, including azithromycin, and Pglycoprotein substrates such as digoxin, has been associated with increased serum levels of the Pglycoprotein substrate. Therefore, if azithromycin and P-gp substrates such as digoxin are administered simultaneously , the possibility of increased serum substrate concentrations should be considered. Some macrolide antibiotics may impair the microbial metabolism of digoxin in the intestine in some patients. digoxin.
Ergotamine
Due to the possible onset of ergotism, the concomitant use of azithromycin and ergotamine derivatives is not recommended (see "Precautions for use").
Zidovudine
Administration of single 1000 mg doses and multiple 1200 mg or 600 mg doses of azithromycin did not substantially alter the plasma pharmacokinetics or urinary excretion of zidovudine or its glucuronide metabolite. concentrations of phosphorylated zidovudine, its clinically active metabolite, in peripheral mononuclear blood cells. The clinical significance of this finding is unclear, but may nevertheless be of benefit to the patient.
Azithromycin does not significantly interact with the hepatic cytochrome P450 system. It is not expected 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. Pharmacokinetic studies have been conducted between azithromycin and the following drugs, for which significant cytochrome-mediated metabolic activity is known P450.
Atorvastatin
Concomitant administration of atorvastatin (10 mg / day) and azithromycin (500 mg / day) did not cause alterations in plasma concentrations of atorvastatin (based on an inhibition test of HMG CoA reductase activity). However, from subsequent experience At marketing, cases of rhabdomyolysis have been reported in patients taking azithromycin and statins at the same time.
Carbamazepine
In a pharmacokinetic interaction study conducted in healthy volunteers, no significant effect on the plasma levels of carbamazepine or its active metabolite was observed in patients taking concomitant azithromycin.
Cimetidine
In a pharmacokinetic study conducted to evaluate the effects of a single dose of cimetidine administered 2 hours prior to azithromycin, there was no evidence of alterations in the pharmacokinetics of azithromycin.
Ciclosporinto
Significant increases in Cmax and AUC0-5 of cyclosporine. Therefore, any concomitant administration of these two drugs requires caution. If co-administration of the two drugs is strictly necessary, cyclosporine levels should be carefully monitored and the dosage should be adjusted accordingly.
Efavirenz
Co-administration of a single daily dose of azithromycin (600 mg) and efavirenz (400 mg) for 7 days produced no clinically significant pharmacokinetic interactions.
Fluconazole
Coadministration 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 co-administration with fluconazole, while a clinically insignificant decrease in Cmax (18%) was observed.
Indinavir
Coadministration 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 in doses of 800 mg.
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 15 mg midazolam dose.
Nelfinavir
Concomitant administration of azithromycin (1200 mg) and nelfinavir at steady state (750 mg three times daily) resulted in increased azithromycin concentrations. No clinically significant adverse reactions were observed and no dose modification is required.
Rifabutin
Concomitant administration of azithromycin and rifabutin does not change the serum concentrations of the two drugs.
Cases of neutropenia have been observed in some patients taking azithromycin and rifabutin at the same time; although rifabutin is known to cause neutropenia, it has not been possible to establish a causal relationship between the above episodes of neutropenia and the combination rifabutinazithromycin (see "Undesirable effects").
Sildenafil
In healthy male volunteers there was no effect of azithromycin (500 mg / day for 3 days) on the AUC and Cmax of sildenafil or its major circulating metabolite.
Theophylline
Co-administration of azithromycin and theophylline to healthy volunteers did not show a clinically significant interaction between the two drugs.
Terfenadine
Pharmacokinetic studies revealed no 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 occurred.
Triazolam
In 14 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 effect 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), on day 7 there was no significant effect on peak concentrations, exposure or urinary excretion either. trimethoprim and sulfamethoxazole. Serum concentrations of azithromycin are similar to those found in other studies.
Coumarin-type oral anticoagulants
In a pharmacokinetic study in healthy volunteers, azithromycin was found not to alter the anticoagulant effect of a single 15 mg dose of warfarin.
In the post-marketing phase, cases of potentiation of anticoagulant action have been reported following the concomitant administration of azithromycin and coumarin-type oral anticoagulants. Although a causal relationship has not been established, it is recommended to re-evaluate the frequency with which to monitor the time to prothrombin when administering azithromycin to patients receiving coumarin-type anticoagulants.
