Iset U.D.

Iset U.D.romycin film-coated tablets are indicated for the treatment of the following bacterial infections, when caused by Iset U.D.romycin-susceptible bacteria.

- Bacterial pharyngitis

- Mild to moderate community acquired pneumonia

- Acute bacterial sinusitis (adequately diagnosed)

- Acute exacerbation of chronic bronchitis

- Skin infections and soft tissue infections of mild to moderate severity,

- In appropriate combination with antibacterial therapeutic regimens and an appropriate ulcer healing agent for the eradication of Helicobacter pylori in patients with Helicobacter pylori associated ulcers.

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

Posology

The dosage of Iset U.D.romycin film-coated tablets depends on the type and severity of the infection and has to be defined in any case by the physician.

Iset U.D.romycin 500 mg film-coated tablet is not suitable for doses below 500 mg. There are other options for this strength available on the market.

Adults and adolescents (12 years and older)

- Standard dosage: The usual dose is 250 mg twice daily (in the morning and in the evening)

- High dosage treatment (severe infections): The usual dose may be increased to 500 mg twice daily in severe infections.

Children younger than 12 years:

Use of Iset U.D.romycin film-coated tablets is not recommended for children younger than 12 years with a body weight less than 30 kg. Clinical trials have been conducted using Iset U.D.romycin pediatric suspension in children 6 months to 12 years of age. Therefore, children under 12 years of age should use Iset U.D.romycin paediatric suspension.

For children with a body weight of more than 30kg, the dose for adults apply.

Dosage in renal functional impairment:

In patients with renal impairment with creatinine clearance less than 30 mL/min, the dosage of Iset U.D.romycin should be reduced by one-half, i.e. 250 mg once daily, or 250 mg twice daily in more severe infections. Treatment should not be continued beyond 14 days in these patients.

Patients with hepatic impairment:

Caution should be exercised when administrating Iset U.D.romycin in patients with hepatic impairment.

H. pylori eradication in peptic ulcer disease

For the eradication of H. pylori the selection of antibiotics should consider the individual patient's drug tolerance, and should be undertaken in accordance with national, regional and local resistance patterns and treatment guidelines.

Usually Iset U.D.romycin is administered in combination with another antibiotic and a proton-pump inhibitor for one week.

The therapy may be repeated if the patient is still H. pylori-positive

Duration of therapy:

The duration of therapy with Iset U.D.romycin film-coated tablets depends on the type and severity of the infection and has to be defined in any case by the physician.

- The usual duration of treatment is 7 to 14 days.

- Therapy should be continued at least for 2 days after symptoms have subsided.

- In Streptococcus pyogenes (group A beta-haemolytic streptococcus) infections the duration of therapy should be at least 10 days.

- Combination therapy for the eradication of H. pylori infection should be continued for 7 days.

Method of administration:

The tablet should be swallowed whole with a sufficient amount of fluid (eg. one glass of water).

Iset U.D.romycin film-coated tablets may be given irrespective of food intake.

Concomitant administration of Iset U.D.romycin and any of the following active substances is contraindicated: astemizole, cisapride, pimozide and terfenadine as this may result in QT prolongation (congenital or documented acquired QT prolongation) and cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation and Torsade de Pointes.

Concomitant administration with ticagrelor or renolazine is contraindicated.

Concomitant administration of Iset U.D.romycin and ergotamine or dihydroergotamine is contraindicated, as this may result in ergot toxicity.

Iset U.D.romycin should not be given to patients with history of QT prolongation or ventricular cardiac arrhythmia, including torsades de pointe.

Iset U.D.romycin should not be used concomitantly with HMG-CoA reductase inhibitors (statins) that are extensively metabolosed by CYP3A4 (lovastatin or simvastatin), due to the increased risk of myopathy, including rhabdomyolysis.

Iset U.D.romycin should not be given to patients with hypokalaemia (risk of prolongation of QT-time).

Iset U.D.romycin should not be used in patients who suffer from severe hepatic failure in combination with renal impairment.

As with other strong CYP3A4 inhibitors, Iset U.D.romycin should not be used in patients taking colchicine.

