Active ingredients: Azithromycin
ZITROMAX Avium 600 mg film-coated tablets
Why is Zithromax avium used? What is it for?
PHARMACOTHERAPEUTIC CATEGORY
Antibacterials for systemic use; macrolides.
THERAPEUTIC INDICATIONS
ZITROMAX Avium (azithromycin) is indicated, as monotherapy or in combination with rifabutin, in the prophylaxis of Mycobacterium avium complex (MAC) infections: opportunistic infections that mainly affect patients with advanced HIV virus.
ZITROMAX Avium (azithromycin) is indicated, in combination with ethambutol, for the treatment of Mycobacterium avium complex (MAC) infections disseminated in patients with advanced HIV virus.
Contraindications When Zithromax avium should not be used
Hypersensitivity to the active substance azithromycin, to 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 Zithromax avium
Altered kidney function
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).
Hepatotoxicity
Since the liver is the major route of elimination of azithromycin, its use in patients with major liver disease should be undertaken with caution. Cases of liver impairment, hepatitis, cholestatic jaundice, hepatic necrosis and fulminant hepatitis have been reported with azithromycin. potentially due to liver failure, some of which have been fatal (see "Side Effects"). Some patients may have had previous liver disease or may have taken other hepatotoxic medicinal products. In cases where signs and symptoms of liver dysfunction develop, such as rapid onset asthenia associated with jaundice, dark urine, bleeding tendency or hepatic encephalopathy, liver function tests / tests should be performed immediately.
Immediately discontinue azithromycin treatment if signs of liver dysfunction occur.
Derivatives of ergotamine
In patients treated with ergotamine derivatives the 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 simultaneously.
Superinfections
As for any other antibiotic preparation, special observation is recommended for the possible occurrence of superinfections with non-sensitive microorganisms including fungi.
Interactions Which drugs or foods can modify the effect of Zithromax avium
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. Therefore, patients in therapy with azithromycin and antacids should not take the two drugs at the same time. Co-administration of azithromycin granules for prolonged-release oral suspension with a single dose of 20 ml of co-magaldrox (aluminum hydroxide and magnesium hydroxide) did not affect the rate and extent of absorption of azithromycin.
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
Co-administration of daily doses of azithromycin 1200 mg / day and didanosine 400 mg / day in six HIV positive patients was observed to have no effect on the steady state pharmacokinetics of didanosine compared to placebo.
Digoxin (P-glycoprotein substrates)
The intake of macrolide antibiotics, including azithromycin with P-glycoprotein substrates such as digoxin, has been reported to cause increased serum levels of P-glycoprotein substrates. Therefore, the possibility of an increase in serum digoxin levels should be considered if azithromycin and P-glycoprotein substrates such as digoxin are taken concomitantly. Clinical monitoring and monitoring for possible elevated digoxin levels are required during and after discontinuation of azithromycin treatment.
Zidovudine
Administration of single 1000 mg doses and multiple 1200 mg or 600 mg doses of azithromycin did not substantially change the plasma pharmacokinetics or urinary excretion of zidovudine or its glucuronide metabolite. concentrations of phosphorylated zidovudine, its clinically active metabolite, in peripheral mononuclear cells. The clinical significance of this finding is unclear, but may nevertheless be of benefit to the patient.
Azithromycin does not interact significantly 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, in fact, there is no induction or inactivation of hepatic cytochrome P450 through 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 "Precautions for use").
Pharmacokinetic studies have been conducted between azithromycin and the following drugs, for which significant cytochrome P450 mediated metabolic activity is known.
HMG-CoA reductase inhibitors (Statins)
Concomitant administration of atorvastatin (10 mg / day) and azithromycin (500 mg / day) did not alter plasma concentrations of atorvastatin (based on an HMG CoA reductase inhibition assay) and therefore did not cause changes in activity. of HMG CoA reductase. However, there have been post-marketing reports of rhabdomyolysis in patients receiving azithromycin and statins.
Carbamazepine
In an interaction study in healthy volunteers, no significant effect on 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 after azithromycin, there was no evidence of alterations in the pharmacokinetics of azithromycin.
