Active ingredients: Azithromycin
RIBOTREX 500 mg film-coated tablets RIBOTREX 200 mg / 5 ml powder for oral suspension
Indications Why is Ribotrex 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 Ribotrex should not be used
The use of the 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 Ribotrex
Altered kidney function
In patients with severe renal impairment (GFR
Altered liver function
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 impaired liver function, hepatitis, cholestatic jaundice, hepatic necrosis and hepatitis have been reported with azithromycin. fulminant, potentially leading to liver failure, some of which have been fatal (see "Side Effects"). In cases where signs and symptoms of impaired liver function develop, such as rapid onset asthenia associated with jaundice, dark urine, tendency bleeding or hepatic encephalopathy, liver function tests / diagnostics should be performed Discontinue treatment with azithromycin immediately if signs and symptoms of hepatitis 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 Ribotrex
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.
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 6 HIV positive patients was observed to have no effect on the steady state pharmacokinetics of didanosine compared to placebo.
Digoxin
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 alter 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 significantly interact with the hepatic cytochrome P450 system. It is not thought 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 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 "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 cause alterations in HMG CoA reductase activity.) However, postmarketing cases of rhabdomyolysis have been reported 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 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 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 for 7 days of trimethoprim / sulfamethoxazole (160mg / 800mg) and azithromycin (1200mg), on day 7 there was no significant effect on peak concentrations, exposure time or urinary excretion of 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), and dermatological reactions including Stevens Johnson syndrome and toxic epidermal necrolysis (rarely fatal), have been observed rarely. Some of these reactions associated with the administration of azithromycin have led to 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, and may range 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. QT prolongation, torsades de pointes, arrhythmia In treatment with macrolides, including azithromycin, Prolongation of cardiac repolarization and QT interval was found on the electrocardiogram, with the risk of developing cardiac arrhythmia and torsades de pointes (see "Undesirable effects"), therefore caution is required in the treatment of patients: with congenital or documented prolongation QT interval; during treatment with other active substances that prolong the QT interval, such as class IA and III antiarrhythmics, cisapride and terfenadine, antipsychotic drugs, antidepressants, and fluoroquinolones; with electrolyte disturbances, especially in cases of hypokalaemia and hypomagnesaemia with clinically relevant bradycardia, cardiac arrhythmia or severe heart failure. elderly who may be more sensitive to drug effects related to the alteration of the QT interval. Myasthenia Gravis Exacerbation of symptoms of myasthenia gravis and initial onset of myasthenic syndrome have been reported in patients receiving azithromycin (see "Undesirable effects"). Ribotrex 200 mg / 5 ml powder for oral suspension contains sucrose (5ml of suspension contains 3.87 g of sucrose). If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product. Furthermore, due to the sucrose content, caution is required in the treatment of diabetic patients. Ribotrex 500 mg film-coated tablets 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 and breast-feeding Ask your doctor or pharmacist for advice before taking any medicine. The risk of harmful effects on the fetus and / or the child following the intake of azithromycin is not excluded; therefore azithromycin should be administered during pregnancy and lactation only when, in the opinion of the physician, the potential benefits exceed possible risks 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 Ribotrex: Dosage
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. Elderly patients may be more susceptible to developing torsades de pointes arrhythmia than younger patients (see section 4.4).
Children
10 mg / kg / day for 3 consecutive days.
For children weighing 45 kg or more, the same dosage as for adults (500 mg / day for three consecutive days) can be used.
For the treatment of acute otitis media in children, the expected dosage is 10 mg / kg / day for 3 consecutive days or 30 mg / kg in a single administration (see also below the "Instructions for preparation and administration of the suspension" ).
For the treatment of streptococcal pharyngitis in children, both the dose of 10 mg / kg and that of 20 mg / kg, both in a single administration and for three consecutive days, have been shown to be effective; however, the daily dose of 500 mg. In clinical trials with the two dosages, overlapping efficacy was observed, but greater bacterial eradication was seen at 20 mg / kg / day. However, in the treatment of Streptococcus pyogenes pharyngitis and in the prophylaxis of rheumatic fever, penicillin is the drug of choice.
The maximum total recommended dose for any pediatric therapy is 1500 mg.
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 <10 mL / min) (see "Precautions for use").
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 "Precautions for use").