The physician should not prescribe Iset U.D.romycin to pregnant women without carefully weighing the benefits against risk, particularly during the first three months of pregnancy.

Caution is advised in patients with severe renal insufficiency.

Iset U.D.romycin is principally excreted by the liver. Therefore, caution should be exercised in administering the antibiotic to patients with impaired hepatic function. Caution should also be exercised when administering Iset U.D.romycin to patients with moderate to severe renal impairment.

Cases of fatal hepatic failure have been reported. Some patients may have had pre-existing hepatic disease or may have been taking other hepatotoxic medicinal products. Patients should be advised to stop treatment and contact their doctor if signs and symptoms of hepatic disease develop, such as anorexia, jaundice, dark urine, pruritus, or tender abdomen.

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including macrolides, and may range in severity from mild to life-threatening. Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents including Iset U.D.romycin, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon, which may lead to overgrowth of C.difficile. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. Therefore, discontinuation of Iset U.D.romycin therapy should be considered regardless of the indication. Microbial testing should be performed and adequate treatment initiated. Drugs inhibiting peristalsis should be avoided.

There have been post-marketing reports of colchicine toxicity with concomitant use of Iset U.D.romycin and colchicine, especially in the elderly, some of which occurred in patients with renal insufficiency. Deaths have been reported in some such patients. Concomitant administration of Iset U.D.romycin and colchicines is contraindicated.

Caution is advised regarding concomitant administration of Iset U.D.romycin and triazolobenzodiazepines, such as triazolam, and midazolam.

Caution is advised regarding concomitant administration of Iset U.D.romycin with other ototoxic drugs, especially with aminoglycosides. Monitoring of vestibular and auditory function should be carried out during and after treatment.

Prolongation of the QT Interval

Prolonged cardiac repolarisation and QT interval, imparting a risk of developing cardiac arrhythmia and torsade de pointes, have been seen in treatment with macrolides including Iset U.D.romycin. Therefore as the following situations may lead to an increased risk for ventricular arrhythmias (including torsade de pointes), Iset U.D.romycin should be used with caution in the following patients;

- Patients with coronary artery disease, severe cardiac insufficiency, conduction disturbances or clinically relevant bradycardia

- Patients with electrolyte disturbances such as hypomagnesaemia. Iset U.D.romycin must not be given to patients with hypokalaemia.

- Patients concomitantly taking other medicinal products associated with QT prolongation.

- Concomitant administration of Iset U.D.romycin with astemizole, cisapride, pimozide and terfendine is contraindicated.

- Iset U.D.romycin must not be used in patients with congenital or documented acquired QT prolongation or history of ventricular arrhythmia.

Pneumonia: In view of the emerging resistance of Streptococcus pneumoniae to macrolides, it is important that sensitivity testing be performed when prescribing Iset U.D.romycin for community-acquired pneumonia. In hospital-acquired pneumonia, Iset U.D.romycin should be used in combination with additional appropriate antibiotics.

Skin and soft tissue infections of mild to moderate severity: These infections are most often caused by Staphylococcus aureus and Streptococcus pyogenes, both of which may be resistant to macrolides. Therefore, it is important that sensitivity testing be performed. In cases where beta-lactam antibiotics cannot be used (e.g. allergy), other antibiotics, such as clindamycin, may be the drug of first choice. Currently, macrolides are only considered to play a role in some skin and soft tissue infections, such as those caused by Corynebacterium minutissimum, acne vulgaris, and erysipelas and in situations where penicillin treatment cannot be used.

In the event of severe acute hypersensitivity reactions, such as anaphylaxis, Stevens-Johnson Syndrome, and toxic epidermal necrolysis, Iset U.D.romycin therapy should be discontinued immediately and appropriate treatment should be urgently initiated.

Iset U.D.romycin should be used with caution when administered concurrently with medications that induce the cytochrome CYP3A4 enzyme.