Warnings It is important to know that:
Hypersensitivity and anaphylactic reactions
As with erythromycin and other macrolides, severe allergic reactions, including angioedema and anaphylaxis (rarely fatal), have been reported rarely. Some of these reactions with azithromycin have resulted in relapses and required a prolonged period of observation and treatment.
In the event of an allergic reaction, the drug should be discontinued and appropriate therapy instituted. Physicians should be aware that allergic symptoms may return once symptomatic therapy is discontinued.
Clostridium difficile associated diarrhea
Cases of Clostridium difficile associated diarrhea (CDAD) have been reported with the use of nearly all antibiotics, including azithromycin, ranging in severity 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 which contribute to the development of diarrhea. Strains of C. difficile that produce excess toxins cause increased morbidity and mortality rates, as these infections are typically refractory to antibacterial therapy and often require colectomy. The possibility of C. difficile-associated diarrhea should be considered in all patients who present with diarrhea following antibiotic treatment. A careful medical history is also required as cases of C. difficile associated diarrhea have been reported even more than two months after antibiotic administration.
Prolongation of the QT interval
Prolongation of cardiac repolarization and QT interval has been found in treatment with other macrolides, including azithromycin, with the risk of developing cardiac arrhythmia and torsades de pointes (see section "Undesirable effects"). Therefore, as the following situations may lead to an increased risk of ventricular arrhythmia (including torsades de pointes) which can lead to cardiac arrest, azithromycin should be used with caution in patients who have ongoing situations which may predispose to arrhythmias ( especially women and elderly patients), such as patients:
- with congenital or documented prolongation of the QT interval;
- being treated with other active substances that prolong the QT interval, such as antiarrhythmics of classes IA (quinidine and procainamide) and III (dofetilide, amiodarone and sotalol), cisapride and terfenadine; antipsychotic agents such as pimozide; antidepressants such as citalopram; and fluoroquinolones such as moxifloxacin and levofloxacin;
- with alteration of electrolytes, especially in cases of hypokalemia and hypomagnesemia;
- with clinically relevant bradycardia, cardiac arrhythmia or severe heart failure.
You should check with your doctor before taking azithromycin if you have liver problems; your doctor may need to check your liver function or stop therapy.
Myasthenia Gravis
Exacerbation of symptoms of myasthenia gravis and initial onset of myasthenic syndrome have been reported in patients receiving azithromycin (see "Side Effects").
The safety and efficacy in the prevention or treatment of Mycobacterium Avium Complex infections in children has not been demonstrated.
The tablets contain lactose.
If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.
Pregnancy, breastfeeding and fertility
Pregnancy
There are no adequate data on the use of azithromycin in pregnant women. In animal reproductive toxicity studies, azithromycin has been shown to cross the placenta but no teratogenic effects have been observed. The safety of azithromycin has not been confirmed with respect to the use of the active substance during pregnancy. Therefore azithromycin should only be used during pregnancy if the benefit outweighs the risk.
Feeding time
Secretion of azithromycin into human breast milk has been observed but there are no adequate and well-controlled clinical studies in breastfeeding women that have determined the pharmacokinetics of azithromycin excretion in human breast milk. Therefore azithromycin should not be used in women during breastfeeding. breastfeeding, except where, in the physician's judgment, the potential benefits justify the potential risk to the baby.
Fertility
In animal fertility studies, a reduction in the pregnancy rate was observed following administration of azithromycin. The relevance of this finding for the human species is unknown.
Ask your doctor or pharmacist for advice before taking any medicine.
Effects on ability to drive and use machines
There is no evidence that azithromycin may affect patients' ability to drive or operate machinery.
Dosage and method of use How to use Azithromycin - Generic Drug: Posology
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 administration, for three consecutive days.
For the treatment of sexually transmitted diseases caused by susceptible strains of Chlamydia trachomatis or Haemophilus ducreyi: 1000 mg, taken once, in a single oral administration.
Senior citizens
The same dosage schedule can be applied to the elderly patient. As situations may exist in elderly patients that may predispose to arrhythmias, particular caution is recommended due to the risk of developing cardiac arrhythmia and torsades de pointes (see section "Special warnings").
Children
For children weighing 45 kg or more, the same dosage as for adults (500 mg / day for three consecutive days) can be used.