The drug should always be administered in a single daily dose.
RIBOTREX (azithromycin) tablets and powder for oral suspension 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.
INSTRUCTIONS FOR THE PREPARATION AND ADMINISTRATION OF THE SUSPENSION
- Shake the bottle containing the powder before adding water. - Use the special dispenser positioned on the closure cap of the package and fill it with water up to the line (corresponding to 19 ml), for one time only. - Pour the water from the dispenser into the bottle. - Shake well so that all the powder passes into suspension.
One milliliter of suspension thus reconstituted contains 40 mg of azithromycin (equal to 200 mg for a 5 ml dose).
Always shake the suspension before use.
The reconstituted suspension must be administered using one of the two graduated dispensers attached to the package:
- "double spoon" graduated dispenser
To be used for children weighing between 15 kg and 45 kg. The dispenser consists of a small teaspoon (capacity 5 ml) on one side, and a large teaspoon (capacity 10 ml) on the other side
- graduated "syringe" dispenser
To be used for children weighing less than 15 kg
1) INSTRUCTIONS FOR USING THE "DOUBLE SPOON" GRADUATED DOSER
2) INSTRUCTIONS FOR USING THE "SYRINGE" GRADUATED DOSER
1. The syringe is calibrated in mg and ml of drug and kg of the child's weight
2. Unscrew the plastic cap and insert the syringe, with the adapter, into the bottle
3. Aspirate the prescribed amount of suspension
4. Detach the syringe from the adapter
5. Administer the suspension with the syringe directly into the child's mouth
Close the bottle with the special cap. Rinse the graduated dispenser used well.
ATTENTION
For the treatment of acute otitis media in children weighing less than 15 kg, the dosage of 30 mg / kg can also be performed in a single administration, filling the graduated "syringe" as many times as necessary until reaching of the prescribed dose.
Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.
Overdose What to do if you have taken too much Ribotrex
Adverse events occurring with higher than recommended doses were similar to those seen with normal doses. In case of accidental ingestion / intake of an excessive dose of RIBOTREX, notify your doctor immediately or go to the nearest hospital. If you have any questions about the use of RIBOTREX, ask your doctor or pharmacist.
Side Effects What are the side effects of Ribotrex
Like all medicines, RIBOTREX 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 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 e
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
** which rarely resulted in death
Expiry and Retention
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. For the tablets there are no special precautions for the storage of the product. After reconstitution, the oral suspension is stable for 10 days at room temperature.
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.
KEEP THE MEDICINAL PRODUCT OUT OF THE REACH AND SIGHT OF CHILDREN.
Composition and pharmaceutical form
COMPOSITION
RIBOTREX 500 mg film-coated tablets
Each film-coated tablet contains:
Active principle
Azithromycin dihydrate 524.110 mg
equal to Azithromycin base 500 mg
Excipients
Pregelatinised starch, anhydrous acid calcium phosphate, carmellose sodium, magnesium stearate, sodium lauryl sulfate, deionized water.
The coating contains: titanium dioxide, lactose, hypromellose, triacetin, deionized water.
RIBOTREX 200 mg / 5 ml powder for oral suspension - 1 bottle of 1500 mg
The reconstituted suspension contains 40 mg of azithromycin per ml (200 mg for a dose of 5 ml).
The composition per 100 grams of powder is as follows:
Active principle
Azithromycin dihydrate 5.01 g
equal to Azithromycin base 4.78 g
Excipients
Anhydrous tribasic sodium phosphate, hydroxypropylcellulose, xanthan gum, cherry flavor, vanilla cream, banana flavor, sucrose.
PHARMACEUTICAL FORM AND CONTENT
- Film-coated tablets: Blister pack containing 3 x 500 mg film-coated tablets.
- Powder for oral suspension: bottle containing 1500 mg of azithromycin. Once reconstituted, the suspension will contain 200 mg / 5ml.
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
RIBOTREX
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
RIBOTREX 500 mg film-coated tablets
Each film-coated tablet contains:
Active principle:
Azithromycin dihydrate 524.110 mg
equal to Azithromycin base 500 mg
RIBOTREX 200 mg / 5 ml powder for oral suspension - 1 bottle of 1500 mg
The reconstituted suspension contains 40 mg of azithromycin per ml (200 mg for a dose of 5 ml).