HMG-CoARreductase Inhibitors (statins): Concomitant use of Iset U.D.romycin with lovastatin or simvastatin is contraindicated. Caution should be exercised when prescribing Iset U.D.romycinwith other statins. Rhabdomyolysis has been reported in patients taking Iset U.D.romycin and statins. Patients should be monitored for signs and symptoms of myopathy. In situations where the concomitant use of Iset U.D.romycin with statins cannot be avoided, it is recommended to prescribe the lowest registered dose of statin. Use of a statin that is not dependent on CYP3A metabolism (e.g. fluvastatin) can be considered.

Oral hypoglycemic agents/Insulin: The concomitant use of Iset U.D.romycin and oral hypoglycemic agents (such as sulfonylurias) and/or insulin can result in significant hypoglycemia. Careful monitoring of glucose is recommended.

Oral anticoagulants: There is a risk of serious hemorrhage and significant elevations in International Normalized Ratio (INR) and prothrombin time when Iset U.D.romycin is co-administered with warfarin. INR and prothrombin times should be frequently monitored while patients are receiving Iset U.D.romycin and oral anticoagulants concurrently.

Use of any antimicrobial therapy, such as Iset U.D.romycin, to treat H. pylori infection may select for drug-resistant organisms.

Long-term use may, as with other antibiotics, result in colonization with increased numbers of non-susceptible bacteria and fungi. If super-infection occur,appropriate therapy should be instituted.

Attention should also be paid to the possibility of cross resistance between Iset U.D.romycin and other macrolide drugs, as well as lincomycin and clindamycin.

There are no data on the effect of Iset U.D.romycin on the ability to drive or use machines. The potential for dizziness, vertigo, confusion and disorientation, which may occur with the medication, should be taken into account before patients drive or use machines.

a. Summary of the safety profile

The most frequent and common adverse reactions related to Iset U.D.romycin therapy for both adult and pediatric populations are abdominal pain, diarrhea, nausea, vomiting and taste perversion. These adverse reactions are usually mild in intensity and are consistent with the known safety profile of macrolide antibiotics.

There was no significant difference in the incidence of these gastrointestinal adverse reactions during clinical trials between the patient population with or without preexisting mycobacterial infections.

b. Tabulated summary of adverse reactions

The following table displays adverse reactions reported in clinical trials and from post-marketing experience with Iset U.D.romycin immediate-release tablets, granules for oral suspension, powder for solution for injection, extended release tablets and modified-release tablets.

The reactions considered at least possibly related to Iset U.D.romycin are displayed by system organ class and frequency using the following convention: very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1,000 to <1/100) and not known (adverse reactions from post-marketing experience; cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness when the seriousness could be assessed.

¹ ADRs reported only for the Powder for Solution for Injection formulation

²ADRs reported only for the Extended-Release Tablets formulation

³ ADRs reported only for the Granules for Oral Suspension formulation

⁴ ADRs reported only for the Immediate-Release Tablets formulation

⁵, ^{7, 9, 10,} See section a)

^{6, 8, 11} See section c)

c. Description of selected adverse reactions

Injection site phlebitis, injection site pain, vessel puncture site pain, and injection site inflammation are specific to the Iset U.D.romycin intravenous formulation.

In some of the reports of rhabdomyolysis, Iset U.D.romycin was administered concomitantly with statins, fibrates, colchicine or allopurinol.

There have been post-marketing reports of colchicine toxicity with concomitant use of Iset U.D.romycin and colchicine, especially in elderly and/or patients with renal insufficiency, some with a fatal outcome.

There have been post-marketing reports of drug interactions and central nervous system (CNS) effects (e.g. somnolence and confusion) with the concomitant use of Iset U.D.romycin and triazolam. Monitoring the patient for increased CNS pharmacological effects is suggested.

There have been rare reports of Iset U.D.romycin ER tablets in the stool, many of which have occurred in patients with anatomic (including ileostomy or colostomy) or functional gastrointestinal disorders with shortened GI transit times. In several reports, tablet residues have occurred in the context of diarrhea. It is recommended that patients who experience tablet residue in the stool and no improvement in their condition should be switched to a different Iset U.D.romycin formulation (e.g. suspension) or another antibiotic.