The maximum total recommended dose for any pediatric therapy is 1500 mg.
Patients with kidney or liver problems
Tell your doctor if you have kidney or liver problems as your doctor may need to change the usual dose of the medicine.
The medicinal product should always be administered as a single daily dose.
AZITHROMYCIN DOC Generici can be taken either on an empty stomach or after meals. Food intake before administering the product may attenuate any gastrointestinal side effects caused by azithromycin.
The tablets should be swallowed whole.
Overdose What to do if you have taken an overdose of Azithromycin - Generic Drug
Adverse events occurring with higher than recommended doses were similar to those seen with normal doses.
In case of accidental ingestion / intake of an overdose of AZITHROMYCIN DOC Generici, notify your doctor immediately or go to the nearest hospital.
If you have any further questions on the use of AZITHROMYCIN DOC Generici, ask your doctor or pharmacist
Side Effects What are the side effects of Azithromycin - Generic Drug
Like all medicines, Azithromycin Accord can cause side effects, although not everybody gets them.
The table below lists the adverse reactions identified during the conduct of clinical studies and during post-marketing surveillance, broken down by system organ class, and by frequency.
Adverse reactions identified during post-marketing surveillance are shown in italics. Frequency is defined using the following convention:
very common (≥ 1/10); common (≥ 1/100,
Adverse reactions with possible or probable correlation to azithromycin based on the results of clinical studies and post-marketing surveillance:
* for the powder for solution for infusion only
Adverse reactions with possible or probable correlation to treatment and prophylaxis for Mycobacterium Avium Complex based on the results of clinical studies and post-marketing surveillance. These adverse reactions differ in both type and frequency from those reported following administration of immediate-release or prolonged-release formulations:
Compliance with the instructions contained in the package leaflet reduces the risk of undesirable effects.
Reporting of side effects
If you get any side effects, including any possible side effects not listed in this leaflet, contact your doctor or pharmacist. Undesirable effects can also be reported directly through the national reporting system at the "address" https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse
By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Expiry: see the expiry date printed on the package.
Warning: do not use AZITHROMYCIN DOC Generici after the expiry date which is stated on the label.
The expiry date refers to the product in intact packaging, correctly stored.
Store at a temperature not exceeding 30 ° C.
DO NOT USE IN CASE OF EVIDENT SIGNS OF DETERIORATION
KEEP AZITHROMYCIN DOC Generici OUT OF THE SIGHT AND REACH OF CHILDREN.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
COMPOSITION
Each film-coated tablet contains:
Active ingredient: azithromycin dihydrate 524.1 mg equal to azithromycin base 500 mg.
Excipients: anhydrous calcium hydrogen phosphate, pregelatinised starch, sodium lauryl sulfate, croscarmellose sodium, carmellose sodium, colloidal anhydrous silica, magnesium stearate.
Coating: hypromellose (E464), titanium dioxide (E171), triacetin (E1518), lactose monohydrate.
PHARMACEUTICAL FORM AND CONTENT
Film-coated tablets.
Blister pack containing 3 x 500 mg film-coated tablets
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
AZITHROMYCIN DOC GENERICI 500 MG TABLETS COATED WITH FILM
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
AZITHROMYCIN DOC Generici 500 mg film-coated tablets.
Each film-coated tablet contains:
Active principle:
Azithromycin dihydrate 524.1 mg
equal to Azithromycin base 500 mg
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Film-coated tablets.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Treatment of infections caused by azithromycin-sensitive germs.
- 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 ulcer (from Haemophilus ducreyi).
04.2 Posology and method 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 administration, for three consecutive days.
For the treatment of sexually transmitted diseases caused by sensitive strains of Chlamydia trachomatis you hate Haemophilus ducreyi: 1000 mg, taken once, in a single oral administration.
Senior citizens
The same dosage schedule can be applied to the elderly patient. Since situations may exist in elderly patients that may predispose to arrhythmias, particular caution is recommended due to the risk of developing cardiac arrhythmia and torsades de pointes (see section 4.4 Special warnings and precautions for use).
Children
For children weighing 45 kg or more, the same dosage as for adults (500 mg / day for three consecutive days) can be used.
The maximum total recommended dose for any pediatric therapy is 1500 mg.
The medicinal product should always be administered as a single daily dose.