The composition per 100 grams of powder is as follows:
Active principle
Azithromycin dihydrate 5.01 g
equal to Azithromycin base 4.78 g
Excipients with known effects:
the tablets contain lactose;
the powder for suspension contains sucrose.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Film-coated tablets.
Powder for oral suspension.
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. Elderly patients may be more susceptible to developing torsades de pointes arrhythmia than younger patients (see section 4.4).
Children
10 mg / kg / day for 3 consecutive days.
For children weighing 45 kg or more, the same dosage as for adults (500 mg / day for three consecutive days) can be used.
For the treatment of acute otitis media in children, the expected dosage is 10 mg / kg / day for 3 consecutive days or 30 mg / kg in a single dose.
For the treatment of streptococcal pharyngitis in children, both the 10 mg / kg and 20 mg / kg doses, both in a single administration and for three consecutive days, have been shown to be effective; however, the daily dose of 500 mg should not be exceeded. In clinical studies with the two dosages, an overlapping efficacy was observed, but with the dosage of 20 mg / kg / day there was a greater bacterial eradication. However, in the treatment of pharyngitis from Streptococcus pyogenes and in rheumatic fever prophylaxis, penicillin is the drug of choice.
The maximum total recommended dose for any pediatric therapy is 1500 mg.
The drug should always be administered in a single daily dose.
RIBOTREX (azithromycin) tablets and oral suspension 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.
Method of administration
The tablets should be swallowed whole.
For instructions on reconstitution and administration of the suspension, see section 6.6.
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 the 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
Hypersensitivity
As with erythromycin and other macrolides, severe allergic reactions, including angioedema and anaphylaxis (rarely fatal), and dermatological reactions including Stevens Johnson syndrome and toxic epidermal necrolysis (rarely fatal), have been reported rarely. Some of these associated reactions the administration of azithromycin 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 significant 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 hepatic failure, some of which have been fatal (see section 4.8 - Undesirable effects). In cases where signs and symptoms of impaired liver function develop, such as rapid onset asthenia associated with jaundice, dark urine, tendency to bleeding or hepatic encephalopathy, liver function tests / diagnostics should be performed.
Immediately discontinue azithromycin treatment if signs and symptoms of hepatitis 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 associated diarrhea C. difficult they have also been reported over two months after antibiotic administration
In patients with severe renal impairment (GFR Pharmacokinetic properties).
Prolongation of the QT interval
In treatment with macrolides, including azithromycin, prolongation of cardiac repolarization and QT interval was found on ECG, with the risk of developing cardiac arrhythmia and torsades de pointes. (see section 4.8 Undesirable effects), therefore caution is required when treating 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 and III antiarrhythmics, cisapride and terfenadine, antipsychotic drugs, antidepressants, and fluoroquinolones;
• with alterations of electrolytes, especially in cases of hypokalaemia and hypomagnesaemia;
• with clinically relevant bradycardia, cardiac arrhythmia or severe heart failure;
• the elderly who may be more sensitive to drug effects related to the alteration of the 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).
Ribotrex 200mg / 5ml powder for oral suspension contains sucrose (5 ml of suspension contain 3.87 g of sucrose).
Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption, or sucrase isomaltase insufficiency should not take this medicine.
Furthermore, due to the sucrose content, caution is required in the treatment of diabetic patients.
Ribotrex 500 mg film-coated tablets
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. Therefore, patients in therapy with azithromycin and antacids 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
Co-administration of daily doses of 1200 mg / day azithromycin and 400 mg / day didanosine in 6 HIV-positive patients was observed to have no effect on overall pharmacokinetics. steady state didanosine compared to placebo.
Digoxin
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 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.
HMG-CoA reductase inhibitors (Statins)
Concomitant administration of atorvastatin (10 mg / day) and azithromycin (500 mg / day) did not cause alterations in HMG CoA reductase activity. However, post-marketing cases of rhabdomyolysis have been reported 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 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 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 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 the 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 advisable to re-evaluate the frequency with which prothrombin time is monitored when administering azithromycin to patients receiving coumarin-type anticoagulants.