Special population: Adverse Reactions in Immunocompromised Patients (see section e)

d. Paediatric populations

Clinical trials have been conducted using Iset U.D.romycin paediatric suspension in children 6 months to 12 years of age. Therefore, children under 12 years of age should use Iset U.D.romycin paediatric suspension. There are insufficient data to recommend a dosage regimen for use of the Iset U.D.romycin IV formulation in patients less than 18 years of age.

Frequency, type and severity of adverse reactions in children are expected to be the same as in adults.

e. Other special populations

Immunocompromised patients

In AIDS and other immunocompromised patients treated with the higher doses of Iset U.D.romycin over long periods of time for mycobacterial infections, it was often difficult to distinguish adverse events possibly associated with Iset U.D.romycin administration from underlying signs of Human Immunodeficiency Virus (HIV) disease or intercurrent illness.

In adult patients, the most frequently reported adverse reactions by patients treated with total daily doses of 1,000 mg and 2,000 mg of Iset U.D.romycin were: nausea, vomiting, taste perversion, abdominal pain, diarrhea, rash, flatulence, headache, constipation, hearing disturbance, Serum Glutamic Oxaloacetic Transaminase (SGOT) and Serum Glutamic Pyruvate Transaminase (SGPT) elevations. Additional low-frequency events included dyspnoea, insomnia and dry mouth. The incidences were comparable for patients treated with 1,000 mg and 2,000 mg, but were generally about 3 to 4 times as frequent for those patients who received total daily doses of 4,000 mg of Iset U.D.romycin.

In these immunocompromised patients, evaluations of laboratory values were made by analysing those values outside the seriously abnormal level (i.e. the extreme high or low limit) for the specified test. On the basis of these criteria, about 2% to 3% of those patients who received 1,000 mg or 2,000 mg of Iset U.D.romycin daily had seriously abnormal elevated levels of SGOT and SGPT, and abnormally low white blood cell and platelet counts. A lower percentage of patients in these two dosage groups also had elevated Blood Urea Nitrogen levels. Slightly higher incidences of abnormal values were noted for patients who received 4,000 mg daily for all parameters except White Blood Cell.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

Symptoms of intoxication:

Reports indicate that the ingestion of large amounts of Iset U.D.romycin can be expected to produce gastrointestinal symptoms. One patient who had a history of bipolar disorder ingested eight grams of Iset U.D.romycin and showed altered mental status, paranoid behaviour, hypokalaemia and hypoxemia.

Therapy of intoxication:

Adverse reactions accompanying overdosage should be treated by the prompt elimination of unabsorbed drug and supportive measures. As with other macrolides, Iset U.D.romycin serum levels are not expected to be appreciably affected by hemodialysis or peritoneal dialysis.

In the case of overdosage, Iset U.D.romycin IV (powder for solution for injection) should be discontinued and all other appropriate supportive measures should be instituted.

Pharmacotherapeutic group: Macrolides

ATC code: J01FA09

Mode of action:

Iset U.D.romycin is a semi-synthetic derivative of erythromycin A. It exerts its antibacterial action by binding to the 50s ribosomal sub-unit of susceptible bacteria and suppresses protein synthesis. It is highly potent against a wide variety of aerobic and anaerobic gram-positive and gram-negative organisms. The minimum inhibitory concentrations (MICs) of Iset U.D.romycin are generally two-fold lower than the MICs of erythromycin.

The 14-hydroxy metabolite of Iset U.D.romycin also has antimicrobial activity. The MICs of this metabolite are equal or twofold higher than the MICs of the parent compound, except for H. influenzae where the 14-hydroxy metabolite is two-fold more active than the parent compound.

PK/PD relationship

Iset U.D.romycin is extensively distributed into body tissues and fluids. Due to the high tissue penetration, intracellular concentrations higher than serum concentrations. The main pharmacodynamic parameters to predict macrolidenactiviteit are unconvincing established. The time above the MIC (T / MIC) is the best determinant for the efficacy of Iset U.D.romycin. Because the concentrations of Iset U.D.romycin in the lung tissues and epithelial tissue fluid reaches the plasma concentrations exceed, the use of plasma concentrations based parameters are insufficient to accurately predict response for respiratory infections.