AZITHROMYCIN DOC Generici (azithromycin) tablets can be taken either on an empty stomach or after meals. Food intake before administering the product may attenuate any gastrointestinal side effects caused by azithromycin.
The tablets should be swallowed whole.
Altered kidney function
No dosage adjustment is required in patients with mild to moderate renal impairment (GFR 10 - 80 ml / min) while caution should be exercised in those with severe impairment (GFR
Altered liver function
The same dosage as in patients with normal hepatic function can be used in patients with mild to moderate hepatic impairment (see 4.4 and 5.2).
04.3 Contraindications
The use of this product is contraindicated in patients with hypersensitivity to azithromycin, erythromycin, to any of the macrolide or ketolide antibiotics, or to any of the excipients listed in section 6.1 (List of excipients).
04.4 Special warnings and appropriate precautions for use
As with erythromycin and other macrolides, severe allergic reactions, including angioedema and anaphylaxis (rarely fatal), have been reported rarely. Some of these reactions with azithromycin have resulted in relapses and required a prolonged period of observation and treatment.
Since the liver is the major route of elimination of azithromycin, its use in patients with significant liver disease should be undertaken with caution. Cases of fulminant hepatitis, potentially causing life-threatening liver failure, have been reported with azithromycin. (See section 4.8) Some of these patients may have suffered from pre-existing liver disease or may have taken other hepatotoxic medicinal products.
In cases where signs and symptoms of impaired liver function develop, such as rapid onset asthenia associated with jaundice, dark urine, bleeding tendency or hepatic encephalopathy, liver function tests / diagnostics should be performed immediately. Administration of azithromycin should be discontinued if hepatic dysfunction emerges.
In patients receiving ergotamine derivatives, co-administration of macrolide antibiotics has aggravated ergotism. 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 derivatives should not be administered simultaneously.
As with any other antibiotic preparation, particular attention is recommended to the signs relating to the onset of superinfections with non-sensitive microorganisms, including fungi.
Cases of diarrhea associated with Clostridium difficile (CDAD), 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. difficult.
The C. difficult produces toxins A and B which contribute to the development of CDAD. The strains of C. difficult that produce excess toxins cause increased morbidity and mortality rates, as these infections are typically refractory to antibacterial therapy and often require a colectomy. The possibility of CDAD should be considered in all patients who present with diarrhea following antibiotic treatment. A careful medical history is also required as cases of CDAD have been reported even more than two months after antibiotic administration.
In patients with severe renal impairment (GFR Pharmacokinetic properties).
Prolongation of cardiac repolarization and QT interval, with the risk of developing cardiac arrhythmia and torsades de pointes, has been found in treatment with other macrolides, including azithromycin (see section 4.8 Undesirable effects). Therefore, as the following situations may lead to an increased risk of ventricular arrhythmia (including torsades de pointes) which can lead to cardiac arrest, azithromycin should be used with caution in patients who have ongoing situations which may predispose to arrhythmias ( especially women and elderly patients), such as patients:
• with congenital or documented prolongation of the QT interval;
• being treated with other active substances 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 and levofloxacin;
• with alterations of electrolytes, especially in cases of hypokalaemia and hypomagnesaemia;
• with clinically relevant bradycardia, cardiac arrhythmia or severe heart failure.
Exacerbation of symptoms of myasthenia gravis and initial onset of myasthenic syndrome have been reported in patients receiving azithromycin (see section 4.8).
The safety and efficacy in the prevention or treatment of infections with Mycobacterium Avium Complex in children it has not been demonstrated.
The tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp-lactase deficiency, or glucose-galactose malabsorption should not take this medicine.
04.5 Interactions with other medicinal products and other forms of interaction
Antacids
In a pharmacokinetic study of the effects of concomitant administration of antacids and azithromycin, no effect on the bioavailability of azithromycin was observed, although an approximately 25% reduction in maximum serum concentrations was observed. with azithromycin and antacids you should not take the two drugs at the same time.
Cetirizine
In healthy volunteers, co-administration of a 5-day regimen of azithromycin and cetirizine 20 mg at steady state showed no pharmacokinetic interactions or significant alterations in the QT interval.
Didanosine (Dideoxinosine)
Co-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 overall pharmacokinetics. steady state didanosine compared to placebo.