Cyclosporine
Significant increases in Cmax and AUC0-5 of cyclosporine. Therefore, the possible simultaneous administration of the two drugs requires caution. If the co-administration of the two drugs is strictly necessary, the levels of cyclosporine should be carefully monitored and the dosage of the latter should be modified accordingly.
Efavirenz
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 dosage adjustment was 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 the two drugs 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 of trimethoprim / sulfamethoxazole (160 mg / 800 mg) and azithromycin (1200 mg) for 7 days, there was no significant effect on peak concentrations, exposure time or urinary excretion on day 7. both 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), dermatological reactions including Stevens Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) (rarely fatal) have been observed. and drug eruption with eosinophilia and systemic symptoms (DRESS). Some of these reactions associated with azithromycin administration have resulted in relapses and therefore require 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
In treatment with macrolides, including azithromycin, prolongation of cardiac repolarization and QT interval was found on ECG, leading to the risk of developing cardiac arrhythmia and torsades de pointes (see "Undesirable Effects"). Therefore, since the following situations may lead to an increased risk of ventricular arrhythmias (including torsades de pointes), which can 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 can be fatal, when evaluating the benefit-risk of azithromycin in patient groups at risk, such as:
- Patients with congenital or documented prolongation of the QT interval;
- Patients treated with other active substances that prolong the QT interval, such as Class IA antiarrhythmics (quinidine and procainamide) and Class III (dofetilide, amiodarone and sotalol), cisapride and terfenadine, antipsychotic drugs such as pimozide, antidepressants such as citalopram, fluoroquinolones such as moxifloxacin, levofloxacin and chloroquine.
- Patients with electrolyte disturbances, especially in cases of hypokalaemia and hypomagnesaemia;
- Patients with clinically relevant bradycardia, cardiac arrhythmia or severe heart failure;
- Women and the elderly who may be more sensitive to the (drug-related) effects of QT interval alteration.
Myasthenia Gravis
Exacerbation of symptoms of myasthenia gravis and initial onset of myasthenic syndrome have been reported in patients receiving azithromycin (see "Undesirable effects").
The safety and efficacy in the prevention or treatment of Mycobacterium avium complex (MAC) infections in children have not been established.
The medicine contains 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.
Fertility, pregnancy and breastfeeding
Ask your doctor or pharmacist for advice before taking any medicine.
There are no adequate data on the use of azithromycin in women during pregnancy. The safety of azithromycin during pregnancy has not been established. Therefore azithromycin should only be used in pregnancy if the benefit outweighs the risk.
Fertility
In fertility studies conducted in rats, a reduction in the fertility rate was noted following administration of azithromycin. The relevance of these findings to humans is unknown.
Pregnancy
Animal reproduction studies have been conducted using scaled doses up to reaching moderately toxic maternal concentrations. From these studies there was no evidence of any hazard to the fetus due to azithromycin. In reproductive toxicology studies in animals azithromycin has shown to pass the placenta, but no teratogenic effects were observed.
Feeding time
Azithromycin has been reported to be secreted into breast milk. Therefore, azithromycin should only be used in breastfeeding women in cases where, in the opinion of the physician, the potential benefit justifies the potential risk to the baby.
Effects on ability to drive and use machines
There are no data showing that azithromycin can affect patients' ability to drive or operate machinery.
Dosage and method of use How to use Zithromax avium: Dosage
ZITROMAX Avium (azithromycin) must be administered in a single daily dose. The tablets can be taken either on an empty stomach or after meals. Intake of food before ingestion of the tablet can mitigate any undesirable gastrointestinal effects caused. from azithromycin.
Adults
For the prophylaxis of MAC infections in HIV-infected patients, the recommended dosage is 1200 mg (2 tablets of 600 mg) once a week once a day.
For the treatment of disseminated MAC infections in advanced HIV infected patients, the recommended dose is 600 mg once daily. Azithromycin should be administered in combination with other antimcobacterials which have shown in vitro activity against MAC, including ethambutol given at recommended doses.
Senior citizens
The same dosage schedule can be applied to the elderly patient. Since elderly patients are more prone to cardiac arrhythmias, particular caution is recommended due to the risk of developing cardiac arrhythmias and torsades de pointes (see "Special Warnings").