Mechanisms of resistance:

Resistance mechanisms against macrolide antibiotics include alteration of the target site of the antibiotic or are based on modification and/or the active efflux of the antibiotic. Resistance development can be mediated via chromosomes or plasmids, be induced or exist constitutively. Macrolideresistant bacteria generate enzymes which lead to methylation of residual adenine at ribosomal RNA and consequently to inhibition of the antibiotic binding to the ribosome. Macrolide-resistant organisms are generally cross-resistant to lincosamides and streptogramine B based on methylation of the ribosomal binding site. Iset U.D.romycin ranks among the strong inducers of this enzyme as well. Furthermore, macrolides have a bacteriostatic action by inhibiting the peptidyl transferase of ribosomes. A complete cross-resistance exists among Iset U.D.romycin, erythromycin and azithromycin. Methicillin-resistant staphylococci and penicillin-resistant Streptococcus pneumoniae are resistant to macrolides such as Iset U.D.romycin.

Breakpoints:

The following breakpoints for Iset U.D.romycin, separating susceptible organisms from resistant organisms, have been established by the European Committee for Antimicrobial Susceptibility Testing (EUCAST) 2010-04-27 (v 1.1)

^A Non-species related breakpoints have been determined mainly on the basis of PK/PD data and are independent of MIC distributions of specific species. They are for use only for species not mentioned in the table or footnotes However, pharmacodynamic data for calculation of macrolide, lincosamines and streptogramins non-species related breakpoints are not robust, hence IE.

^B Erythromycin can be used to determine the susceptibility of the listed bacteria to the other macrolides (azithromycin, Iset U.D.romycin and roxithromycin

^C Iset U.D.romycin is used for the eradication of H. pylori (MIC ≤0.25 mg/L for wild type isolates).

^D The correlation between H. influenzae macrolide MICs and clinical outcome is weak. Therefore, breakpoints for macrolides and related antibiotics were set to categorise wild type H. influenzae as intermediate.

Iset U.D.romycin is used for the eradication of H. pylori; minimum inhibitory concentration (MIC) ≤ 0.25 μg/ml which has been established as the susceptible breakpoint by the Clinical and Laboratory Standards Institute (CLSI).

Susceptibility:

The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalance of resistance is such that the utility of the agent in atleast some types of infections is questionable.

# > 10% resistance in at least one country of the European Union

* Species against efficacy has been demonstrated in clinical investigations (if susceptible)

+ Indicates species for which a high rate of resistance (i.e. greater than 50%) have been observed in one or more area/country/region(s) of the EU

§ Breakpoints for macrolides and related antibiotics were set to categorise wild type H. influenzae as intermediate

Other information:

Susceptibility and resistance of Streptococcus pneumoniae and Streptococcus spp. to Iset U.D.romycin can be predicted by testing erythromycin.

Most available clinical experience from controlled randomised clinical trials indicate that Iset U.D.romycin 500 mg twice daily in combination with another antibiotic e.g. amoxicillin or metronidazole and e.g. omeprazole (given at approved levels) for 7 days achieve > 80% H. pylori eradication rate in patients with gastro-duodenal ulcers. As expected, significantly lower eradication rates were observed in patients with baseline metronidazole-resistant H. pylori isolates. Hence, local information on the prevalence of resistance and local therapeutic guidelines should be taken into account in the choice of an appropriate combination regimen for H. pylori eradication therapy. Furthermore, in patients with persistent infection, potential development of secondary resistance (in patients with primary susceptible strains) to an antimicrobial agent should be taken into the considerations for a new retreatment regimen.

