Symptoms of intoxication:
Reports indicate that the ingestion of large amounts of Klacid ODromycin can be expected to produce gastrointestinal symptoms. One patient who had a history of bipolar disorder ingested eight grams of Klacid ODromycin 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, Klacid ODromycin serum levels are not expected to be appreciably affected by hemodialysis or peritoneal dialysis.
In the case of overdosage, Klacid ODromycin IV (powder for solution for injection) should be discontinued and all other appropriate supportive measures should be instituted.
Not applicable.
a. Summary of the safety profile
The most frequent and common adverse reactions related to Klacid ODromycin 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 Klacid ODromycin 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 Klacid ODromycin 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.
| System Organ Class | Very common (>1/10 | Common > 1/100 to < 1/10 | Uncommon >1/1,000 to < 1/100 | Not Known (cannot be estimated from the available data) |
| Infections and infestations | Cellulitis1, candidiasis, gastroenteritis2, infection3, vaginal infection | Pseudomembranous colitis, erysipelas | ||
| Blood and lymphatic system | Leukopenia, neutropenia4, thrombocythemia3, eosinophilia4 | Agranulocytosis, thrombocytopenia | ||
| Immune system disorders5 | Anaphylactoid reaction1, Hypersensitivity | Anaphylactic reaction, angioedema | ||
| Metabolism and nutrition disorders | Anorexia, decreased appetite | |||
| Psychiatric disorders | Insomnia | Anxiety, nervousness3, | Psychotic disorder, confusional state, depersonalisation, depression, disorientation, hallucination, abnormal dreams, mania | |
| Nervous system disorders | Dysgeusia, headache, taste perversion | Loss of consciousness1, dyskinesia1, dizziness, somnolence6, tremor | Convulsion, ageusia, parosmia, anosmia, paraesthesia | |
| Ear and labyrinth disorders | Vertigo, hearing, impaired, tinnitus | Deafness | ||
| Cardiac disorders | Cardiac arrest1, atrial fibrillation1, electrocardiogram QT prolonged7, extrasystoles1, palpitations | Torsade de pointes7, ventricular tachycardia7 ventricular fibrillation | ||
| Vascular disorders | Vasodilation1 | Hemorrhage8 | ||
| Respiratory, thoracic and mediastinal disorder | Asthma1, epistaxis2, pulmonary embolism1 | |||
| Gastrointestinal disorders | Diarrhea9, vomiting, dyspepsia, nausea, abdominal pain | Esophagitis1, gastrooesophageal reflux disease2, gastritis, proctalgia2, stomatitis, glossitis, abdominal distension4, constipation, dry mouth, eructation, flatulence | Pancreatitis acute, tongue discolouration, tooth discoloration | |
| Hepatobiliary disorders | Liver function test abnormal | Cholestasis4, hepatitis4, alanine aminotransferase increased, aspartate aminotransferase increased, gamma-glutamyltransferase increased4 | Hepatic failure10, jaundice hepatocellular | |
| Skin and subcutaneous tissue disorders | Rash, hyperhidrosis | Dermatitis bullous1, pruritus, urticaria, rash maculo-papular3 | Stevens-Johnson syndrome5, toxic epidermal necrolysis5, drug rash with eosinophilia and systemic symptoms (DRESS), acne | |
| Musculoskeletal and connective tissue disorders | Muscle spasms3, musculoskeletal stiffness1, myalgia2 | Rhabdomyolysis2, 11, myopathy | ||
| Renal and urinary disorders | Blood creatinine increased1, blood urea increased1 | Renal failure, nephritis interstitial | ||
| General disorders and administration site conditions | Injection site phlebitis1 | Injection site pain1, injection site inflammation1 | Malaise4, pyrexia3, asthenia, chest pain4, chills4, fatigue4 | |
| Investigations | Albumin globulin ratio abnormal1 , blood alkaline phosphatase increased4, blood lactate dehydrogenase increased4 | International normalised ratio increased8, prothrombin time prolonged8, urine color abnormal |
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 Klacid ODromycin intravenous formulation.
In some of the reports of rhabdomyolysis, Klacid ODromycin was administered concomitantly with statins, fibrates, colchicine or allopurinol.
There have been post-marketing reports of colchicine toxicity with concomitant use of Klacid ODromycin 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 Klacid ODromycin and triazolam. Monitoring the patient for increased CNS pharmacological effects is suggested.
There have been rare reports of Klacid ODromycin 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 Klacid ODromycin 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 Klacid ODromycin paediatric suspension in children 6 months to 12 years of age. Therefore, children under 12 years of age should use Klacid ODromycin paediatric suspension. There are insufficient data to recommend a dosage regimen for use of the Klacid ODromycin 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 Klacid ODromycin over long periods of time for mycobacterial infections, it was often difficult to distinguish adverse events possibly associated with Klacid ODromycin 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 Klacid ODromycin 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 Klacid ODromycin.