Pediatric population
The efficacy and tolerability of azithromycin in the prevention or treatment of MAC infections in children have not been established. Pharmacokinetic data showed that a dose of 20 mg / kg administered to pediatric patients results in a drug exposure similar to that obtained in adults with a dose of 1200 mg, albeit with a higher Cmax.
Patients with liver or kidney problems:
Patients with liver or kidney problems should inform their doctor, as this may need to change the normal dosage. No dosage adjustment is required in patients with mild to moderate renal impairment (GFR 10 - 80 mL / min) and caution should be exercised in those with severe renal impairment (GFR <10 mL / min) (see "Precautions for The "use") 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").
ZITROMAX Avium (azithromycin) tablets should be swallowed whole or divided if patients have difficulty swallowing.
Overdose What to do if you have taken too much Zithromax avium
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 ZITROMAX Avium, notify your doctor immediately or go to the nearest hospital.
If you have any questions about the use of ZITROMAX Avium, ask your doctor or pharmacist.
Side Effects What are the side effects of Zithromax avium
Like all medicines, ZITROMAX 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, divided by system organ class and frequency. Adverse reactions identified during postmarketing surveillance are shown in italics. Frequency is defined using the following parameters: 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 possibly or probably related to prophylaxis and treatment of Mycobacterium avium Complex based on experience from clinical trials and post-marketing surveillance. These adverse reactions differ from those reported with immediate-release or prolonged-release formulations, in type or in frequency:
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, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. Undesirable effects can also be reported directly through the national reporting system at the "address www.agenziafarmaco.it/it/responsabili". By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
This medicine does not require any special storage conditions.
Expiry: see the expiry date indicated on the package. The expiry date indicated refers to the product in intact and correctly stored packaging.
Warning: do not use the medicine after the expiry date indicated on the package.
DO NOT USE IN CASE OF EVIDENT SIGNS OF DETERIORATION.
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.
Other information
COMPOSITION
Each film-coated tablet contains:
- Active ingredient: Azithromycin dihydrate 628.93 mg equal to Azithromycin 600 mg
- Excipients: Pregelatinised starch, anhydrous acid calcium phosphate, carmellose sodium, magnesium stearate, sodium lauryl sulfate.
- The coating contains: titanium dioxide, lactose, hypromellose, triacetin.
PHARMACEUTICAL FORM AND CONTENT
Film-coated tablets.
PVC / Al blister containing 8 x 600 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
ZITROMAX AVIUM 600 MG TABLETS COATED WITH FILM
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains:
Active principle:
Azithromycin dihydrate 628.93 mg
equal to Azithromycin base 600 mg.
Excipients with known effects: the medicinal product contains lactose.
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
ZITROMAX Avium (azithromycin) is indicated as monotherapy or in combination with rifabutin in the prophylaxis of Mycobacterium avium complex (MAC): opportunistic infections that mainly affect patients with advanced HIV virus.
ZITROMAX Avium (azithromycin) is indicated, in combination with ethambutol, for the treatment of Mycobacterium avium complex (MAC) disseminated in patients with advanced HIV virus.
04.2 Posology and method of administration
ZITROMAX Avium (azithromycin) must be administered in a single daily dose. The tablets can be taken either on an empty stomach or after meals. Intake of food before ingestion of the tablet can mitigate any undesirable gastrointestinal effects caused. from azithromycin.
Adults
For the prophylaxis of MAC infections in HIV-infected patients, the recommended dosage is 1200 mg (2 tablets of 600 mg) once a week once a day.
For the treatment of disseminated MAC infections in advanced HIV infected patients, the recommended dose is 600 mg once daily. Azithromycin should be administered in combination with other antimcobacterials which have shown activity in vitro against MAC, including ethambutol administered at recommended doses.
Senior citizens
The same dosage schedule can be applied to the elderly patient.
Since elderly patients are more prone to cardiac arrhythmias, particular caution is recommended due to the risk of developing cardiac arrhythmias and torsades de pointes (see section 4.4).