Digoxin (substrates of P-gp)
Concomitant administration of macrolide antibiotics, including azithromycin, and P-glycoprotein substrates such as digoxin, has been associated with increased serum levels of the P-glycoprotein substrate. Therefore, if azithromycin and P-gp substrates such as digoxin are administered simultaneously, the possibility of increased serum substrate concentrations should be considered.
Some macrolide antibiotics may impair the microbial metabolism of digoxin in the intestine in some patients. Patients taking azithromycin and digoxin at the same time should take into account the possible increase in digoxin levels.
Zidovudine
Administration of single 1000 mg doses and multiple 1200 mg or 600 mg doses of azithromycin did not substantially alter the plasma pharmacokinetics or urinary excretion of zidovudine or its glucuronide metabolite. concentrations of phosphorylated zidovudine, its clinically active metabolite, in peripheral mononuclear blood cells. The clinical significance of this finding is unclear, but may nevertheless be of benefit to the patient.
Azithromycin does not significantly interact with the hepatic cytochrome P450 system. It is not expected to be involved in pharmacokinetic interactions as found with erythromycin and other macrolides. With azithromycin, there is no induction or inactivation of hepatic cytochrome P450 via the complex of its metabolites.
Ergotamine
Due to the possible onset of ergotism, the concomitant use of azithromycin and ergotamine derivatives is not recommended (see section 4.4 Special warnings and precautions for use).
Pharmacokinetic studies have been conducted between azithromycin and the following drugs for which significant cytochrome P450 mediated metabolic activity is known.
Atorvastatin
Concomitant administration of atorvastatin (10 mg / day) and azithromycin (500 mg / day) did not cause alterations in plasma concentrations of atorvastatin (based on an inhibition test of HMG CoA reductase activity). However, from subsequent experience At marketing, cases of rhabdomyolysis have been reported in patients taking azithromycin and statins at the same time.
Carbamazepine
In a pharmacokinetic interaction study conducted in healthy volunteers, no significant effect on the plasma levels of carbamazepine or its active metabolite was observed in patients taking concomitant azithromycin.
Cimetidine
In a pharmacokinetic study conducted to evaluate the effects of a single dose of cimetidine administered 2 hours prior to azithromycin, there was no evidence of alterations in the pharmacokinetics of azithromycin.
Cyclosporine
Significant increases in Cmax and AUC0-5 of cyclosporine. Therefore, any concomitant administration of these two drugs requires caution. If co-administration of the two drugs is strictly necessary, cyclosporine levels should be carefully monitored and the dosage should be adjusted accordingly.
Efavirenz
Co-administration of a single daily dose of azithromycin (600 mg) and efavirenz (400 mg) for 7 days produced no clinically significant pharmacokinetic interactions.
Fluconazole
Coadministration 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 co-administration with fluconazole, while a clinically insignificant decrease in Cmax (18%) was observed.
Indinavir
Coadministration 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 in doses of 800 mg.
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 15 mg midazolam dose.
Nelfinavir
Concomitant administration of azithromycin (1200 mg) and nelfinavir allo steady state (750 mg three times daily) resulted in increased azithromycin concentrations. No clinically significant adverse reactions were observed and no dose modification is required.
Rifabutin
Concomitant administration of azithromycin and rifabutin does not change the serum concentrations of the two drugs.
Cases of neutropenia have been observed in some patients taking azithromycin and rifabutin at the same time; although rifabutin is known to cause neutropenia, it has not been possible to establish a causal relationship between the above episodes of neutropenia and the rifabutin-azithromycin combination (see section 4.8 Undesirable effects).
Sildenafil
In healthy male volunteers, there was no effect of azithromycin (500 mg / day for 3 days) on the AUC and Cmax of sildenafil or its major circulating metabolite.
Theophylline
Co-administration of azithromycin and theophylline to healthy volunteers did not show a clinically significant interaction between the two drugs.
Terfenadine
Pharmacokinetic studies revealed no 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 occurred.
Triazolam
In 14 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 effect 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), on day 7 there was no significant effect on peak concentrations, exposure or urinary excretion either. trimethoprim and sulfamethoxazole. Serum concentrations of azithromycin are similar to those found in other studies.
Coumarin-type oral anticoagulants
In a pharmacokinetic study in healthy volunteers, azithromycin was found not to alter the anticoagulant effect of a single 15 mg dose of warfarin.