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 Klacid ODromycin 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.
In 4-week-studies in animals, toxicity of Klacid ODromycin 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 Klacid ODromycin
Studies on reproduction toxicity showed that administration of Klacid ODromycin 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%).
Klacid ODromycin 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.
Klacid ODromycin has not been tested for carcinogenicity.
Pharmacotherapeutic group: Macrolides
ATC code: J01FA09
Mode of action:
Klacid ODromycin 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 Klacid ODromycin are generally two-fold lower than the MICs of erythromycin.
The 14-hydroxy metabolite of Klacid ODromycin 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
Klacid ODromycin 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 Klacid ODromycin. Because the concentrations of Klacid ODromycin 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. Klacid ODromycin 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 Klacid ODromycin, erythromycin and azithromycin. Methicillin-resistant staphylococci and penicillin-resistant Streptococcus pneumoniae are resistant to macrolides such as Klacid ODromycin.
Breakpoints:
The following breakpoints for Klacid ODromycin, 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, Klacid ODromycin and roxithromycin
C Klacid ODromycin 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.
Klacid ODromycin 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.
| Commonly susceptible species |
| Aerobic, Gram-positive microorganisms |
| Streptococcus group F |
| Corynebacterium diptheriae |
| Aerobic, Gram-negative microorganisms |
| Bordetella pertusis |
| Moraxella catarrhalis |
| Pasteurella multocida |
| Legionella spp. |
| Anaerobic microorganisms |
| Clostridium spp., other than C. difficile |
| Other microorganisms |
| Mycoplasma pneumoniae |
| Chlamydia trachomatis |
| Clamydophila pneumoniae |
| Clamydophilapsitacci |
| Mycobacterium spp. |
| Species for which acquired resistance may be a problem# |
| Aerobic, Gram-positive microorganisms |
| Streptococcus group A*, C, G |
| Streptococcus group B |
| Streptococcus viridans |
| Enterococcus spp+ |
| Staphylococcus aureus, methicillin-susceptible and methicillin-resistant+ |
| Streptococcus pneumoniae*+ |
| Staphylococcus epidermidis+ |
| Aerobic, Gram-negative microorganisms |
| Haemophilus influenzae$ |
| Helicobacter pylori |
| Anaerobic microorganisms |
| Bacteroides spp. |
| Peptococcus/Peptostreptococcus spp. |
| Inherently resistant microorganisms |
| Aerobic, Gram-negative microorganisms |
| Pseudomonas aeruginosa |
| Acinetobacter |
| Enterobacteriacea |
| Anaerobic microorganisms |
| Fusobacterium spp. |
| Other microorganisms |
| Mycobacterium tuberculosis |
# > 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 Klacid ODromycin can be predicted by testing erythromycin.
Most available clinical experience from controlled randomised clinical trials indicate that Klacid ODromycin 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:
Klacid ODromycin 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 Klacid ODromycin tablet is approximately 50%. Food slightly delays the absorption but does not affect the extent of bioavailability. Therefore, Klacid ODromycin tablets may be given without regard to food. Due to its chemical structure (6-O-Methylerythromycin) Klacid ODromycin is quite resistant to degradation by stomach acid. Peak plasma levels of 1 - 2 μg/ml Klacid ODromycin were observed in adults after oral administration of 250 mg twice daily. After administration of 500 mg Klacid ODromycin twice daily the peak plasma level was 2.8 μg/ml. After administration of 250 mg Klacid ODromycin 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:
Klacid ODromycin penetrates well into different compartments with an estimated volume of distribution of 200-400 l. Klacid ODromycin 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. Klacid ODromycin also penetrates the gastric mucus.
Klacid ODromycin is approximately 70% bound to plasma proteins at therapeutic levels.
Biotransformation and elimination:
Klacid ODromycin is rapidly and extensively metabolised in the liver. Metabolism is in the liver involving the P450 cytochrome system. Three metabolites are described: N-demethyl Klacid ODromycin, decladinosyl Klacid ODromycin and 14-hydroxy Klacid ODromycin. The pharmacokinetics of Klacid ODromycin 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 Klacid ODromycin twice daily to 5 hours following administration of 500 mg Klacid ODromycin twice daily. The half-life of the active 14-hydroxy metabolite ranges between 5 to 6 hours following administration of 250 mg Klacid ODromycin twice daily.
Approximately 20 -40% of Klacid ODromycin 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 Klacid ODromycin 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 Klacid ODromycin and the active metabolite levels in plasma.
There are no data on the effect of Klacid ODromycin 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.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