Pediatric population
The efficacy and tolerability of azithromycin in preventing MAC infections in children have not been established. Pharmacokinetic data showed that a dose of 20 mg / kg administered to pediatric patients results in a drug exposure similar to that obtained in adults with a dose of 1200 mg, albeit with a higher Cmax.
ZITROMAX Avium (azithromycin) tablets should be swallowed whole or divided if patients have difficulty swallowing.
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 sections 4.4 and 5.2).
04.3 Contraindications
Hypersensitivity to the active substance, to erythromycin, to any of the macrolide or ketolide antibiotics, or to any of the excipients listed in section 6.1.
04.4 Special warnings and appropriate precautions for use
Hypersensitivity
As with erythromycin and other macrolides, severe 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). Some of these reactions associated with azithromycin administration have resulted in relapses and therefore require 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.
Hepatotoxicity
Since the liver is the major route of elimination of azithromycin, its use in patients with major liver disease should be undertaken with caution. 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 previous liver disease or may have taken other hepatotoxic medicinal products. In cases where signs and symptoms of liver dysfunction develop, such as asthenia rapid onset associated with jaundice, dark urine, bleeding tendency or hepatic encephalopathy, liver function tests / diagnostics should be performed immediately.
Immediately discontinue azithromycin treatment if signs of liver dysfunction occur.
Derivatives of ergotamine
In patients treated with ergotamine derivatives the 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 simultaneously.
As with any other antibiotic preparation, particular observation is recommended for the possible occurrence of superinfections with non-sensitive microorganisms including fungi.
Diarrhea associated with Clostridium difficile
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 diarrhea. 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 associated diarrhea should be considered C. difficult in all patients who present with diarrhea following antibiotic treatment. A careful medical history is also required since cases of diarrhea associated with C. difficult they have also been reported over two months after antibiotic administration.
In patients with severe renal impairment (GFR
Prolongation of the QT interval
In treatment with macrolides, including azithromycin, prolonged cardiac repolarization and QT interval were found on ECG, leading to the risk of developing cardiac arrhythmia and torsades de pointes (see section 4.8). Therefore, since the following situations may lead to an increased risk of ventricular arrhythmias (including torsades de pointes), which can 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 can be fatal, when evaluating the benefit-risk of azithromycin in patient groups at risk, such as:
• Patients with congenital or documented prolongation of the QT interval;
• Patients being treated with other active substances that prolong the QT interval, such as Class IA antiarrhythmics (quinidine and procainamide) and Class III (dofetilide, amiodarone and sotalol), cisapride and terfenadine, antipsychotic drugs such as pimozide, antidepressants such as citalopram, fluoroquinolones such as moxifloxacin, levofloxacin and chloroquine.
• Patients with electrolyte disturbances, especially in cases of hypokalaemia and hypomagnesaemia;
• Patients with clinically relevant bradycardia, cardiac arrhythmia or severe heart failure;
• Women and the elderly who may be more sensitive to the (drug-related) effects of altered QT interval.
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 (MAC) in children has not been established.
The medicine contains 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. Therefore, patients in therapy with azithromycin and antacids should not take the two drugs at the same time.
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 alterations in the QT interval.
Didanosine
Co-administration of daily doses of azithromycin 1200 mg / day and didanosine 400 mg / day in six HIV-positive patients was observed to have no effect on overall pharmacokinetics. steady state didanosine compared to placebo.
Digoxin (P-glycoprotein substrates)
The intake of macrolide antibiotics, including azithromycin with P-glycoprotein substrates such as digoxin, has been reported to cause an increase in serum levels of P-glycoprotein substrates. Therefore the possibility of increased levels should be considered. serum digoxin in case of concomitant intake of azithromycin and substrates of P-glycoprotein, such as digoxin. Clinical monitoring and monitoring of possible elevated digoxin levels are required during and after discontinuation of azithromycin treatment.
Zidovudine
Administration of single 1000 mg doses and multiple 1200 mg or 600 mg doses of azithromycin did not substantially change the plasma pharmacokinetics or urinary excretion of zidovudine or its glucuronide metabolite. concentrations of phosphorylated zidovudine, its clinically active metabolite, in peripheral mononuclear cells. The clinical significance of this finding is unclear, but may nevertheless be of benefit to the patient.