Absorption:

Iset U.D.romycin is rapidly and well absorbed from the gastrointestinal tract - primarily in the jejunum - but undergoes extensive first-pass metabolism after oral administration. The absolute bioavailability of a 250-mg Iset U.D.romycin tablet is approximately 50%. Food slightly delays the absorption but does not affect the extent of bioavailability. Therefore, Iset U.D.romycin tablets may be given without regard to food. Due to its chemical structure (6-O-Methylerythromycin) Iset U.D.romycin is quite resistant to degradation by stomach acid. Peak plasma levels of 1 - 2 μg/ml Iset U.D.romycin were observed in adults after oral administration of 250 mg twice daily. After administration of 500 mg Iset U.D.romycin twice daily the peak plasma level was 2.8 μg/ml. After administration of 250 mg Iset U.D.romycin twice daily the microbiologically active 14-hydroxy metabolite attains peak plasma concentrations of 0.6 μg/ml. Steady state is attained within 2 days of dosing.

Distribution:

Iset U.D.romycin penetrates well into different compartments with an estimated volume of distribution of 200-400 l. Iset U.D.romycin provides concentrations in some tissues that are several times higher than the circulating drug levels. Increased levels have been found in both tonsils and lung tissue. Iset U.D.romycin also penetrates the gastric mucus.

Iset U.D.romycin is approximately 70% bound to plasma proteins at therapeutic levels.

Biotransformation and elimination:

Iset U.D.romycin is rapidly and extensively metabolised in the liver. Metabolism is in the liver involving the P450 cytochrome system. Three metabolites are described: N-demethyl Iset U.D.romycin, decladinosyl Iset U.D.romycin and 14-hydroxy Iset U.D.romycin. The pharmacokinetics of Iset U.D.romycin is non-linear due to saturation of hepatic metabolism at high doses. Elimination half-life increased from 2-4 hours following administration of 250 mg Iset U.D.romycin twice daily to 5 hours following administration of 500 mg Iset U.D.romycin twice daily. The half-life of the active 14-hydroxy metabolite ranges between 5 to 6 hours following administration of 250 mg Iset U.D.romycin twice daily.

Approximately 20 -40% of Iset U.D.romycin is excreted as the unchanged active substance in the urine. This proportion is increased when the dose is increased. An additional 10% to 15% is excreted in the urine as 14-hydroxy metabolite. The rest is excreted in the faeces.Renal insufficiency increases Iset U.D.romycin levels in plasma, if the dose is not decreased. Total plasma clearance has been estimated to approximately 700 mL/min (11,7 mL/s), with a renal clearance of approximately 170 mL/min (2,8 mL/s).

Special populations:

Renal impairment: Reduced renal insufficiency function results in increased plasma levels of Iset U.D.romycin and the active metabolite levels in plasma.

In 4-week-studies in animals, toxicity of Iset U.D.romycin was found to be related to the dose and to the duration of the treatment. In all species, the first signs of toxicity were observed in the liver, in which lesions were seen within 14 days in dogs and monkeys. The systemic levels of exposure, related to this toxicity, are not known in detail, but toxic doses were clearly higher than the therapeutic doses recommended for humans. Other tissues affected included the stomach, thymus and other lymphoid tissues as well as the kidneys. At near therapeutic doses conjunctival injection and lacrimation occurred only in dogs. At a dose of 400 mg/kg/day some dogs and monkeys developed corneal opacities and/or oedema.

No mutagenic effects were found in in vitro- and in vivo -studies with Iset U.D.romycin

Studies on reproduction toxicity showed that administration of Iset U.D.romycin at doses 2x the clinical dose in rabbit (i.v.) and x10 the clinical dose in monkey (p.o.) resulted in an increased incidence of spontaneous abortions. These doses were related to maternal toxicity. No embryotoxicity or teratogenicity was noted in rat studies. Cardiovascular malformations were observed in rats treated with doses of 150 mg/kg/d. In mouse at doses x70 the clinical dose cleft palate occurred at varying incidence (3-30%).

Iset U.D.romycin has been found in the milk of lactating animals.

In 3-day old mice and rats, the LD50 values were approximately half those in adult animals. Juvenile animals presented similar toxicity profiles to mature animals although enhanced nephrotoxicity in neonatal rats has been reported in some studies. Slight reductions in erythrocytes, platelets and leukocytes have also been found in juvenile animals.

Iset U.D.romycin has not been tested for carcinogenicity.

Not applicable.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.