In the post-marketing phase, cases of potentiation of anticoagulant action have been reported following the concomitant administration of azithromycin and coumarin-type oral anticoagulants. Although a causal relationship has not been established, it is recommended to re-evaluate the frequency with which to monitor the time to prothrombin when administering azithromycin to patients receiving coumarin-type anticoagulants.
04.6 Pregnancy and lactation
Pregnancy
There are no adequate data on the use of azithromycin in pregnant women. In animal reproductive toxicity studies, azithromycin has been shown to cross the placenta but no teratogenic effects have been observed. The safety of azithromycin has not been confirmed with respect to the use of the active substance during pregnancy. Therefore azithromycin should only be used during pregnancy if the benefit outweighs the risk.
Feeding time
Secretion of azithromycin into human breast milk has been observed but there are no adequate and well-controlled clinical studies in breastfeeding women that have determined the pharmacokinetics of azithromycin excretion in human breast milk. Therefore azithromycin should not be used in women during breastfeeding. breastfeeding, except where, in the physician's judgment, the potential benefits justify the potential risk to the baby.
Fertility
In fertility studies in rats, a reduction in the pregnancy rate was observed following administration of azithromycin. The relevance of this finding for the human species is unknown.
04.7 Effects on ability to drive and use machines
There is no evidence that azithromycin may affect patients' ability to drive or operate machinery.
04.8 Undesirable effects
The table below lists the adverse reactions identified during the conduct of clinical studies and during post-marketing surveillance, broken down by system organ class, and by frequency. Adverse reactions identified during post-marketing surveillance are shown in italics. Frequency is defined using the following convention: very common (≥1 / 10); common (≥1 / 100,
Adverse reactions with possible or probable correlation to azithromycin based on the results of clinical studies and post-marketing surveillance:
* for the powder for solution for infusion only
Adverse reactions with possible or probable correlation to treatment and prophylaxis for Mycobacterium Avium Complex based on the results of clinical studies and post-marketing surveillance. These adverse reactions differ in both type and frequency from those reported following administration of immediate-release or prolonged-release formulations:
04.9 Overdose
Adverse events occurring with higher than recommended doses were similar to those seen with normal doses. In the event of an overdose, appropriate general symptomatic and supportive measures are indicated.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antibacterials for systemic use - Macrolides. ATC code: J01FA10.
Azithromycin is the first of a sub-class of macrolide antibiotics, called azalides, and is chemically different from erythromycin.Chemically it is derived from the insertion of a nitrogen atom into the lactone ring of erythromycin A.
Its chemical name is: 9-deoxy-9a-aza-9a-methyl-9a-homoerythromycin A. The molecular weight is 749.0.
Azithromycin exerts its activity by inhibiting bacterial protein synthesis by binding to the 50s ribosomal subunits and thus preventing peptide translocation, but without affecting nucleic acid synthesis. The azithromycin proves in vitro activity against a "wide range of bacteria which includes:
Gram-positive aerobes: Staphylococcus aureus, Streptococcus pyogenes (Streptococcus beta-hemolytic group A), Streptococcus pneumoniae, Alpha haemolytic streptococci (viridant group), other streptococci e Corynebacterium diphteriae. Erythromycin-resistant gram-positive bacteria such asStreptococcus faecalis (enterococcus) and many strains of methicillin-resistant Staphilococci show cross-resistance even against azithromycin;
Gram-negative aerobes: Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, Acinetobacter spp., Yersinia spp., Legionella pneumophila, Bordetella pertussis, Bordetella parapertussis, Shigella spp., Pasteurella spp., Vibrio cholerae and parahaemolyticus, Pleisiomonas shigelloides.
Azithromycin demonstrates variable activity against Escherichia coli, Salmonella enteritidis, Salmonella typhi, Enterobacter spp., Aeromonas hydrophila And Klebsiella spp.
In case of infections with such bacterial species in vitro susceptibility tests should be performed. Proteus spp., Serratia spp., Morganellaspp. and Pseudomonas aeruginosa they are usually hardy.
Anaerobic bacteria: Bacteroides fragilis, Bacteroides spp., Clostridium perfringens, Peptococcus spp., Peptostreptococcus spp., Fusobacterium necrophorum And Propionibacterium acnes.
Microorganisms that cause venereal diseases: Chlamydia trachomatis, Treponema pallidum, Neisseria gonorrhoeae and Haemophilus ducreyi.