Azithromycin does not interact significantly 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, in fact, there is no induction or inactivation of hepatic cytochrome P450 through 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).
Pharmacokinetic studies have been conducted between azithromycin and the following drugs, for which significant cytochrome P450 mediated metabolic activity is known.
HMG-CoA reductase inhibitors (Statins)
Concomitant administration of atorvastatin (10 mg / day) and azithromycin (500 mg / day) did not alter plasma concentrations of atorvastatin (based on an HMG CoA reductase inhibition assay) and therefore did not cause changes in activity. of HMG CoA reductase. However, there have been post-marketing reports of rhabdomyolysis in patients receiving azithromycin and statins.
Carbamazepine
In an interaction study in healthy volunteers, no significant effect on 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 after azithromycin, there was no evidence of alterations in the pharmacokinetics of azithromycin.
Cyclosporine
Significant increases in Cmax and AUC0-5 of cyclosporine. Therefore, the possible simultaneous administration of the two drugs requires caution. If the co-administration of the two drugs is strictly necessary, the levels of cyclosporine should be carefully monitored and the dosage of the latter should be modified accordingly.
Efavirenz
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 dosage adjustment was 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 the two drugs 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).
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, co-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 of trimethoprim / sulfamethoxazole (160 mg / 800 mg) and azithromycin (1200 mg) for 7 days, there was no significant effect on peak concentrations, exposure time or urinary excretion on day 7. both 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
There are no adequate data on the use of azithromycin in women during pregnancy. The safety of azithromycin during pregnancy has not been established. Therefore azithromycin should only be used in pregnancy if the benefit outweighs the risk.
Fertility
In fertility studies conducted in rats, a reduction in the fertility rate was noted following administration of azithromycin. The relevance of these findings to humans is unknown.
Pregnancy
Animal reproduction studies have been conducted using scaled doses up to reaching moderately toxic maternal concentrations. From these studies there was no evidence of any hazard to the fetus due to azithromycin. In reproductive toxicology studies in animals azithromycin has shown to pass 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 during pregnancy should only be used if strictly necessary.
Feeding time
Azithromycin has been reported to be secreted into breast milk, but there are no adequate and well controlled studies in breastfeeding women that can describe the pharmacokinetics of azithromycin excretion in human breast milk. Therefore, azithromycin should be used in breastfeeding women only in cases where, in the opinion of the physician, the potential benefit justifies the potential risk to the baby.
04.7 Effects on ability to drive and use machines
There are no data showing that azithromycin can 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, divided by system organ class and frequency. Adverse reactions identified during post-marketing surveillance are shown in italics. Frequency is defined using the following parameters: 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 possibly or probably related to prophylaxis and treatment of Mycobacterium avium Complex based on experience from clinical trials and post-marketing surveillance. These adverse reactions differ from those reported with immediate-release or prolonged-release formulations, in type or in frequency:
Reporting of suspected adverse reactions.
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address www.agenziafarmaco.gov.it/it/responsabili.
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: macrolides.
ATC code: J01FA10.
Azithromycin is the first drug in a subclass of macrolide antibiotics, called azalides, and is chemically different from erythromycin. Chemically it is derived from the insertion of a nitrogen atom in 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 .
Mode of action:
Azithromycin binds to the 23S rRNA of the 50S ribosomal subunit. Azithromycin blocks protein synthesis by inhibiting the transpeptidation / translocation step of protein synthesis and inhibiting the assembly of the 50S ribosomal subunit.
Cardiac electrophysiology:
QT interval prolongation was studied in a randomized, placebo-controlled, parallel group study of 116 healthy subjects taking either chloroquine (1000 mg) alone or in combination with azithromycin (500 mg, 1000 mg, 1500 mg a once daily) Co-administration with azithromycin resulted in an increase in the QTc interval in a dose- and concentration-dependent manner. The maximum increases in QTcF compared to chloroquine alone (the observed differences from placebo vary in the range between 18.4 and 35 ms) were on average (upper limit of the 95% confidence interval) of 5 ms, 7 ms and 9 ms following co-administration of 500 mg, 1000 mg, 1500 mg of azithromycin respectively.