04.6 Pregnancy and lactation
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 were conducted using scaled doses until maternal toxic concentrations were reached. From these studies there was no evidence of any hazard to the fetus due to azithromycin. However, there are no adequate and well-controlled studies in pregnant women. 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 is no evidence that azithromycin could 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 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 e
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
** which rarely resulted in death
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.
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.
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 post-transcriptional (N) - 6 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.
The European Committee on Antimicrobial Susceptibility Testing (EUCAST) has also established susceptibility breakpoints for azithromycin based on MIC determination. EUCAST susceptibility criteria are listed in the table below.
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 as necessary 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 hemolytic streptococci b (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
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 main route of elimination of unchanged drug after oral administration. Very high concentrations of unchanged drug have been found in human bile together with 10 metabolites, the latter formed by N- and O-demethylation processes, by hydroxylation of the desosamine and the aglyconic ring and by cleavage of the cladinose-conjugates. Studies conducted by 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. 0.2ml / 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
RIBOTREX 500 mg film-coated tablets: pregelatinised starch, anhydrous acid calcium phosphate, carmellose sodium, magnesium stearate, sodium lauryl sulfate, deionized water.
The lining contains: titanium dioxide, lactose, hypromellose, triacetin, deionized water.
RIBOTREX 200 mg / 5 ml powder for oral suspension: anhydrous tribasic sodium phosphate, hydroxypropylcellulose, xanthan gum, cherry flavor, vanilla cream, banana flavor, sucrose.
06.2 Incompatibility
Not relevant.
06.3 Period of validity
RIBOTREX 500 mg film-coated tablets: 2 years.
RIBOTREX 200 mg / 5 ml powder for oral suspension: 2 years in intact packaging.
Once reconstituted, the powder for oral suspension can be stored for 10 days at room temperature.
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
RIBOTREX 500 mg film-coated tablets: PVC blister containing 3 x 500 mg film-coated scored tablets.
RIBOTREX 200mg / 5ml powder for oral suspension: High density polyethylene bottle containing 1500 mg of active ingredient with child resistant closure and suitable dispenser.
Once reconstituted the suspension will contain 200 mg / 5 ml.
06.6 Instructions for use and handling
INSTRUCTIONS FOR THE PREPARATION AND ADMINISTRATION OF THE SUSPENSION
- Shake the bottle containing the powder before adding water.
- Use the special dispenser positioned on the closing cap of the package and fill it with water up to the line (corresponding to 19 ml), for one time only.
- Pour the water from the dispenser into the bottle.
- Shake well so that all the powder passes into suspension.
One ml of the thus reconstituted suspension contains 40 mg of azithromycin (equal to 200 mg for a 5 ml dose).
Always shake the suspension before use.
The reconstituted suspension must be administered using one of the two graduated dispensers attached to the package:
• "double spoon" graduated dispenser
To be used for children weighing between 15 kg and 45 kg. The dispenser consists of a small teaspoon (capacity 5 ml) on one side, and a large teaspoon (capacity 10 ml) on the other side
• graduated "syringe" dispenser
To be used for children weighing less than 15 kg
1) INSTRUCTIONS FOR USING THE "DOUBLE SPOON" GRADUATED DOSER
2) INSTRUCTIONS FOR USING THE "SYRINGE" GRADUATED DOSER
1. The syringe is calibrated in mg and ml of drug and kg of the child's weight
2. Unscrew the plastic cap and insert the syringe, with the adapter, into the bottle
3. Aspirate the prescribed amount of suspension
4. Detach the syringe from the adapter
5. Administer the suspension with the syringe directly into the child's mouth
Close the bottle with the special cap. Rinse the graduated dispenser used well.
ATTENTION
For the treatment of acute otitis media in children weighing less than 15 kg, the dosage of 30 mg / kg can also be performed in a single administration, filling the graduated "syringe" as many times as necessary until reaching of the prescribed dose.
Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
Pierre Fabre Pharma S.r.l. - Via G. G. Winckelmann, 1 - MILAN
08.0 MARKETING AUTHORIZATION NUMBER
"RIBOTREX 500 mg film-coated tablets" 3 tablets A.I.C. n. 028177032
"RIBOTREX 200 mg / 5 ml powder for oral suspension" 1 bottle of 1500 mg - A.I.C. n. 028177020
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
May 1992 - May 2007
10.0 DATE OF REVISION OF THE TEXT
June 2013