Other microorganisms: Borrelia burgdorferi (Lyme disease agent), Chlamydia pneumoniae, Toxoplasma gondii, Mycoplasma pneumoniae, Mycoplasma hominis, Ureaplasma urealyticum, Pneumocystis carinii, Mycobacterium avium, Campylobacter spp. , And Listeria monocytogenes.
05.2 "Pharmacokinetic properties
Absorption
Azithromycin is more stable at gastric pH compared to erythromycin.
In humans, after oral administration, azithromycin is rapidly and widely distributed throughout the body; the time required to obtain peak plasma levels is 2-3 hours.
Distribution
In animal studies, high concentrations of azithromycin have been observed within phagocytic cells. In experimental models, moreover, high concentrations of azithromycin are released by activated phagocytes compared to non-activated phagocytes. This phenomenon determines, in the animal model, high concentrations of azithromycin. at the site of infection.
Pharmacokinetic studies in humans have shown tissue levels of azithromycin higher than those in plasma (up to 50 times the maximum concentrations observed in plasma), thus indicating that the drug is highly bound to tissues. Concentrations in target organs such as the lung , tonsils and prostate, exceed the MIC90 values for the most common pathogens, after a single oral administration of 500 mg.
Elimination
The terminal plasma half-life closely reflects the tissue depletion half-life (2 to 4 days). Approximately 12% of an IV dose is excreted in the urine as unchanged drug over 3 days, most of it in the first 24 hours. Biliary elimination is the major route of elimination of unchanged drug after oral administration. Very high concentrations of unchanged drug were found in human bile together with 10 metabolites, the latter formed by N- and O-demethylation processes, by hydroxylation of desosamine and the aglyconic ring and by cleavage of cladinose-conjugates. HPLC and a microbiological method to evaluate the tissue concentrations of these metabolites have shown that they play no role in the antimicrobial activity of azithromycin.
Pharmacokinetics in special categories of patients
Senior citizens
A study conducted on healthy volunteers showed that after a 5-day regimen the AUC values are slightly higher in elderly subjects (> 65 years) than in younger subjects (
Altered kidney function
Following once oral administration of 1 gram azithromycin, no pharmacokinetic effects have been observed in patients with mild to moderate renal dysfunction (GFR 10 - 80 ml / min.). Statistically significant differences were found in AUC0-120 (8.8 mcg hr / ml vs 11.7 mcg hr / ml), Cmax (1.0 mcg / ml vs 1.6 mcg / ml) and CLr (2.3 ml / min) values. / kg vs. 0.2 ml / min / kg) among the severe renal dysfunction group (GFR
Altered liver function
In patients with mild (Class A) to moderate (Class B) hepatic impairment, there was no evidence of significant changes in serum azithromycin pharmacokinetics compared to subjects with normal hepatic function. In these patients, elimination of azithromycin through urine it appears to increase, probably as a compensation for decreased hepatic clearance.
05.3 Preclinical safety data
In animal studies conducted with high doses that exceeded 40 times the maximum dose used in clinical practice, azithromycin was found to cause reversible phospholipidosis, generally without obvious toxicological consequences. The effect was shown to be reversible on discontinuation of the drug. treatment with azithromycin The significance of these findings for both animals and humans is unknown.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Excipients: anhydrous calcium hydrogen phosphate, pregelatinised starch, sodium lauryl sulfate, croscarmellose sodium, carmellose sodium, colloidal anhydrous silica, magnesium stearate.
Coating: hypromellose (E464), titanium dioxide (E171), triacetin (E1518), lactose monohydrate.
06.2 Incompatibility
Not relevant.
06.3 Period of validity
36 months.
06.4 Special precautions for storage
Store at a temperature not exceeding 30 ° C.
06.5 Nature of the immediate packaging and contents of the package
PVC blister containing 3 x 500 mg film-coated tablets.
06.6 Instructions for use and handling
Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
DOC Generici S.r.l. - Via Turati 40 - 20121 Milan - Italy.
08.0 MARKETING AUTHORIZATION NUMBER
AZITHROMYCIN DOC Generici 500 mg film-coated tablets 3 tablets - A.I.C. n. 039508015.
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
July 2010
10.0 DATE OF REVISION OF THE TEXT
August 2013
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