Resistance mechanism:
The two most frequent known mechanisms of resistance to macrolides, including azithromycin, are target modification (most often through 23S rRNA methylation) and "active extrusion. The establishment of these resistance mechanisms varies from species to species." , within the species, the frequency of resistance varies according to the geographical position.
The main ribosomal modification that determines the reduction of macrolide binding is the (N) - 6 post-transcriptional demethylation of adenine at nucleotide A2058 (numbering system of E. coli) of the 23S rRNA operated by the methylases encoded by the gene erm (ribosomal erythromycin methylase).
Ribosomal modifications often result in cross-resistance (MLSB phenotype) to other classes of antibiotics whose ribosomal binding sites overlap with those of macrolides: lincosamides (including clindamycin), and type B streptogramins (which include for example component quinupristin quinupristin / dalfopristin). Different genes erm they are present in different bacterial species, in particular streptococci and staphylococci. Sensitivity to macrolides may also be affected by mutational changes found less frequently in nucleotides A2058 and A2059, and in some other positions of the 23S rRNA, or in proteins L4 and L22 of the major ribosomal subunit.
Extrusion pumps are present in a number of species, including Gram-negative, such as Haemophilus influenzae (where they can inherently lead to higher MICs) and staphylococci. In streptococci and enterococci, an extrusion pump that recognizes 14- and 15-atom macrolides (which include erythromycin and azithromycin, respectively) is encoded by the genes mef (TO).
Methodology for the determination of the in vitro sensitivity of bacteria to azithromycin
Sensitivity tests should be conducted using standardized laboratory methods, such as those described by the Clinical and Laboratory Standards Institute (CLSI). These include the dilution method (MIC determination) and the disk sensitivity determination method.
Both CLSI and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) provide interpretative criteria for these methods.
Based on a number of studies, it is recommended that the activity in vitro of azithromycin should be tested in an aerobic environment to ensure the physiological pH of the growth medium. High CO2 pressures, as often used for streptococci and anaerobic bacteria, and occasionally for other species, result in a reduction in the pH of the medium. This has a major negative effect on the apparent potency of azithromycin and other macrolides.
EUCAST also established sensitivity breakpoints for azithromycin based on MIC determination. The EUCAST sensitivity criteria are listed in the table below.
Sensitivity breakpoints for azithromycin
a includes groups A, B, C, G. EUCAST = European Committee on Antimicrobial Susceptibility Testing; MIC = Minimum Inhibitory Concentration.
Antibacterial spectrum:
The prevalence of acquired resistance may vary geographically and over time for selected species, and local information on resistance is desirable, particularly when treating severe infections. Expert advice should be sought if the local prevalence of resistant strains is such that the utility of the agents in at least some types of infections is questionable.
Azithromycin shows cross-resistance with erythromycin-resistant Gram-positive germs. As described above, some ribosomal modifications cause cross-resistance with other classes of antibiotics whose ribosomal binding sites overlap those of macrolides: lincosamides (including clindamycin) , and Streptogramins type B (which include for example quinupristin component of quinupristin / dalfopristin). A decrease in sensitivity to macrolides has been noted over time, particularly in Streptococcus pneumoniae and in Staphylococcus aureus, and was also observed in the streptococci group viridans and in Streptococcus agalactiae.
Organisms commonly sensitive to azithromycin include:
Facultative aerobic gram-positive bacteria (erythromycin-sensitive isolates): S. aureus, Streptococcus agalactiae*, S. pneumoniae*, Streptococcus pyogenes*, other streptococci? hemolytics (groups C, F, G), group streptococci viridans. Macrolide-resistant germs are found isolated quite frequently among facultative aerobic Gram-positive bacteria, particularly among S. aureus methicillin-resistant (MRSA) e S. pneumoniae penicillin-resistant (PRSP).
Optional aerobic Gram-negative bacteria: Bordetella pertussis, Campylobacter jejuni, Haemophilus ducreyi*, Haemophilus influenzae*, Haemophilus parainfluenzae*, Legionella pneumophila, Moraxella catarrhalis*, And Neisseria gonorrhoeae*. Pseudomonas spp. and most of Enterobacteriaceae are inherently resistant to azithromycin, although azithromycin has been used to treat infections from Salmonella enterica.
Anaerobes: Clostridium perfringens, Peptostreptococcus spp. And Prevotella bivia.
Other bacterial species: Borrelia burgdorferi, Chlamydia trachomatis, Chlamydophila pneumoniae*, Mycoplasma pneumoniae*, Treponema pallidum, And Ureaplasma urealyticum.
Opportunistic pathogens associated with HIV infection. MAC *, and eukaryotic microorganisms Pneumocystis jirovecii And Toxoplasma gondii.
* The efficacy of azithromycin against the species described has been demonstrated in clinical studies.
In a placebo-controlled study, patients taking azithromycin were found to have less than 50% chance of MAC bacteraemia compared to patients taking placebo. The overall 1-year incidence rate of disseminated MAC infections was 8.24% for azithromycin compared to 20.22% for placebo.
In a clinical study it was calculated that the risk of developing MAC bacteraemia in patients taking azithromycin was lower than that observed for patients taking rifabutin. Among patients taking a combination of azithromycin and rifabutin the chance of developing MAC bacteremia was reduced by one third compared to patients taking only one of the two drugs.The overall incidence rate of disseminated MAC infections calculated over one year was 7.62% among patients receiving azithromycin, 15.25% among those taking rifabutin and 2.75% among patients treated. with the association rifabutin and azithromycin. However, among the latter, a greater number of patients discontinued therapy due to poor tolerability.
During the studies on the prophylaxis of MAC infections, the percentage of other bacterial infections also decreased thanks to the intake of azithromycin.
Clinical Pharmacology
Treatment of disseminated MAC infections
In the pivotal clinical study, daily doses of azithromycin (600 mg) and clarithromycin (500 mg twice daily) both were administered in combination with ethambutol (800 or 1200 mg according to body weight). 71% (22 / 31) of patients treated with azithromycin showed clinical improvement compared to 74% (17/23) of those treated with clarithromycin. Furthermore, a positive bacteriological response was observed at week 24 in 76% (52/68) of treated patients. with azithromycin compared with 74% (42/57) of patients treated with clarithromycin.
05.2 Pharmacokinetic properties
Absorption
In humans, after oral administration, azithromycin is rapidly and widely distributed throughout the body, with a bioavailability of approximately 37%. No significant reduction in bioavailability was observed when azithromycin tablets were administered after a high fat meal The time required to achieve 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 MIC90 values for the most common pathogens after a single oral administration of 500 mg.
Following oral administration of 600 mg daily doses, the mean plasma concentration (Cmax) is 0.33 mcg / mL and 0.55 mcg / mL on day 1 and day 22, respectively. The time required to reach the maximum concentration (Tmax) does not change. The mean peak concentrations observed in leukocytes, the major site of disseminated MAC infection, are 252 mcg / ml (± 49%) and remain above 146 mcg / ml (± 33%) for 24 hours at steady state.
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 glyconic 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 impairment (GFR 10 - 80 ml / min). Statistically significant differences were found in AUC0-120 (8.8 mcg-h / mL vs. 11.7 mcg-h / mL), Cmax (1.0 mcg / mL vs. 1.6 mcg / mL) values. ) and CLr (2.3 ml / min / kg vs. 0.2 ml / min / kg) among the group with severe renal impairment (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
Pregelatinised starch, anhydrous acid calcium phosphate, carmellose sodium, magnesium stearate, sodium lauryl sulfate.
The lining contains: titanium dioxide, lactose, hypromellose, triacetin.
06.2 Incompatibility
Not relevant.
06.3 Period of validity
3 years.
06.4 Special precautions for storage
This medicine does not require any special storage conditions.
06.5 Nature of the immediate packaging and contents of the package
PVC / Al blister containing 8 x 600 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
Pfizer Italia S.r.l.
Via Isonzo, 71 - 04100 Latina
08.0 MARKETING AUTHORIZATION NUMBER
"Avium 600 mg film-coated tablets" 8 tablets AIC n. 027860143
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
12 January 1998/30 April 2012
10.0 DATE OF REVISION OF THE TEXT
AIFA determination of 11 January 2016
